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Item 1. Business

2022-03-15 compared with 2021-03-05 · 481 added, 1674 removed, 624 unchanged (78% of the section changed)

We are a clinical-stage biopharmaceutical company dedicated to developing and commercializing novel therapeutics to treat patients suffering from rare inherited genetic disorders of hemoglobin, known as hemoglobinopathies.

Our pipeline is built on the differentiated therapeutic potential of our initial product candidate, IMR-687, which is an oral, once-a-day, potentially disease-modifying treatment for sickle cell disease, or SCD, and β-thalassemia.

IMR-687 is a highly selective, potent small molecule inhibitor of phosphodiesterase-9, or PDE9, that has a multimodal mechanism of action that acts primarily on red blood cells, or RBCs, and has the potential to act on white blood cells, or WBCs, adhesion mediators and other cell types that are implicated in these disorders.

We recently completed a Phase 2a clinical trial of IMR-687 in adult patients with SCD and are currently conducting an open label extension, or OLE, clinical trial, which allows patients from the Phase 2a clinical trial to continue into a long-term four-year trial to test safety and measure tolerability of IMR-687.

In the second quarter of 2020, we initiated a Phase 2b clinical trial for the treatment of patients with SCD and a Phase 2b clinical trial for the treatment of patients with β-thalassemia.

We are currently enrolling patients in each Phase 2b clinical trial and expect to report interim data from each of these trials in the second half of 2021.

We continue to evaluate the impact of the COVID-19 pandemic on these Phase 2b clinical trials, and therefore, our estimated timelines for these clinical trials could be delayed.

Our goal is to leverage IMR-687’s differentiated mechanism of action, its ease of administration and stable drug properties to potentially serve a broad range of patients suffering from hemoglobinopathies around the world, including those in underserved regions.

In addition, we recently completed preclinical research of IMR-687 in heart failure with preserved ejection fraction, or HFpEF, and are developing a Phase 2 protocol to support potential future clinical development of IMR-687 in this indication.

Hemoglobinopathies are a diverse range of rare inherited genetic disorders in which there is abnormal production or absence of hemoglobin, the iron-containing protein in RBCs responsible for transporting oxygen in the blood.

Our pipeline is built on the differentiated therapeutic potential of our lead product candidate, tovinontrine (IMR-687), which is an oral, highly selective, potent small molecule inhibitor of phosphodiesterase-9, or PDE9.

Tovinontrine is currently in Phase 2b clinical development for the treatment of sickle cell disease, or SCD, and β-thalassemia and we expect to begin clinical development of tovinontrine in heart failure with preserved ejection fraction, or HFpEF, in the second quarter of 2022.

We are also advancing IMR-261, an oral, clinic-ready activator of nuclear factor erythroid 2–related factor 2, or Nrf2.

Disease Areas

Hemoglobinopathies

Hemoglobinopathies are a diverse range of rare inherited genetic disorders in which there is abnormal or decreased production of hemoglobin, the iron-containing protein in red blood cells, or RBCs, responsible for transporting oxygen in the blood.

Hemoglobinopathies can be broadly categorized into two groups.

The first group of hemoglobinopathies, which includes SCD, results from structural abnormalities in hemoglobin that cause RBCs to become inflexible and elongated, ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises, or VOCs.

The first group, which includes SCD, results from structural abnormalities in hemoglobin that cause RBCs to become inflexible and elongated (sickle-shaped), ultimately blocking blood flow to organs, which can lead to vaso-occlusive crises, or VOCs.

SCD is characterized by debilitating pain, progressive multi-organ damage and early death.

The second group of hemoglobinopathies, which includes β-thalassemia, results from decreased or absent production of hemoglobin, thereby producing smaller, paler RBCs that do not deliver adequate oxygen to vital tissues.

The global prevalence of SCD is estimated to be approximately 4.4 million patients, including approximately 100,000 patients in the United States and 134,000 patients in the European Union.

The second group of hemoglobinopathies, which includes β-thalassemia, results from decreased production of hemoglobin or ineffective erythropoiesis (RBC production), leading to fewer, smaller, paler RBCs and chronic anemia.

β-thalassemia is often grouped into two subsets:

patients who are non-transfusion dependent, or NTDT, or patients who are transfusion dependent, or TDT.

If left untreated, β-thalassemia causes severe anemia, splenomegaly, skeletal abnormalities, organ failure and early death.

Both groups of hemoglobinopathies share similar pathophysiology and have limited treatment options, which results in a significant unmet medical need for patients.

The global prevalence of SCD and β-thalassemia are estimated to be approximately 4.4 million and 288,000 patients, respectively.

patients with non-transfusion dependent thalassemia, or NTDT, and patients with transfusion dependent thalassemia, or TDT.

If left untreated, β-thalassemia causes severe anemia, splenomegaly, skeletal abnormalities, leg ulcers, iron overload, and organ failure, often leading to early death.

The global prevalence of β-thalassemia is estimated to be approximately 288,000 patients, with the total combined prevalence in the United States and the European Union estimated to be approximately 19,000 patients.

SCD and β-thalassemia are both designated as rare diseases in the United States and the European Union.

For SCD, prevalence is estimated to be approximately 100,000 patients in the United States and 134,000 patients in the European Union.

For β-thalassemia, total combined prevalence in the United States and the European Union is estimated to be approximately 19,000 patients.

Our product candidate, IMR-687, is a highly selective and potent small molecule inhibitor of PDE9.

PDE9 selectively degrades cyclic guanosine monophosphate, or cyclic GMP, an active signaling molecule that plays an important role in vascular biology.

Lower levels of cyclic GMP are found in patients with SCD and β-thalassemia and are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation.

Blocking PDE9 acts to increase cyclic GMP levels, which is associated with reactivation of fetal hemoglobin, or HbF, a natural hemoglobin produced during fetal development.

Increased levels of HbF in RBCs have been demonstrated to improve symptomology and substantially lower disease burden in both patients with SCD and patients with β-thalassemia.

Increasing cyclic GMP is associated with lower WBC activation and reduced adhesion across various cell types, both of which also contribute to SCD.

Finally, activation of the nitric oxide-cyclic GMP pathway has been shown to induce red cell maturation and production, which are particularly relevant in treating β-thalassemia.

We believe IMR-687 has several differentiating features that make it an optimal therapeutic for SCD and β-thalassemia, as supported by our preclinical data:

Highly Potent PDE9 Inhibitor :

IMR-687 is a highly potent PDE9 inhibitor, as measured by induction of cyclic GMP across escalating doses.

IMR-687 has been designed to rapidly increase cyclic GMP, which translates to HbF induction and potentially reduced WBC adhesion.

Differentiated Selectivity and Tolerability Profile :

IMR-687 is highly specific to PDE9 and not selective for other phosphodiesterase family members.

Toxicology studies of IMR-687, including fertility and juvenile studies, support its potential benefit as a long-term therapy in adults and children.

We believe this selectivity will allow us to optimize dose while minimizing off-target effects.

Minimal Brain Penetration :

IMR-687 was observed to have minimal brain penetration in preclinical in vivo models relative to other PDE9 inhibitors that have been studied.

We believe this will reduce the potential impact of PDE9 inhibition on central nervous system development and function.

Drug Product Stability :

IMR-687 has been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in underserved regions where SCD and β-thalassemia are endemic.

Managing hemoglobinopathies and their various clinical manifestations is complex and patients have had limited treatment options.

In November 2019, the U.S.

Food and Drug Administration, or FDA, approved Oxbryta™ (voxelotor) and Adakveo ® (crizanlizumab) for the treatment of SCD, which are important milestones for patients with SCD as previously approved therapies for SCD all have significant limitations, including safety concerns, complex dosing regimens, variable response rates and potential adverse effects from long term use.

We believe that IMR-687’s differentiated mechanism of action that seeks to increase HbF in patients with SCD, and the association between increases in HbF and reductions in disease risk, have the potential to provide IMR-687, if approved, with competitive advantages over Oxbryta, where the correlation between increases in hemoglobin and disease risk is being tested in a post-approval confirmatory trial, and Adakveo, which is administered intravenously and does not target RBC sickling.

There are no currently approved oral therapies for β-thalassemia;

however, in November 2019, the FDA approved REBLOZYL™ (luspatercept-aamt), which is dosed subcutaneously, for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.

Blood transfusions are used to treat both SCD and β-thalassemia, but are suboptimal due to limited patient access and potential serious complications that include iron overload, adverse immune response and transmission of transfusion-associated infections.

Allogeneic hematopoietic stem cell transplant, or HSCT, is a potentially curative treatment for both disorders, but is rarely used due to the difficulty in finding a matched donor and an approximately 5% mortality rate.

More recent approaches to treating both disorders are emerging, such as gene therapy and gene editing, with promising early clinical data being observed in each.

These approaches, however, are complex, costly, difficult to administer and potentially only suitable for a limited subset of patients.

Based on promising preclinical data and data from a Phase 1 clinical trial of IMR-687 in healthy volunteers, in 2018 we initiated our Phase 2a randomized, double-blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD.

The goals of this trial were to evaluate the safety, tolerability, pharmacokinetics, or PK, exploratory pharmacodynamics, or PD, and clinical outcomes of IMR-687 administered once daily for 16 or 24 weeks in two populations of patients with SCD:

one on monotherapy IMR-687 and one on background hydroxyurea, or HU, in combination with IMR-687 to test drug-drug interaction.

In January 2021, we reported final results from the Phase 2a clinical trial.

The results showed a lower rate of vaso-occlusive crises/sickle cell-related pain crises, or VOCs/SCPCs, as part of the safety analysis, and VOC-related hospitalizations in specified monotherapy IMR-687 treated patients, as compared to placebo.

Changes in HbF and F-cells varied across patient populations in the clinical trial.

The results further showed IMR-687 was well tolerated as a monotherapy and in combination with HU.

We are also conducting an OLE clinical trial, which allows patients from the Phase 2a trial to continue into a long-term, four-year trial to evaluate safety and tolerability of IMR-687.

A review of approximately 12 patients with evaluable PD biomarker data for at least four months of treatment on the OLE clinical trial as of December 31, 2020, demonstrated increases in both HbF and F-cells and minimal changes in total hemoglobin.

In the second quarter of 2020, we initiated a Phase 2b clinical trial of IMR-687 in adult patients with SCD and a Phase 2b clinical trial of IMR-687 in adult patients with ß-thalassemia.

We are currently enrolling patients in each trial and expect to report interim data from each of these trials in the second half of 2021.

Based on the supportive safety and PK data from the Phase 2a interim analyses, we designed the Phase 2b clinical trials to evaluate higher doses, longer treatment periods, and additional clinical endpoints as compared to the Phase 2a clinical trial.

In addition to our clinical programs with IMR-687 in patients with SCD and β- thalassemia, in the second quarter of 2020, we commenced preclinical development of IMR-687 in HFpEF .

Published literature suggests that the inhibition of PDE9, and resulting increases in c yclic GMP through natriuretic peptide modulation, can serve as an attractive target for the prevention and treatment of vascular disease, including HFpEF .

An exploratory analysis co-led by Vanderbilt University Medical Center, or VUMC, on data from the second interim analysis from our Phase 2a clinical trial of IMR-687 demonstrated the potential of IMR-687 to reduce N-terminal pro-B-type natriuretic peptide, or NT- proBNP , a well-established biomarker of cardiovascular risk in patients with SCD.

In April 2020, we entered into an agreement with the Necker Institute of Paris, France to conduct preclinical studies with IMR-687 in HFpEF .

The preclinical data from three established mouse models for HFpEF suggest potential benefits of IMR-687 across several relevant cardiac biomarkers.

We are collaborating with VUMC and have engaged additional key opinion leaders in heart failure, with the aim of developing a Phase 2 protocol to support potential future clinical development of IMR-687 in this indication .

Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction, or HFpEF, also known as diastolic heart failure, is typically caused by abnormalities of cardiac filling, which leads to symptoms such as shortness of breath, exercise intolerance and fluid retention.

Characteristics of HFpEF are heterogeneous, but commonly include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance, and inflammation.

Comorbidities, such as hypertension, anemia, chronic kidney disease, diabetes, and obesity, are also common in HFpEF and are thought to contribute to its development.

HFpEF accounts for approximately half of all cases of heart failure and has become the predominant form of heart failure over time.

Prevalence in the United States is estimated to be approximately 3-4 million patients.

In contrast to heart failure with reduced ejection fraction, or HFrEF, there are relatively few treatment options to improve symptoms and outcomes for patients and there are currently only two FDA-approved products (Entresto and Jardiance) for the treatment of HFpEF.

Product Candidates

Tovinontrine (IMR-687)

Our lead candidate, tovinontrine, is a highly selective and potent small molecule inhibitor of PDE9.

PDE9 selectively degrades cyclic guanosine monophosphate, or cGMP, an active signaling molecule that plays an important role in vascular biology.

Lower levels of cGMP are found in patients with SCD and β-thalassemia and are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation.

Blocking PDE9 acts to increase cGMP levels, which is associated with several benefits including the potential reactivation of fetal hemoglobin, or HbF, a natural hemoglobin produced during fetal development, lower white blood cell, or WBC, activation and reduced adhesion across various cell types.

Increased levels of HbF in RBCs have been demonstrated to improve symptomology and substantially lower disease burden in both patients with SCD and patients with β-thalassemia and, along with reduced WBC adhesion and platelet aggregation, may result in fewer VOCs for SCD patients.

In addition, levels of cGMP are often reduced in patients with heart failure.

Augmenting cGMP through the natriuretic peptide-cGMP pathway has been shown to mediate cardioprotective effects that lead to reduced heart failure disease progression and fewer cardiac events .

We believe tovinontrine may have advantages over other therapies, including having a multimodal approach and being an oral dosing regimen.

In addition, tovinontrine tablets have been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in areas where SCD and ß-thalassemia are endemic.

We are currently conducting the Ardent Phase 2b clinical trial of tovinontrine, a randomized, double-blind, placebo-controlled trial in approximately 115 adult patients with SCD.

We have completed enrollment in the Ardent clinical trial and expect to report interim data from this trial in the first week of April 2022 and final data in the second half of 2022.

In November 2021, we made the decision to change the primary endpoint of the Ardent trial to annualized rate of VOCs following a written recommendation from the FDA.

HbF response, which was previously the primary endpoint, will continue to be evaluated as a key secondary endpoint.

The Ardent trial follows completion of our Phase 2a clinical trial of tovinontrine in SCD, which demonstrated a well-tolerated safety profile for tovinontrine and potential benefits from tovinontrine with respect to VOCs.

Changes in SCD-related biomarkers were variable.

We are also conducting a long-term open label extension, or OLE, clinical trial of tovinontrine, which is comprised of patients who completed our Phase 2a clinical trial of tovinontrine.

Data from the OLE trial presented at the American Society of Hematology (ASH) Annual Meeting in December 2021 demonstrated a well-tolerated safety profile for tovinontrine, potential benefits from tovinontrine with respect to VOCs and improvements in certain SCD-related biomarkers, including HbF and F-cells, through 12 months of treatment on the OLE trial.

In the second quarter of 2022, we expect to initiate a new, long-term OLE trial of tovinontrine for patients who complete the Ardent Phase 2b clinical trial in SCD.

In addition to patients from the Ardent trial, we expect patients from the ongoing Phase 2a OLE trial to roll over into this new OLE trial, resulting in one OLE trial with patients from both the Phase 2a clinical trial and the Ardent Phase 2b clinical trial.

ß-thalassemia Program

We are also conducting the Forte Phase 2b clinical trial of tovinontrine, a randomized, double-blind, placebo-controlled trial in approximately 120 TDT and NTDT patients with ß-thalassemia.

In November 2021, we presented data from a pre-specified interim analysis from the Forte trial in TDT patients.

The interim analysis data demonstrated a well-tolerated safety profile for tovinontrine and a trend for reduced transfusion burden in the higher dose cohort.

We expect to report additional interim data for TDT and NTDT patients from the Forte trial in the first week of April 2022 and data from the final analysis of the Forte clinical trial in the second half of 2022.

HFpEF Program

In the second quarter of 2022, we expect to dose the first patient in the SP 9 IN Phase 2 clinical trial of tovinontrine in HFpEF.

The SP 9 IN trial will be a randomized, placebo-controlled trial of approximately 170 patients 45 years of age or older with enriched PDE9 expression and persistent symptoms of HFpEF.

The primary endpoint of the trial will be the change in N-terminal pro b-type natriuretic peptide, or NT-proBNP, levels.

We have commenced research activities for IMR-261 (formerly CXA-10), an oral, clinical-ready activator of Nrf2 .

In pre-clinical models of SCD, IMR-261 was observed to activate expression of HbF and reduce VOCs.

Furthermore, in a preclinical model of ß-thalassemia, IMR-261 was observed to increase hemoglobin and enhance RBC maturation.

We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths in hemoglobinopathies, iron disorders and potentially other areas.

Prior to its acquisition by us , IMR-261 was evaluated by Complexa, Inc.

in Phase 2 clinical trials in focal segmental glomerulosclerosis, or FSGS, and pulmonary arterial hypertension, or PAH, and independent medical literature suggests potential in a broad array of RBC diseases, including disorders of hemoglobin, and iron overload diseases.

We are advancing a pipeline of therapeutic programs to address diseases with significant unmet medical need.

The following chart summarizes key information about our programs:

Our goal is to become a leading biopharmaceutical company focused on the development and commercialization of novel therapies for the treatment of hemoglobinopathies.

Our goal is to become a leading biopharmaceutical company focused on the development and commercialization of novel therapies.

To achieve this, we are focused on the following key strategies:

Rapidly advance IMR-687 through clinical development for the treatment of SCD.

There remains a significant need to develop additional differentiated disease-modifying, oral therapies to treat SCD.

We recently completed a Phase 2a clinical trial of IMR-687 in adult patients with SCD and are conducting a Phase 2b clinical trial of IMR-687 for SCD.

We currently expect to report interim data from the Phase 2b clinical trial in the second half of 2021.

In addition, we intend to expand clinical development of IMR-687 by initiating a pediatric program in the first half of 2021.

Expand clinical development of IMR-687 for the treatment of ß-thalassemia.

Based on the similar pathophysiology and symptomology shared between SCD and β-thalassemia, we believe there is a compelling rationale to expand clinical development of IMR-687 into β-thalassemia.

Various preclinical studies, as well as favorable safety data from our Phase 1 and Phase 2a clinical trials, further support the development of IMR-687 in this indication.

We are conducting a Phase 2b clinical trial in adult patients with β-thalassemia.

We currently expect to report interim data from this trial in the second half of 2021.

Rapidly advance tovinontrine through clinical development for the treatment of SCD and ß-thalassemia.

There remains a significant need to develop additional differentiated disease-modifying, oral therapies to treat SCD and β-thalassemia.

We are currently conducting Phase 2b clinical trials of tovinontrine for SCD and ß-thalassemia and expect to report interim data from each trial in the first week of April 2022.

Expand clinical development of tovinontrine for the treatment of HFpEF.

P ublished literature suggests that the inhibition of PDE9, and resulting increases in cGMP through natriuretic peptide modulation, can serve as an attractive target for the prevention and treatment of vascular disease, including HFpEF .

Data from three preclinical mouse models of tovinontrine showed that selective inhibition of PDE9 with tovinontrine was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction, indicating that tovinontrine may be a promising treatment option for patients suffering from HFpEF.

We expect to begin clinical development of tovinontrine in HFpEF in the second quarter of 2022.

Continue efforts to expand our pipeline.

We believe that our extensive expertise and experience with IMR-687 will allow us to expand development of IMR-687 into additional hemoglobinopathies and diseases where PDE9

is overexpressed, including HFpEF .

We recently completed preclinical research of IMR-687 in HFpEF and are developing a Phase 2 protocol to support potential future clinical development of IMR-687 in this indication.

We have commenced research activities for IMR-261, an activator of Nrf2.

In pre-clinical models of SCD, IMR-261 was observed to activate expression of HbF and reduce VOCs.

Furthermore, in a preclinical model of ß-thalassemia, IMR-261 was observed to increase hemoglobin and enhance RBC maturation.

We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths.

We are also exploring business development opportunities to identify novel product candidates.

Maximize the commercial opportunity of our product portfolio.

We have retained worldwide development and commercial rights to IMR-687 and are pursuing a clinical and regulatory development strategy for IMR-687 in the United States, Europe and certain other international regions.

As we advance IMR-687 through clinical development, we intend to establish a focused marketing and sales infrastructure in order to maximize the commercial opportunity in the United States and Europe, and potentially other international regions.

We have retained worldwide development and commercial rights to tovinontrine and are pursuing a clinical and regulatory development strategy for tovinontrine in the United States, Europe and certain other international regions.

As we advance tovinontrine through clinical development, we intend to establish a focused marketing and sales infrastructure in order to maximize the commercial opportunity in the United States and Europe, and potentially other international regions.

Strategically evaluate licensing and collaboration opportunities to maximize value.

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Although the sickled RBC may convert back into a regular RBC in oxygen rich environments, it will return to its sickled form in lower oxygen environments and ultimately may be permanently sickled and/or be destroyed.

There are several genetic variations of SCD, including:

HbSS, also known as sickle cell anemia, is the most common and severe form of SCD where patients inherit one mutated beta-globin gene from each parent.

Approximately 60% of patients with SCD have HbSS.

HbS/ b -0 thalassemia is a form of SCD where patients inherit one mutated beta-globin gene and one mutated ß-thalassemia gene, and is often clinically indistinguishable from patients with HbSS.

Approximately 10% of patients with SCD have HbS/ß-0 thalassemia.

HbSC is a form of SCD where patients inherit one mutated beta-globin gene and one mutated hemoglobin C gene.

Approximately 30% of patients with SCD have HbSC, which is a milder form of disease.

Although patients with SCD often present a spectrum of symptoms that can vary over time, patients are often grouped by their predominant symptomology:

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A promising approach to enhance hemoglobin-oxygen affinity is to reactivate production of inactive HbF, which we refer to as HbF induction.

HbF is a natural hemoglobin that is activated during fetal development and is designed to give the growing

fetus better access to oxygen from the maternal bloodstream.

HbF is a natural hemoglobin that is activated during fetal development and is designed to give the growing fetus better access to oxygen from the maternal bloodstream.

HbF has higher affinity for oxygen and ceases production approximately six months after birth, at which time it is replaced by adult hemoglobin that has lower oxygen affinity.

Accordingly, newborns with SCD do not experience RBC sickling and resulting symptomology in the first four to five months of life.

Accordingly, newborns with SCD do not experience RBC sickling or resulting symptomology in the first four to five months of life.

As HbF production declines and mutated HbS is produced in its place, SCD clinical manifestations begin to rapidly emerge.

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In some cases, these patients are essentially asymptomatic.

We believe that the protective aspects of naturally occurring HbF supports the development of therapies that induce HbF as a means to treat SCD.

The image below depicts how RBCs can change shape in low oxygen environments.

In healthy individuals, there is no change to the hemoglobin organization or RBC structure.

In SCD, hydrophobic interactions with the hemoglobin subunits lead to polymerization and cause RBC distortion.

In cells with reactivated HbF, polymerization is avoided because HbF reduces the ability of mutated hemoglobin to polymerize.

Reactivation of HbF occurs in immature RBCs, known as erythroblasts and reticulocytes.

These cells are found in the bone marrow and have the cellular machinery to produce HbF.

Once HbF is induced in nascent RBCs, they eventually grow into mature RBCs that contain HbF.

Mature RBCs that are already in circulation are not viable targets for HbF induction because they do not contain DNA.

Over time, these mature RBCs without HbF die out and are replaced by newly mature RBCs that contain HbF, further increasing the population of HbF containing RBCs.

This time course can be up to 120 days, which is the lifespan of a normal RBC, or substantially shorter, as sickled RBCs live for only eight to 40 days.

Therapies that increase HbF must focus on immature RBCs to ensure HbF is increasingly part of the mature and circulating RBC population.

Measuring the reactivation of HbF is accomplished in two interrelated ways.

The first assay confirms if an RBC contains HbF, in which case it is known as an F-cell.

We believe that measurements of the percentage of F-cells relative to total RBCs, which we refer to as %F-cells, establish whether a therapy is reactivating HbF production.

The second assay quantifies the amount of HbF across RBCs, expressed as a percentage of total hemoglobin, or HbF%.

Increasing HbF% is key to addressing SCD disease pathology and ultimately drives the improved hemoglobin-oxygen affinity.

As illustrated in the graphic below, which is based on data from 242 pediatric patients with SCD across various genotypes, the relationship between %F-cells and HbF% is exponentially correlated in that linear increases in %F-cells yield multi-fold increases in HbF%.

Relationship Between %F-cells and HbF %

While %F-cells increases are important measurements, absolute increases in HbF% ultimately drive reduction in disease risk.

We commissioned a third-party to perform a systematic literature review and series of quantitative meta-analyses to identify evidence for clinical outcomes associated with HbF% in patients with SCD.

Statistically significant associations between HbF% and clinical outcomes in SCD were found for the following:

mortality, stroke, acute chest syndrome, pain, blood transfusion, retinopathy and splenomegaly.

The figure below shows how absolute increases in HbF% are associated with reduced disease risk across several of these parameters.

Association Between Increases in HbF% and Disease Risk

A systematic literature review and series of quantitative meta-analyses revealed statistically significant associations between increases in HbF and clinical outcomes in SCD including mortality, stroke, acute chest syndrome, pain, blood transfusion, retinopathy and splenomegaly.

The Role of Other Cell Types in SCD

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WBCs also interact with sickled RBCs and endothelial cells causing both cell aggregation and adhesion within the blood vessel.

As a result, endothelial cells are damaged and secrete inflammatory signals that can ultimately lead to organ damage.

Platelets exacerbate this inflammatory cascade by releasing cell signaling molecules known as cytokines and further

contribute to the cellular blockage in blood vessels that causes VOCs and clinical pathology.

The following image describes the role of each of these cells and how they may be implicated in SCD .

As a result, endothelial cells are damaged and secrete inflammatory signals that can ultimately lead to organ

Platelets exacerbate this inflammatory cascade by releasing cell signaling molecules known as cytokines and further contribute to the cellular blockage in blood vessels that causes VOCs.

The Role of Adhesion Mediators in SCD

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Adhesion mediators can also be easily measured and therefore serve as reproducible biomarkers across RBCs, WBCs, endothelial cells and platelets.

These include P-selectin, E-selectin, vascular cell adhesion molecule 1, or VCAM-1, and intercellular adhesion molecule 1, or ICAM-1.

Addressable Patient Population

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Managing SCD and its various clinical manifestations is complex, and patients have historically had limited options for treatment.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in adults and children 12 years of age and older.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in patients 12 years of age and older and its label has subsequently been expanded to include patients four years of age and older.

In February 2022, the European Commission approved Oxbryta for the treatment of hemolytic anemia in patients with SCD 12 years of age and older.

Oxbryta is an oral therapy taken once daily and is the first approved treatment that directly inhibits sickle hemoglobin polymerization.

The accelerated approval of Oxbryta was based on clinically meaningful and statistically significant improvements in hemoglobin levels, accompanied by reductions in red blood cell destruction, known as hemolysis.

In November 2019, the FDA also approved Adakveo (crizanlizumab), which has been demonstrated to reduce the frequency of VOCs in adult and pediatric patients aged 16 years and older with SCD.

Adakveo is administered intravenously and binds to P-selectin, which is a cell adhesion protein that plays a central role in the multicellular interactions that can lead to vaso-occlusion.

While these two approvals are important milestones for patients with SCD, we believe that there remains a significant unmet need for SCD therapies.

Oxbryta was approved on an accelerated basis based on improvements in hemoglobin levels as a surrogate endpoint reasonably likely to predict clinical benefit .

Adakveo received conditional approval in the European Union in October 2020 for the prevention of recurrent VOCs in SCD patients aged 16 years and older.

Adakveo is administered intravenously and binds to P-selectin, which is a cell adhesion protein that plays a central role in the multicellular interactions that can lead to VOCs.

While these approvals are important milestones for patients with SCD, we believe that there remains a significant unmet need for SCD therapies.

Oxbryta was approved by the FDA on an accelerated basis based on improvements in hemoglobin levels as a surrogate endpoint reasonably likely to predict clinical benefit.

Continued approval for this indication may be contingent upon verification and description of the clinical benefit in a confirmatory study which is currently ongoing and is evaluating cerebral blood flow velocity.

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Prior to the approval of Oxbryta and Adakveo for SCD, there were only two FDA-approved drugs in the United States to treat SCD:

HU and L-glutamine (marketed as Endari).

Hydroxyurea, or HU, and Endari (L-glutamine);

and only one approved drug in the European Union:

These therapies have significant limitations in their safety, dosing regimen, efficacy and long-term effects.

HU, an oral chemotherapy that induces HbF and decreases sickling of the RBC, was first approved by the FDA for the treatment of SCD in 1998.

In the seminal trial for HU that led to its approval, patients on average saw increased HbF induction of 3.2% over a two-year treatment period, which resulted in improved clinical outcomes, such as reduction of acute chest syndrome.

Despite these benefits, HU remains a suboptimal therapy for several reasons:

HU, an oral chemotherapy that induces HbF and decreases sickling of the RBC, was first approved by the FDA for the treatment of SCD in 1998 and approved in the European Union in 2007.

Despite numerous benefits, HU remains a suboptimal therapy for several reasons:

Safety Concerns:

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Long-term effects include the potential for infertility in both males and females.

Due to HU’s various limitations, only approximately 30% and 22% of patients with SCD in the United States and certain countries in Europe, respectively, are treated with HU.

Of those patients treated with HU in the United States, approximately 50% discontinue use within six months.

Endari, an oral powder form of L-glutamine, was approved by the FDA in 2017, becoming the first new FDA-approved treatment for SCD in nearly 20 years.

Endari, an oral powder form of L-glutamine, was approved by the FDA in 2017.

L-glutamine is an amino acid precursor to nicotinamide adenine dinucleotide, or NAD, and is thought to reduce the oxidative stress that is present in patients with SCD.

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Due to the lack of uniform accessibility to blood transfusions, they are not widely employed for the treatment of SCD.

HSCT is available as a potentially curative treatment for SCD and acts by halting sickled RBC production from the affected marrow and replacing it with healthy hematopoietic stem cells from a matched donor.

Allogeneic hematopoietic stem cell transplant , or HSCT, is available as a potentially curative treatment for SCD and acts by halting sickled RBC production from the affected marrow and replacing it with healthy hematopoietic stem cells from a matched donor.

HSCT is rarely used due to the difficulty in finding a matched donor, the potential for infection and an approximately 5% mortality rate.

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Anti-Polymerization Agents:

Oxbryta is designed to prevent polymerization of hemoglobin and sickling of RBCs by increasing hemoglobin’s affinity for oxygen and maintaining hemoglobin in an oxygenated state.

Anti-polymerization agents, such as Oxbryta, are designed to prevent polymerization of hemoglobin and sickling of RBCs by increasing hemoglobin’s affinity for oxygen and maintaining hemoglobin in an oxygenated state.

However, approaches that are solely focused on reducing polymerization may not address the complex symptomology of SCD and the clinical impact of Oxbryta on VOCs remains a question.

HbF Inducers :

In addition to IMR-687, several other novel HbF inducers are in clinical development.

Fulcrum Therapeutics, Inc.

is in Phase 1 clinical development of FTX-6058 , a small molecule embryonic ectoderm development inhibitor designed to induce expression of HbF .

Novo Nordisk A/S (in collaboration with EpiDestiny , Inc.) is in Phase 1 clinical development of EPI-01 , a DNA methyltransferase inhibitor .

HbF inducers seek to r eactivate production of HbF in an effort to enhance hemoglobin-oxygen affinity.

Examples include FTX-6058, under development by Fulcrum Therapeutics, Inc., or Fulcrum, and EPI-01, under development by Novo Nordisk A/S, or Novo Nordisk (in collaboration with EpiDestiny, Inc., or EpiDestiny).

PKR Activators:

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Mutations in PKR cause deficiencies in this process which results in a shortened lifespan for RBCs.

This has led to the hypothesis that PKR activation can overturn this deficiency and may lead to a therapeutic benefit in patients with SCD (and potentially ß-thalassemia).

Agios Pharmaceuticals, Inc.

is developing mitapivat (AG-348), which is in Phase 1/2 clinical development, and Forma Therapeutics, Inc.

is developing FT-4202, which is in Phase 3 clinical development.

This has led to the hypothesis that PKR activation can overturn this deficiency and may lead to a therapeutic benefit in patients with SCD.

Examples include mitapivat (AG-348), under development by Agios Pharmaceuticals, Inc., or Agios, and etavopivat (FT-4202), which is under development by Forma Therapeutics, Inc., or Forma.

Selectin Inhibitors :

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Furthermore, Adakveo requires lengthy infusion treatments every three to four weeks.

Global Blood Therapeutics, Inc.

is developing inclacumab, a specific P-selectin inhibitor that was previously under development for non-SCD indications.

In preclinical studies, inclacumab demonstrated longer duration of exposure and greater inhibition of platelet-leukocyte aggregation as compared to Adakveo, which may create the potential for quarterly dosing, but inclacumab has yet to be tested in SCD patients (although Global Blood Therapeutics has reported that a Phase 3 clinical trial is planned for 2021).

Global Blood Therapeutics, Inc, or GBT, is also developing inclacumab, a specific P-selectin inhibitor that was previously under development for non-SCD indications.

Gene Therapy/Editing :

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Like HSCT, gene therapy for SCD involves several pre-treatment steps that can include chemotherapy, which carry significant standalone risks.

Recent data from a gene therapy trial indicated that chemotherapeutic pre-treatment resulted in a patient with SCD developing myelodysplastic syndrome, where the blood-forming cells in the bone marrow become abnormal.

bluebird bio, Inc.

and Aruvant Sciences, Inc.

are each developing gene therapies which aim to deliver a functional copy of the human beta-globin gene (LentiGlobin, which is in Phase 3 clinical development, and ARU-1801, which is in Phase 2 clinical development, respectively) .

bluebird bio, Inc., or bluebird, and Aruvant Sciences, Inc., or Aruvant, are each developing gene therapies which aim to deliver a functional copy of the human beta-globin gene.

Gene editing, including CRISPR-Cas9, is an alternative approach to gene modification that has recently advanced in clinical development.

Examples of gene editing approaches include CTX-001, currently in Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated), BIVV-003, currently in Phase 1/2 clinical development by Sangamo Therapeutics, Inc.

(in collaboration with Sanofi), and OTQ923, currently in Phase 1/2 clinical development by Intellia Therapeutics, Inc.

(in collaboration with Novartis).

Examples of gene editing approaches include CTX-001, currently in development by CRISPR Therapeutics AG, or CRISPR (in collaboration with Vertex Pharmaceuticals Incorporated, or Vertex).

Numerous questions remain with respect to the gene editing approach, including off-target mutagenesis and the ultimate potential reach of such therapeutics.

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The Role of Phosphodiesterase-9 in SCD

IMR-687 is being developed to inhibit PDE9.

PDE9 decreases cyclic GMP, an active signaling molecule that plays an important role in vascular biology.

Lower levels of cyclic GMP, as found in patients with SCD, are associated with reduced blood flow, increased inflammation, greater cell adhesion and reduced nitric oxide mediated vasodilation.

The figure below illustrates the role of PDE9 inhibition and its potential benefits on SCD pathophysiology.

Nitric oxide, a chemical that supports blood vessel health, drives increases in a broadly expressed enzyme, soluble guanyl cyclase, or sGC, which drives the conversion of Guanosine-5’-triphosphate, or GTP, into cyclic GMP.

Cyclic GMP levels are decreased by the PDE9 enzyme, which actively converts cyclic GMP to GMP.

Increasing cyclic GMP by inhibiting PDE9 has several potential advantageous downstream impacts, including to increase HbF, reduce cell adhesion, decrease WBC activation and ultimately increase nitric oxide levels.

Novel cyclic GMP Degrader:

PDE9 belongs to a family of 11 cyclic nucleotide phosphodiesterases, or PDEs.

In general, PDEs degrade both cyclic GMP and cyclic adenosine monophosphate, or cAMP.

However, PDE9 solely degrades cyclic GMP, has the highest affinity for cyclic GMP of all PDEs, and does not degrade cAMP.

Inhibiting PDE9 offers a novel way to increase cyclic GMP levels by limiting cyclic GMP degradation.

We believe that other approaches that increase cyclic GMP levels without addressing its degradation, such as HU, are unlikely to confer persistent and robust increases in cyclic GMP.

Conversely, preventing degradation of cyclic GMP by targeting PDE9 may enable long-term benefits that include sustained HbF induction, reduced activation of WBCs, positive effects on other cell types and reduced cell adhesion.

High Expression in SCD Cells of Interest:

PDE9 is highly expressed in cells of interest in SCD, specifically reticulocytes, which are an important cell type for HbF induction.

Tovinontrine is being developed to inhibit PDE9.

PDE9 decreases cGMP, an active signaling molecule that plays an important role in vascular biology.

Lower levels of cGMP, as found in patients with SCD, are associated with reduced blood

flow, increased inflammation, greater cell adhesion and reduced nitric oxide - mediated vasodilation .

In addition, PDE9 is highly expressed in cells of interest in SCD, specifically reticulocytes, which are an important cell type for HbF induction.

Furthermore, PDE9 has high expression in WBCs and in areas where RBCs are formed.

A potential drawback of inhibiting PDE9 for the treatment of SCD is that PDE9 is also highly expressed in the brain, which in part explains why PDE9 inhibitors have been extensively studied in neurodegenerative diseases.

While several PDE9 inhibitors have been shown to be well-tolerated in adults, preclinical data suggests that brain penetrant PDE9 inhibition causes mice to have changes in fear response, which may reflect memory impairment.

This could be concerning in pediatric patients with SCD who continue to have ongoing brain development.

Thus, any PDE9 inhibitor broadly targeting SCD should minimally cross the blood-brain barrier.

Multimodal Method of Action:

In preclinical studies, PDE9 inhibitors have been shown to increase cyclic GMP concentrations, induce HbF and F-cells, reduce WBC activation and adhesion across other cell types and modulate adhesion mediators.

A brain penetrant PDE9 inhibitor developed by Bayer known as BAY73-6691, which was originally developed for the treatment of neurodegenerative diseases, was observed to increase cyclic GMP and HbF transcription in a representative human cell line for SCD.

Furthermore, BAY73-6691 was observed to reduce WBC activation and adhesion to endothelial cells in patient-derived WBCs, however development was subsequently discontinued and we are not aware of any further development of this compound.

Another brain penetrant PDE9 inhibitor developed by Pfizer known as PF-04447943

was originally developed for Alzheimer’s disease and tested in patients with SCD.

In Pfizer’s Phase 1b clinical trial in patients with SCD, there were some reductions in adhesion markers but no significant HbF induction was observed.

Development of PF-04447943 was subsequently discontinued and we are not aware of any further development of this compound.

In preclinical studies, PDE9 inhibitors have been shown to increase cGMP concentrations, induce HbF and F-cells, reduce WBC activation and adhesion across other cell types and modulate adhesion mediators.

This was further demonstrated in preclinical SCD models of tovinontrine, where we observed that tovinontrine is a potent cGMP inducer and had a multimodal mechanism of action, acting to increase HbF expression in RBCs, reduce RBC sickling and decrease expression of WBC adhesion molecules .

Our Solution for Sickle Cell Disease:

IMR-687 as a Differentiated PDE9 Inhibitor

Tovinontrine as a Differentiated PDE9 Inhibitor

Our approach to address SCD is fundamentally distinct from other therapies.

IMR-687 is being developed to directly and potently inhibit PDE9, which represents a differentiated approach to increase cyclic GMP levels, with a selectivity for PDE9 that we believe will make it amenable for long-term use.

We recently completed a Phase 2a randomized, double blinded, placebo-controlled clinical trial of IMR-687 in adult patients with SCD and we are currently conducting a Phase 2b clinical trial in this patient population.

We believe IMR-687 may have advantages over other therapies, including speed of onset of HbF induction, a multimodal approach and a once daily dosing regimen.

In addition, IMR-687 has been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in areas where SCD and ß-thalassemia are endemic.

We believe IMR-687 has several differentiating features relative to other PDE9 inhibitors:

Tovinontrine is being developed to directly and potently inhibit PDE9, which represents a differentiated approach to increase cGMP levels, with a selectivity for PDE9 that we believe will make it amenable for long-term use.

We believe tovinontrine may have advantages over other therapies in SCD, including a multimodal approach and an oral, once daily dosing regimen.

We believe tovinontrine has several differentiating features relative to other PDE9 inhibitors:

Highly Potent PDE9 Inhibitor :

IMR-687 is a highly potent PDE9 inhibitor, as measured by induction of cyclic GMP across various doses.

We have specifically studied the potency of PDE9 inhibition of IMR-687 as compared to HU and analogues of BAY73-6691 and PF-04447943 by analyzing cyclic GMP levels across various doses in an in vitro assay.

We studied analogues of BAY73-6691 and PF-04447943 because BAY73-6691 and PF-04447943 are proprietary compounds to which we did not have direct access.

The analogues we used were based on the well-defined crystal structures of BAY73-6691 and PF-04447943 that are publicly available in published patent filings.

When compared to these agents, IMR-687 was observed to be more potent across all dose groups.

Tovinontrine is a highly potent PDE9 inhibitor, as measured by induction of cGMP across escalating doses.

Tovinontrine has been designed to rapidly increase cGMP, which translates to HbF induction and potentially reduced WBC adhesion .

Differentiated Selectivity and Tolerability Profile :

IMR-687 is a highly selective PDE9 inhibitor.

We compared the selectivity of IMR-687 and an analog of PF-04447943 against a panel of related PDEs.

We chose not to test BAY73-6691 or an analog thereof because BAY73-6691’s lack of potency led us to conclude there was little merit to further testing.

For the isoform PDE9A1, IMR-687 was observed to be more than eight times more selective than the PF-04447943 analog and for the isoform PDE9A2, IMR-687 was observed to be more than four times more selective than the same compound.

Isoforms are functionally similar proteins within each PDE family that have slightly different genetic coding.

We believe the selectivity of IMR-687 will allow us to optimize dose while minimizing off-target effects.

IMR-687 has exhibited lower interaction with other PDE family members compared to the PF-04447943 analog, or did not have measurable inhibition.

We also conducted toxicology studies of IMR-687.

In a 26-week female rat infertility study and in early embryonic development studies, once-daily dosing of IMR-687 was observed to be well tolerated with no effects on fertility or embryonic development at any dose level studied.

In addition to standard adult animal toxicology studies, a juvenile rat study was completed where once daily administration of IMR-687 was observed to be well tolerated with no indication of toxicity.

Tovinontrine is highly specific to PDE9 and not selective for other phosphodiesterase family members.

Toxicology studies of tovinontrine, including fertility and juvenile studies, support its potential benefit as a long-term therapy in adults and children.

We believe this selectivity will allow us to optimize dose while minimizing off-target effects .

Minimal Brain Penetration :

We are developing IMR-687 specifically because it was observed to have low brain penetration in animal models.

We believe this will reduce the potential impact of PDE9 inhibition on central nervous system, or CNS, development and function.

Historically, most early PDE9 inhibitors were developed for potential CNS indications and thus were specifically designed to cross the blood-brain barrier.

We observed in a mouse model that while plasma concentrations were similar, brain exposure to levels of IMR-687 were observed to be five times lower than those seen with the PF-04447943 analog at 10mg/kg.

Additionally, IMR-687 showed no effect on locomotor activity or in a classical fear conditioning mouse model of learning and memory.

In contrast, the brain penetrant PF-04447943 analog was observed to significantly increase conditioned fear responses in mice at an equivalent dose.

Tovinontrine was observed to have minimal brain penetration in preclinical in vivo models relative to other PDE9 inhibitors that have been studied.

We believe this will reduce the potential impact of PDE9 inhibition on central nervous system development and function.

Drug Product Stability :

IMR-687 has been observed to exhibit a durable shelf life at both standard and elevated room temperature and humidity conditions.

For example, at standard room temperature and humidity conditions, we have observed consistent stability results at doses of 50 mg, 100 mg, and 200 mg at the 24-month time point.

In addition, we have observed consistent stability results under accelerated stress conditions that mimic the high heat (40° Celsius, 104° Fahrenheit) and increased humidity (75%) of the tropics.

We believe this observed stability of IMR-687 provides us with a potential opportunity to treat patients in areas where other treatments may not be accessible, including in the tropical climates where SCD and β-thalassemia are endemic.

Preclinical and Phase 1 Data

In preclinical SCD models, we observed that IMR-687 is a potent cyclic GMP inducer and had a multimodal mechanism of action, acting to increase RBC HbF expression, reduce RBC sickling and decrease expression of WBC adhesion molecules.

In an SCD in vitro model, we measured the ability of IMR-687 to increase cyclic GMP levels in an RBC cell line as compared to HU.

In this study, we observed that IMR-687 induced cyclic GMP production in a dose-dependent manner at an approximately 30-fold lower drug concentration than HU.

In addition, at an equivalent drug concentration of 10 µM of IMR-687, we observed an approximately ten-fold increase in cyclic GMP levels as compared to HU.

We also evaluated IMR-687 in a mouse model of SCD that expresses human sickle hemoglobin.

We observed that IMR-687 demonstrated statistically significant increases in HbF-positive RBCs, statistically significant decreases in the percentage of sickled RBCs and decreases in markers of hemolysis, or destruction of RBCs, and WBC adhesion.

In our Phase 1 randomized, double-blind, placebo-controlled clinical trial in healthy volunteers, single and multiple ascending doses of IMR-687 were reported to be well tolerated to a maximum dose of 4.5 mg/kg per day and no serious adverse events were reported.

SCD Phase 2a Clinical Trial

Our Phase 2a clinical trial was a randomized, double-blind, placebo-controlled clinical trial in adult patients with the HbSS and HbS/ß-0 thalassemia genotypes of SCD and was conducted at clinical centers in the United States and the United Kingdom.

The trial evaluated the safety, tolerability, PK and exploratory PD and clinical outcomes of IMR-687 in two groups of SCD patients:

patients receiving IMR-687 administered as a monotherapy agent once daily for 24 weeks and patients receiving IMR-687 administered at lower doses in combination with HU for 16 weeks.

The design of the Phase 2a trial separated out the monotherapy and combination arms into separate sub-studies.

The combination sub-study was purposefully designed in consultation with the FDA, taking into account HU and IMR-687’s overlap in the nitric oxide-cyclic GMP pathway, which ultimately drives cyclic GMP expression.

This low-dose, short duration sub-study was thus created to test how the two drugs interact when dosed in combination.

Patients in the combination sub-study were required to have been receiving HU for at least 60 days prior to screening and then continue to receive the same dose of HU throughout the duration of the trial.

A total of 93 patients were dosed in the trial, of which 58 patients were dosed in the monotherapy sub-study and 35 patients were dosed in the combination sub-study.

We initially commenced the monotherapy sub-study with patients receiving IMR-687 at doses of 50 mg or 100 mg through 12 weeks and then escalating to higher doses of 100 mg or 200 mg, respectively, through 24 weeks if approved by the Safety Review Committee, or SRC, after review of vital signs and treatment emergent adverse events, or TEAEs.

After dosing 40 monotherapy patients (referred to as Pop A), in the second quarter of 2019 we amended the trial protocol for the monotherapy sub-study to (i) accelerate the time of dose escalation for the 100 mg/200 mg dose group from week 13 to the end of the first month, (ii) allow for patients to be administered the higher dose for five months instead of three months and (iii) eliminate the 50 mg/100 mg dose group.

Following the amendment of the protocol, we dosed a further 18 patients (referred to as Pop A1) in the monotherapy sub-study.

All patients in the monotherapy sub-study who were dosed with placebo continued to receive placebo for the duration of the trial.

We initially commenced the combination sub-study with patients receiving IMR-687 at an initial dose of 50 mg on top of a stable dose of HU, with escalation after one month to 100 mg for the remaining portion of the trial (through week 16) upon SRC approval.

After dosing 21 combination patients (referred to as Pop B), in the second quarter of 2019, we amended the trial protocol for the combination sub-study to extended dosing for an additional month.

Following the amendment of the protocol, we dosed a further 14 patients (referred to as Pop B1) in the combination sub-study.

All patients in the combination sub-study who were dosed with placebo continued to receive placebo for the duration of the trial.

The design of the Pop A/A1 and B/B1 sub-studies are shown in the graphics below .

We conducted two planned interim analyses of data from our Phase 2a clinical trial as described below.

November 2018 Interim Analysis

The first interim analysis was blinded at the individual patient level and consisted of an evaluation of low dose IMR-687 in at least 18 patients that had completed one month of treatment in the Pop A monotherapy sub-study and was carried out as pre-specified in the protocol.

The data cut-off for this interim analysis was October 8, 2018.

At 13 weeks, we observed an increase of approximately 110% from baseline in the percentage of F-cells in the group receiving 100 mg of IMR-687 as monotherapy.

We also observed decreases in absolute reticulocytes and percent reticulocytes in the 100 mg IMR-687 monotherapy group.

The data for WBC and adhesion markers were inconclusive.

Blinded safety and tolerability data as of the data cutoff date showed that treatment with IMR-687 was reported to be generally well tolerated, with no clinically significant changes in WBC counts and no evidence of neutropenia.

August 2019 Interim Analysis

The second interim analysis was triggered when at least 18 patients completed the 24 weeks of dosing in this trial in the Pop A monotherapy sub-study and had a cut-off date of July 8, 2019.

Patients in the Pop B combination sub-study were evaluated for the first time to measure safety and PK related to HU being dosed in combination with IMR-687.

In the second interim analysis, IMR-687 was generally reported to be well tolerated across all doses in the monotherapy and combination sub-studies.

All Comers Analysis (n=37)

The first analysis involved all Pop A monotherapy patients, regardless of where they were in the trial, referred to as all comers.

We observed a statistically significant (p=0.022) increase in F-cells for the IMR-687 high dose cohort (100 mg/200 mg) compared to placebo after 24 weeks of dosing.

We observed a relative increase in F-cell percentage of 18.1 percentage points, with the mean values for the absolute percentage of F-cells observed in patients increasing from 13.6% to 31.7%.

We observed a mean absolute increase in HbF% of 1.7 percentage points in the IMR-687 high dose cohort (100 mg/200 mg) after 24 weeks of dosing.

Patients in the IMR-687 high dose cohort had a mean baseline HbF% of 6.7%, which increased to 8.4% after 24 weeks of dosing.

In addition, we observed a mean increase in mean corpuscular volume of 4.3 femtoliters in the IMR-687 high dose cohort.

While we saw individual changes in other related downstream RBC biomarkers (including variable responses in reticulocytes, LDH, indirect bilirubin and hemoglobin) and white cell adhesion biomarkers (including sP -selectin, sE -selectin, iVCAM-1 and iCAM-1), we did not see consistent trends across the mean values.

Completer Analysis (n = 18)

The second analysis was a pre-specified protocol-driven analysis of the efficacy parameters for the 18 completers.

For the measurements of F-cells, 100% of completers showed an increase in F-cells and no completer saw a decrease in F-cells in the high dose arm (100 mg/200 mg).

While there was more variability in the lower dose arm (50 mg/100 mg), most completers saw F-cell increases, though they did not have the magnitude of increases as observed for the higher dose (100 mg/200 mg).

Placebo completers, as expected, showed the most variability in changes in F-cells, with 50% showing increases in F-cells and 50% showing decreases, netting out to an overall slight decrease in F-cells.

These data allowed us to create a relevant PK/PD model to potentially provide greater understanding of how dose impacts efficacy markers, including F-cells and HbF%.

Pharmacokinetics (PK) Summary

PK data from the monotherapy sub-study were analyzed to compare IMR-687 exposure for patients in the Phase 2a trial to exposure observed in preclinical studies and in healthy volunteers in the multiple ascending dose stage of our Phase 1 trial, in each case through an analysis of Area Under the Curve 0-24 , or AUC 0-24 , which measures drug concentration in blood plasma over the first 24 hours following dosing.

As shown in the far-left column of the figure below, a preclinical female dog model established a No Observed Adverse Effect Level, or NOAEL, which is the highest experimental point that does not have adverse effects, of 90,239 hours x ng/mL, or h x ng/mL.

As shown in the second-from-left column of the figure below, the 6 mg/kg highest dose in the fasted single ascending dose stage of our Phase 1 trial resulted in a mean exposure of 31,000 h x ng/mL.

As shown in the set of middle columns of the figure below, exposure in the fed multiple ascending dose stage of the trial ranged from 5,630 h x ng/mL at a dose of 1 mg/kg to 23,930 h x ng/mL at a dose of 4.5 mg/kg, which was the maximum tolerated dose, or MTD.

As shown in the far-right columns of the figure below, mean exposure in the interim analysis of the Phase 2a trial ranged from 2,880 h x ng/mL at the 50 mg dose to 16,300 h x ng/mL at the 200 mg dose.

Also as reflected in the far-right columns in the figure below, we generated a PK model based on these values that predicted exposure of 21,976 h x ng/mL and 32,000 h x ng/mL for possible future higher doses of 300 mg and 400 mg, respectively.

The observed mean exposure for 200 mg dosing of IMR-687 in the interim analysis of the Phase 2a trial and the predicted exposure for 300 mg dosing of IMR-687 are below the mean exposure at the 4.5 mg/kg MTD in the multiple ascending dose stage of our Phase 1 trial and are less than 25% of the NOAEL observed in preclinical dog experiments.

While the predicted exposure for 400 mg dosing of IMR-687 surpasses the mean exposure at the 4.5mg/kg MTD in the multiple ascending dose stage of our Phase 1 trial, it is substantially lower than the established female dog NOAEL.

We believe the exposure data we have observed to date and the exposure data predicted by our PK modeling support our decision to increase dosage to 300 mg, and potentially 400mg, in our ongoing Phase 2b clinical trial in SCD.

The second interim analysis also included analyses of additional PK exposure metrics from the monotherapy sub-study, including C max values, which are the peak concentrations achieved by a drug, and concentrations of a drug after 24 hours, or C 24 values.

The C 24 parameter provides an understanding of target coverage over a 24-hour period and is particularly

important when matched with the measure of inhibitory concentrations above 90%, or IC 90 .

We estimated an IC 90 value of 160 ng/mL for IMR-687 from the in vitro dose-response curve using IMR-687 in combination with the isolated PDE9 enzyme.

Patients in the 50 mg/100 mg group of the monotherapy sub-study were, on average, above this estimated IC 90 for approximately six to 12 hours, depending on dose, and patients in the 100 mg/200 mg group were, on average, above this estimated IC 90 for approximately 12 to 17 hours, depending on dose.

Our PK modeling predicts that a 300 mg dose of IMR-687 will result in concentrations above the estimated IC 90 for approximately 22 hours and a 400 mg dose will result in concentrations above the estimated IC 90 for over 24 hours.

In addition, the C max and C 24 levels observed for 200 mg dosing and predicted for 300 mg dosing of IMR-687 were below those observed at the 4.5 mg/kg MTD dose in the multiple ascending dose stage of our Phase 1 trial.

Our PK modeling predicts that the C max and C 24 levels for 400 mg dosing of IMR-687 will be higher than those observed at the 4.5 mg/kg MTD in the multiple ascending dose stage of the Phase 1 trial.

Examination of the of the PK for the combination of IMR-687 + HU as compared to HU alone was the key objective for the combination sub-study of the Phase 2a trial and was recommended by the FDA in our pre-IND discussions.

We measured HU PK on its own prior to the commencement of combination dosing as well as HU PK following the commencement of combination dosing at weeks five and 17.

The PK data in the second interim analysis indicated that treatment with IMR-687 + HU did not result in changes in the HU PK observed prior to combination dosing and that there were no drug-drug interactions between IMR-687 and HU, which we believe supports our use of higher doses of IMR-687 in combination with HU in our Phase 2b clinical trial of IMR-687 in SCD.

These findings also allowed us to combine monotherapy and combination dosing into a single trial population for our ongoing Phase 2b clinical trial of IMR-687 in SCD.

PK/PD Modeling with Completer Data

Noncompartmental PK results were combined with the completer data from the second interim analysis to establish PK/PD correlations for use in connection with our Phase 2b trials.

There were two key correlations that helped us better understand HbF response in light of the PK data.

The first of these was the correlation between F-cell response data and PK data.

We defined responders as patients that had a ≥ 7% increase from baseline, which included all patients from the 100 mg/200 mg dose group and one patient from the 50 mg/100 mg dose group (total n=6).

PK/PD analysis showed that completers that responded to IMR-687 had both higher median AUC 0-24 and C max values with respect to IMR-687 as compared to completer non-responders.

Although the median C 24 values were similar for all completers, the 25th and 75th percentile values were higher for responders.

The second correlation we examined was between HbF response data and PK data.

We defined responders as patients that had a ≥ 1% absolute increase in HbF from baseline, which included three patients from the 100 mg/200 mg dose group and one patient from the 50 mg/100 mg dose group (n =4).

Similar to what we observed in our analysis of the F-cell data, PK/PD analysis showed that completers that responded to IMR-687 had higher median AUC 0-24 levels as compared to non-responders.

While the median C 24 and C max values were similar for all completers, the 25th and 75th percentile values for C 24 were higher for responders.

Future dose modeling predicts that exposure in AUC 0-24 , C max and C 24 for IMR-687 should increase with dose levels above 200 mg and should achieve drug concentration levels above the estimated IC 90 for approximately 22 hours at a 300 mg dose and over 24 hours at a 400 mg dose.

We believe this PK/PD modeling further justifies our evaluation of higher doses of IMR-687 in our Phase 2b clinical trials.

January 2021 Topline Results

In January 2021, we disclosed topline results of the Phase 2a clinical trial, which are summarized below.

We are continuing to conduct additional analyses with respect to this data, including final PK data, and expect to report results from these additional analyses at a future medical meeting in 2021.

As described above, in the second quarter of 2019 we amended the trial protocol for the monotherapy sub-study to create Pop A1, which was comprised of patients who received either placebo or IMR-687 at a once-daily dose of 100 mg through 4 weeks and then 200 mg for an additional 20 weeks (24 weeks total).

At the same time, we amended the trial protocol for the combination sub-study to create Pop B1, which was comprised of patients who received either placebo or IMR-687 once-daily at 50 mg on top of a stable dose of standard of care HU, with escalation after 4 weeks to 100 mg for an additional 20 weeks (24 weeks total).

None of the patients enrolled in Pop A1 or Pop B1 were included as part of the August 2019 interim analysis described above.

Summary of Safety and Tolerability Data

Overall, the data demonstrated that IMR-687 was well tolerated as a monotherapy and in combination with HU at all dose levels.

In the monotherapy sub-studies (Pop A and Pop A1), the most frequent adverse events in the IMR-687 treatment arm included sickle cell anemia with crisis, nausea, headache and back pain.

In the combination sub-studies (Pop B and Pop B1), the most frequent adverse events in the IMR-687 + HU treatment arm included headache, sickle cell anemia with crisis, nausea, fatigue and ocular icterus.

There were no observed clinically significant shifts in vital signs or electrocardiogram data, including no hypotension or neutropenia in either the monotherapy or combination arms.

A 30% lower rate of VOCs/SCPCs, as part of the safety analysis, was observed in the Pop A1 IMR-687 treatment group when compared to placebo.

58% of patients (7 of 12 patients, 9 events total) experienced at least one VOC/SCPC in the Pop A1 IMR-687 treatment group as compared to 83% (5 of 6 patients, 14 events total) in the placebo population.

Furthermore, the rate of VOC-related hospitalizations was lower in the Pop A1 IMR-687 treatment group when compared to placebo.

33% of patients (4 of 12) experienced one VOC-related hospitalization in the Pop A1 IMR-687 treatment group as compared to 66% (4 of 6) in the placebo population.

There were no meaningful differences in VOCs/SCPCs or VOC related hospitalizations, between the Pop B1 IMR-687 + HU and HU + placebo groups.

Population A1 Monotherapy (n=18)

Biomarker results showed minimal changes in F-cells, HbF levels and total Hb levels from baseline through week 24.

However, a dose-dependent increase in HbF (1.3% absolute increase) was seen when patients dose escalated from 100 mg to 200 mg, starting after 4 weeks (n=10) and through 24 weeks (n=7).

One of seven evaluable patients (14%) in Pop A1 recorded an absolute increase in HbF percentage from baseline of greater than 1% (increase of 3.2%).

Placebo patients from Pop A1 did not have evaluable week 24 PD biomarker results due in part to missing study visits and are therefore not included in the table below.

Biomarkers related to hemoglobin, hemolysis, inflammation, and cardiac stress are summarized below for the IMR-687 treatment arm:

Percent Difference

HbF percentage (%)

F-cell percentage (%)

Markers of Hemolysis

Percent reticulocytes (%)

Absolute reticulocyte count (×10 9 /L)

Indirect bilirubin (µmol/L)

Markers of Inflammation & Cardiac Stress

NTproBNP (ng/L)

* With respect to F-cell percentage, n=9 at baseline and n=6 at Week 24.

Population B1 Combination Therapy (n=14)

Biomarker results in IMR-687+HU treated patients showed an overall increase in F-cells and HbF levels from baseline to week 24, while Hb levels did not meaningfully change.

Three of the eight evaluable patients (33%) had absolute increases in HbF percentage of greater than 1%, with a mean absolute increase in HbF percentage of 4.3% in that subset of patients.

There was a single placebo patient from Pop B1, as other patients did not have evaluable week 24 pharmacodynamics biomarker data due in part to missing study visits.

Therefore, this single patient is not included in the table below.

Biomarkers related to hemoglobin, hemolysis, inflammation, and cardiac stress are summarized below for the IMR-687+HU treatment arm :

Percent Difference

HbF percentage (%)

F-cell percentage (%)

Markers of Hemolysis

Reticulocytes (%)

Absolute reticulocyte count

Indirect bilirubin (µmol/L)

Markers of Inflammation &

Cardiac Stress

NTproBNP (ng/L)

* With respect to F-cell percentage, n=8 at baseline and n=7 at Week 24.

Population A Monotherapy (n=40)

Subsequent to the August 2019 interim analysis described above, four additional patients completed 24 weeks of dosing in the Pop A monotherapy arm.

A completers analysis in this group showed that the high dose of IMR-687 (100 mg/200 mg) resulted in an absolute increase in F-cell percentage of 13.3% from baseline (p=0.025) and a mean absolute increase in HbF percentage from baseline of 0.9%.

Three of the eight evaluable patients (38%) in Pop A recorded absolute HbF percentage increases of greater than 1%, with a mean absolute increase in HbF percentage of 3.1% in that subset of patients.

We are in the process of conducting multiple post-hoc analyses of the Phase 2a clinical trial data that include, amongst other analyses, reviewing pooled data across the sub-studies from the trial.

Preliminary review of certain of these analyses demonstrate potential benefits from IMR-687 with respect to certain SCD biomarkers, including F-Cells.

We expect to report results from these analyses at a future medical meeting.

Phase 2a Open Label Extension

We are conducting a four-year OLE clinical trial which allows patients from the Phase 2a clinical trial to enroll in a long-term safety and tolerability study of IMR-687 following completion of the Phase 2a clinical trial.

The OLE clinical trial was initially designed so that patients were administered a daily dose of 100 mg of IMR-687, and in the second quarter of 2020, a protocol amendment increased the daily dose to 200 mg.

Patients from the combination sub-study continue to receive the same dose of HU that they received while on the Phase 2a clinical trial throughout the duration of the OLE clinical trial.

Based on the tolerability profile of IMR-687 observed thus far in the OLE clinical trial, the safety review committee, or SRC, has approved, subject to the contingency below, dose escalation in the OLE clinical trial to a minimum daily dose of 300mg, with certain patients being eligible for a daily dose of 400mg based upon their weight.

This weight-based approach is similar to that being used in our ongoing Ardent Phase 2b clinical trial in SCD.

The SRC approved the dose adjustments contingent on the independent data monitoring committee, or DMC, for the Ardent Phase 2b clinical trial in SCD opening the higher-dose IMR-687 arm of that trial.

We expect the Ardent Phase 2b clinical trial DMC to make a decision on opening the higher dose arm in March 2021.

We conducted a preliminary review of 24 patients enrolled in the OLE clinical as of December 31, 2020.

As of data cutoff date, approximately 12 of these patients had evaluable PD biomarker data for at least four months of treatment on the OLE clinical trial.

We organized the patients with evaluable PD biomarkers into two sub-groups.

The first sub-group, which we refer to as the treatment interrupted sub-group, was comprised of approximately 8 patients who initiated treatment on the OLE clinical trial more than 12 weeks after completing treatment for the Phase 2a clinical trial.

The second sub-group, which we refer to as the direct roll-over sub-group, was comprised of approximately 4 patients who initiated treatment on the OLE clinical trial within 12 weeks of completing treatment for the Phase 2a clinical trial.

For purposes of analyzing PD biomarker results, patients in the direct roll-over sub-group were analyzed using the baseline value from the Phase 2a clinical trial, while patients in the treatment interrupted sub-group were analyzed using a new baseline established upon initiation of the OLE clinical trial.

Four - Month Data Review

Overall, data from the 24 patients enrolled in the OLE clinical trial as of December 31, 2020 demonstrated that IMR-687 was well tolerated.

The most common adverse events (in more than 5% of subjects) were sickle cell anemia with crisis, headache, pain in extremity, nausea, upper abdominal pain and back pain, and were generally consistent with those observed in the Phase 2a clinical trial.

16 of the 24 patients (67%) experienced at least one adverse event, with a majority of the adverse events being mild or moderate in severity.

There were no observed clinically significant shifts in vital signs, safety laboratory data, or electrocardiogram data.

Biomarker results demonstrated increases in both HbF and F-cells after four-months of treatment in both the treatment interrupted sub-group and the direct roll-over sub-group.

Specifically, there was a mean absolute increase in HbF percentage of 1.7% and 2.3% in the treatment interrupted sub-group and direct roll-over sub-group, respectively, and a mean absolute increase in F-cells of 5.9% and 10.2% in the treatment interrupted sub-group and the direct roll-over sub-group, respectively, in each case after four months of treatment.

There were minimal changes in total Hb in both sub-groups.

Patients in the treatment interrupted sub-group also demonstrated improvements in several markers of hemolysis after four months of treatment, whereas the direct roll-over sub-group showed variable changes in these measures.

The preliminary biomarker results for the OLE clinical trial are shown in the table below.

Treatment Interrupted Sub-Group

Direct Roll-Over Sub-Group

Mean (median) absolute change (4-month vs baseline)

Mean percent change (4-month vs baseline)

Mean (median) absolute change (4-month vs baseline)

Mean percent change (4-month vs baseline)

Reticulocytes (%)

Absolute reticulocyte count (×10 9 /L)

Indirect bilirubin (µmol/L)

NTproBNP (ng/L)

* Patients in the direct roll-over sub-group did not have data for NTproBNP or CRP as of December 31, 2020.

We are in the process of analyzing outcomes with respect to VOCs from the OLE clinical trial and expect to report this information at a future medical meeting.

Case Narratives

In the third quarter of 2020, we presented case narratives on the first two patients in the OLE clinical trial to complete at least six-months of treatment.

Below we have provided an update on each of these two patients who remain on the OLE clinical trial as of the filing of this Annual Report on Form 10-K.

Patient #1 was part of the Pop A monotherapy sub-study of the Phase 2a clinical trial and enrolled in the OLE clinical trial shortly following completion of the Phase 2a clinical trial and was therefore a direct roll-over patient.

As of December

31, 2020, Patient #1 had been on the OLE clinical trial for approximately 18 months (and on IMR-687 for 24 months) and has shown continued increases in levels of HbF and F-cells, as well as improvements in several SCD disease biomarkers.

The table below presents biomarker results for this patient at baseline, 12 months on study (as presented in the third quarter of 2020) and 18 months on study (the most recent OLE visit for this patient):

Absolute change (18-month vs baseline)

Percent change

(18-month vs baseline)

* As Patient #1 was a direct roll-over patient, baseline was established using the baseline of the Phase 2a clinical trial (mean of screening and randomization values).

In addition, a comparison of VOC data for the 24-month period that Patient #1 has been on IMR-687 (six months on the Phase 2a and 18 months on the OLE) versus information from a retrospective review of the patient’s medical records for the 24-month period prior to initiation of IMR-687 indicate potential benefits of IMR-687.

In the 24-month period on IMR-687, the patient had a 64% reduction (55 to 20 events) in reported VOCs, as compared to the 24-month period prior to IMR-687 administration.

Patient #2 was part of the HU combination sub-study in the Phase 2a clinical trial and was randomized to the placebo dose group, and therefore never received IMR-687 during the Phase 2a clinical trial.

The patient started the OLE clinical trial 14 months after completing the Phase 2a clinical trial, and was therefore a treatment interrupted patient, but remained on a stable HU dose (3000mg daily) during this interim period and while on the OLE clinical trial.

As of December 31, 2020, we had data on Patient #2 through eight months of treatment, reflecting the most recent OLE visit for this patient.

Patient #2 has shown sustained increases in levels of HbF and F-cells over baseline, however this patient has also shown increasing variability in other SCD biomarkers subsequent to the original case narrative presented in August 2020.

The table below presents biomarker results for this patient at baseline, four months on study (as presented in the third quarter of 2020) and eight months on study (the most recent OLE visit for this patient):

Absolute change (18-month vs baseline)

Percent change

(18-month vs baseline)

* As Patient #2 was a treatment interrupted patient, baseline was reestablished upon initiation of the OLE clinical trial (to the extent each are available, mean of baseline at screening and initiation of treatment).

In addition, a comparison of VOC data for Patient #2 for the eight-month OLE clinical trial period versus information from a retrospective review of the patient’s medical records for the eight-month period prior to initiation of the OLE clinical trial indicate potential benefits of IMR-687 being administered in combination with HU.

In the eight-month period on IMR-687, the patient had a 69% reduction (16 to 5 events) in reported VOCs, as compared to the eight-month period prior to IMR-687 administration.

We caution that the case narratives reflect data from only two patients at specified intervals in the OLE clinical trial and reported VOC comparisons involve retrospective reviews of the patients’ medical records.

As a result, we cannot assure you that future data on these patients will continue to be favorable or that data on other patients in the OLE clinical trial will demonstrate potential benefit of IMR-687.

We plan to present more data on these patients at future medical meetings.

Ardent Phase 2b Clinical Trial of IMR-687 in SCD

In the second quarter of 2020, we initiated a Phase 2b clinical trial, which we refer to as the Ardent trial, of IMR-687 in SCD and enrollment is ongoing.

The Ardent trial is designed as a randomized, double-blind, placebo-controlled, multicenter study of approximately 99 patients, aged 18 to 65 years with SCD and one to 12 VOC episodes within the 12 months preceding enrollment.

Patients concomitantly receiving a stable dose of HU according to the patient’s established treatment plan are eligible for enrollment.

Patient randomization will be stratified by use of HU as well as by region.

We plan to utilize weight-based dosing due to the possible wide range of patient weights in the trial and the increased drug exposure resulting from our use of 300 mg and 400 mg doses.

We believe this use of weight-based dosing will more precisely manage drug exposure and tolerability, so that patients with below average weights do not receive too high of a dose and patients with above average weight do not receive too low of a dose.

The lower-dose IMR-687 arm will test a range of 3.0 mg/kg up to 4.5 mg/kg (including up to a 300 mg dose) and patients will be randomly assigned in a 2:1 ratio to receive either IMR-687 or placebo.

The higher-dose IMR-687 arm will test a range of 4.5mg/kg up to 6.7 mg/kg (including up to a 400 mg dose).

Prior to enrolling the higher-dose IMR-687 arm, the independent DMC will review the then-available safety and tolerability data and, if the DMC recommends inclusion of the higher dose, randomization will then proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose or placebo).

We expect the DMC to make a decision on opening the higher-dose IMR-687 arm in March 2021.

The dose levels to be administered in the Ardent trial are designed to provide meaningful exposure to IMR-687 that could be up to two-fold that employed in the Phase 2a trial and utilize the 300 mg and potentially 400 mg dose for the first time.

The planned primary efficacy objective of the Ardent trial is to evaluate the proportion of patients with HbF response, defined as an increase of ≥ 3% in HbF from baseline to week 24, compared to placebo, and the trial is powered for statistical significance with respect to this endpoint.

Planned secondary objectives include the evaluation of the effect of IMR-687 versus placebo on (i) HbF-associated biomarkers, (ii) indices of red cell hemolysis, (iii) indices of WBC adhesion, (iv) the incidence of VOCs in relation to HbF levels, and (v) quality of life measures.

In addition, the Ardent trial will examine exploratory clinical endpoints, based in part, on the published FDA-ASH Guide to Clinical Development of Sickle Cell Disease Therapies .

While the primary efficacy endpoint for the trial will assess results after 24 weeks of treatment, patients will continue on treatment through 52 weeks to provide data for additional exploratory endpoints and to measure the incidence of VOCs over the course of a one-year period.

Following the completion of 52 weeks of dosing in the trial, patients will be eligible to enroll in an open-label extension study.

In addition, there are pre-specified interim analyses planned in the trial, with the first such interim analysis being conducted when 33 patients have reached 24 weeks of dosing.

We expect to report data from this first interim analysis in the second half of 2021.

Our systematic literature review and series of meta-analyses support our belief that HbF has the potential to predict clinical benefit and thus could serve as a surrogate endpoint for accelerated approval in SCD.

Drugs that could qualify for accelerated approval are those that treat a serious or life threatening condition, generally provide a meaningful advantage over available therapies, and demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

In the first quarter of 2020, we held a face-to-face Type B meeting with the FDA under our Fast Track designation for IMR-687 to discuss both the potential for HbF to serve as a surrogate endpoint for accelerated approval as well as the design of later stage SCD trials seeking to establish the effect of HbF on important clinical outcomes in SCD.

In the preliminary meeting comments, the FDA recommended that we conduct a Phase 2b dose finding trial instead of a Phase 2b/3 trial design that we proposed.

At the Type B meeting, the FDA commented that our revised Phase 2b trial design and approach to data collection to support HbF as a potential surrogate endpoint was acceptable.

The FDA also stated that it would welcome further discussion as the data from the Phase 2b trial matures to discuss the concept of the acceptability of HbF and a potential threshold of 3% from baseline as an acceptable surrogate endpoint.

The FDA stressed the importance of defining clear and strong assumptions and having robust results, which would be evaluated by the FDA to test if 3% HbF or higher would provide meaningful clinical benefit and therefore constitute an acceptable surrogate endpoint for a future pivotal trial of IMR-687 in SCD.

Pediatric Development Program of IMR-687 in SCD

We currently anticipate initiating our pediatric clinical program of IMR-687 in SCD in the first half of 2021.

We expect to conduct a Phase 1/2 clinical trial in adolescents (12-17 years old) comprised of a single ascending dose, followed by a 36-week multiple dose expansion phase.

In December 2020 we held a Type C meeting with the FDA, during which the agency expressed general alignment with the overall clinical trial design and indicated the study could be submitted with the adult study data in the same NDA.

SAD/MAD Clinical Study in Health Volunteers

In the first half of 2021, we expect to initiate a single ascending dose, or SAD, followed by a multiple dose clinical trial of IMR-687 to explore the safety, tolerability, and PK of higher doses of IMR-687.

This short duration study in healthy volunteers under fed conditions will sequentially assess doses of IMR-687 up to 800 mg per day administered once daily or twice daily.

Based on the safety, tolerability and PK profile observed in the SAD portion of the trial, the multi-dose portion of the trial will evaluate multiple doses of IMR-687 at the maximum tolerated dose observed for both the once daily and twice daily administrations from the SAD portion of the trial.

Tovinontrine tablets have been shown to be stable at high temperatures and in humid conditions, potentially enabling worldwide access, including in underserved regions where SCD and β-thalassemia are endemic .

Preclinical and Healthy Volunteer Data

In preclinical SCD models, we observed that tovinontrine is a potent cGMP inducer and had a multimodal mechanism of action, acting to increase HbF expression in RBCs, reduce RBC sickling and decrease expression of WBC adhesion molecules.

In an SCD in vitro model, we measured the ability of tovinontrine to increase cGMP levels in an RBC cell line as compared to HU.

In this study, we observed that tovinontrine induced cGMP production in a dose-dependent manner at an approximately 30-fold lower drug concentration than HU.

In addition, at an equivalent drug concentration of 10 µM of tovinontrine, we observed an approximately ten-fold increase in cGMP levels as compared to HU.

We also evaluated tovinontrine in a mouse model of SCD that expresses human sickle hemoglobin.

We observed that tovinontrine demonstrated statistically significant increases in F-cells, statistically significant decreases in the percentage of sickled RBCs and decreases in markers of hemolysis, or destruction of RBCs, and WBC adhesion.

In 2016, we initiated a Phase 1 randomized, double-blind, placebo-controlled clinical trial of tovinontrine in healthy volunteers.

In that trial, single and multiple ascending doses of tovinontrine were reported to be well tolerated to a maximum dose of 4.5 mg/kg per day and no serious adverse events were reported.

In 2021, we conducted a second healthy volunteer clinical trial of tovinontrine to explore higher doses of tovinontrine.

This single ascending dose followed by a multiple dose trial tested doses of up to 13 mg/kg per day.

The results demonstrated that doses of up to 8 mg/kg per day were well tolerated and no dose limiting toxicities or serious adverse events were reported at any dose tested .

Phase 2a Clinical Trial of Tovinontrine in SCD

Our Phase 2a clinical trial was a randomized, double-blind, placebo-controlled clinical trial in adult patients with SCD and was conducted at clinical centers in the United States and the United Kingdom.

The trial evaluated the safety, tolerability, pharmacokinetics, or PK, and exploratory pharmacodynamic, or PD, and clinical outcomes of escalating doses of tovinontrine administered once daily for 16 to 24 weeks, either as a monotherapy or in combination with HU.

A total of 93 patients were dosed in the trial, of which 58 patients were on monotherapy and 35 patients were treated in combination with HU.

Patients on treatment in the monotherapy arm received an escalating dose of tovinontrine of up to 200 mg per day, while patients in the combination arm received an escalating dose of tovinontrine of up to 100 mg per day in addition to HU.

The data from the Phase 2a clinical trial demonstrated that tovinontrine was well tolerated as a monotherapy and in combination with HU at all dose levels.

Changes in SCD-related biomarkers were variable across the trial.

A post-hoc analysis of the pooled results further showed that when compared to placebo (N=30), patients on tovinontrine (N=63) had:

a 40% lower mean annualized rate of VOCs;

a 38% lower mean annualized rate of VOC-related hospitalizations;

an increase in time to first VOC of 169 days for patients treated with tovinontrine versus 87 days for placebo groups;

improvements in the patient-reported VOC pain severity score.

Phase 2a Open Label Extension of Tovinontrine in SCD

We are conducting a four-year OLE clinical trial which allows patients from the Phase 2a clinical trial to enroll in a long-term safety and tolerability study of tovinontrine following completion of the Phase 2a clinical trial.

Patients in the OLE clinical trial initially received a once-daily dose of tovinontrine of 200 mg and have subsequently been escalated to a once-daily dose of up to 400 mg.

In December 2021, we presented 12-month data from the OLE trial at the American Society of Hematology (ASH) Annual Meeting.

Of the 26 subjects enrolled, 21 were evaluable at month 12 (as of the data cut-off).

Tovinontrine was generally well-tolerated as a monotherapy as well as in combination with HU.

There were no clinically significant changes in lab safety data, electrocardiogram data or vital signs, and no patients discontinued from the study due to adverse events.

The median annualized VOC rate was reduced by 38% in subjects previously in the placebo group in the Phase 2a clinical trial (N=7), with median annualized VOC rates of 5.0 (Phase 2a) and 3.1 (OLE) per year, with a median duration of treatment of 6.4 months and 11.6 months, respectively.

The low median annualized VOC rate for tovinontrine-treated patients in the Phase 2a clinical trial was maintained in subjects in the OLE clinical trial (N=14), with median annualized VOC rates of 0 (Phase 2a) and 2.0 (OLE) per year, with a median duration of treatment of 6.4 months and 11.8 months, respectively.

22% (4/18) of evaluable patients had an absolute increase in HbF greater than 3%.

47% (9/19) of patients had an absolute increase in F-cells greater than 6%, and F-cell increases were observed in 18 out of 19 evaluable patients.

Ardent Phase 2b Clinical Trial of Tovinontrine in SCD

We are currently conducting the Ardent Phase 2b clinical trial of tovinontrine in SCD, a randomized, double-blind, placebo-controlled, multicenter study of approximately 115 adult patients with SCD.

Patients were initially randomly assigned in a 2:1 ratio to receive either low dose tovinontrine ( once daily dose of 200 mg or 300 mg based on patient weight) or placebo.

I n the first quarter of 2021, an independent data monitoring committee for the Ardent trial recommended opening of the high dose tovinontrine treatment arm following review of available safety and tolerability data.

After this point, patients were randomly assigned in a 1:2:1 ratio to receive low dose tovinontrine ( once daily dose of 200 mg or 300 mg based on patient weight), high dose tovinontrine (once daily dose of 300 mg or 400 mg based on patient weight) or placebo.

We completed enrollment in the Ardent trial in the third quarter of 2021.

The planned primary efficacy endpoint of the Ardent trial is annualized rate of VOCs, and the trial is powered for statistical significance with respect to this endpoint.

We decided to change the primary endpoint of the Ardent trial from HbF response, defined as an increase of ≥ 3% in HbF, to annualized rate of VOCs following a written recommendation from the FDA in November 2021.

HbF response will continue to be evaluated as one of two key secondary endpoints, with an

evaluation of time to first VOC as the other key secondary endpoint .

In addition, other secondary endpoints include the evaluation of the effect of tovinontrine versus placebo on (i) the percent of patients who are VOC - free, time to second VOC, VOC-related hospitalizations, (ii) HbF-associated biomarkers, ( i ii) indices of red cell hemolysis, (i v ) indices of WBC adhesion, and (v) quality of life measures.

We plan to conduct an interim analysis from the Ardent trial of patients who have reached at least 24 weeks of dosing and expect to report data related to the primary endpoint from this interim analysis in the first week of April 2022.

We expect to report final data from the Ardent trial through 52 weeks of treatment in the second half of 2022.

In the second quarter of 2022, we expect to initiate long-term OLE clinical trial of tovinontrine for patients who complete the Ardent Phase 2b clinical trial in SCD.

β-thalassemia Disorder Overview

β-thalassemia, which is part of the second group of hemoglobinopathies, is a rare inherited RBC disorder.

β-thalassemia is a rare inherited RBC disorder.

Unlike patients with SCD, patients with β-thalassemia have a mutation that causes the absence or decreased synthesis of the beta globin subunit of hemoglobin, thereby creating an over-abundance of the alpha globin subunit.

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These benefits have the potential to result in increased functional RBC production, higher hemoglobin levels, reduced hemolysis and the reduction of adhesion and inflammation.

Like in SCD, infants with β-thalassemia major do not present clinical symptoms of their disorder until age six to 24 months, and sometimes later, when their HbF is replaced by mutated adult hemoglobin.

Natural history data show that patients with β-thalassemia who have high HbF levels, due to hereditary persistence of HbF, have less severe forms of the disorder.

In addition, genetic variations associated with increased HbF production have been shown to correlate with reduced β-thalassemia severity.

The image below depicts how RBCs and hemoglobin can change as a result of gene mutations in β-thalassemia.

In healthy individuals, there are equal amounts of alpha globin and beta globin subunits, which form normal hemoglobin.

In β-thalassemia, the absence and/or mutation of beta globin subunits cause excessive alpha subunits that often aggregate into clusters.

In cells with reactivated HbF, the gamma subunit reduces the effects of free-floating alpha chains and may improve hemoglobin efficiency and RBC health.

The potential of HbF induction has been observed through off-label use of HU to treat patients with β-thalassemia and has been explored in numerous clinical trials in both NTDT and TDT patients.

Most of these efforts were not randomized controlled trials, and many of them lacked a placebo comparator.

Nevertheless, HbF induction by HU showed promising early response in TDT and NTDT patients.

In fact, there are numerous documented cases both in clinical trials and in off-label real world use where TDT patients have a reduced need for transfusions with continued HU treatment.

Despite these observed benefits, and similar to SCD, there continue to be limitations with HU as a therapy in β-thalassemia, including its toxicity, dosing schedule and potential long-term effects.

In addition to HbF induction, independent research suggests activation of the nitric oxide-cyclic GMP signaling pathway may induce RBC production, which is associated with increases in RBC counts and hemoglobin levels.

In addition to HbF induction, independent research suggests activation of the nitric oxide-cGMP signaling pathway may induce RBC production, which is associated with increases in RBC counts and hemoglobin levels.

We believe this is an important mechanism of action to that could be relevant in reducing disease burden.

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Furthermore, there is evidence that WBCs in patients with β-thalassemia express higher levels of CD11b and CD18, two important biomarkers in the WBC activation cascade.

In preclinical SCD studies, we observed that IMR-687 reduced levels of CD11a and CD11b and CD18.

Addressable Patient Population

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In November 2019, the FDA approved Reblozyl (luspatercept-aamt) for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions.

Reblozyl was approved by the European Commission in June 2020 to treat adult patients with transfusion-dependent anemia associated with ß-thalassemia.

Reblozyl is a modified receptor protein that promotes RBC maturation and increases overall RBC production, but does not address other cell types implicated in β-thalassemia.

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Clinical stage programs in this category generally are aimed at promoting RBC maturation and/or increasing overall RBC production, but do not address other cell types implicated in b -thalassemia.

Several molecules targeting this pathway, which includes the key regulators hepcidin and ferroportin, are in Phase 2 clinical development in patients with b -thalassemia to treat chronic anemia associated with ineffective erythropoiesis and iron overload.

These include IONIS-TMPRss6-LRx, an antisense drug under development by Ionis Pharmaceuticals, andVIT-2763, a ferroportin inhibitor under development by Vifor Pharma.

Several molecules targeting this pathway to treat chronic anemia associated with ineffective erythropoiesis and iron overload are in development.

These include IONIS-TMPRss6-LRx, under development by Ionis Pharmaceuticals, Inc., or Ionis Pharmaceuticals, SLN-124, under development by Silence Therapeutics PLC, or Silence Therapeutics, and VIT-2763, under development by Vifor Pharma Ltd, or Vifor.

Gene Therapy/Editing :

As with SCD, gene therapy and gene editing approaches are also being developed as potential curative therapies for b -thalassemia.

Lentiglobin is a gene therapy treatment in Phase 3 clinical development by bluebird bio, while CTX-001 and ST-400 are gene editing therapies currently in Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated) and Sangamo Therapeutics, Inc.

(in collaboration with Sanofi), respectively.

beti-cel is a gene therapy treatment in development by bluebird, while CTX-001 is a gene editing therapy currently in development by CRISPR (in collaboration with Vertex).

Gene therapy involves pretreatment regimens associated with standalone risk which may limit its use in broad patient populations, and gene editing approaches still have many unanswered questions, including off-target mutagenesis.

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Drug candidates are being developed that activate PKR, an enzyme that is involved in the conversion of sugar into energy and is critical for the survival of RBCs.

Agios Pharmaceuticals, Inc.

is evaluating mitapivat in a Phase 2 clinical trial in non-transfusion-dependent patients with ß-thalassemia.

Forma Therapeutics has reported that it plans to initiate clinical development of its PKR activator, FT-4202, in patients with ß-thalassemia.

Examples include mitapivat, under development by Agios, and etavopivat, under development by Forma in TDT and NTDT patients with ß-thalassemia.

Our Solution for β-thalassemia:

IMR-687 as a Differentiated PDE9 Inhibitor

PDE9 is a potent and highly selective mechanism that uniquely targets cyclic GMP degradation, making it a promising pathway to increase cyclic GMP, reactivate HbF, enhance RBC production, enable RBC maturation, and reduce WBC activation in β-thalassemia.

We believe IMR-687 is a differentiated PDE9 inhibitor that is highly potent, selective for its target, minimally brain penetrating, and is delivered in an oral once-a-day therapy, which could be used globally.

Preclinical Data of IMR-687 in ß-thalassemia

Tovinontrine as a Differentiated PDE9 Inhibitor

PDE9 is a potent and highly selective mechanism that uniquely targets cGMP degradation, making it a promising pathway to increase cGMP, reactivate HbF, enhance RBC production, enable RBC maturation, and reduce WBC activation in β-thalassemia.

We believe tovinontrine is a differentiated PDE9 inhibitor that is highly potent, selective for its target, minimally brain penetrating, and is delivered in an oral, once-a-day therapy, which could be used globally.

Preclinical Data of Tovinontrine in ß-thalassemia

We conducted preclinical studies in a ß-thalassemia mouse model that recapitulates the human NTDT condition.

This mouse model lacks a functional beta globin subunit, leading to deficits in hemoglobin and RBCs, as well as slowed RBC maturation.

After 30 days of treatment at two different doses, we observed that IMR-687 induced statistically significant increases in functional hemoglobin and total RBC counts in a dose dependent way, with the 60mg/kg dose outperforming the 30mg/kg dose.

After 30 days of treatment at two different doses, we observed that tovinontrine induced statistically significant increases in functional hemoglobin and total RBC counts in a dose dependent way, with the 60mg/kg dose outperforming the 30mg/kg dose.

Allometric scaling to reflect dose conversion from mouse to human indicates that the 30mg/kg mouse dose is equivalent to a human dose of approximately 2.4mg/kg and the 60mg/kg mouse dose is equivalent to a human dose of approximately 4.9mg/kg.

Promotion of RBC maturation, a key mechanistic component in reducing ß-thalassemia pathology, was also observed in preclinical studies.

After 30 days of once-a-day treatment with 30 mg/kg and 60 mg/kg of IMR-687, we observed that erythroblast maturation was significantly improved as a result of increasing the amount of Ery.C, which is the population of mature erythroblasts, in comparison to Ery.B, which are more immature erythroblasts.

After 30 days of once-a-day treatment with 30 mg/kg and 60 mg/kg of tovinontrine, we observed that erythroblast maturation was significantly improved as reflected by an increase in the amount of Ery.C, which is the population of mature erythroblasts, in comparison to Ery.B, which are more immature erythroblasts.

These changes were also associated with a decrease on the ratio of Ery.B to Ery.C, otherwise known as a maturation index, where lower ratio indicates progression to maturity.

We believe the NTDT mouse model provides promising in vivo proof of concept that IMR-687 can improve the RBC-mediated aspects of ß-thalassemia.

In addition, we believe the preclinical activity observed in NTDT models will translate to TDT preclinical models and supports clinical development in both populations.

While SCD and ß-thalassemia are distinct hemoglobinopathies, they share similar pathophysiology and symptomology which support our strategy of developing IMR-687 across these indications.

Forte Phase 2b Clinical Trial of IMR-687 in ß-thalassemia

In the second quarter of 2020, we initiated a randomized, double-blind, placebo-controlled Phase 2b clinical trial, which we refer to as the Forte trial, in adult patients with ß-thalassemia and enrollment is ongoing.

The trial will evaluate the safety and tolerability of IMR-687 in approximately 60 TDT patients and approximately 60 NTDT patients.

Additionally, for TDT patients, we plan to evaluate the effect of IMR-687 versus placebo in reducing the average number of days between red blood cell transfusions, or transfusion burden, and change in iron load rate as the result of transfusion, for the treatment period as compared to the 12 weeks prior to screening.

Frequent transfusions in TDT patients lead to iron overload, which is a common complication often leading to the development of organ damage and increased mortality in these patients.

Accordingly, improvement in iron load rate is an important measure of an effective therapy for TDT patients.

For NTDT patients, we plan to evaluate the effect of IMR-687 versus placebo on HbF as well as on anemia.

Forte Phase 2b Clinical Trial of Tovinontrine in ß-thalassemia

We are currently conducting the Forte Phase 2b clinical trial of tovinontrine in ß-thalassemia, a randomized, double-blind, placebo-controlled trial, evaluating the safety and tolerability of tovinontrine in approximately 120 adult patients with ß-thalassemia.

Similar to the Ardent SCD trial, patients were initially randomly assigned in a 2:1 ratio to receive either low dose tovinontrine ( once daily dose of 200 mg or 300 mg based on patient weight) or placebo.

I n the first quarter of 2021, an independent data monitoring committee for the Forte trial recommended opening of the high dose tovinontrine treatment arm following review of available safety and tolerability data.

After this point, patients have been randomly assigned in a 1:2:1 ratio to receive low dose tovinontrine ( once daily dose of 200 mg or 300 mg based on patient weight), high dose tovinontrine (once daily dose of 300 mg or 400 mg based on patient weight) or placebo.

In addition to safety, for TDT patients, we are evaluating the effect of tovinontrine versus placebo in reducing the number of RBC units transfused in any 12-week interval as compared to the 12-week interval prior to randomization, known as the transfusion burden.

For NTDT patients, we are evaluating the effect of tovinontrine versus placebo on HbF and hemoglobin, or Hb.

The Forte trial will also examine additional exploratory efficacy endpoints as well as additional safety and PK endpoints.

The Forte trial will consist of a retrospective data collection period, a screening period, a double-blind treatment period and a safety follow-up period.

Similar to our Phase 2b trial of IMR-687 for SCD, we plan to utilize weight-based dosing.

The lower-dose IMR-687 arm will test a range of 3.0mg/kg up to 4.5mg/kg (including up to a 300 mg dose) and patients will be randomly assigned in a 2:1 ratio to receive either IMR-687 or placebo.

The higher-dose IMR-687 arm will test a range of >4.5mg/kg up to 6.7mg/kg (including up to a 400 mg dose).

In January 2021, an independent DMC reviewed available safety and tolerability data and recommended inclusion of the higher dose arm.

Going forward, randomization will proceed in a 1:2:1 ratio (IMR-687 lower dose, IMR-687 higher dose, or placebo).

Safety and tolerability will be assessed after 24 weeks of dosing.

There are pre-specified protocol-driven interim analyses planned in the trial, with the first such interim analysis being conducted when 30 patients have reached 24 weeks of dosing and an additional interim analysis being conducted when 30 patients have reached 36 weeks of dosing.

We expect to report data from the first interim analysis in the second half of 2021.

Preclinical Pipeline

We are advancing a pipeline of development-stage programs utilizing IMR-687 targeting additional indications, including HFpEF, for which we began preclinical research in the second quarter of 2020.

Heart failure affects approximately 26 million people worldwide.

HFpEF represents almost half of all cases of heart failure with approximately 2.5-3 million affected adults in the United States alone.

Pathophysiologic characteristics of HFpEF include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance and inflammation and many of these have also been described in SCD.

Cyclic GMP is known to play a pivotal role in cardiovascular and metabolic health.

For example, increased cyclic GMP signaling promotes vasodilation, natriuresis, diuresis, insulin sensitivity and lipolysis, and can inhibit cardiac hypertrophy, inflammation and adverse platelet-leukocyte-endothelial interactions, the latter of which have also been implicated in SCD.

Therefore, increasing cyclic GMP by PDE9 inhibition may be an attractive target for the treatment of HFpEF and a natural extension from our lead program in SCD.

To investigate this hypothesis, we leveraged our existing clinical program in SCD and tested IMR-687 in preclinical models of HFpEF.

In October 2020, the results of an exploratory analysis co-led by VUMC on data from the second interim analysis from our Phase 2a clinical trial of IMR-687 in adult patients with SCD were presented.

The exploratory analysis examined the potential of IMR-687 to reduce cardiovascular risk in patients with SCD.

We measured plasma concentrations of NT-proBNP, a well-established biomarker of cardiovascular risk (higher levels associate with greater risk).

We found patients treated with IMR-687 in combination with HU saw a mean decrease in NT-proBNP of 27.3% from baseline over four months.

In contrast, patients on background HU alone saw a mean increase in NT-ProBNP levels of 27% from baseline over four months.

The magnitude of this difference in treatment effect was more pronounced among patients with higher baseline NT-proBNP levels.

Specifically, among patients with baseline NT-proBNP values greater than 400 pg/ml, treatment with IMR-687 in combination with HU led to a mean reduction of 67.9% from baseline in NT-proBNP over four months, as compared with a mean increase of 28.0% from baseline in patients who received HU alone.

As SCD is a condition characterized by acute and chronic vasculopathy as well as high cardiovascular morbidity and mortality, this exploratory analysis by VUMC provides exploratory human data supporting our belief that PDE9 inhibition with IMR-687 may serve as an attractive target for the prevention and treatment of cardiovascular disease, such as HFpEF.

To compliment the observed human data, we also entered into an agreement with the Necker Institute of Paris, France in the second quarter of 2020 to conduct in vivo studies with IMR-687 in three different established mouse models for HFpEF.

In the first model we tested whether IMR-687 could prevent the development of HFpEF induced by unilateral nephrectomy and six-week continuous infusion of d-aldosterone.

IMR-687 was administered at doses of 60 mg/kg or 100

mg/kg concurrently with d-aldosterone for six weeks.

The results showed that IMR-687 significantly attenuated the development of c ardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.

In November 2021, we conducted a pre-specified protocol-driven interim analyses in approximately 43 TDT patients, 35 of whom completed at least 12 weeks of treatment and were in the analysis population for transfusion burden.

The median baseline transfusion burden in each of the high dose tovinontrine and placebo groups was 7.5 RBC units/12 weeks.

Furthermore, 54% of the subjects in the analysis population (19/35) had the more severe β 0 /β 0 genotype.

The interim data demonstrated tovinontrine was well-tolerated, with the most frequent adverse events (at least 10% of subjects in pooled tovinontrine dose groups) being nausea, headache and dizziness.

Four (9.3%) patients discontinued due to adverse events considered at least possibly related to study drug.

The proportion of patients who had at least a33% reduction in transfusion burden (of at least 2 units) in any 12-week interval as compared to the 12-week interval prior to randomization was greater in the high dose tovinontrine group (7/8) versus placebo, despite an unexpectedly high response rate in the placebo group (8/12).

Additionally, the proportion of patients who had at least a 33% reduction in transfusion burden (of at least 2 units) in any 14-week interval as compared to the 12-week interval prior to randomization was also greater in the high dose tovinontrine group (5/8) versus the placebo group (5/12).

Low dose tovinontrine did not show a higher response rate when compared to the placebo group.

No substantial differences between groups were observed in transfusion burden response rate using a fixed interval (weeks 13-24).

RBC markers were not evaluable in these regularly transfused subjects.

We expect to report data from an additional interim analysis in approximately 50 TDT patients and 30 NTDT patients through 24 weeks of dosing in the first week of April 2022 and final data from the Forte trial in the second half of 2022.

HFpEF Disease Overview

HFpEF, also known as diastolic heart failure, is typically caused by abnormalities of cardiac filling, which leads to symptoms such as shortness of breath, exercise intolerance and fluid retention.

Characteristics of HFpEF are heterogeneous, but commonly include ventricular hypertrophy, diastolic dysfunction, endothelial dysfunction, insulin resistance, and inflammation.

Comorbidities, such as hypertension, anemia, chronic kidney disease, diabetes, and obesity, are also common

in HFpEF, which are thought to contribute to its development .

HFpEF accounts for approximately half of all cases of heart failure and is becoming the predominant form of heart failure over time .

Prevalence in the United States is estimated to be approximately 3-4 million patients.

In contrast to heart failure with reduced ejection fractio n, or HFrEF, there are relatively few treatment options to improve symptoms and outcomes for patients.

Our Solution for HFpEF:

Tovinontrine as a Differentiated PDE9 Inhibitor

cGMP is known to play a pivotal role in cardiovascular and metabolic health.

For example, increased cGMP signaling promotes vasodilation, natriuresis, diuresis, insulin sensitivity and lipolysis, and can inhibit cardiac hypertrophy, inflammation and adverse platelet-leukocyte-endothelial interactions.

Therefore, increasing cGMP by PDE9 inhibition may be an attractive target for the treatment of HFpEF.

We believe tovinontrine is a differentiated PDE9 inhibitor that is highly potent, selective for its target, minimally brain penetrating, and is delivered in an oral, once-a-day therapy.

Preclinical Data of Tovinontrine in HFpEF

We conducted in vivo studies with tovinontrine in three different established mouse models for HFpEF in collaboration with the Necker Institute of Paris, France.

In the first model, we tested whether tovinontrine could prevent the development of HFpEF induced by unilateral nephrectomy and six-week continuous infusion of d-aldosterone.

Tovinontrine was administered at doses of 60 mg/kg or 100 mg/kg concurrently with d-aldosterone for six weeks.

The results showed that tovinontrine significantly attenuated the development of cardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.

Congruent findings were obtained in the second model, in which mice received continuous infusion of angiotensin II for six weeks to produce the HFpEF phenotype.

IMR-687 was administered at doses of 60 or 100 mg/kg concurrently with angiotensin II infusion for six weeks.

The results showed that IMR-687 attenuated c ardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.

In addition to these two preventive models, a third model was employed to test the therapeutic potential of IMR-687 to treat prevalent HFpEF .

In this study, twenty-week-old diabetic prone obese mice that previously displayed the HFpEF phenotype were assigned to receive vehicle or IMR-687 at 60- or 100-mg/kg for eight weeks.

The mice treated with IMR-687 displayed significantly less cardiomyocyte hypertrophy and lower levels of biomarkers of myocardial inflammation and fibrosis.

In the control arms of all three models, we found increased myocardial transcript levels of PDE9, atrial natriuretic peptide, or ANP, and B-type natriuretic peptide, or BNP , providing possible evidence for HFpEF being a condition of PDE9 excess.

In all three models, we found IMR-687 significantly reduced PDE9, ANP and BNP transcript levels in a dose-dependent manner.

We are collaborating with VUMC and have engaged additional key opinion leaders in heart failure, with the aim of developing a Phase 2 protocol with the potential to establish proof-of-concept of IMR-687 in the treatment of patients with HFpEF.

Additionally, we have begun work on a new formulation of IMR-687 that potentially could be used in this indication.

Exclusive License Agreement

In April 2016, we entered into an agreement with H.

Lundbeck A/S, or Lundbeck, for a worldwide license under certain patent rights and certain know-how owned or otherwise controlled by Lundbeck within the field of prevention, treatment or diagnosis of hemoglobinopathy disorders and/or other diseases or disorders, including those directly or indirectly related to hemoglobinopathies, which we refer to as the field.

This agreement was amended in July 2016 and October 2017.

The agreement grants us an exclusive license under the licensed technology, including the right to grant sublicenses with certain restrictions, to research, develop, make, have made, use, sell, have sold, offer to sell, import, export and commercialize any product comprising or containing certain PDE9 inhibitors, in the field.

We call such products licensed products.

Subject to certain restrictions, under the agreement, we grant Lundbeck a non-exclusive, irrevocable, perpetual, worldwide, sub-licenseable, and fully paid-up right and license under patent rights we control to the extent necessary for Lundbeck to research, develop, make, have made, use, sell, have sold, offer to sell, import, export and commercialize licensed products outside of the field.

The agreement also grants us a non-exclusive license under the licensed technology to research and develop, and make, have made, use, import and export for purposes of enabling such research and development, enhancements, improvements, modifications or derivatives to licensed products, until but not beyond a specified pre-commercialization developmental stage with respect to each such enhancement, improvement, modification or derivative.

Tovinontrine was administered at doses of 60 or 100 mg/kg concurrently with angiotensin II infusion for six weeks.

The results showed that tovinontrine attenuated cardiac and cardiomyocyte hypertrophy and limited the increase in biomarkers of myocardial inflammation and fibrosis.

In addition to these two preventive models, a third model was employed to test the therapeutic potential of tovinontrine to treat prevalent HFpEF.

In this study, 20 week-old diabetic prone obese mice that displayed the HFpEF phenotype were assigned to receive vehicle or tovinontrine at 60- or 100-mg/kg for eight weeks.

The mice treated with tovinontrine displayed significantly less cardiomyocyte hypertrophy and lower levels of biomarkers of myocardial inflammation and fibrosis.

In the control arms of all three models, we found increased myocardial transcript levels of PDE9, atrial natriuretic peptide, or ANP, and B-type natriuretic peptide, or BNP .

In all three models, we found that tovinontrine significantly reduced PDE9, ANP and BNP transcript levels in a dose-dependent manner.

Planned Phase 2 Clinical Trial of Tovinontrine in HFpEF

I n the second quarter of 2022, we expect to dose the first patient in the SP 9 IN Phase 2 clinical trial of tovinontrine in HFpEF.

The SP 9 IN trial will be a randomized, placebo-controlled trial of approximately 170 patients 45 years of age or older with enriched PDE9 expression and persistent symptoms of HFpEF.

Patients will receive either tovinontrine (twice daily dose of 300 mg or 400 mg based on patient weight) or placebo for 16 weeks.

The primary endpoint will be the change in NT-proBNP levels, with secondary endpoints that include safety and tolerability as well as quality of life measures such as Kansas City Cardiomyopathy Questionnaire (KCCQ) and New York Heart Association (NYHA) classification.

Exploratory measures are expected to include a clinical composite score, 6-minute walk test and evaluation of cardiac structure and function.

IMR-261 (formerly CXA-10)

We have commenced research activities for IMR-261 (formerly CXA-10), an oral, clinic-ready activator of Nrf2.

Nrf2 coordinates the expression of antioxidant genes in response to oxidative stress, regulates inflammation, inhibits the NF-kB pathway and has been shown to increase HbF.

Prior to its acquisition by us, IMR-261 was evaluated by Complexa, Inc.

in Phase 2 clinical trials in FSGS and PAH, and independent medical literature suggests potential in a broad array of RBC diseases, including disorders of hemoglobin and iron overload diseases.

We have initiated work on drug product manufacturing for IMR-261 as we explore potential clinical development paths in hemoglobinopathies, iron disorders and potentially other areas.

Preclinical Data for IMR-261

We evaluated IMR-261 in preclinical studies using in-vitro cell cultures and in-vivo mouse models of SCD and b -thalassemia.

In CD34+ cells from sickle cell and healthy donors, high dose IMR-261 increased HbF expression by approximately 7-fold versus placebo, whereas lower dose IMR-261 increased HbF expression by approximately 4-fold versus placebo.

Furthermore, an approximately 3-fold increase in F-cells was seen in both high dose and low dose groups when compared to placebo.

In the Townes mouse model of SCD, high dose IMR-261 induced HbF by approximately 2.2-fold when compared to placebo (8.3 ng/ml versus 3.7 ng/ml).

In addition, high dose tovinontrine significantly decreased select markers of hemolysis and increased Hb by approximately 1.1 g/dL when compared to placebo (8.7 g/dL versus 7.6 g/dL).

In a separate experiment in Townes SCD mice that assessed VOC reduction after administration of TNF-alpha, IMR-261 significantly reduced the presence of RBC on occluded vessels when compared to placebo.

IMR-261 was also tested in a mouse model of b -thalassemia (Hbb th1/th1 ) and showed significant increases in Hb and improvements in ineffective erythropoiesis at the high dose.

License and Acquisition Agreements

Tovinontrine – Exclusive License with Lundbeck

In April 2016, we entered into an agreement, or the Lundbeck Agreement, with H.

Lundbeck A/S, or Lundbeck, for a worldwide license under certain patent rights and certain know-how owned or otherwise controlled by Lundbeck within the field of prevention, treatment or diagnosis of hemoglobinopathy disorders and/or other diseases or disorders, excluding diseases or disorders of the central nervous system, which we refer to as the Lundbeck Field.

The Lundbeck Agreement was amended in July 2016 and October 2017.

The Lundbeck Agreement grants us an exclusive license under the licensed technology, including the right to grant sublicenses with certain restrictions, to research, develop, make, have made, use, sell, have sold, offer to sell, import, export and commercialize any product comprising or containing certain PDE9 inhibitors, in the Lundbeck Field.

We call such products Lundbeck Licensed Products.

The Lundbeck Agreement also grants us a non-exclusive license under the licensed technology to research and develop, and make, have made, use, import and export for purposes of enabling such research and development, enhancements, improvements, modifications or derivatives to licensed products, until but not beyond a specified pre-commercialization developmental stage with respect to each such enhancement, improvement, modification or derivative.

We have the right to request that Lundbeck grant us an exclusive development and commercialization license to one or more compounds identified through these activities as a back-up compound.

As partial consideration for the licenses granted under the agreement, we issued 167,523 shares of our common stock to Lundbeck in April 2016.

We issued 127,002 shares of our common stock to Lundbeck in December 2016 and 148,746 shares of our common stock in August 2017 as a result of antidilution provisions contained in the exclusive license agreement triggered by subsequent closings of our series A preferred stock financing.

We are also obligated to make milestone payments to Lundbeck aggregating up to (i) $23.5 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any licensed product and (ii) $11.8 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any Imara product that is or comprises a PDE9 inhibitor but is not a licensed product, which is referred to as a PDE9 product, if any.

We are obligated to pay tiered royalties of low-to-mid single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of licensed products, and tiered royalties of low single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of PDE9 products, if any.

As partial consideration for the licenses granted under the Lundbeck Agreement, we issued an aggregate of 443,271 shares of our common stock to Lundbeck between April 2016 and August 2017.

We are also obligated to make milestone payments to Lundbeck aggregating up to (i) $23.5 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any licensed product and (ii) $11.8 million upon the achievement of specified clinical, regulatory and first commercial sale milestones by any Imara product that is or comprises a PDE9 inhibitor but is not a Lundbeck Licensed Product, which is referred to as a PDE9 Product, if any.

We are obligated to pay tiered royalties of low-to-mid single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of Lundbeck Licensed Products, and tiered royalties of low single-digit percentages to Lundbeck based on our, and any of our affiliates’ and sublicensees’, net sales of PDE9 Products, if any.

The royalties are payable on a product-by-product and country-by-country basis.

Our obligation to make royalty payments extends with respect to a licensed product in a country until the later of ten years after the first commercial sale of that licensed product in that country and the expiration of the last-to-expire valid claim of a patent or patent application licensed from Lundbeck covering the licensed product or any constituent licensed compound in that country.

Our obligation to make royalty payments extends with respect to a PDE9 product in a country until the ten years

after the first commercial sale of such PDE9 product in that country.

Our obligation to make royalty payments extends with respect to a Lundbeck Licensed Products in a country until the later of ten years after the first commercial sale of that Lundbeck Licensed Product in that country and the expiration of the last-to-expire valid claim of a patent or patent application licensed from Lundbeck covering the Lundbeck Licensed Product or any constituent licensed compound in that country.

Our obligation to make royalty payments extends with respect to a PDE9 Product in a country until the ten years after the first commercial sale of such PDE9 Product in that country.

To date pursuant to this agreement, we have made cash payments to Lundbeck of $1.8 million consisting of an upfront payment and ongoing milestone payments.

The agreement obligates us to use commercially reasonable efforts to develop, seek regulatory approval for, manufacture, market and otherwise commercialize at least one licensed product, in accordance with a development plan and a development milestone timetable specified in the agreement.

The Lundbeck Agreement obligates us to use commercially reasonable efforts to develop, seek regulatory approval for, manufacture, market and otherwise commercialize at least one licensed product, in accordance with a development plan and a development milestone timetable specified in the Lundbeck Agreement.

We have the option to extend the development milestone timetable up to two times by agreeing to additional payment obligations.

Both we and Lundbeck have the right to terminate the agreement if the other party materially breaches the agreement and fails to cure such breach within specified cure periods or in the event the other party undergoes certain bankruptcy events.

Lundbeck may terminate the agreement if we or any of our affiliates, sublicensees or subcontractors bring specified patent challenges against Lundbeck or assist others in bringing such a patent challenge against Lundbeck and fail to cease such challenge within a specified period of time.

We have the right to terminate the agreement for our convenience at any time on six months’ prior written notice to Lundbeck.

Both we and Lundbeck have the right to terminate the Lundbeck Agreement if the other party materially breaches the Lundbeck Agreement and fails to cure such breach within specified cure periods or in the event the other party undergoes certain bankruptcy events.

Lundbeck may terminate the Lundbeck Agreement if we or any of our affiliates, sublicensees or subcontractors bring specified patent challenges against Lundbeck or assist others in bringing such a patent challenge against Lundbeck and fail to cease such challenge within a specified period of time.

We have the right to terminate the Lundbeck Agreement for our convenience at any time on six months’ prior written notice to Lundbeck.

IMR-261 – Asset Purchase Agreement with Complexa (assignment for the benefit of creditors), LLC

In October 2020, we entered into an asset purchase agreement, or the Complexa APA, with Complexa (assignment for the benefit of creditors), LLC, or Complexa ABC, pursuant to which we acquired all of Complexa ABC’s right, title and interest in and to the assets comprising the Nrf2 program, including CXA-10 (subsequently renamed IMR-261), previously held by Complexa, Inc.

Complexa, Inc.

had previously assigned all such assets to Complexa ABC pursuant to a general assignment entered into in August 2020 between Complexa, Inc.

and Complexa ABC.

As consideration for the assets acquired under the Complexa APA, we made a one-time payment of approximately $0.1 million and agreed to pay up to an additional approximately $3.8 million in milestone payments based on the achievement of specified clinical and commercial sale milestones as set for the in the Complexa APA.

As part of the acquisition, Complexa ABC assigned to us all of its rights under license agreements with The UAB Research Foundation and the University of Pittsburgh, each as discussed below.

IMR-261 – Exclusive License Agreement with UAB Foundation

In October 2020, we took assignment to an exclusive license agreement, or the UAB Agreement, originally entered into between The UAB Research Foundation, or UAB, and Complexa, Inc.

in April 2012.

The UAB Agreement grants us an exclusive worldwide license to practice and fully exploit certain patent rights and to make, have made, develop, use, lease, offer to sell, sell, import and export products covered by such patents within the field of human therapeutics and diagnostics.

We call such products UAB Licensed Products.

We have the right to grant sublicenses with certain restrictions, including obtaining the consent of UAB, which consent may not be unreasonably withheld, conditioned or delayed.

We are obligated to make milestone payments to UAB aggregating up to approximately $0.3 million upon the achievement of specified commercial sale milestones by any UAB Licensed Product and to pay a low single-digit percentage royalty to UAB based on our, and any of our affiliates’ and sublicensees’, net sales of UAB Licensed Products, if any, subject to a minimum annual royalty payment specified in the UAB Agreement.

Our obligation to make royalty payments extends with respect to a UAB Licensed Product until the expiration of the last-to-expire valid claim of a patent licensed from UAB covering the UAB Licensed Product.

The patents subject to the license under the UAB Agreement only have valid claims in the United States.

The royalties are payable on a product-by-product basis.

The UAB Agreement obligates us to use commercially reasonable efforts to develop, manufacture, commercialize and market at least one UAB Licensed Product, in accordance with a development plan and a development milestone timetable specified in the UAB Agreement.

The UAB Agreement expires based upon the expiration of the last-to-expire valid claim of a patent licensed from UAB.

We have the right to terminate the UAB Agreement for our convenience at any time on 90 days’ prior written notice to UAB.

UAB has the right to terminate the UAB Agreement if, amongst other reasons, we are in material default of the UAB Agreement and fail to cure such breach within specified cure periods or in the event we undergo certain bankruptcy events.

IMR-261 – Non-Exclusive License Agreement with University of Pittsburgh

In October 2020, we took assignment to an exclusive license agreement, or the Original Pittsburgh Agreement, originally entered into between University of Pittsburgh – Of the Commonwealth System of Higher Education, or University

of Pittsburgh, and Complexa, Inc.

in August 2014.

The Original Pittsburgh Agreement was terminated in its entirety in November 2020 and in May 2021, we and the University of Pittsburgh entered into a new license agreement, or the New Pittsburgh Agreement, to replace the Original Pittsburgh Agreement.

The New Pittsburgh Agreement was amended in December 2021.

The New Pittsburgh Agreement grants us a non-exclusive worldwide license to make, have made, manufacture, research, develop, use, sell, offer for sale and commercialize certain products covered by certain patents within the field of hemoglobinopathies, red cell anemias and iron disorders.

We call such products Pittsburgh Licensed Products.

We have the right to grant sublicenses with certain restrictions, including obtaining the consent of Pittsburgh, which consent may not be unreasonably withheld.

As partial consideration New Pittsburgh Agreement, we made upfront payments aggregating to less than $0.1 million.

We are obligated to make milestone payments to the University of Pittsburgh of up to approximately $0.3 million in the aggregate upon the achievement of specified clinical and commercial sale milestones by any Pittsburgh Licensed Product and to pay a low single-digit percentage royalty to the University of Pittsburgh based on our, and any of our affiliates’ and sublicensees’, net sales of Pittsburgh Licensed Product, if any, subject to a minimum annual royalty payment specified in the New Pittsburgh Agreement.

Our obligation to make royalty payments extends with respect to a Pittsburgh Licensed Products until the expiration of the last-to-expire valid claim of a patent licensed from the University of Pittsburgh covering the Pittsburgh Licensed Product.

The patents subject to the license under the New Pittsburgh Agreement only have valid claims in the United States.

The New Pittsburgh Agreement obligates us to use commercially reasonable efforts to develop and obtain FDA approval for Pittsburgh Licensed Products, in accordance with a development milestone timetable specified in the New Pittsburgh Agreement.

The New Pittsburgh Agreement expires upon the expiration of the last-to-expire valid claim of a patent licensed from the University of Pittsburgh.

We have the right to terminate the New Pittsburgh Agreement for our convenience at any time on 90 days’ prior written notice to the University of Pittsburgh.

The University of Pittsburgh has the right to terminate the New Pittsburgh Agreement if, amongst other reasons, we default in the performance of any of our obligations under the New Pittsburgh Agreement and fail to cure such breach within specified cure periods or in the event we undergo certain bankruptcy events.

The biopharmaceutical industry is characterized by rapidly advancing technologies, intense competition and strong emphasis on proprietary products.

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Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

If our lead product candidate, IMR-687, is approved for the indications that we are currently targeting, it will likely compete with the currently marketed drugs and, if approved, the therapies in development discussed below.

If our lead product candidate tovinontrine is approved for the indications that we are currently targeting, it will likely compete with the currently marketed drugs and, if approved, the therapies in development discussed below.

Sickle Cell Disease

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HU and Endari;

HU, marketed under trade names including DROXIA by Bristol-Myers Squibb Company, as well as in generic form, is approved for the treatment of anemia related to SCD, to reduce the frequency of VOCs and the need for blood transfusions.

and only one approved drug treatment in the European Union:

HU, marketed under trade names including Droxia by Bristol-Myers Squibb Company, as well as in generic form, is approved for the treatment of anemia related to SCD, to reduce the frequency of

VOCs and the need for blood transfusions.

Endari, marketed by Emmaus Life Sciences, Inc., is an oral powder form of L-glutamine approved to reduce severe complications associated with the disorder.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in adults and children 12 years of age and older.

In November 2019, the FDA granted accelerated approval for Oxbryta (voxelotor) for the treatment of SCD in patients 12 years of age and older and its label was subsequently expanded to include patients four years of age and older.

Oxbryta is an oral therapy taken once daily and is the first approved treatment that directly inhibits sickle hemoglobin polymerization.

In February 2022, the European Commission approved Oxbryta for the treatment of hemolytic anemia in patients with SCD 12 years of age and older.

In addition, in November 2019, the FDA approved Adakveo (crizanlizumab), to reduce the frequency of VOCs in adult and pediatric patients aged 16 years and older with SCD.

Adakveo received conditional approval in the European Union in October 2020 for the prevention of recurrent VOCs in SCD patients aged 16 years and older.

Adakveo is administered intravenously and binds to P-selectin, which is a cell adhesion protein that plays a central role in the multicellular interactions that can lead to vaso-occlusion.

These two recent approvals represent important milestones for patients with SCD.

Further, IMR-687 acts primarily on red blood cells and has the potential to act on white blood cells, adhesion markers and other cell types that are implicated in SCD.

We believe that IMR-687’s multimodal mechanism-of-action has the potential to demonstrate significant benefit to patients with SCD.

Blood transfusions are also used to treat SCD and can transiently bolster hemoglobin levels by adding functional RBCs.

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HSCT is more commonly offered to pediatric patients with available sibling-matched donors.

IMR-687 could face competition from a number of different therapeutic approaches in development for patients with SCD.

For example, bluebird bio has reported that it plans to submit a biologic license application, or BLA, for LentiGlobin for the treatment of SCD in 2022 based on the results of its ongoing Phase 2 clinical trial.

Aruvant Sciences, Inc.

is developing ARU-1801, a gene therapy treatment in Phase 2 clinical development.

There are also several gene editing approaches to treating SCD under evaluation, including CTX-001, currently in Phase 2 clinical development by CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Incorporated), BIVV-003, currently in Phase 1/2 clinical development by Sangamo Therapeutics, Inc.

(in collaboration with Sanofi), and OTQ923, currently in Phase 1/2 clinical development by Intellia Therapeutics, Inc.

(in collaboration with Novartis).

There are also several therapeutic approaches under development outside of gene editing/therapy.

Novo Nordisk A/S (in collaboration with EpiDestiny, Inc.) is evaluating EPI-01, a small molecule designed to increase production of HbF, in Phase 1 clinical trials.

Fulcrum Therapeutics, Inc.

is developing FTX-HbF, a small molecule designed to upregulate HbF.

Agios Pharmaceuticals, Inc.

is developing the PKR activator mitapivat (AG-348), which is in Phase 1/2 clinical development, and Forma Therapeutics, Inc.

is developing the PKR activator FT-4202, which is in Phase 3 clinical development.

In addition, Syros Pharmaceuticals, Inc., in collaboration with Global Blood Therapeutics, is using its gene control platform to discover and develop product candidates to activate gamma globin expression to induce the production of HbF for the treatment of SCD.

Tovinontrine could face competition from a number of different therapeutic approaches in development for patients with SCD.

For example, there are a number of companies in clinical development for gene editing/therapy treatments, including bluebird, Aruvant, CRISPR (in collaboration with Vertex), Sangamo Therapeutics, Inc.

(in collaboration with Sanofi), Intellia Therapeutics, Inc.

(in collaboration with Novartis), Graphite Bio, Inc.

and Editas Medicine, Inc.

There are also several companies advancing therapeutic approaches outside of gene editing/therapy, including GBT, Agios, Forma, Vifor, Novo Nordisk (in collaboration with EpiDestiny), Fulcrum, CSL Ltd.

ß-thalassemia

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A potentially curative therapy for ß-thalassemia is HSCT, which is associated with serious risk and is limited to patients with a suitable donor.

In November 2019, the FDA approved REBLOZYL (luspatercept-aamt) for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions.

In November 2019, the FDA approved Reblozyl for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions.

Reblozyl was approved by the European Commission in June 2020 to treat adult patients with transfusion-dependent anemia associated with ß-thalassemia.

Reblozyl is a modified receptor protein that promotes RBC maturation and increases overall RBC production, but does not address other cell types implicated in ß-thalassemia.

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Bluebird bio submitted its rolling BLA to the FDA which it has announced that it plans to complete in 2021.

IMR-687 could face competition from a number of different therapeutic approaches that are in development as a therapeutic option for patients with transfusion-dependent or non-transfusion-dependent ß-thalassemia.

For example, Ionis Pharmaceuticals and Vifor Pharma have ongoing Phase 2 trials to evaluate therapies targeting RBC maturation (IONIS-TMPRss6-LRx andVIT-2763, respectively).

Agios Pharmaceuticals, Inc.

is evaluating mitapivat, a PKR activator, in a Phase 2 clinical trial in non-transfusion-dependent patients with ß-thalassemia.

Forma Therapeutics has reported that it plans to initiate clinical development of its PKR activator, FT-4202, in patients with ß-thalassemia.

Sangamo (in collaboration with Sanofi) is conducting a Phase 1/2 clinical trial of ST-400, which uses a genome-edited cell therapy approach designed to produce functional RBCs using HbF.

CRISPR Therapeutics AG, in collaboration with Vertex, is conducting a Phase 1/2 clinical trial of CTX-001, which uses a gene editing approach to upregulate the expression of HbF, in patients with transfusion-dependent ß-thalassemia.

Syros Pharmaceuticals, Inc., in collaboration with Global Blood Therapeutics, is using its gene control platform to identify and develop product candidates to activate gamma globin expression to induce the production of HbF for the treatment of ß-thalassemia.

We believe that IMR-687’s differentiated mechanism of action and oral route of administration have the potential to provide IMR-687, if approved, with competitive advantages over approved therapies for ß-thalassemia, including REBLOZYL.

Tovinontrine could face competition from a number of different therapeutic approaches that are in development as a therapeutic option for patients with TDT or NTDT ß-thalassemia.

For example, there are a number of companies in clinical development for gene editing/therapy treatments, including bluebird, CRISPR (in collaboration with Vertex) and Ionis Pharmaceuticals.

There are also several companies advancing therapeutic approaches outside of gene editing/therapy, including Agios, Forma, Silence Therapeutics and Vifor.

In the area of HFpEF, tovinontrine could face competition from Entresto (marketed by Novartis) and Jardiance (marketed by Eli Lilly & Co.) which are currently the only FDA-approved therapies for HFpEF.

We are also aware of several drugs approved for other indications that are likely to seek near-term marketing approval for the treatment of HFpEF including Farxiga (Astra Zeneca, PLC), Invokana (Johnson & Johnson) and Zynquista (Lexicon Pharmaceuticals, Inc).

addition, Bristol-Myers Squibb Co., Cytokinetics, Inc., Acceleron Pharma, Inc., Palatin Technologies, Inc., Cardurion Pharmaceuticals, Inc.

and TransThera Biosciences Co., Ltd., among potentially other companies, are also developing therapeutic approaches for patients with HFpEF.

Intellectual Property

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We generally file patent applications directed to our key programs in an effort to secure our intellectual property positions vis-a-vis these programs.

As of December 31, 2020, we owned, co-owned, or held exclusive license rights to numerous patent and patent applications, including at least six issued or allowed U.S.

patents, five U.S.

pending non-provisional patent applications, 29 issued or allowed non-U.S.

patents, including four European patent applications which have been validated among individual European Patent Convention nations, 76 non-U.S.

pending patent applications, and three pending Patent Cooperation Treaty, or PCT, applications.

The intellectual property portfolio for our most advanced program as of December 31, 2020, is summarized below.

The intellectual property portfolio for tovinontrine and IMR-261, is summarized below.

Prosecution is a lengthy process, during which the scope of the claims initially submitted for examination by the U.S.

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We expect this may be the case with respect to some of our pending patent applications referred to below.

The patent portfolio for our IMR-687 program includes at least six published patent families.

Tovinontrine (IMR-687)

The patent portfolio for our tovinontrine program includes at least six published patent families.

As of December 31, 2021, we owned, co-owned, or held exclusive license rights to numerous patent and patent applications, including at least six issued or allowed U.S.

patents, five U.S.

patents, nine U.S.

pending non-provisional patent applications, 82 issued or allowed non-U.S.

patents, including four European patent applications which have been validated among individual European Patent Convention nations, 76 non-U.S.

pending patent applications, and three pending PCT applications relating to our IMR-687 program.

patents, including five European patent applications which have been validated among individual European Patent Convention nations, 95 non-U.S.

pending patent applications, and four pending Patent Cooperation Treaty, or PCT, applications relating to our tovinontrine program.

These patents and patent applications comprise the following patent families:

The issued patents include coverage of the IMR-687 composition of matter.

The issued patents include coverage of the tovinontrine composition of matter.

The issued patents include US 9,643,970 (exclusively licensed to us from Lundbeck A/S), which issued May 2017.

patent and related international family members are directed to the IMR-687 composition of matter, including racemic mixtures.

The expected expiry date of US 9,643,970, including 63 days of Patent Term Adjustment, based on a 20-year term, of US 9,643,970, is December 2032, absent any other patent term extensions available.

patent and related international family members are directed to the tovinontrine composition of matter, including racemic mixtures.

The expected expiry date of US 9,643,970, including 63 days of Patent Term Adjustment, based on a 20-year term, is December 2032, absent any other patent term extensions available.

The issued patents also include US 9,434,733 (exclusively licensed to us from Lundbeck A/S), which issued September 2016.

patent and related international family members are directed to the alternative PDE9 inhibitor compositions of matter, including racemic mixtures.

The expected expiry date, based on a 20-year term, of US 9,434,733, is January 2033, absent any patent term extensions available.

The expected expiry date, based on a 20-year term is January 2033, absent any patent term extensions available.

The issued patents also include US 10,513,524 (exclusively licensed to us from Lundbeck A/S), which issued December 2019.

patent and related international family members provide further protection for the IMR-687 composition of matter, including the enantiomer, in addition to coverage of therapeutic methods of treating sickle cell disease with IMR-687.

The expected expiry date, based on a 20-year term, of US 10,513,524 is July 2036, absent any patent term extensions available.

patent and related international family members provide further protection for the tovinontrine

composition of matter, including the enantiomer, in addition to coverage of therapeutic methods of treating sickle cell disease with tovinontrine .

The expected expiry date, based on a 20-year term , is July 2036, absent any patent term extensions available.

The pending applications include an additional patent family directed to therapeutic methods with a priority filing date of July 2016.

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No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2038, absent any patent term extensions available.

The PCT applications include a patent family directed to polymorphs of IMR-687 with a priority filing date of May 2018.

The PCT applications include a patent family directed to polymorphs of tovinontrine with a priority filing date of May 2018.

No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2039, absent any patent term extensions available.

The pending PCT applications also include a PCT application directed to solid dose formulations of IMR-687 with a priority filing date of August 2018.

The pending PCT applications also include a PCT application directed to solid dose formulations of tovinontrine with a priority filing date of August 2018.

No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is August 2039, absent any patent term extensions available.

The pending PCT applications also include a PCT application directed to liquid solution formulations of IMR-687 with a priority filing date of April 2019.

The pending PCT applications also include a PCT application directed to liquid solution formulations of tovinontrine with a priority filing date of April 2019.

No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is April 2040, absent any patent term extensions available.

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While we believe that the specific and generic claims contained in our owned and licensed pending U.S., non-U.S., and PCT applications provide protection for the claimed pharmaceutical compositions and methods of use, third parties may nevertheless challenge such claims.

The patent portfolio for our IMR-261 program includes at least four published patent families.

As of December 31, 2021, we owned, co-owned, or held exclusive license rights to numerous patent and patent applications, including at least seven issued or allowed U.S.

patents, one U.S.

pending non-provisional patent applications, 20 non-U.S.

pending patent applications, and two pending PCT application relating to our IMR-261 program.

These patents and patent applications comprise the following patent families:

The issued patents include coverage of the IMR-261 composition of matter.

The issued patents include US 8,309,526 (exclusively licensed to us from UAB), which issued November 13, 2012.

The expected expiry date of US 8,309,526, based on a 20-year term, is April 2025, absent any other patent term extensions available.

The issued patents also include four patents (US 7,776,916, US 9,522,156, US 9,006,473 and 9,867,795, each exclusively licensed to us from UAB), which issued between August 17, 2010 and January 16, 2018.

patents provide coverage of therapeutic methods of treating certain inflammatory and vascular diseases, including sickle cell disease, with IMR-261.

The expected expiry date of these patents, based on a 20-year term, ranges between April 2025 and March 2027, absent any patent term extensions available.

The pending applications include a patent family directed to therapeutic methods of treating certain diseases, including sickle cell disease, at specified doses, with a priority date of October 2015.

No patents covering therapeutic methods of treating sickle cell disease have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is October 2036, absent any patent term extensions available.

The PCT applications include a patent family directed to therapeutic methods of treating certain diseases, including sickle cell disease, at additional specified doses, with a priority filing date of May 2020.

No patents have issued in this patent family, and the expected expiry date of this patent family, based on a 20-year term, is May 2041, absent any patent term extensions available.

In addition to the above, we have licensed on a non-exclusive basis from the University of Pittsburgh, rights to U.S.

issued patents covering pharmaceutical compositions of nitro oleic acids, including IMR-261.

The expected expiry date of these patents, based on a 20-year term, is in mid-2028, absent any other patent term extensions available.

The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained.

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It is possible that issued U.S.

patents covering IMR-687 may be entitled to patent term extensions.

patents covering tovinontrine may be entitled to patent term extensions.

If our use of drug candidates or the drug candidate itself receive FDA approval, we intend to apply for patent term extensions, if available, to extend the term of patents that cover the approved use or drug candidate.

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These agreements may also be breached, and we may not have an adequate remedy for any such breach.

In addition, our trade secrets and/or confidential know-how may become known or be

independently developed by a third party, or misused by any collaborator to whom we disclose such information.

In addition, our trade secrets and/or confidential know-how may become known or be independently developed by a third party, or misused by any collaborator to whom we disclose such information.

Despite any measures taken to protect our intellectual property, unauthorized parties may attempt to copy aspects of our products or to obtain or use information that we regard as proprietary.

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In the United States, drug products are approved and regulated under the Federal Food, Drug and Cosmetic Act, or FDCA, and applicable implementing regulations and guidance.

The failure of an applicant to comply with the applicable regulatory requirements at any time during the product development process may result in delays to the conduct of a study, regulatory review and approval and/or administrative or judicial sanctions.

An applicant seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA:

A company, institution or organization that takes responsibility for the initiation and management of a clinical development program for such products, and for their regulatory approval, is typically referred to as a sponsor.

The failure of a sponsor to comply with the applicable regulatory requirements at any time during the product development process may result in delays to the conduct of a study, regulatory review and approval and/or administrative or judicial sanctions.

A sponsor seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following steps before the product candidate will be approved by the FDA:

preclinical testing including laboratory tests, animal studies and formulation studies, which must be performed in accordance with the FDA’s good laboratory practice, or GLP, regulations and standards;

submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin;

design of a clinical protocol and submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin;

approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;

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Preclinical Studies

Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.

Before a sponsor begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing stage.

Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among other things, the toxicity of the product candidate.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards.

The conduct of the preclinical tests and formulation of the compounds for testing must comply with federal regulations and requirements, including GLP regulations and standards and the United States Department of Agriculture’s Animal Welfare Act, if applicable.

Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and long-term toxicity studies may continue after the IND is submitted.

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Such authorization must be secured prior to interstate shipment and administration of any product candidate that is not the subject of an approved NDA.

In support of a request for an IND, applicants must submit a protocol for the clinical trial, and any subsequent protocol amendments must be submitted to the FDA as part of the IND application.

In support of a request for an IND, sponsors must submit a protocol for the clinical trial, and any subsequent protocol amendments must be submitted to the FDA as part of the IND application.

In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, must be submitted to the FDA as part of an IND.

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Other reasons for suspension or termination may be made by us based on evolving business objectives and/or the competitive climate.

Information about clinical trials must be submitted within specific timeframes to the National Institutes of Health, or NIH, for public dissemination on its ClinicalTrials.gov website.

Expanded Access to an Investigational Drug for Treatment Use

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Sponsors of one or more investigational drugs for the treatment of a serious disease(s) or condition(s) must make publicly available their policy for evaluating and responding to requests for expanded access for individual patients.

There is no obligation for a sponsor to make its drug products available for expanded access;

however, as required by the 21st Century Cures Act, or Cures Act, passed in 2016, if a sponsor has a policy regarding how it responds to expanded access requests, it must make that policy publicly available.

Sponsors are required to make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 trial;

or 15 days after the investigational drug or biologic receives designation as a breakthrough therapy, fast-track product, or regenerative medicine advanced therapy.

In addition, on May 30, 2018, the Right to Try Act, was signed into law.

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Failure to exhibit due diligence with regard to fulfilling post-marketing commitments or post-marketing requirements could result in withdrawal of approval for products.

A clinical trial may combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate.

A company’s designation of a clinical trial as being of a particular phase is not necessarily indicative that the trial will be sufficient to satisfy the FDA requirements of that phase because this determination cannot be made until the protocol and data have been submitted to and reviewed by the FDA.

Generally, pivotal trials are Phase 3 trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.

Progress reports detailing the status and a brief description of available results of the clinical trials must be submitted at least annually to the FDA.

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The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.

Finally, sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S.

National Institutes of Health, or NIH.

In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of the registration of the clinical trial.

Both the NIH and the FDA have recently signaled the government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors.

The failure to submit clinical trial information to clinicaltrials.gov, as required, is a prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.

Concurrent with clinical trials, companies often complete additional animal studies and they must also develop additional information about the chemistry and physical characteristics of the investigational drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

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Pediatric Studies

Under the Pediatric Research Equity Act of 2003, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Under the Pediatric Research Equity Act of 2003, or PREA, an NDA or supplement thereto must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

Sponsors must also submit pediatric study plans prior to the assessment data.

Those plans must contain an outline of the proposed pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation.

The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other and agree upon a final plan.

The FDA or the applicant may request an amendment to the plan at any time.

For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of an applicant, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.

In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors, and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety (90) days after the FDA’s receipt of the study plan.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

Additional requirements and procedures relating to deferral requests and requests for extension of deferrals are contained in the Food and Drug Administration Safety and Innovation Act, or FDASIA, in 2012.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation.

Those plans must contain an outline of the proposed pediatric study or studies the sponsor plans to conduct, including study objectives and design, any deferral or waiver requests and other information required by regulation.

The sponsor, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each other and agree upon a final plan.

The FDA or the sponsor may request an amendment to the plan at any time.

For drugs intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial pediatric study plan or to discuss deferral or waiver of pediatric assessments.

In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors,

and the FDA must meet with sponsors by no later than the end-of-phase 1 meeting for serious or life-threatening diseases and by no later than ninety (90) days after the FDA’s receipt of the study plan.

The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults before pediatric trials are complete.

Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although the FDA has recently taken steps to limit what it considers abuse of this statutory exemption in the PREA.

Rare Pediatric Disease Priority Review Voucher Program

With enactment of the FDASIA in 2012, and subsequent passage of the Advancing Hope Act of 2016, Congress authorized the FDA to award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in the law.

With enactment of the Food and Drug Administration Safety and Innovation Act in 2012, and subsequent passage of the Advancing Hope Act of 2016, Congress authorized the FDA to award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in the law.

This provision is designed to encourage development of new drug and biological products for prevention and treatment of certain rare pediatric diseases.

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In addition, sponsors who choose not to submit a rare pediatric disease designation request may nonetheless receive a priority review voucher if they request such a voucher in their original marketing application and meet all of the eligibility criteria.

In December 2016, the 21st Century Cures Act extended the Rare Pediatric Disease Priority Review Voucher Program, authorizing the FDA to award vouchers through September 30, 2022, limited to drugs with rare pediatric disease designation granted by September 30, 2020.

In December 2016, the Cures Act extended the Rare Pediatric Disease Priority Review Voucher Program, authorizing the FDA to award vouchers through September 30, 2022, limited to drugs with rare pediatric disease designation granted by September 30, 2020.

On September 30, 2020, Congress provided a short-term extension of the Priority Review Voucher Program.

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After September 30, 2026, the FDA may not award any rare pediatric disease priority review vouchers.

Review and Approval of an NDA

Submission and Filing of an NDA

In order to obtain approval to market a drug product in the United States, a marketing application must be submitted to the FDA that provides sufficient data establishing the safety, purity and potency of the proposed drug product for its intended indication.

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To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety, purity and potency of the drug product to the satisfaction of the FDA.

The NDA is a vehicle through which applicants formally propose that the FDA approve a new product for marketing and sale in the United States for one or more indications.

The NDA is a vehicle through which sponsors formally propose that the FDA approve a new product for marketing and sale in the United States for one or more indications.

Every new drug product candidate must be the subject of an approved NDA before it may be commercialized in the United States.

Under federal law, the submission of most NDAs is subject to an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data.

The sponsor of an approved NDA is also subject to an annual program fee, which for fiscal year 2021 is $336,432.

The sponsor of an approved NDA is also subject to an annual program fee, which for federal fiscal year 2022 is $369,413.

Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a waiver for certain small businesses.

Following submission of an NDA, the FDA conducts a preliminary review of the application, generally within 60 calendar days of its receipt, and strives to inform the sponsor within 74 days of the FDA’s receipt of the submission whether the application is sufficiently complete to permit substantive review.

If the FDA determines that the application is incomplete, it may request additional information rather than accept the application for filing.

In this event, the application

must be resubmitted with the additional information.

The resubmitted application is also subject to review before the FDA accepts it for filing.

Following submission of an NDA, the FDA conducts a preliminary review of the application within 60 days of receipt and must inform the sponsor at that time or before whether an application is sufficiently complete to permit substantive review.

If the FDA determines that the application is incomplete, it will issue a Refuse to File, or RFT, letter and may request additional information and studies.

In this event, the application must be resubmitted with the additional information and is subject to review before the FDA accepts it for filing.

Once the submission is accepted for filing, the FDA begins an in-depth substantive review.

The FDA has agreed to specified performance goals in the review process of NDAs but the review process and the Prescription Drug User Fee Act, or PDUFA, goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.

Before approving an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.

The FDA has agreed to specified performance goals in the review process of NDAs but the review process and the Prescription Drug User Fee Act, or PDUFA, goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to address an outstanding deficiency identified by the FDA following the original submission.

Under that agreement, 90% of applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed within 10 months from the date on which the FDA accepts the application for filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six months of the filing date.

In connection with its review of an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured.

These pre-approval inspections may cover all facilities associated with an NDA submission, including component manufacturing, finished product manufacturing and control testing laboratories.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

In addition, as a condition of approval, the FDA may require an applicant to develop a REMS.

Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the data supporting the application.

In addition, as a condition of approval, the FDA may require a sponsor to develop a REMS.

A REMS uses risk-minimization strategies beyond the professional labeling to ensure that the benefits of the product outweigh the potential risks.

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These programs are referred to as Fast Track designation, Breakthrough Therapy designation, Priority Review designation and Regenerative Advanced Therapy designation.

None of these expedited programs change the standards for approval but they may help expedite the development or approval process of product candidates.

Specifically, the FDA may designate a new product for Fast Track review if it is intended for the treatment of a serious or life-threatening disease or condition and it demonstrates the potential to address unmet medical needs for such a disease or condition.

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The FDA may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor throughout the development process;

providing timely advice to the product sponsor regarding development and approval;

providing timely advice to the product sponsor

regarding development and approval;

involving more senior staff in the review process;

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Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation.

A Priority Review

designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

With passage of the 21st Century Cures Act, or the Cures Act, in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as Regenerative Advanced Therapies.

A Priority Review designation is intended to direct overall attention and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.

With passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as Regenerative Advanced Therapies.

A product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and if preliminary clinical evidence indicates that the product has the potential to address unmet medical needs for such disease or condition.

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The FDA’s Decision on an NDA

On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing facilities, the FDA may issue an approval letter or a complete response letter.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter.

To reach this determination, the FDA must determine that there is substantial evidence that the drug product is effective and that its expected benefits outweigh its potential risks to patients.

This “benefit-risk” assessment is informed by the extensive body of evidence about the product’s safety and efficacy in the NDA.

A CRL generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the application.

If and when those deficiencies have been addressed to the FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter.

The FDA has committed to reviewing such resubmissions in two or six months depending on the type of information included.

Even with submission of

this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If the FDA approves a new product, it may limit the approved indications for use of the product.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If a CRL is issued, the sponsor will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application withdrawn or, in its discretion, grant the sponsor an additional six month extension to respond.

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

It may limit the approved indications for use of the product.

The agency may also require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including a REMS, to help ensure that the benefits of the product outweigh the potential risks.

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It may be permissible, under very specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as distributing scientific or medical journal information as part of bona fide scientific exchange.

If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.

In September 2021, the FDA published final regulations which describe the types of evidence that the agency will consider in determining the intended use of a drug product.

This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or distributes drug products.

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The Best Pharmaceuticals for Children Act provides an incentive of additional marketing exclusivity in the United States to sponsors who voluntarily complete certain pediatric clinical studies.

If granted, pediatric exclusivity provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity, including the non-patent and orphan exclusivity.

If granted, pediatric exclusivity provides for the attachment of an additional six months of regulatory exclusivity to the term of any patent or existing regulatory exclusivity, including the orphan drug exclusivity.

This six-month exclusivity may be granted if an NDA sponsor submits pediatric data that fairly respond to a pediatric written request from the FDA for such data.

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Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same drug for the same condition is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

This is the case despite an earlier court opinion holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan drug exclusivity regardless of a showing of clinical superiority.

In September 2021, the Court of Appeals for the 11th Circuit held that, for the purpose of determining the scope of market exclusivity, the term “same disease or condition” in the statute means the designated “rare disease or condition” and could not be interpreted by the FDA to mean the “indication or use.” Thus, the court concluded, orphan drug exclusivity applies to the entire designated disease or condition rather than the “indication or use.” It is unclear how this court decision will be implemented by the FDA.

Patent Term Restoration and Extension

A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost during product development and the FDA regulatory review.

The restoration period granted on a patent covering a product is typically one-half the time between the effective date of a clinical investigation involving human beings is begun and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

The restoration period granted on a patent covering a product is typically one-half the time between the effective date the IND for the clinical investigation and the submission date of an application, plus the time between the submission date of an application and the ultimate approval date.

Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the product’s approval date.

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officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;

the federal transparency requirements known as the federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians and teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members.

the federal transparency requirements known as the federal Physician Payments Sunshine Act, which requires certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within HHS, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as ownership and investment interests held by physicians, other healthcare providers and their immediate family members.

Further, some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government in addition to requiring manufacturers to report information related to payments to physicians and other health care providers or marketing expenditures.

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These changes included aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and will remain in effect through 2031 under the Coronavirus Aid, Relief, and Economic Security Act, or the CARES Act.

These Medicare sequester reductions have been suspended through the end of March 2022.

From April 2022 through June 2022 a 1% sequester cut will be in effect, with the full 2% cut resuming thereafter.

The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

For example, with enactment of the Tax Cuts and Jobs Act of 2017, or TCJA, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019.

Further, on December 14, 2018, a U.S.

District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA are invalid as well.

On December 18, 2019, the Court of Appeals for the Fifth Circuit affirmed the lower court’s ruling that the individual mandate portion of the ACA is unconstitutional and it remanded the case to the district court for reconsideration of the severability question and additional analysis of the provisions of the ACA.

Thereafter, the U.S.

Supreme Court agreed to hear this case.

Oral argument in the case took place on November 10, 2020, and a ruling by the Court is expected sometime this year.

District Court judge in the Northern District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the TCJA, the remaining provisions of the ACA are invalid as well.

Supreme Court heard this case on November 10, 2020 and, on June 17, 2021, dismissed this action after finding that the plaintiffs do not have standing to challenge the constitutionality of the ACA.

Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results .

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and policies that reduce affordability of coverage or financial assistance, including for dependents.

The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.

To date, there have been several recent U.S.

congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement methodologies for drug products.

To those ends, President Trump issued five executive orders intended to lower the costs of prescription drug products but it is unclear whether, and to what extent, these orders will remain in force under the Biden

Administration.

Further on September 24, 2020, the Trump Administration finalized a rulemaking allowing states or certain other non-federal government entities to submit importation program proposals to the FDA for review and approval.

Applicants are required to demonstrate that their importation plans pose no additional risk to public health and safety and will result in significant cost savings for consumers.

The FDA has issued draft guidance that would allow manufacturers to import their own FDA-approved drugs that are authorized for sale in other countries (multi-market approved products).

The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States.

There have been several recent U.S.

congressional inquiries, as well as proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid.

In 2020, President Trump issued several executive orders intended to lower the costs of prescription products and certain provisions in these orders have been incorporated into regulations.

These regulations include an interim final rule implementing a most favored nation model for prices that would tie Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021.

That rule, however, has been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it.

With issuance of this rule, CMS stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to evidence-based care.

In addition, in October 2020, HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program, or SIP, to import certain prescription drugs from Canada into the United States.

The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire) have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA.

Further, on November 20, 2020, HHS finalized a regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the price reduction is required by law.

The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation.

The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.

At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers, pharmacy benefit managers, wholesale distributors, to disclose information about pricing of pharmaceuticals.

In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs.

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In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of products.

Whether or not it obtains FDA approval for a product, an applicant will need to obtain the necessary approvals by the comparable non-U.S.

Whether or not it obtains FDA approval for a product, a sponsor will need to obtain the necessary approvals by the comparable non-U.S.

regulatory authorities before it can commence clinical trials or marketing of the product in those countries or jurisdictions.

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Clinical Trial Approval

The Clinical Trials Directive 2001/20/EC, the Directive 2005/28/EC on GCP and the related national implementing provisions of the individual member states of the European Union, or EU Member States, govern the system for the approval of clinical trials in the European Union.

Under this system, an applicant must obtain prior approval from the competent national authority of the EU Member States in which the clinical trial is to be conducted.

Furthermore, the applicant may only start a clinical trial at a specific study site after the competent ethics committee has issued a favorable opinion.

The clinical trial application must be accompanied by, among other documents, an investigational medicinal product dossier (the Common Technical Document) with supporting information prescribed by Directive 2001/20/EC, Directive 2005/28/EC, where relevant the implementing national provisions of the individual EU Member States and further detailed in applicable guidance documents.

In April 2014, the new Clinical Trials Regulation, (EU) No 536/2014, or Clinical Trials Regulation, was adopted.

The Clinical Trials Regulation will be directly applicable in all the EU Member States, repealing the current Clinical Trials Directive 2001/20/EC and replacing any national legislation that was put in place to implement the Directive.

Conduct of all clinical trials performed in the EU will continue to be bound by currently applicable provisions until the new Clinical Trials Regulation becomes applicable.

The extent to which on-going clinical trials will be governed by the Clinical Trials Regulation will depend on when the Clinical Trials Regulation becomes applicable and on the duration of the individual clinical trial.

If a clinical trial continues for more than three years from the day on which the Clinical Trials Regulation becomes applicable the Clinical Trials Regulation will at that time begin to apply to the clinical trial.

The Clinical Trials Regulation was published on June 16, 2014 but has not yet become effective.

As of January 1, 2020, the website of the European Commission reported that the implementation of the Clinical Trials Regulation was dependent on the development of a fully functional clinical trials portal and database, which would be confirmed by an independent audit, and that the new legislation would come into effect six months after the European Commission publishes a notice of this confirmation.

The website indicated that the audit was expected to commence in December 2020.

2020, the EMA indicated that it plans to focus on the findings of a system audit;

improving the usability, quality and stability of the clinical trial information system;

and knowledge transfer to prepare users and their organizations for the new clinical trial system.

The EMA has indicated that the system will go live in December 2021.

On January 31, 2022, the new Clinical Trials Regulation (EU) No 536/2014 became effective in the European Union and replaced the prior Clinical Trials Directive 2001/20/EC.

The new regulation aims at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the European Union.

Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical trial to be conducted in more than one Member State of the European Union, or EU Member State, will only be required to submit a single application for approval.

The submission will be made through the Clinical Trials Information System, a new clinical trials portal overseen by the EMA and available to clinical trial sponsors, competent authorities of the EU Member States and the public.

The main characteristics of the regulation include:

a streamlined application procedure via a single entry point, the “EU Portal and Database”;

a single set of documents to be prepared and submitted for the application as well as simplified reporting procedures for clinical trial sponsors;

and a harmonized procedure for the assessment of applications for clinical trials, which is divided in two parts.

Part I is assessed by the appointed reporting EU Member State, whose assessment report is submitted for review by the sponsor and all other competent authorities of all EU Member States in which an application for authorization of a clinical trial has been submitted, or Concerned Member States.

Part II is assessed separately by each Concerned Member State.

Strict deadlines have been established for the assessment of clinical trial applications.

The role of the relevant ethics committees in the assessment procedure will continue to be governed by the national law of the Concerned Member State.

However, overall related timelines will be defined by the Clinical Trials Regulation.

The new regulation did not change the preexisting requirement that a sponsor must obtain prior approval from the competent national authority of the EU Member State in which the clinical trial is to be conducted.

If the clinical trial is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of the clinical trial.

Furthermore, the sponsor may only start a clinical trial at a specific study site after the applicable ethics committee has issued a favorable opinion.

As in the United States, parties conducting certain clinical trials must post clinical trial information in the EU at the EudraCT website:

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Marketing Authorization

To obtain a marketing authorization for a product under EU regulatory systems, an applicant must submit an MAA either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in the EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

A marketing authorization may be granted only to an applicant established in the EU.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the EU, applicants have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted (1) a product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP.

To obtain a marketing authorization for a product under EU regulatory systems, a sponsor must submit an MAA either under a centralized procedure administered by the EMA, or one of the procedures administered by competent authorities in

the EU Member States (decentralized procedure, national procedure or mutual recognition procedure).

A marketing authorization may be granted only to a sponsor established in the EU.

Regulation (EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the EU, sponsors have to demonstrate compliance with all measures included in an EMA-approved Paediatric Investigation Plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted (1) a product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP .

The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid across the European Economic Area (i.e.

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For products with a new active substance indicated for the treatment of other diseases and products that are highly innovative or for which a centralized process is in the interest of patients, the centralized procedure may be optional.

The centralized procedure may at the request of the applicant also be used in certain other cases.

The centralized procedure may at the request of the sponsor also be used in certain other cases.

We anticipate that the centralized procedure will be mandatory for the product candidates we are developing.

Under the centralized procedure, the CHMP is also responsible for conducting the initial assessment of a product and for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Under the centralized procedure in the EU, the maximum timeframe for the evaluation of an MAA is 210 days, excluding clock stops, when additional information or written or oral explanation is to be provided by the applicant in response to questions of the CHMP.

Under the centralized procedure, the Committee for Human Medicinal Products, or CHMP, is also responsible for conducting the initial assessment of a product and for several post-authorization and maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization.

Accelerated evaluation might be granted by the CHMP in exceptional cases when a medicinal product is of major interest from the point of view of public health and in particular from the viewpoint of therapeutic innovation.

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The European Commission may grant a so-called “marketing authorization under exceptional circumstances”.

Such authorization is intended for products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information.

Such authorization is intended for products for which the sponsor can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because the indications for which the product in question is intended are encountered so rarely that the sponsor cannot reasonably be expected to provide comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to generally accepted principles of medical ethics to collect such information.

Consequently, marketing authorization under exceptional circumstances may be granted subject to certain specific obligations, which may include the following:

the applicant must complete an identified program of studies within a time period specified by the competent authority, the results of which form the basis of a reassessment of the benefit/risk profile;

the sponsor must complete an identified program of studies within a time period specified by the competent authority, the results of which form the basis of a reassessment of the benefit/risk profile;

the medicinal product in question may be supplied on medical prescription only and may in certain cases be administered only under strict medical supervision, possibly in a hospital and in the case of a radiopharmaceutical, by an authorized person;

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Regulation (EC) No 726/2004 repeats this entitlement for medicinal products authorized in accordance the centralized authorization procedure.

Data exclusivity prevents applicants for authorization of generics of these innovative products from referencing the innovator’s data to assess a generic (abridged) application for a period of eight years.

Data exclusivity prevents sponsors for authorization of generics of these

innovative products from referencing the innovator’s data to assess a generic (abridged) application for a period of eight years.

During an additional two-year period of market exclusivity, a generic marketing authorization application can be submitted and authorized, and the innovator’s data may be referenced, but no generic medicinal product can be placed on the EU market until the expiration of the market exclusivity.

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Pediatric Studies and Exclusivity

Prior to obtaining a marketing authorization in the EU, applicants must demonstrate compliance with all measures included in an EMA-approved PIP covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP.

Prior to obtaining a marketing authorization in the EU, sponsors must demonstrate compliance with all measures included in an EMA-approved PIP covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of the measures included in the PIP.

The respective requirements for all marketing authorization procedures are laid down in Regulation (EC) No 1901/2006, the so-called Paediatric Regulation.

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Before an MAA can be filed, or an existing marketing authorization can be amended, the EMA determines that companies actually comply with the agreed studies and measures listed in each relevant PIP.

If an applicant obtains a marketing authorization in all EU Member States, or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection through extension of the term of the Supplementary Protection Certificate, or SPC.

If a sponsor obtains a marketing authorization in all EU Member States, or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection through extension of the term of the Supplementary Protection Certificate, or SPC.

Orphan Drug Designation and Exclusivity

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that the product is intended for the diagnosis, prevention or treatment of (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the EU when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment.

For either of these conditions, the applicant must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU or, if such method exists, the drug will be of significant benefit to those affected by that condition.

For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the EU or, if such method exists, the drug will be of significant benefit to those affected by that condition.

Once authorized, orphan medicinal products are entitled to ten years of market exclusivity in all EU Member States and in addition a range of other benefits during the development and regulatory review process including scientific assistance for study protocols, authorization through the centralized marketing authorization procedure covering all member countries and a reduction or elimination of registration and marketing authorization fees.

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Reference pricing used by various Member States, and parallel trade, i.e., arbitrage between low-priced and high-priced Member States, can further reduce prices.

There can be no assurance that any country that has price controls or

reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries

There can be no assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries

Brexit and the Regulatory Framework in the United Kingdom

On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the EU, commonly referred to as Brexit.

Following protracted negotiations, the United Kingdom left the EU on January 31, 2020.

Under the withdrawal agreement, there is a transitional period until December 31, 2020 (extendable by up to two years).

On December 24, 2020, the United Kingdom and the EU entered into a Trade and Cooperation Agreement.

The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.

Since the regulatory framework for pharmaceutical products in the United Kingdom covering quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU directives and regulations, Brexit could materially impact the future regulatory regime that applies to products and the approval of product candidates in the United Kingdom.

The United Kingdom’s withdrawal from the EU took place on January 31, 2020.

The EU and the United Kingdom reached an agreement on their new partnership in the Trade and Cooperation Agreement, or the Agreement, which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021.

The Agreement focuses primarily on free trade by ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products.

Thereafter, the EU and the United Kingdom will form two separate markets governed by two distinct regulatory and legal regimes.

As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the United Kingdom is no longer part of the single market.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol.

The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines.

The HMR has incorporated into the domestic law of the United Kingdom the body of EU law governing medicinal products that pre-existed prior to the United Kingdom’s withdrawal from the EU.

General Data Protection Regulation

The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the European Union, including personal health data, is subject to the GDPR, which became effective on May 25, 2018.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, including requirements

relating to processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal data, providing notification of data breaches, and taking certain measures when engaging third-party processors.

The GDPR also imposes strict rules on the transfer of personal data to countries outside the European Union, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

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Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require companies to change their business practices to ensure full compliance.

As of December 31, 2020, we had 27 full-time employees, including a total of 3 employees with M.D., Pharm.D.

Employees and Human Capital Resources

As of December 31, 2021, we had 41 full-time employees, including a total of 5 employees with M.D.

Of these full-time employees, 29 employees are engaged in research and development.

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Our website and the information contained on, or that can be accessed through, our website will not be deemed to be incorporated by reference in, and are not considered part of, this Annual Report on Form 10-K.

Ris k Factors.

Investing in our common stock involves a high degree of risk.

You should carefully consider the risks and uncertainties described below together with all of the other information contained in this Annual Report on Form 10-K, including our consolidated financial statements and the related notes appearing elsewhere in this Annual Report on Form 10-K and in our other filings with the Securities and Exchange Commission, before deciding to invest in our common stock.

Such risks and uncertainties may be amplified by the COVID-19 pandemic and its potential impact on our business and the global economy.

The risks described below are not the only risks facing our company.

The occurrence of any of the following risks, or of additional risks and uncertainties not presently known to us, could cause our business, prospects, operating results and financial condition to suffer materially.

In such event, the trading price of our common stock could decline, and you might lose all or part of your investment.

Risks Related to Our Financial Position and Need for Additional Capital

We have incurred significant losses since our inception, and we expect to incur losses over the next several years.

Since inception, we have incurred significant operating losses.

Our net loss was $23.5 million for the year ended December 31, 2019 and $41.4 million for the year ended December 31, 2020.

As of December 31, 2020, we had an accumulated deficit of $96.1 million.

To date, we have financed our operations primarily through the sale of common stock in our initial public offering, or IPO, and the sale of convertible preferred stock.

We have devoted substantially all of our financial resources and efforts to research and development, including clinical trials and preclinical studies of IMR-687.

We are still in the early stages of development of our only product candidate, IMR-687.

We expect to continue to incur significant expenses and operating losses over the next several years.

Our operating expenses and net losses may fluctuate significantly from quarter to quarter and year to year.

We anticipate that our expenses will increase substantially as we:

navigate the impacts of COVID-19 and our response to it;

continue to advance clinical development of IMR-687, including our ongoing open label extension, or OLE, clinical trial in patients with sickle cell disease, or SCD, and our ongoing Phase 2b clinical trials in patients with SCD and β-thalassemia;

expand our planned research and development efforts for IMR-687 and potentially pursue clinical activities for IMR-687 in heart failure with preserved ejection fraction, or HFpEF;

continue to incur third-party manufacturing costs to support our clinical trials of IMR-687 and, if approved, commercialization;

seek regulatory and marketing approvals for IMR-687;

establish a sales, marketing and distribution infrastructure to commercialize IMR-687, if approved;

commence development activities for any additional product candidates we may identify;

acquire or in-license products, product candidates, technologies and/or data referencing rights;

maintain, expand, enforce, defend and protect our intellectual property;

hire additional clinical, quality control, manufacturing and other scientific personnel;

add operational, financial and management information systems and personnel, including personnel to support our product development and planned future commercialization efforts and our operations as a public company;

make any milestone payments to H.

Lundbeck A/S, or Lundbeck, under our exclusive license agreement with Lundbeck, or the Lundbeck Agreement, upon the achievement of specified clinical or regulatory milestones.

We have never generated revenue from product sales and may never achieve or maintain profitability.

To become and remain profitable, we must succeed in developing, and eventually commercializing, a product or products that generate significant revenue.

The ability to achieve this success will require us to be effective in a range of challenging activities, including completing preclinical testing and clinical trials of IMR-687 and any other product candidates we may identify and pursue, obtaining regulatory approval for these product candidates and manufacturing, marketing and selling any products for which we may obtain regulatory approval.

We are only in the preliminary stages of most of these activities.

We may never succeed in these activities and, even if we do, may never generate revenues that are significant enough to achieve profitability.

Because of the numerous risks and uncertainties associated with pharmaceutical product development, we are unable to accurately predict the timing or amount of increased expenses or when, or if, we will be able to achieve profitability.

Even if we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or annual basis.

Our failure to become and remain profitable would depress the value of our company and could impair our ability to raise capital, expand our business, maintain our research and development efforts, diversify our pipeline of product candidates or even continue our operations.

A decline in the value of our company could also cause our stockholders to lose all or part of their investment .

We are heavily dependent on the success of IMR-687, our only product candidate.

We currently have no products that are approved for commercial sale and may never be able to develop marketable products.

We expect that a substantial portion of our efforts and expenditures over the next several years will be devoted to IMR-687, which is currently our only product candidate.

Accordingly, our business currently depends heavily on the successful development, regulatory approval and commercialization of IMR-687.

We cannot be certain that IMR-687 will receive regulatory approval or be successfully commercialized even if we receive regulatory approval.

If we were required to discontinue development of IMR-687 or if IMR-687 does not receive regulatory approval or fails to achieve significant market acceptance, we would be delayed by many years in our ability to achieve profitability, if ever, and may not be able to generate sufficient revenue to continue our business.

We will need substantial additional funding.

If we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our product development programs or commercialization efforts.

We expect to devote substantial financial resources to our ongoing and planned activities, including our OLE and Phase 2b clinical trials of IMR-687 in patients with SCD and our Phase 2b clinical trial in patients with β-thalassemia.

We expect our expenses to increase substantially in connection with our ongoing and planned activities, particularly as we advance our preclinical activities and clinical trials of and seek regulatory approval for IMR-687 and other product candidates we may identify.

In addition, if we obtain regulatory approval for IMR-687 and any other product candidates we may identify and pursue, we expect to incur significant commercialization expenses related to product manufacturing, sales, marketing and distribution.

Furthermore, we expect to incur additional costs associated with operating as a public company.

Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive and uncertain process that takes years to complete, and we may never generate the necessary data or results required to obtain regulatory approval and achieve product sales.

In addition, any product candidates, if approved, may not achieve commercial success.

Commercial revenues, if any, will not be derived unless and until we can achieve sales of products, which we do not anticipate for many years, if at all.

Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations.

As of December 31, 2020, we had cash, cash equivalents and investments of $88.2 million.

We believe that our existing cash, cash equivalents and investments will enable us to fund our operating expenses and capital expenditure requirements into mid-2022.

However, we have based this estimate on assumptions that may prove to be wrong, and our operating plan may change as a result of many factors currently unknown to us.

As a result, we could deplete our capital resources sooner than we currently expect.

Our future capital requirements will depend on many factors, including:

the impact of the COVID-19 pandemic and our response to it;

the time and cost necessary to complete our ongoing OLE and Phase 2b clinical trials of IMR-687 in patients with SCD, to initiate and complete one or more pivotal clinical trials of IMR-687 in SCD, and to pursue regulatory approvals for IMR-687 in SCD, and the costs of post-marketing studies that could be required by regulatory authorities;

the time and cost necessary to complete our Phase 2b clinical trial of IMR-687 in patients with β-thalassemia, to initiate and complete one or more pivotal clinical trials of IMR-687 in β-thalassemia, and to pursue regulatory approvals for IMR-687 in β-thalassemia, and the costs of post-marketing studies that could be required by regulatory authorities;

our ability to advance IMR-687 in HFpEF into and through clinical development, and the timing and scope of these development activities;

the costs of obtaining clinical and commercial supplies of IMR-687 and any other product candidates we may identify and develop;

our ability to successfully commercialize IMR-687 and any other product candidates we may identify and develop;

the manufacturing, selling and marketing costs associated with IMR-687 and any other product candidates we may identify and develop, including the cost and timing of establishing our sales and marketing capabilities;

the amount and timing of sales and other revenues from IMR-687 and any other product candidates we may identify and develop, including the sales price and the availability of coverage and adequate third-party reimbursement;

the time and cost necessary to respond to technological and market developments;

the extent to which we may acquire or in-license other product candidates and technologies;

our ability to attract, hire and retain qualified personnel;

the costs of maintaining, expanding and protecting our intellectual property portfolio.

We will continue to rely on additional financing to achieve our business objectives.

Adequate additional financing may not be available to us on acceptable terms, or at all.

For example, the global COVID-19 pandemic created significant uncertainty in the global financial markets, which may reduce our ability to raise additional capital.

In addition, we may seek additional capital when market conditions are favorable, or for strategic considerations, even if we believe we have sufficient funds for our current or future operating plans.

If adequate funds are not available to us on a timely basis or on terms acceptable to us, we may be required to delay, limit, reduce or terminate preclinical studies, clinical trials or other development activities for one or more product candidates or discovery stage programs or delay, limit, reduce or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize any product candidates.

Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or product candidates.

Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements.

We do not have any committed external source of funds.

To the extent that we raise additional capital through the sale of equity or convertible debt securities, our stockholders’ ownership interests will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect our stockholders’ rights as common stockholders.

Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability to take specific actions, such as incurring additional debt, selling or licensing our assets, making capital expenditures or declaring dividends.

If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or grant licenses on terms that may not be favorable to us.

If we are unable to raise additional funds through equity or debt financings when needed or on terms acceptable to us, we may be required to delay, limit, reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would otherwise prefer to develop and market ourselves.

Our limited operating history may make it difficult to evaluate the success of our business to date and to assess our future viability.

We commenced activities in 2016 and are a clinical-stage company.

Our operations to date have been limited to organizing and staffing our company, business planning, raising capital, developing our technology, and undertaking preclinical studies and early-stage clinical trials of our sole product candidate, IMR-687.

We have not yet demonstrated our ability to successfully develop any product candidate, obtain regulatory approvals, manufacture a commercial scale product or arrange for a third-party to do so on our behalf, or conduct sales and marketing activities necessary for successful product commercialization.

Consequently, any predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history or a history of successfully developing and commercializing products.

In addition, as our business grows, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown factors.

We will need to transition at some point from a company with a research and development focus to a company capable of supporting commercial activities.

We may not be successful in such a transition.

We expect our financial condition and operating results to fluctuate significantly from quarter-to-quarter and year-to-year due to a variety of factors, many of which are beyond our control.

Accordingly, our stockholders should not rely upon the results of any quarterly or annual periods as indications of future operating performance .

Our ability to use our net operating losses, or NOLs, and research and development tax credit carryforwards to offset future taxable income may be subject to certain limitations.

We have a history of cumulative losses and anticipate that we will continue to incur significant losses in the foreseeable future;

thus, we do not know whether or when we will generate taxable income necessary to utilize our NOLs or research and development tax credit carryforwards.

As of December 31, 2020, we had federal NOLs of $91.7 million and state NOLs of $85.5 million.

In general, under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, and corresponding provisions of state law, a corporation that undergoes an “ownership change,” generally defined as a greater than 50 percentage point change (by value) in its equity ownership by certain stockholders over a three year period, is subject to limitations on its ability to utilize its pre-change NOLs and research and development tax credit carryforwards to offset future taxable income.

We have not conducted a study to assess whether any such ownership changes have occurred.

We may have experienced such ownership changes in the past and may experience such ownership changes in the future as a result of subsequent changes in our stock ownership (which may be outside our control).

As a result, if, and to the extent that, we earn net taxable income, our ability to use our pre-change NOLs and research and development tax credit carryforwards to offset such taxable income may be subject to limitations.

There is also a risk that due to regulatory changes, such as suspensions on the use of NOLs, or other unforeseen reasons, our existing NOLs could expire or otherwise become unavailable to offset future income tax liabilities.

As described below in “Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition,” the Tax Cuts and Jobs Act, or the TCJA, as amended by the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, includes changes to U.S.

federal tax rates and the rules governing NOL carryforwards that may significantly impact our ability to utilize our NOLs to offset taxable income in the future.

Additionally, state NOLs generated in one state cannot be used to offset income generated in another state.

For these reasons, even if we attain profitability, we may be unable to use a material portion of our NOLs and other tax attributes.

Our business and operations have been and may continue to be adversely affected by the ongoing COVID-19 pandemic, as may the operations of our suppliers and manufacturers and other third-party service providers.

In December 2019, a novel strain of coronavirus, called COVID-19, emerged in Wuhan, Hubei Province, China, which has now spread globally, including to the United States, the United Kingdom and the European Union.

The pandemic and government measures taken in response have had a significant impact, both direct and indirect, on businesses and commerce, as worker shortages have occurred;

supply chains have been disrupted;

facilities and production have been suspended;

and demand for certain goods and services, such as medical services and supplies, has spiked, while demand for other goods and services, such as travel, has fallen.

The future progression of the pandemic and its effects on our business and operations are uncertain.

The spread of COVID-19 has affected our operations to date, including by causing delays in the conduct of our clinical trials.

While we have not experienced any significant disruptions with the third parties on which we rely, the spread of COVID-19, or another infectious disease, could also negatively affect the operations of our third-party manufacturers, which could result in disruptions in the supply of IMR-687.

In addition, most of our employees are currently working remotely, and we are temporarily restricting travel and attendance at industry events by our employees.

The COVID-19 pandemic continues to rapidly evolve and could more significantly impact our operations in the future.

We have enrolled and seek to enroll patients in our ongoing clinical trials at sites located both in the United States and internationally.

The COVID-19 pandemic has delayed and may continue to delay or otherwise adversely affect these clinical development activities, including our ability to recruit and retain patients in our ongoing clinical trials, as a result of many factors, including:

diversion of healthcare resources away from the conduct of our clinical trials in order to focus on pandemic concerns, including the availability of necessary materials, the attention of physicians serving as our clinical trial investigators, access to hospitals serving as our clinical trial sites, availability of hospital staff supporting the conduct of our clinical trials and the reluctance of patients enrolled in our clinical trials to visit clinical trial sites;

potential interruptions in global shipping affecting the transport of clinical trial materials, such as investigational drug product, patient samples and other supplies used in our clinical trials;

the impact of further limitations on travel that could interrupt key clinical trial activities, such as clinical trial site initiations and monitoring activities, travel by our employees, contractors or patients to clinical trial sites, or the ability of employees at any of our contract manufacturers or contract research organizations, or CROs, to report to work, any of which could delay or adversely impact the conduct or progress of our clinical trials, and limit the amount of clinical data we will be able to report;

any future interruption of, or delays in receiving, supplies of clinical trial material from our contract manufacturing organizations, or CMOs, due to staffing shortages, production slowdowns or stoppages or disruptions in delivery systems;

availability of future capacity at contract manufacturers to produce sufficient drug substance and drug product to meet forecasted clinical trial demand if any of these manufacturers elect or are required to divert attention or resources to the manufacture of other pharmaceutical products.

For example, the COVID-19 pandemic has resulted in disruptions to our clinical trial operations, including some missed and incomplete patient visits in our recently completed Phase 2a clinical trial of IMR-687 in SCD and site activation and enrollment delays and delays in review of our regulatory submissions with respect to our Phase 2b clinical trials of IMR-687 in SCD and β-thalassemia.

In addition, the COVID-19 pandemic may affect the operations of the U.S.

Food and Drug Administration, or FDA, and other health authorities, which could result in delays of regulatory actions related to our programs, including with respect to IMR-687.

Any negative impact that the COVID-19 pandemic has on recruiting or retaining patients in our clinical trials, the ability of our suppliers to provide materials for our product candidates, or the regulatory review process could cause additional delays which could materially and adversely affect our ability to obtain regulatory approval for and to commercialize our product candidates, increase our operating expenses, affect our ability to raise additional capital and have a material adverse effect on our financial results.

In addition, if any of our clinical trial patients contract COVID-19, they may have adverse health outcomes that could impact the results of our clinical trials.

Additionally, while the potential economic impact and the duration of the COVID-19 pandemic is difficult to assess or predict, the impact of the COVID-19 pandemic on the global financial markets may reduce our ability to access capital, which could negatively impact our short-term and long-term liquidity.

While we expect the impacts of COVID-19 will continue to have some adverse effect on our business, the extent to which COVID-19 impacts our clinical trials, research and development activities and operations will depend on future developments, which are highly uncertain and cannot be predicted with confidence, including the duration of the pandemic, new information which may emerge concerning the severity of COVID-19, the actions to contain COVID-19 or treat its impact and changes in government spending or priorities, among others.

The COVID-19 pandemic is a widespread health crisis that continues to adversely affect the global economy and financial markets of many countries, resulting in an economic downturn that could also affect our operations, our ability to conduct our clinical trials, our ability to raise additional funds through public offerings and the volatility of our stock price and trading in our stock.

Even after the COVID-19 pandemic has subsided, we may continue to experience adverse impacts to our business as a result of any economic recession or depression that has occurred or may occur in the future.

Risks Related to the Discovery, Development and Commercialization of Our Product Candidates

We are early in our development efforts and heavily dependent on the success of our sole product candidate, IMR-687.

If we are unable to successfully complete clinical development, obtain regulatory approval for, or commercialize IMR-687, or experience delays in doing so, our business will be materially harmed.

To date, we have invested a majority of our efforts and financial resources in the preclinical and clinical development of IMR-687.

Our future success is heavily dependent on our ability to successfully develop, obtain regulatory approval for and commercialize IMR-687.

IMR-687 is currently our only product candidate and we are currently testing it as part of our OLE clinical trial in SCD and our Phase 2b clinical trials in SCD and β-thalassemia.

It may be a significant time before IMR-687 can advance into a pivotal trial, if at all.

We cannot be certain that IMR-687 will be successful in clinical trials or receive regulatory approval.

The success of IMR-687 will depend on several factors, including the following:

our ability to effectively manage any adverse impact of COVID-19;

successfully completing clinical trials;

acceptance by the FDA or other regulatory agencies of regulatory filings for IMR-687;

expanding and maintaining a workforce of experienced clinical-stage drug development professionals and others to continue to develop IMR-687;

obtaining and maintaining intellectual property protection and regulatory exclusivity for IMR-687;

making arrangements with third-party manufacturers for, or establishing, commercial manufacturing capabilities;

establishing sales, marketing and distribution capabilities and successfully launching commercial sales, if and when approved, whether alone or in collaboration with others;

acceptance of IMR-687, if and when approved, by patients, the medical community and third-party payors;

effectively competing with other therapies, including Oxbryta (voxelotor) and Adakveo (crizanlizumab) in SCD and ZYNTEGLO (INN autologous CD34+ cells encoding βA-T87Q-globin gene) (currently only approved in Europe and for which FDA approval is currently being sought), as well as REBLOZYL (luspatercept-aamt) for the treatment of ß-thalassemia;

obtaining and maintaining coverage, adequate pricing and adequate reimbursement from third-party payors, including government payors;

patients’ willingness to pay out-of-pocket for IMR-687 in the absence of coverage and/or adequate reimbursement from third-party payors;

maintaining a continued acceptable safety profile following receipt of any regulatory approvals.

Many of these factors are beyond our control, including clinical outcomes, the regulatory review process, potential threats to our intellectual property rights and the manufacturing, marketing and sales efforts of any future collaborator.

If we are unable to develop, receive marketing approval for and successfully commercialize IMR-687, or if we experience delays as a result of any of these factors or otherwise, we may need to spend significant additional time and resources to identify other product candidates, advance them through preclinical and clinical development and apply for regulatory approvals, which would adversely affect our business, prospects, financial condition and results of operations.

Clinical drug development involves a lengthy and expensive process, with an uncertain outcome.

We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of any product candidates.

The risk of failure for IMR-687 and any other product candidates we may develop is high.

It is impossible to predict when or if IMR-687 and any other product candidates we may develop will prove effective or safe in humans or will receive regulatory approval.

Before obtaining marketing approval from regulatory authorities for the sale of any product candidate, we must complete preclinical development and then conduct extensive clinical trials to demonstrate the safety and efficacy of such product candidate in humans.

We have not yet begun or completed a pivotal clinical trial of IMR-687, which is currently our only product candidate.

Clinical trials may fail to demonstrate that IMR-687 and any other product candidates we may develop are safe for humans and effective for indicated uses.

Even if the clinical trials are successful, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes, regulations or guidance or changes in regulatory review for each submitted product application may cause delays in the approval or rejection of an application.

Before we can commence clinical trials for a product candidate, we must complete extensive preclinical testing and studies that support our planned investigational new drug applications, or INDs, and other regulatory filings in the United States and abroad.

We cannot be certain of the timely completion or outcome of our preclinical testing and studies, and cannot predict if the FDA or other regulatory agencies will accept our proposed clinical programs or if the outcome of our preclinical testing and studies will ultimately support the further development of any product candidates.

As a result, we cannot be sure that we will be able to submit INDs or similar applications for our preclinical programs on the timelines we expect, if at all, and we cannot be sure that submission of INDs or similar applications will result in the FDA or other regulatory authorities allowing clinical trials to begin.

Furthermore, product candidates are subject to continued preclinical safety studies, which may be conducted concurrent with our clinical testing.

The outcomes of these safety studies may delay the launch of or enrollment in future clinical trials and could impact our ability to continue to conduct our clinical trials.

Clinical trials are expensive, difficult to design and implement, can take many years to complete and are uncertain as to outcome.

We cannot guarantee that any clinical trials will be conducted as planned or completed on schedule, or at all.

A failure of one or more clinical trials can occur at any stage of testing, which may result from a multitude of factors, including,

but not limited to, flaws in study design, dose selection issues, placebo effects, patient enrollment criteria and failure to demonstrate favorable safety or efficacy traits .

We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing approval or commercialize IMR-687 and any other product candidates we may develop, including:

regulators or institutional review boards, or IRBs, may not authorize us or our investigators to commence a clinical trial or conduct a clinical trial at a prospective trial site;

we may experience delays in reaching, or fail to reach, agreement on acceptable clinical trial contracts or clinical trial protocols with prospective trial sites;

regulators may decide the design of our clinical trials is flawed, for example if our trial protocol does not evaluate treatment effects in trial subjects for a sufficient length of time;

clinical trials of IMR-687 and any other product candidates we may develop may produce negative or inconclusive results, and we may decide, or regulators may require us, to conduct additional clinical trials or abandon product development programs;

we may be unable to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful, or, if we seek accelerated approval, biomarker efficacy endpoints that applicable regulatory authorities would consider likely to predict clinical benefit;

the number of patients required for clinical trials of IMR-687 and any other product candidates we may develop may be larger than we anticipate, enrollment in these clinical trials may be slower than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate;

our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at all;

we may decide, or regulators or IRBs may require us, to suspend or terminate clinical trials of IMR-687 and any other product candidates we may develop for various reasons, including non-compliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;

regulators or IRBs may require us to perform additional or unanticipated clinical trials to obtain approval or we may be subject to additional post-marketing testing requirements to maintain regulatory approval;

regulators may revise the requirements for approving IMR-687 and any other product candidates we may develop, or such requirements may not be as we anticipate;

the cost of clinical trials of IMR-687 and any other product candidates we may develop may be greater than we anticipate;

the supply or quality of IMR-687 and any other product candidates we may develop or other materials necessary to conduct clinical trials of such product candidates may be insufficient or inadequate;

IMR-687 and any other product candidates we may develop may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators or IRBs to suspend or terminate the trials;

regulators may withdraw their approval of a product or impose restrictions on its distribution, such as in the form of a risk evaluation and mitigation strategy, or REMS.

We face additional important risks related to the enrollment and completion of our clinical trials of IMR-687 as a result of the COVID-19 pandemic, which are further described in “—Our business and operations have been and may continue to be adversely affected by the ongoing COVID-19 pandemic as may the operations of our suppliers and manufacturers and other third-party service providers.”

If we are required to conduct additional clinical trials or other testing of IMR-687 beyond those that we currently contemplate, if we are unable to successfully complete clinical trials or other testing of IMR-687 or any other product candidates we may develop, if the results of these trials or tests are not positive or are only modestly positive or if there are safety concerns, we may:

be delayed in obtaining marketing approval for any product candidates;

not obtain marketing approval at all;

obtain approval for indications or patient populations that are not as broad as intended or desired;

obtain approval with labeling or a REMS that includes significant use or distribution restrictions or safety warnings;

be subject to additional post-marketing testing requirements;

have the product removed from the market after obtaining marketing approval.

Our product development costs will also increase if we experience delays in testing or in obtaining marketing approvals.

We do not know whether any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all.

We may also change the design or protocol of one or more of our clinical trials, including to add additional patients or arms, which could result in increased costs and expenses and/or delays.

Significant preclinical study or clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize any product candidates or allow our competitors to bring products to market before we do and impair our ability to successfully commercialize any product candidates and may harm our business and results of operations.

Because we are developing IMR-687 using new endpoints and methodologies, the FDA or other regulatory authorities may not consider the endpoints of our clinical trials to predict or provide clinically meaningful results.

There are currently limited therapies approved to treat SCD.

To date, we have concentrated a significant portion of our product research and development efforts on developing a novel therapeutic for the treatment of SCD, and our future success depends on the success of this therapeutic approach.

The clinical trial requirements of the FDA and other comparable regulatory agencies and the criteria these regulators use to determine the safety and efficacy of any product candidate vary substantially according to the type, complexity, novelty and intended use and market of the potential product.

To date, there are only four FDA-approved drugs for SCD:

voxelotor (marketed as Oxbryta), crizanlizumab (marketed as Adakveo), hydroxyurea and L-glutamine (marketed as Endari), and there are no approved therapies that target phosphodiesterase 9, or PDE9.

As a result, the design and conduct of clinical trials for a therapeutic product candidate such as IMR-687 that targets PDE9 in SCD patients is subject to unknown risks, and we may experience setbacks with our ongoing or planned clinical trials of IMR-687 in SCD because of the limited clinical experience with its mechanism of action in these patients.

In particular, regulatory authorities in the United States and the European Union have not issued definitive guidance as to how to measure and achieve efficacy in treatments for SCD.

As a result, the design and conduct of clinical trials of IMR-687 may take longer, be more costly or be less effective as part of the novelty of development in SCD.

We may use new or novel endpoints or methodologies, such as both red and white blood cell biomarkers in our IMR-687 clinical trials, and the FDA or other regulatory authorities may not consider the endpoints of our clinical trials to provide clinically meaningful results.

Even if applicable regulatory authorities do not object to our proposed endpoints in an earlier stage clinical trial, such regulatory authorities may require evaluation of additional or different clinical endpoints in later-stage clinical trials.

Additionally, if we pursue accelerated approval or other expedited regulatory approval mechanisms for IMR-687, the FDA or another regulatory authority may determine that the biomarker efficacy endpoint we select for evaluation is not sufficiently predictive of clinical benefit to support accelerated approval.

For example, while the FDA commented at our face-to-face Type B meeting that our revised Phase 2b trial design and approach to data collection to support HbF as a potential surrogate endpoint was acceptable, the FDA stressed the importance of defining clear and strong assumptions and having robust results, which would be evaluated by the FDA to test if an increase of at least 3% in HbF would provide meaningful clinical benefit and therefore constitute an acceptable surrogate endpoint for a future pivotal trial of IMR-687 in SCD.

If we are not able to demonstrate clinical benefit related to this endpoint to the FDA’s satisfaction, we will have to consider other endpoints for the pivotal program, which may include greater levels of HbF increases.

Even if the FDA does find our clinical trial success criteria to be sufficiently validated and clinically meaningful, we may not achieve the pre-specified endpoint to a degree of statistical significance deemed approvable in any pivotal or other clinical trials we may conduct for IMR-687.

Further, even if we do achieve the pre-specified criteria, our trials may produce results that are unpredictable or inconsistent with the results of the more traditional efficacy endpoints in the trial.

The FDA also could give overriding weight to other efficacy endpoints over a primary endpoint, even if we achieve statistically significant results on that primary endpoint, if we do not do so on our secondary or other efficacy endpoints.

The FDA also weighs the benefits of a product against its risks and the FDA may view the efficacy results in the context of safety as not being supportive of approval.

Other regulatory authorities in the European Union and other countries may make similar findings with respect to these endpoints.

The outcome of preclinical studies and earlier-stage clinical trials may not be predictive of the success of later-stage clinical trials.

The outcome of preclinical testing and earlier-stage clinical trials may not be predictive of the success of later-stage clinical trials.

IMR-687 and any other product candidates we may develop may fail to show the desired safety and efficacy in clinical development despite positive results in preclinical studies or having successfully advanced through initial clinical trials.

For example, in clinical trials, IMR-687 may not be effective at increasing red blood cell biomarkers that include HbF, F-cells, hemoglobin, and reducing reticulocytes, indirect bilirubin, and LDH.

Furthermore, in clinical trials, IMR-687 may not impact adhesion/white blood cell markers such as P-selectin, E-selectin, or VCAM.

Even if IMR-687 successfully increases or decreases, as applicable, these biomarkers in clinical trials, such increase or decrease may not result in overall clinical benefit.

A lack of clinical benefit may be due to insufficient dosing or for other reasons.

Additionally, any positive results generated in our Phase 2a, OLE or Phase 2b clinical trials of IMR-687 in adults with SCD would not ensure that we will achieve similar results in larger, pivotal clinical trials or in clinical trials of IMR-687 in adolescent and pediatric populations with SCD.

Several companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in preclinical testing and earlier-stage clinical trials, and we cannot be certain that we will not face similar setbacks.

Moreover, preclinical and clinical data are often susceptible to varying interpretations and analyses, and many companies that have believed their product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.

Furthermore, the failure of any product candidate to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of any other product candidates then under development and/or cause the FDA or other regulatory authorities to require additional testing before approving any other product candidates.

Interim top-line and preliminary results from our clinical trials that we announce or publish from time to time may change as more patient data become available and are subject to audit and verification procedures, which could result in material changes in the final data.

From time to time, we may publish interim top-line or preliminary results from our clinical trials.

Interim results from clinical trials that we may complete are subject to the risk that one or more of the clinical outcomes may materially change as patient enrollment continues and more patient data become available.

Preliminary or top-line results also remain subject to audit and verification procedures that may result in the final data being materially different from the preliminary data we previously published.

As a result, interim and preliminary data should be viewed with caution until the final data are available.

Differences between preliminary or interim data and final data could significantly harm our business prospects and may cause the trading price of our common stock to fluctuate significantly.

As an organization, we have never conducted pivotal clinical trials, and we may be unable to do so for IMR-687 or any other product candidates we may develop.

We will need to successfully complete pivotal clinical trials in order to obtain the approval of the FDA, the European Medicines Agency, or EMA, or other regulatory agencies to market IMR-687 or any future product candidate.

Carrying out later-stage clinical trials is a complicated process.

As an organization, we have not previously conducted any later stage or pivotal clinical trials.

In order to do so, we will need to expand our clinical development and regulatory capabilities, and we may be unable to recruit qualified personnel.

Consequently, we may be unable to successfully and efficiently execute and complete necessary clinical trials in a way that leads to approval of IMR-687 or future product candidates.

We may require more time and incur greater costs than our competitors and may not succeed in obtaining regulatory approvals of product candidates that we develop.

Failure to commence or complete, or delays in, our planned clinical trials, could prevent us from or delay us in commercializing our product candidates.

If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or prevented.

Identifying and qualifying patients to participate in clinical trials for IMR-687 and any other product candidates we may develop is critical to our success.

Successful and timely completion of clinical trials will require that we enroll a sufficient number of patients who remain in the trial until its conclusion.

We may not be able to initiate or continue clinical trials for IMR-687 and any other product candidates we may develop if we are unable to locate and enroll a sufficient number of eligible patients to participate in these trials as required by the FDA or similar regulatory authorities outside of the United States.

For example, the prevalence of patients with SCD and β-thalassemia in the United States and Europe is estimated to be low.

Accordingly, there are limited patient pools from which to draw for clinical trials of IMR-687.

We may not be able to identify, recruit, and enroll a sufficient number of patients to complete our clinical trials of IMR-687 because of the perceived

risks and benefits of IMR-687, the availability of competing therapies and clinical trials, the proximity and availability of clinical trial sites for prospective subjects and the subject referral practices of physicians, among other factors.

Patient enrollment is affected by a variety of other factors, including:

the prevalence and severity of the disease under investigation;

the eligibility criteria for the trial in question;

the perceived risks and benefits of the product candidate under trial;

the requirements of the trial protocols;

the availability of existing commercially-available treatments for the indications for which we are conducting clinical trials;

the ability to recruit clinical trial investigators with the appropriate competencies and experience;

efforts to facilitate timely enrollment in clinical trials;

the patient referral practices of physicians;

the ability to monitor patients adequately during and after treatment;

the proximity and availability of clinical trial sites for prospective patients;

the conduct of clinical trials by competitors for product candidates that treat the same indications as IMR-687 and any other product candidates we may develop;

the ability to identify specific patient populations for biomarker-defined trial cohort(s);

the cost to, or lack of adequate compensation for, prospective patients.

In addition, the COVID-19 pandemic has impacted, and is likely to continue to directly or indirectly impact the pace of enrollment in our clinical trials for at least the next several months and possibly longer as patients may avoid, may not be allowed to, or may not be able to travel to healthcare facilities and physicians’ offices unless due to a health emergency.

Our inability to locate and enroll a sufficient number of patients for our clinical trials would result in significant delays, could require us to abandon one or more clinical trials altogether and could delay or prevent our receipt of necessary regulatory approvals.

Enrollment delays in our clinical trials may result in increased development costs for IMR-687 and any other product candidates we may develop, which would cause the value of our company to decline and limit our ability to obtain additional financing.

Changes in methods of product candidate manufacturing or formulation may result in additional costs or delay.

As product candidates proceed through preclinical studies to late-stage clinical trials towards potential approval and commercialization, it is common that various aspects of the development program, such as manufacturing methods and formulation, are altered along the way in an effort to optimize processes and results.

As an example, we expect to utilize an oral solution formulation of IMR-687 for clinical development in pediatric populations with SCD that will differ from the oral tablet formulation of IMR-687 we have used in our clinical trials to date.

Such changes carry the risk that they will not achieve these intended objectives.

Any of these changes could cause IMR-687 to perform differently and affect the results of planned clinical trials or other future clinical trials conducted with the materials manufactured using altered processes.

Such changes may also require additional testing, FDA notification or FDA approval.

This could delay completion of clinical trials, require the conduct of bridging clinical trials or the repetition of one or more clinical trials, increase clinical trial costs, delay approval of IMR-687 and jeopardize our ability to commence sales and generate revenue.

If serious adverse events or unacceptable side effects are identified during the development of IMR-687 and any other product candidates we may develop, we may need to abandon or limit our development of those product candidates.

Clinical trials by their nature utilize a sample of the potential patient population.

We have only begun to evaluate IMR-687 in a limited number of subjects at a limited duration of exposure.

Accordingly, any rare and severe side effects of IMR-687 may be uncovered only in later stages of our current and future clinical development.

Many product candidates that initially showed promise in early stage testing have later been found to cause side effects that prevented their further development.

If IMR-687 and any other product candidates we may develop are associated with undesirable side effects in clinical trials or have characteristics that are unexpected in clinical trials or preclinical testing, we may need to abandon their

development or limit development to more narrow uses or subpopulations in which the side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit perspective.

In pharmaceutical development, many compounds that initially show promise in early-stage or clinical testing are later found to cause side effects that delay or prevent further development of the compound.

Additionally, if results of our clinical trials reveal unacceptable side effects, we, the FDA or similar regulatory authorities outside of the United States, or the IRBs or Ethics Committees at the institutions in which our studies are conducted could suspend or terminate our clinical trials or the FDA or similar foreign regulatory authorities could order us to cease clinical trials or deny approval of IMR-687 and any other product candidates we may develop for any or all targeted indications.

Treatment-related side effects could also affect patient recruitment or the ability of enrolled patients to complete any of our clinical trials.

In addition, while not considered adverse events, in our Phase 1 clinical trial of IMR-687 in healthy volunteers, individual subjects were noted to have sporadic heart rates of greater than 100 bpm, including placebo subjects.

One subject at 4.5 mg/kg per day had multiple readings greater than 100 bpm, including at study start, prior to any administration of study drug.

If we elect or are forced to suspend or terminate any clinical trial of IMR-687 and any other product candidates we may develop, the commercial prospects of such product candidate will be harmed, and our ability to generate product revenue from such product candidate will be delayed or eliminated.

Any of these occurrences could materially harm our business.

We are also developing IMR-687 in combination with other therapies, which exposes us to additional risks.

We are developing IMR-687 both as a monotherapy and in combination with hydroxyurea, a currently approved therapy for SCD, and may develop future product candidates in combination with one or more currently approved therapies.

Even if any product candidate we develop were to receive marketing approval or be commercialized for use in combination with other existing therapies, we would continue to be subject to the risks that the FDA or similar regulatory authorities outside of the United States could revoke approval of the therapy used in combination with our product candidate or that safety, efficacy, manufacturing or supply issues could arise with these existing therapies.

This could result in our own products being removed from the market or being less successful commercially.

If any product candidate receives marketing approval and we, or others, later discover that the drug is less effective than previously believed or causes undesirable side effects that were not previously identified, our ability to market the drug could be compromised.

We conduct, and intend to conduct in the future, clinical trials of product candidates in carefully defined subsets of patients who have agreed to enter into clinical trials.

Consequently, it is possible that our clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify undesirable side effects.

If any product candidate receives regulatory approval, and we, or others, later discover that it is less effective than previously believed, or causes undesirable side effects, a number of potentially significant negative consequences could result, including:

withdrawal or limitation by regulatory authorities of approvals of such product;

seizure of the product by regulatory authorities;

recall of the product;

restrictions on the marketing of the product or the manufacturing process for any component thereof;

requirement by regulatory authorities of additional warnings on the label, such as a “black box” warning or contraindication;

decrease or elimination of third-party reimbursement;

requirement that we implement a REMS or create a medication guide outlining the risks of such side effects for distribution to patients;

commitment to expensive post-marketing studies as a prerequisite of approval by regulatory authorities of such product;

the product may become less competitive;

initiation of regulatory investigations and government enforcement actions;

initiation of legal action against us to hold us liable for harm caused to patients;

harm to our reputation and resulting harm to physician or patient acceptance of our products.

Any of these events could prevent us from achieving or maintaining market acceptance of a particular product candidate, if approved, and could significantly harm our business, financial condition, and results of operations.

We may not be successful in our efforts to identify or discover additional product candidates and may fail to capitalize on programs or product candidates that may present a greater commercial opportunity or for which there is a greater likelihood of success.

If we do not successfully develop and eventually commercialize products, we will not obtain product revenue in future periods, resulting in significant harm to our financial position and adversely affecting our share price.

We recently completed a Phase 2a clinical trial of IMR-687 in patients with SCD and are currently conducting an OLE clinical trial and Phase 2b clinical trial of IMR-687 in patients with SCD.

In addition, a key element of our business plan is to expand the breadth of indications for IMR-687 for the treatment of β-thalassemia and HFpEF.

We are currently conducting a Phase 2b clinical trial of IMR-687 in patients with β-thalassemia and recently completed pre-clinical research in HFpEF.

A failure to establish IMR-687 as a viable treatment for β-thalassemia and/or HFpEF could harm our business prospects.

In addition, we may explore IMR-687 in other indications or acquire additional product candidates for development.

However, there can be no assurance that we will be successful in our efforts to identify or acquire other potential product candidates.

Even if we identify or acquire other product candidates, there can be no assurance that our development efforts will be successful.

Additionally, because we have limited resources, we may forego or delay pursuit of opportunities with certain programs or product candidates or for indications that later prove to have greater commercial potential.

For example, we currently intend to focus our capital resources primarily on the development of IMR-687.

However, the development of IMR-687 may ultimately prove to be unsuccessful or less successful than another potential product candidate in our pipeline that we might have chosen to pursue on a more aggressive basis with our capital resources.

If we do not accurately evaluate the commercial potential for a particular product candidate, we may relinquish valuable rights to that product candidate through strategic collaboration, licensing or other arrangements in cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate.

Alternatively, we may allocate internal resources to a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement.

We are conducting clinical trials of IMR-687 at clinical trial sites outside the United States, and the FDA may not accept data from trials conducted in such international locations.

In addition to our clinical sites in the United States, we are currently conducting clinical trials of IMR-687 at clinical sites outside of the United States.

For example, our Phase 2b clinical trials of IMR-687 in SCD and β-thalassemia are currently being conducted or expected to be conducted at clinical sites in Europe, Asia and Africa.

Although the FDA may accept data from clinical trials conducted outside the United States, acceptance of these data is subject to conditions imposed by the FDA.

For example, the clinical trial must be well designed and conducted and be performed by qualified investigators in accordance with ethical and Good Clinical Practice, or GCP, principles.

The trial population must also adequately represent the U.S.

population, and the data must be applicable to the U.S.

population and U.S.

medical practice in ways that the FDA deems clinically meaningful.

In addition, while these clinical trials are subject to the applicable local laws, FDA acceptance of the data will depend on its determination that the trials also complied with all applicable U.S.

laws and regulations.

If the FDA does not accept the data from any trial conducted or from particular clinical trial sites located outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and could delay or permanently halt our development of the applicable product candidates.

Even if any product candidate receives marketing approval, it may fail to achieve the degree of market acceptance by physicians, patients, third-party payors and others in the medical community necessary for commercial success.

If any product candidate receives marketing approval, it may nonetheless fail to gain sufficient market acceptance by physicians, patients, third-party payors and others in the medical community.

Sales of medical products depend in part on the willingness of physicians to prescribe the treatment, which is likely to be based on a determination by these physicians that the products are safe, therapeutically effective and cost effective.

In addition, the inclusion or exclusion of products from treatment guidelines established by various physician groups and the viewpoints of influential physicians can affect the willingness of other physicians to prescribe the treatment.

We cannot predict whether physicians, physicians’ organizations, hospitals, other healthcare providers, government agencies or private insurers will determine that our product is safe, therapeutically effective and cost effective as compared with competing treatments.

Efforts to educate the medical

community and third-party payors on the benefits of IMR-687 and any other product candidates we may develop may require significant resources and may not be successful.

If IMR-687 and any other product candidates we may develop do not achieve an adequate level of acceptance, we may not generate significant product revenues and we may not become profitable.

The degree of market acceptance of IMR-687 and any other product candidates we may develop, if approved for commercial sale, will depend on a number of factors, including:

the efficacy and potential advantages compared to alternative treatments, such as, in the case of IMR-687, Oxbryta, Adakveo, hydroxyurea, ZYNTEGLO and REBLOZYL;

the effectiveness of sales and marketing efforts;

the cost of treatment in relation to alternative treatments, including any similar generic treatments;

the clinical indications for which the product is approved;

the convenience and ease of administration compared to alternative treatments;

the willingness of the target patient population to try new therapies and to continue treatment over time and of physicians to prescribe these therapies;

the strength of marketing and distribution support;

the timing of market introduction of competitive products;

the availability of third-party coverage and adequate reimbursement, and patients’ willingness to pay out of pocket for required co-payments or in the absence of third-party coverage or adequate reimbursement;

the prevalence and severity of any side effects;

any restrictions on the use of our products, if approved, together with other medications.

If we are unable to establish sales, marketing and distribution capabilities or enter into sales, marketing and distribution agreements with third parties, we may not be successful in commercializing any product candidates if and when they are approved.

We do not have a sales or marketing infrastructure and have no experience in the sale, marketing or distribution of pharmaceutical products.

To achieve commercial success for any product for which we have obtained marketing approval, we will need to establish a sales, marketing and distribution organization, either ourselves or through collaborations or other arrangements with third parties.

In the future, we expect that we would begin to build a sales and marketing infrastructure to market IMR-687 and any other product candidates we may develop in the United States and potentially in Europe, if and when approved by the applicable regulatory authority.

There are risks involved with establishing our own sales, marketing and distribution capabilities.

For example, recruiting and training a sales force is expensive and time-consuming and could delay any product launch.

If the commercial launch of a product candidate for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or unnecessarily incurred these commercialization expenses.

These efforts may be costly, and our investment would be lost if we cannot retain or reposition our sales and marketing personnel.

Factors that may inhibit our efforts to commercialize our products on our own include:

our inability to recruit, train and retain adequate numbers of effective sales, marketing, coverage or reimbursement, customer service, medical affairs and other support personnel;

the inability of sales personnel to educate adequate numbers of physicians on the benefits of any future products;

the inability of reimbursement professionals to negotiate arrangements for formulary access, reimbursement and other acceptance by payors;

the inability to price our products at a sufficient price point to ensure an adequate and attractive level of profitability;

restricted or closed distribution channels that make it difficult to distribute our products to segments of the patient population;

the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with more extensive product lines;

unforeseen costs and expenses associated with creating an independent sales and marketing organization.

If we are unable to establish our own sales, marketing and distribution capabilities and we enter into arrangements with third parties to perform these services, our product revenues and our profitability, if any, are likely to be lower than if we were to market, sell and distribute any products that we develop ourselves.

In addition, we may not be successful in entering into arrangements with third parties to sell, market and distribute any product candidates or may be unable to do so on terms that are acceptable to us.

We likely will have little control over such third parties, and any of them may fail to devote the necessary resources and attention to sell and market our products effectively.

If we do not establish sales, marketing and distribution capabilities successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing any product candidates.

We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we do.

The development and commercialization of new drug products is highly competitive.

We face competition with respect to IMR-687, and will face competition with respect to any product candidates that we may seek to develop or commercialize in the future, from major pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide.

There are a number of large pharmaceutical and biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of the same disease indications we are pursuing.

Some of these competitive products and therapies are based on scientific approaches that are the same as or similar to our approach, and others are based on entirely different approaches.

Potential competitors also include academic institutions, government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative arrangements for research, development, manufacturing and commercialization.

In the area of SCD, we expect to face competition from voxelotor (marketed as Oxbryta by Global Blood Therapeutics, Inc., or GBT), crizanlizumab (marketed as Adakveo by Novartis AG, or Novartis), HU (marketed under trade names including DROXIA by Bristol-Myers Squibb Company, as well as in generic form) and L-glutamine, which are currently the only FDA-approved therapies for the treatment of SCD.

In the area of ß-thalassemia, we expect to face competition from ZYNTEGLO (marketed by bluebird bio, Inc.), which is currently only approved in Europe for the treatment of ß-thalassemia and for which FDA approval is currently being sought, as well as REBLOZYL (marketed by Bristol-Myers Squibb Co.

and Acceleron Pharma Inc.), which is approved in the United States for the treatment of anemia in adult patients with ß-thalassemia who require regular RBC transfusions.

In addition, with respect to SCD, we are aware of several product candidates in clinical development, including several product candidates for which FDA approval is currently being sought, which could be competitive with product candidates that we may successfully develop and commercialize.

Novo Nordisk A/S (in collaboration with EpiDestiny, Inc.), Aruvant Sciences, Inc., Sangamo Therapeutics Inc., or Sangamo (in collaboration with Sanofi), Fulcrum Therapeutics, Inc., Agios Pharmaceuticals, Inc., Forma Therapeutics, Inc., Intellia Therapeutics, Inc.

(in collaboration with Novartis), Editas Medicine, Inc., CRISPR Therapeutics AG, or CRISPR (in collaboration with Vertex Pharmaceuticals Incorporated, or Vertex) and Syros Pharmaceuticals, Inc.

(in collaboration with GBT), among potentially other companies, are developing therapeutic approaches for patients with SCD.

Novo Nordisk A/S (in collaboration with EpiDestiny, Inc.), Sangamo (in collaboration with Sanofi), CRISPR (in collaboration with Vertex), Agios Pharmaceuticals, Inc.

and Syros Pharmaceuticals, Inc.

(in collaboration with GBT), among potentially other companies, are developing therapeutic approaches for patients with transfusion-dependent or non-transfusion-dependent b -thalassemia.

See “Business—Competition” for additional information regarding competing products and product candidates .

Our commercial opportunity could be reduced or eliminated if our competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are more convenient or are less expensive than any products that we may develop.

Our competitors also may obtain FDA or other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our competitors establishing a strong market position before we are able to enter the market.

In addition, our ability to compete may be affected in many cases by insurers or other third-party payors seeking to encourage the use of generic products.

If any product candidates achieve marketing approval, we expect that they would be priced at a significant premium over competitive generic products.

Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing approved products than we do.

Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller number of our competitors.

Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large and established companies.

These third parties compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs.

If the market opportunities for IMR-687 and any other product candidates we may develop are smaller than we believe they are, our revenue may be adversely affected and our business may suffer.

Moreover, because the target patient populations we are seeking to treat are small, and the addressable patient population even smaller, we must be able to successfully identify patients and capture a significant market share to achieve profitability and growth.

We focus our research and product development on treatments for rare inherited genetic disorders of hemoglobin.

The prevalence of SCD is approximately 100,000 individuals in the United States and 134,000 individuals in the European Union.

Similarly, the prevalence of β-thalassemia globally is estimated to be 288,000 individuals and the aggregate prevalence of β-thalassemia in the European Union and United States is estimated to be 19,000 individuals.

Given the small number of patients who have the diseases that we are targeting, it is critical to our ability to grow and become profitable that we continue to successfully identify patients with these rare diseases.

Our projections of both the number of people who have these diseases, as well as the subset of people with these diseases who have the potential to benefit from treatment with IMR-687 and any other product candidates we may develop, are based on our beliefs and estimates.

These estimates have been derived from a variety of sources, including the scientific literature, surveys of clinics, patient foundations or market research that we conducted, and may prove to be incorrect or contain errors.

New studies may change the estimated incidence or prevalence of these diseases.

The number of patients may turn out to be lower than expected.

The effort to identify patients with diseases we seek to treat is in early stages, and we cannot accurately predict the number of patients for whom treatment might be possible.

Additionally, the potentially addressable patient population for IMR-687 and any other product candidates we may develop may be limited or may not be amenable to treatment with IMR-687 and any other product candidates we may develop, and new patients may become increasingly difficult to identify or gain access to, which would adversely affect our results of operations and our business.

Further, even if we obtain significant market share for IMR-687 and any other product candidates we may develop, because the potential target populations are very small, we may never achieve profitability despite obtaining such significant market share.

Our target patient populations are relatively small, and there are currently limited standard of care treatments directed at SCD.

As a result, the pricing and reimbursement of IMR-687 and any other product candidates we may develop, if approved, is uncertain, but must be adequate to support commercial infrastructure.

If we are unable to obtain adequate levels of reimbursement, our ability to successfully market and sell IMR-687 and any other product candidates we may develop will be adversely affected.

We rely on CMOs to manufacture IMR-687 and expect to rely on CMOs to manufacture any other product candidates we may develop.

If we are unable to enter into such arrangements as expected or if such organizations do not meet our supply requirements, development and/or commercialization of IMR-687 and any other product candidates we may develop may be delayed.

We do not have any manufacturing facilities.

We currently rely on a single manufacturer of active pharmaceutical ingredient, or API, for IMR-687 and a different single manufacturer for finished drug product, and we expect to continue to rely on third parties to manufacture clinical supplies of IMR-687 and any other product candidates we may develop and commercial supplies of our products, if and when approved for marketing by applicable regulatory authorities, as well as for packaging, sterilization, storage, distribution and other production logistics.

If we are unable to enter into such arrangements on the terms or timeline we expect, development and/or commercialization of IMR-687 and any other product candidates we may develop may be delayed.

Reliance on third-party manufacturers may expose us to different risks than if we were to manufacture product candidates ourselves.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or manufacture any product candidates in accordance with regulatory requirements, if there are disagreements between us and such parties or if such parties are unable to expand capacities to support commercialization of any product candidates for which we obtain marketing approval, we may not be able to fulfill, or may be delayed in producing sufficient product candidates to meet, our supply requirements.

These facilities may also be affected by natural disasters, such as floods or fire, or geopolitical developments, or such facilities could face manufacturing issues, such as contamination or regulatory concerns following a regulatory inspection of such facility.

In such instances, we may need to locate an appropriate replacement third-party facility and establish a contractual relationship, which may not be readily

available or on acceptable terms, which would cause additional delay and increased expense, and may have a material adverse effect on our business .

Our third-party manufacturers are subject to regulatory inspection from time to time, including inspection and approval by the FDA and similar foreign regulators before we can commence the manufacture and sale of any product candidates, and thereafter.

Failure by our third-party manufacturers to pass such inspections and otherwise satisfactorily complete the approval regimen with respect to IMR-687 and any other product candidates we may develop may result in regulatory actions such as the issuance of FDA Form 483 notices of observations, warning letters or injunctions or the loss of operating licenses.

We or our third-party manufacturers may also encounter shortages in the raw materials or API necessary to produce IMR-687 and any other product candidates we may develop in the quantities needed for our clinical trials or, if IMR-687 and any other product candidates we may develop are approved, in sufficient quantities for commercialization or to meet an increase in demand, as a result of capacity constraints or delays or disruptions in the market for the raw materials or API, including shortages caused by the purchase of such raw materials or API by our competitors or others.

Even if raw materials or API are available, we may be unable to obtain sufficient quantities at an acceptable cost or quality.

The failure of us or our third-party manufacturers to obtain the raw materials or API necessary to manufacture sufficient quantities of IMR-687 and any other product candidates we may develop could delay, prevent or impair our development efforts and may have a material adverse effect on our business.

We face additional important risks related to our reliance on CMOs to meet our current and future supply needs of IMR-687 as a result of the COVID-19 pandemic, which are further described in “—Our business and operations have been and may continue to be adversely affected by the ongoing COVID-19 pandemic as may the operations of our suppliers and manufacturers and other third-party service providers.”

Even if we are able to commercialize any product candidates, the products may become subject to unfavorable pricing regulations, third-party coverage or reimbursement practices or healthcare reform initiatives, which could harm our business.

The regulations that govern marketing approvals, pricing, coverage and reimbursement for new drug products vary widely from country to country.

Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining approvals.

Some countries require approval of the sale price of a drug before it can be marketed.

In many countries, the pricing review period begins after marketing or product licensing approval is granted.

In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted.

As a result, we might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we are able to generate from the sale of the product in that country.

Adverse pricing limitations may hinder our ability to recoup our investment in one or more product candidates, even if any product candidates obtain marketing approval.

Our ability to commercialize any product candidates successfully will depend in part on the extent to which coverage and adequate reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which medications they will pay for and establish reimbursement levels.

A primary trend in the U.S.

healthcare industry and elsewhere is cost containment.

Government authorities and other third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular medications.

Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products.

Coverage and reimbursement may not be available for any product that we commercialize and, even if these are available, the level of reimbursement may not be satisfactory.

Reimbursement may affect the demand for, or the price of, any product candidate for which we obtain marketing approval.

Obtaining and maintaining adequate reimbursement for our products may be difficult.

There can be no assurance that any product candidates, even if they are approved for sale in the United States or in other countries, will be considered medically reasonable and necessary for a specific indication or cost-effective by third-party payors.

We may be required to conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies.

If coverage and adequate reimbursement are not available, we may not be able to successfully commercialize any product candidate for which we obtain marketing approval.

There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the purposes for which the drug is approved by the FDA or similar regulatory authorities outside of

the United States.

Moreover, eligibility for coverage and reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale and distribution expenses.

Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made permanent.

Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement levels already set for lower cost drugs and may be incorporated into existing payments for other services.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the United States.

Further, no uniform policy for coverage and reimbursement exists in the United States.

Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement policies, but also have their own methods and process apart from Medicare determinations.

As a result, obtaining and maintaining coverage and adequate reimbursement is often time-consuming and costly.

Our inability to promptly obtain coverage and adequate reimbursement rates from both government-funded and private payors for any approved products that we develop could have a material adverse effect on our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.

Our future growth depends, in part, on our ability to penetrate foreign markets, where we would be subject to additional regulatory burdens and other risks and uncertainties that, if they materialize, could harm our business.

Our future profitability will depend, in part, on our ability to commercialize IMR-687 in markets outside of the United States and the European Union.

If we commercialize IMR-687 and any other product candidates we may develop in foreign markets, we will be subject to additional risks and uncertainties, including:

economic weakness, including inflation, or political instability in particular economies and markets;

the burden of complying with complex and changing foreign regulatory, tax, accounting and legal requirements, many of which vary between countries;

different medical practices and customs in foreign countries affecting acceptance in the marketplace;

tariffs and trade barriers, as well as other governmental controls and trade restrictions;

other trade protection measures, import or export licensing requirements or other restrictive actions by U.S.

or foreign governments;

longer accounts receivable collection times;

longer lead times for shipping;

compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

workforce uncertainty in countries where labor unrest is common;

language barriers for technical training;

reduced protection of intellectual property rights in some foreign countries, and related prevalence of generic alternatives to therapeutics;

foreign currency exchange rate fluctuations and currency controls;

differing foreign reimbursement landscapes;

uncertain and potentially inadequate reimbursement of our products;

the interpretation of contractual provisions governed by foreign laws in the event of a contract dispute.

If risks related to any of these uncertainties materializes, it could have a material adverse effect on our business.

Clinical trial and product liability lawsuits against us could divert our resources, could cause us to incur substantial liabilities and could limit commercialization of any products that we may develop.

We face an inherent risk of clinical trial and product liability exposure related to the testing of IMR-687 and any other product candidates we may develop in clinical trials, and we will face an even greater risk if we commercially sell any products that we may develop.

While we currently have no products that have been approved for commercial sale, the current and future use of product candidates by us in clinical trials, and the sale of any approved products in the future, may expose us to liability claims.

These claims might be made by patients that use the product, healthcare providers, pharmaceutical

companies or others selling such products.

If we cannot successfully defend ourselves against claims that IMR-687 and any other product candidates or products we may develop caused injuries, we will incur substantial liabilities.

Regardless of merit or eventual outcome, liability claims may result in:

decreased demand for IMR-687 and any other product candidates or products that we may develop;

injury to our reputation and significant negative media attention;

withdrawal of clinical trial participants;

significant costs to defend any related litigation;

substantial monetary awards to trial participants or patients;

loss of revenue;

reduced resources of our management to pursue our business strategy;

the inability to commercialize any products that we may develop.

Although we currently hold clinical trial liability insurance coverage in amounts we believe to be adequate, we may need to increase our insurance coverage as we expand our clinical trials or if we commence commercialization of any product candidates.

Insurance coverage is increasingly expensive.

We may not be able to maintain insurance coverage at a reasonable cost or in an amount adequate to satisfy any liability that may arise.

If a successful clinical trial or product liability claim or series of claims is brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover such claims and our business operations could be impaired.

Risks Related to Our Dependence on Third Parties

We rely, and expect to continue to rely, on third parties to conduct our clinical trials, and those third parties may not perform satisfactorily, including failing to meet deadlines for the completion of such trials, which may harm our business.

We currently rely on third-party clinical research organizations to conduct our ongoing Phase 2b clinical trials in SCD and in β-thalassemia.

We do not plan to independently conduct clinical trials of any other product candidates.

We expect to continue to rely on third parties, such as clinical research organizations, clinical data management organizations, medical institutions and clinical investigators, to conduct our clinical trials.

These agreements might terminate for a variety of reasons, including a failure to perform by the third parties.

If we need to enter into alternative arrangements, our product development activities might be delayed.

Our reliance on these third parties for research and development activities will reduce our control over these activities but will not relieve us of our responsibilities.

For example, we will remain responsible for ensuring that each of our clinical trials is conducted in accordance with the general investigational plan and protocols for the trial.

Moreover, the FDA requires us to comply with standards, commonly referred to as good clinical practices, or GCPs, for conducting, recording and reporting the results of clinical trials to assure that data and reported results are credible and accurate and that the rights, integrity and confidentiality of trial participants are protected.

We also are required to register clinical trials and post the results of completed clinical trials on a government-sponsored database, ClinicalTrials.gov, within specified timeframes.

Failure to do so can result in fines, adverse publicity and civil and criminal sanctions.

If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our clinical trials in accordance with regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for any product candidates and will not be able to, or may be delayed in our efforts to, successfully develop and commercialize any product candidates.

Furthermore, these third parties may also have relationships with other entities, some of which may be our competitors.

We also expect to rely on other third parties to store and distribute drug supplies for our clinical trials.

Any performance failure on the part of our distributors could delay clinical development or marketing approval of any product candidates we may successfully develop and commercialization of our products, producing additional losses and depriving us of potential product revenue.

We face additional important risks related to our dependence on third parties as a result of the COVID-19 pandemic, which are further described in “—Our business and operations have been and may continue to be adversely affected by the ongoing COVID-19 pandemic as may the operations of our suppliers and manufacturers and other third-party service providers.”

We contract with a third - party for the manufacture of IMR-687, plan to contract with third parties for any other product candidates we may develop for preclinical and clinical testing and expect to continue to do so for commercialization.

This reliance on third parties entails risks, including that such third parties may not be able to comply with applicable regulatory requirements.

Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval.

We rely on a third-party for the manufacture of IMR-687, and we expect to rely on third parties for the future manufacture of any other product candidates for preclinical and clinical testing.

Reliance on third-party manufacturers entails additional risks, including:

reliance on the third-party for regulatory compliance and quality assurance;

the possible breach of the manufacturing agreement by the third-party;

the possible misappropriation of our proprietary information, including our trade secrets and know-how;

the possible termination or nonrenewal of the agreement by the third-party at a time that is costly or inconvenient for us.

Third-party manufacturers may not be able to comply with current good manufacturing practices, or cGMP, regulations or similar regulatory requirements outside of the United States.

Our failure, or the failure of our third-party manufacturers, to comply with applicable regulations could result in sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension or withdrawal of approvals, license revocation, seizures or recalls of product candidates or products, operating restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our products.

IMR-687 and any other product candidates or products that we may develop may compete with other product candidates and products for access to manufacturing facilities.

There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for us.

Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval.

We do not currently have arrangements in place for redundant supply or a source for bulk drug substance.

If any of our future contract manufacturers cannot perform as agreed, we may be required to replace such manufacturers.

Although we believe that there are several potential alternative manufacturers who could manufacture IMR-687 and any other product candidates we may develop, we may incur added costs and delays in identifying and qualifying any such replacement.

Our current and anticipated future dependence upon others for the manufacture of IMR-687 and any other product candidates or products we may develop may adversely affect our future profit margins and our ability to commercialize any products that receive marketing approval on a timely and competitive basis.

We face additional important risks related to our reliance on third parties for the manufacture of IMR-687 and other services as a result of the COVID-19 pandemic, which are further described in “—Our business and operations have been and may continue to be adversely affected by the ongoing COVID-19 pandemic as may the operations of our suppliers and manufacturers and other third-party service providers.”

We may enter into collaborations with third parties for the development or commercialization of product candidates.

If our collaborations are not successful, we may not be able to capitalize on the market potential of these product candidates and our business could be adversely affected.

While we have retained all rights to and are developing IMR-687 on our own, we may in the future enter into development, distribution or marketing arrangements with third parties with respect to IMR-687 or future product candidates.

Our likely collaborators for any sales, marketing, distribution, development, licensing or broader collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies.

We are not currently party to any such arrangement.

However, if we do enter into any such arrangements with any third parties in the future, we will likely have limited control over the amount and timing of resources that our collaborators dedicate to the development or commercialization of IMR-687 and any other product candidates we may develop.

Our ability to generate revenues from these arrangements will depend on our collaborators’ abilities and efforts to successfully perform the functions assigned to them in these arrangements.

Collaborations that we enter into may not be successful, and any success will depend heavily on the efforts and activities of such collaborators.

Collaborations pose a number of risks, including the following:

collaborators have significant discretion in determining the amount and timing of efforts and resources that they will apply to these collaborations;

collaborators may not perform their obligations as expected;

collaborators may not pursue commercialization of IMR-687 and any other product candidates we may develop that achieve regulatory approval or may elect not to continue or renew commercialization programs based on results of clinical trials or other studies, changes in the collaborators’ strategic focus or available funding, or external factors, such as an acquisition, that may divert resources or create competing priorities;

collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with any product candidates and products if the collaborators believe that the competitive products are more likely to be successfully developed or can be commercialized under terms that are more economically attractive than ours;

product candidates discovered in collaboration with us may be viewed by our collaborators as competitive with their own product candidates or products, which may cause collaborators to cease to devote resources to the commercialization of any product candidates;

a collaborator may fail to comply with applicable regulatory requirements regarding the development, manufacture, distribution or marketing of a product candidate or product;

disagreements with collaborators, including disagreements over intellectual property or proprietary rights, contract interpretation or the preferred course of development, might cause delays or terminations of the research, development or commercialization of product candidates, might lead to additional responsibilities for us with respect to product candidates, or might result in litigation or arbitration, any of which would be time-consuming and expensive;

collaborators may not properly obtain, maintain, enforce, defend or protect our intellectual property or proprietary rights or may use our proprietary information in such a way as to potentially lead to disputes or legal proceedings that could jeopardize or invalidate our intellectual property or proprietary information or expose us to potential litigation;

collaborators may infringe, misappropriate or otherwise violate the intellectual property or proprietary rights of third parties, which may expose us to litigation and potential liability;

collaborations may be terminated for the convenience of the collaborator, and, if terminated, we could be required to raise additional capital to pursue further development or commercialization of the applicable product candidates.

Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner, or at all.

If any collaborations that we enter into do not result in the successful development and commercialization of products or if one of our collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty payments under the collaboration.

If we do not receive the funding we expect under these agreements, our development of any product candidates could be delayed and we may need additional resources to develop any product candidates.

All of the risks relating to product development, regulatory approval and commercialization described in this Annual Report on Form 10-K also apply to the activities of our collaborators.

Additionally, subject to its contractual obligations to us, if a collaborator of ours is involved in a business combination, the collaborator might deemphasize or terminate the development or commercialization of any product candidate licensed to it by us.

If one of our collaborators terminates its agreement with us, we may find it more difficult to attract new collaborators and our perception in the business and financial communities could be adversely affected.

If we are not able to establish or maintain collaborations, we may have to alter our development and commercialization plans and our business could be adversely affected.

For some product candidates we may develop, we may decide to collaborate with pharmaceutical or biotechnology companies for the development and potential commercialization of those product candidates.

We face significant competition in seeking appropriate collaborators, and a number of more established companies may also be pursuing strategies to license or acquire third-party intellectual property rights that we consider attractive.

These established companies may have a

competitive advantage over us due to their size, financial resources and greater clinical development and commercialization capabilities.

In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us.

Whether we reach a definitive agreement for a collaboration will depend, among other things, upon our assessment of the collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s evaluation of a number of factors.

Those factors may include the design or results of clinical trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject product candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the challenge, and industry and market conditions generally.

The collaborator may also consider alternative product candidates or technologies for similar indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for our product candidate.

Collaborations are complex and time-consuming to negotiate and document.

In addition, there have been a significant number of recent business combinations among large pharmaceutical and biotechnology companies that have resulted in a reduced number of potential future collaborators.

If we are unable to reach agreements with suitable collaborators on a timely basis, on acceptable terms or at all, we may have to curtail the development of a product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization activities at our own expense.

If we elect to fund and undertake development or commercialization activities on our own, we may need to obtain additional expertise and additional capital, which may not be available to us on acceptable terms or at all.

If we fail to enter into collaborations and do not have sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop any product candidates or bring them to market.

Risks Related to our Intellectual Property

If we fail to comply with our obligations under our existing license agreement with Lundbeck, or under any future intellectual property licenses, or otherwise experience disruptions to our business relationships with our current or any future licensors, we could lose intellectual property rights that are important to our business.

We are party to a license agreement with Lundbeck pursuant to which we have been granted an exclusive worldwide license within the field of prevention, treatment or diagnosis of hemoglobinopathy disorders and/or other diseases or disorders, including those directly or indirectly related to hemoglobinopathies.

The agreement grants us an exclusive license under the licensed technology to, among other things, develop and commercialize any product comprising or containing certain PDE9 inhibitors, including IMR-687.

For further information regarding our exclusive license agreement with Lundbeck, see “Business – Exclusive License Agreement.” We may enter into additional license agreements in the future .

We may enter into additional license agreements in the future.

Our license agreement with Lundbeck imposes, and we expect that future licenses will impose, specified diligence, milestone payment, royalty and other obligations on us.

Furthermore, Lundbeck has the right to terminate the agreement if we materially breach the agreement and fail to cure such breach within a specified period or in the event we undergo certain bankruptcy events.

Lundbeck may also terminate the agreement if we or any of our affiliates, sublicensees or subcontractors bring specified patent challenges against Lundbeck or assist others in bringing such a patent challenge against Lundbeck and fail to cease such challenge within a specified period of time.

In spite of our best efforts, our current or any future licensors might conclude that we have materially breached our license agreements and might therefore terminate the license agreements, thereby removing our ability to develop and commercialize product candidates and technology covered by these license agreements.

If these in-licenses are terminated, or if the underlying intellectual property fails to provide the intended exclusivity, competitors would have the freedom to seek regulatory approval of, and to market, products and technologies identical to ours.

This could have a material adverse effect on our competitive position, business, financial condition, results of operations and prospects.

Disputes may arise regarding intellectual property subject to a licensing agreement, including:

the scope of rights granted under the license agreement and other interpretation related issues;

the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement;

the sublicensing of patent and other rights under our collaborative development relationships;

our diligence obligations under the license agreement and what activities satisfy those diligence obligations;

the inventorship and ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our current or future licensors and us and our partners;

the priority of invention of patented technology.

In addition, license agreements are complex, and certain provisions in such agreements may be susceptible to multiple interpretations.

The resolution of any contract interpretation disagreement that may arise could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

Moreover, if disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and commercialize the affected technology and product candidates, which could have a material adverse effect on our business, financial conditions, results of operations and prospects.

If we are unable to obtain, maintain, enforce and protect patent protection for our technology and product candidates or if the scope of the patent protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and products similar or identical to ours, and our ability to successfully develop and commercialize our technology and product candidates may be adversely affected.

Our success depends in large part on our ability to obtain and maintain protection of the intellectual property we may own solely and jointly with others or may license from others, particularly patents, in the United States and other countries with respect to any proprietary technology and product candidates we develop.

We seek to protect our proprietary position by filing patent applications in the United States and abroad related to IMR-687 and any other product candidates we may develop that are important to our business and by in-licensing intellectual property related to our technologies and product candidates.

If we are unable to obtain or maintain patent protection with respect to any proprietary technology or product candidate, our business, financial condition, results of operations and prospects could be materially harmed.

The patent prosecution process is expensive, time-consuming and complex, and we may not be able to file, prosecute, maintain, defend or license all necessary or desirable patent applications at a reasonable cost or in a timely manner.

It is also possible that we will fail to identify patentable aspects of our research and development output before it is too late to obtain patent protection.

Moreover, in some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or to maintain, enforce and defend the patents, covering technology that we license from third parties.

Therefore, these in-licensed patents and applications may not be prepared, filed, prosecuted, maintained, defended and enforced in a manner consistent with the best interests of our business.

The patent position of pharmaceutical and biotechnology companies generally is highly uncertain, involves complex legal and factual questions and has in recent years been the subject of much litigation.

In addition, the scope of patent protection outside of the United States is uncertain and laws of non-U.S.

countries may not protect our rights to the same extent as the laws of the United States or vice versa.

For example, European patent law restricts the patentability of methods of treatment of the human body more than United States law does.

With respect to both owned and in-licensed patent rights, we cannot predict whether the patent applications we and our licensor are currently pursuing will issue as patents in any particular jurisdiction or whether the claims of any issued patents will provide sufficient protection from competitors.

Further, we may not be aware of all third-party intellectual property rights potentially relating to IMR-687 and any other product candidates we may develop.

In addition, publications of discoveries in the scientific literature often lag behind the actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing of the priority application, or in some cases not published at all.

Therefore, neither we nor our licensor can know with certainty whether either we or our licensor were the first to make the inventions claimed in the patents and patent applications we own or in-license now or in the future, or that either we or our licensor were the first to file for patent protection of such inventions.

As a result, the issuance, scope, validity, enforceability and commercial value of our owned and in-licensed patent rights are highly uncertain.

Moreover, our owned and in-licensed pending and future patent applications may not result in patents being issued that protect our technology and product candidates, in whole or in part, or that effectively prevent others from commercializing competitive technologies and products.

Changes in either the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents and our ability to obtain, protect, maintain, defend and enforce our patent rights, narrow the scope of our patent protection and, more generally, could affect the value of, or narrow the scope of, our patent rights.

Currently, we have no issued U.S.

patents directed to methods of treating SCD or β-thalassemia.

However, we do have pending Patent Cooperation Treaty and U.S.

non-provisional applications directed to methods of treating SCD and β-thalassemia.

In order to continue to pursue protection based on provisional patent applications, we will need to file Patent

Cooperation Treaty applications, non-U.S.

applications and/or U.S.

non-provisional patent applications prior to applicable deadlines.

Even then, as highlighted above, patents may never issue from our patent applications, or the scope of any patent may not be sufficient to provide a competitive advantage.

With respect to IMR-687, the patents covering IMR-687 licensed from Lundbeck are expected to expire in 203 6 .

Moreover, we or our licensor may be subject to a third-party preissuance submission of prior art to the United States Patent and Trademark Office, or USPTO, or become involved in opposition, derivation, revocation, reexamination, inter partes review, post-grant review or interference proceedings challenging our patent rights or the patent rights of others.

An adverse determination in any such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or product candidates and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing third-party patent rights.

If the breadth or strength of protection provided by our patents and patent applications is threatened, regardless of the outcome, it could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates.

Additionally, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted after issuance.

Even if our owned and in-licensed patent applications issue as patents, they may not issue in a form that will provide us with any meaningful protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage.

The issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, and our owned and in-licensed patents may be challenged in the courts or patent offices in the United States and abroad.

Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products, or limit the duration of the patent protection of our technology and product candidates.

Such proceedings also may result in substantial cost and require significant time from our management and employees, even if the eventual outcome is favorable to us.

Given the amount of time required for the development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized.

Furthermore, our competitors may be able to circumvent our owned or in-licensed patents by developing similar or alternative technologies or products in a non-infringing manner.

As a result, our owned and in-licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing technology and products similar or identical to any of our technology and product candidates.

Patent terms may be inadequate to protect our competitive position on any product candidates for an adequate amount of time.

Patents have a limited lifespan.

In the United States, if all maintenance fees are timely paid, the natural expiration of a patent is generally 20 years from its earliest U.S.

non-provisional filing date.

Various extensions may be available, but the life of a patent, and the protection it affords, is limited.

Even if patents covering any product candidates are obtained, once the patent life has expired, we may be open to competition from competitive products, including generics or biosimilars.

As a result, our owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.

For example, the composition of matter patents covering IMR-687, licensed from Lundbeck, are expected to expire in 2036.

Given the expected expiration date of these patents, and the fact that safe harbor protections in many jurisdictions permit third parties to engage in development, including clinical trials, these patents may not provide us with a meaningful competitive advantage.

If we are unable to obtain licenses from third parties on commercially reasonable terms or fail to comply with our obligations under such agreements, our business could be harmed.

It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products, in which case we would be required to obtain a license from these third parties.

If we are unable to license such technology, or if we are forced to license such technology on unfavorable terms, our business could be materially harmed.

If we are unable to obtain a necessary license, we may be unable to develop or commercialize the affected product candidates, which could materially harm our business and the third parties owning such intellectual property rights could seek either an injunction prohibiting our sales or an obligation on our part to pay royalties and/or other forms of compensation.

Even if we are able to obtain a license, it may be non-exclusive, thereby giving our competitors access to the same technologies licensed to us.

If we are unable to obtain rights to required third-party intellectual property rights or maintain the existing intellectual property rights we have, we may be required to expend significant time and resources to redesign our technology, product candidates, or the methods for manufacturing them or to develop or license replacement technology, all of which may not be feasible on a technical or commercial basis.

If we are unable to do so, we may be unable to develop or commercialize the affected technology and product candidates, which could harm our business, financial condition, results of operations and prospects significantly.

Additionally, if we fail to comply with our obligations under license agreements, our counterparties may have the right to terminate these agreements, in which event we might not be able to develop, manufacture or market, or may be forced to cease developing, manufacturing or marketing, any product that is covered by these agreements or may face other penalties under such agreements.

Such an occurrence could materially adversely affect the value of the product candidate being developed under any such agreement.

Termination of these agreements or reduction or elimination of our rights under these agreements, or restrictions on our ability to freely assign or sublicense our rights under such agreements when it is in the interest of our business to do so, may result in our having to negotiate new or reinstated agreements with less favorable terms, cause us to lose our rights under these agreements, including our rights to important intellectual property or technology or impede, or delay or prohibit the further development or commercialization of one or more product candidates that rely on such agreements.

If we do not obtain patent term extension in the United States under the Hatch-Waxman Act and in non-U.S.

countries under similar legislation, thereby potentially extending the term of our marketing exclusivity for any product candidates we may develop, our business may be materially harmed.

In the United States, the patent term of a patent that covers an FDA-approved drug may be eligible for limited patent term extension, which permits patent term restoration as compensation for the patent term lost during the FDA regulatory review process.

The Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act, permits a patent term extension of up to five years beyond the expiration of the patent.

The length of the patent term extension is related to the length of time the drug is under regulatory review.

Patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and only one patent applicable to an approved drug may be extended and only those claims covering the approved drug, a method for using it, or a method for manufacturing it may be extended.

Similar provisions are available in Europe and certain other non-United States jurisdictions to extend the term of a patent that covers an approved drug.

While, in the future, if and when any product candidates receive FDA approval, we expect to apply for patent term extensions on patents covering those product candidates, there is no guarantee that the applicable authorities will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.

We may not be granted patent term extension either in the United States or in any non-U.S.

country because of, for example, failing to exercise due diligence during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or otherwise failing to satisfy applicable requirements.

Moreover, the term of extension, as well as the scope of patent protection during any such extension, afforded by the governmental authority could be less than we request.

If we are unable to obtain any patent term extension or the term of any such extension is less than we request, our competitors may obtain approval of competing products following the expiration of our patent rights, and our business, financial condition, results of operations and prospects could be materially harmed.

It is possible that we will not obtain patent term extension under the Hatch-Waxman Act for a U.S.

patent covering any of any product candidates that we may identify even where that patent is eligible for patent term extension, or if we obtain such an extension, it may be for a shorter period than we had sought.

Further, for our licensed patents, we may not have the right to control prosecution, including filing with the USPTO a petition for patent term extension under the Hatch-Waxman Act.

Thus, if one of our licensed patents is eligible for patent term extension under the Hatch-Waxman Act, we may not be able to control whether a petition to obtain a patent term extension is filed, or obtained, from the USPTO.

Also, there are detailed rules and requirements regarding the patents that may be submitted to the FDA for listing in the Approved Drug Products with Therapeutic Equivalence Evaluations, or the Orange Book.

We may be unable to obtain patents covering any product candidates that contain one or more claims that satisfy the requirements for listing in the Orange Book.

Even if we submit a patent for listing in the Orange Book, the FDA may decline to list the patent, or a manufacturer of generic drugs may challenge the listing.

If a product candidate is approved and a patent covering that product candidate is not listed in the Orange Book, a manufacturer of generic drugs would not have to provide advance notice to us of any abbreviated new drug application filed with the FDA to obtain permission to sell a generic version of such product candidate.

Changes to patent laws in the United States and other jurisdictions could diminish the value of patents in general, thereby impairing our ability to protect our products.

Changes in either the patent laws or interpretation of patent laws in the United States, including patent reform legislation such as the Leahy-Smith America Invents Act, or the Leahy-Smith Act, could increase the uncertainties and costs surrounding the prosecution of our owned and in-licensed patent applications and the maintenance, enforcement or defense of our owned and in-licensed issued patents.

The Leahy-Smith Act includes a number of significant changes to United States patent law.

These changes include provisions that affect the way patent applications are prosecuted, redefine prior art, provide more efficient and cost-effective avenues for competitors to challenge the validity of patents, and enable third-party submission of prior art to the USPTO during patent prosecution and additional procedures to attack the validity of a patent at USPTO-administered post-grant proceedings, including post-grant review, inter partes review, and derivation proceedings.

Assuming that other requirements for patentability are met, prior to March 2013, in the United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was entitled to the patent.

After March 2013, under the Leahy-Smith Act, the United States transitioned to a first-to-file system in which, assuming that the other statutory requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third-party was the first to invent the claimed invention.

As such, the Leahy-Smith Act and its implementation could increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of which could have a material adverse effect on our business, financial condition, results of operations and prospects.

In addition, the patent positions of companies in the development and commercialization of biologics and pharmaceuticals are particularly uncertain.

Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations.

This combination of events has created uncertainty with respect to the validity and enforceability of patents once obtained.

Depending on future actions by the U.S.

Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in unpredictable ways that could have a material adverse effect on our patent rights and our ability to protect, defend and enforce our patent rights in the future.

We and our licensor, and any future licensors, may become involved in lawsuits to protect or enforce our patent or other intellectual property rights, which could be expensive, time-consuming and unsuccessful.

Competitors and other third parties may infringe, misappropriate or otherwise violate our or our current and future licensors’ issued patents or other intellectual property.

As a result, we or any current or future licensor may need to file infringement, misappropriation or other intellectual property related claims, which can be expensive and time-consuming.

Any claims we assert against perceived infringers could provoke such parties to assert counterclaims against us alleging that we infringe, misappropriate or otherwise violate their intellectual property.

In addition, in a patent infringement proceeding, such parties could counterclaim that the patents we or our licensors have asserted are invalid or unenforceable.

In patent litigation in the United States, defendant counterclaims alleging invalidity or unenforceability are commonplace.

Grounds for a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness, or non-enablement.

Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution.

Third parties may institute such claims before administrative bodies in the United States or abroad, even outside the context of litigation.

Such mechanisms include re-examination, post-grant review, inter partes review, interference proceedings, derivation proceedings, and equivalent proceedings in non-U.S.

jurisdictions (e.g., opposition proceedings).

The outcome following legal assertions of invalidity and unenforceability is unpredictable.

An adverse result in any such proceeding could put one or more of our owned or in-licensed patents at risk of being invalidated or interpreted narrowly and could put any of our owned or in-licensed patent applications at risk of not yielding an issued patent.

A court may also refuse to stop the third-party from using the technology at issue in a proceeding on the grounds that our owned or in-licensed patents do not cover such technology.

Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of our confidential information or trade secrets could be compromised by disclosure during this type of litigation.

Any of the foregoing could allow such third parties to develop and commercialize competing technologies and products and have a material adverse impact on our business, financial condition, results of operations and prospects.

Interference or derivation proceedings provoked by third parties, or brought by us or by our licensor, or declared by the USPTO may be necessary to determine the priority of inventions with respect to our patents or patent applications.

An unfavorable outcome could require us to cease using the related technology or to attempt to license rights to it from the prevailing party.

Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable

terms or at all, or if a non-exclusive license is offered and our competitors gain access to the same technology.

Our defense of litigation or interference or derivation proceedings may fail and, even if successful, may result in substantial costs and distract our management and other employees.

In addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, continue our research programs, license necessary technology from third parties, or enter into development partnerships that would help us bring any product candidates to market.

Third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights, the outcome of which would be uncertain and could have a material adverse effect on the success of our business.

Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell any product candidates we may develop and use our proprietary technologies without infringing, misappropriating or otherwise violating the intellectual property and proprietary rights of third parties.

There is considerable patent and other intellectual property litigation in the pharmaceutical and biotechnology industries.

We may become party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our technology and product candidates, including interference proceedings, post grant review, inter partes review, and derivation proceedings before the USPTO and similar proceedings in non-U.S.

jurisdictions such as oppositions before the European Patent Office.

Numerous U.S.

issued patents and pending patent applications, which are owned by third parties, exist in the fields in which we are pursuing development candidates.

As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that our technologies or product candidates that we may identify may be subject to claims of infringement of the patent rights of third parties.

The legal threshold for initiating litigation or contested proceedings is low, so that even lawsuits or proceedings with a low probability of success might be initiated and require significant resources to defend.

Litigation and contested proceedings can also be expensive and time-consuming, and our adversaries in these proceedings may have the ability to dedicate substantially greater resources to prosecuting these legal actions than we can.

The risks of being involved in such litigation and proceedings may increase if and as any product candidates near commercialization and as we gain the greater visibility associated with being a public company.

Third parties may assert infringement claims against us based on existing patents or patents that may be granted in the future, regardless of merit.

We may not be aware of all such intellectual property rights potentially relating to our technology and product candidates and their uses, or we may incorrectly conclude that third-party intellectual property is invalid or that our activities and product candidates do not infringe such intellectual property.

Thus, we do not know with certainty that our technology and product candidates, or our development and commercialization thereof, do not and will not infringe, misappropriate or otherwise violate any third-party’s intellectual property.

Third parties may assert that we are employing their proprietary technology without authorization.

There may be third-party patents or patent applications with claims to materials, formulations or methods, such as methods of manufacture or methods for treatment, related to the discovery, use or manufacture of the product candidates that we may identify or related to our technologies.

Because patent applications can take many years to issue, there may be currently pending patent applications which may later result in issued patents that the product candidates that we may identify may infringe.

In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents.

Moreover, as noted above, there may be existing patents that we are not aware of or that we have incorrectly concluded are invalid or not infringed by our activities.

If any third-party patents were held by a court of competent jurisdiction to cover, for example, the manufacturing process of the product candidates that we may identify, any molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block our ability to commercialize such product candidate unless we obtained a license under the applicable patents, or until such patents expire.

Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize the product candidates that we may identify.

Defense of these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from our business.

In the event of a successful claim of infringement against us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products, be forced to indemnify our customers or collaborators or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure.

We may choose to take a license or, if we are found to infringe, misappropriate or otherwise violate a third-party’s intellectual property rights, we could also be required to obtain a license from such third-party to continue developing, manufacturing and marketing our technology and product candidates.

However, we may not be able to obtain any required

license on commercially reasonable terms or at all.

Even if we were able to obtain a license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us and could require us to make substantial licensing and royalty payments.

We could be forced, including by court order, to cease developing, manufacturing and commercializing the infringing technology or product.

A finding of infringement could prevent us from commercializing any product candidates or force us to cease some of our business operations, which could materially harm our business.

In addition, we may be forced to redesign any product candidates, seek new regulatory approvals and indemnify third parties pursuant to contractual agreements.

Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar material adverse effect on our business, financial condition, results of operations and prospects.

Intellectual property litigation or other legal proceedings relating to intellectual property could cause us to spend substantial resources and distract our personnel from their normal responsibilities.

Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses and could distract our technical and management personnel from their normal responsibilities.

In addition, there could be public announcements of the results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it could have a substantial adverse effect on the price of our common stock.

Such litigation or proceedings could substantially increase our operating losses and reduce the resources available for development activities or any future sales, marketing or distribution activities.

We may not have sufficient financial or other resources to conduct such litigation or proceedings adequately.

Some of our competitors may be able to sustain the costs of such litigation or proceedings more effectively than we can because of their greater financial resources and may also have an advantage in such proceedings due to their more mature and developed intellectual property portfolios.

Uncertainties resulting from the initiation and continuation of intellectual property litigation or other proceedings could compromise our ability to compete in the marketplace.

Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment and other requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these requirements.

Periodic maintenance, renewal and annuity fees and various other government fees on any issued patent and pending patent application must be paid to the USPTO and non-U.S.

patent agencies in several stages or annually over the lifetime of our owned and in-licensed patents and patent applications.

The USPTO and various non-U.S.

governmental patent agencies also require compliance with a number of procedural, documentary and other similar provisions during the patent application process.

In certain circumstances, we may rely on our licensing partners to pay these fees to, or comply with the procedural and documentary rules of, the relevant patent agency.

With respect to our patents, we rely on an annuity service, outside firms and outside counsel to remind us of the due dates and to make payment after we instruct them to do so.

While an inadvertent lapse can in many cases be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction.

Non-compliance events that could result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of fees and failure to properly legalize and submit formal documents.

In such an event, potential competitors might be able to enter the market with similar or identical products or technology.

If we or our current or future licensors fail to maintain the patents and patent applications covering any product candidates, it may have a material adverse effect on our business, financial condition, results of operations and prospects.

We may not be able to protect our intellectual property and proprietary rights throughout the world.

Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and the laws of non-U.S.

countries may not protect our rights to the same extent as the laws of the United States.

In addition, the laws of some non-U.S.

countries do not protect intellectual property rights to the same extent as federal and state laws in the United States, and even where such protection is nominally available, judicial and governmental enforcement of such intellectual property rights may be lacking.

Consequently, we may not be able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our inventions in and into the United States or other jurisdictions.

Competitors may use our technologies in jurisdictions where we have not obtained patent protection to develop their own products and, further, may export otherwise infringing products to territories where we have patent protection or licenses but enforcement is not as strong as that in the United States.

These products may compete with our products, and our patents or other intellectual property rights may not be effective or sufficient to prevent them from competing.

Many companies have encountered significant problems in protecting and defending intellectual property rights in non-U.S.

jurisdictions.

The legal systems of certain countries do not favor the enforcement of patents, trade secrets, and other intellectual property rights, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of our intellectual property and proprietary rights generally.

In addition, certain jurisdictions do not protect to the same extent or at all inventions that constitute new methods of treatment.

Proceedings to enforce our intellectual property and proprietary rights in non-U.S.

jurisdictions could result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted narrowly, could put our patent applications at risk of not issuing, and could provoke third parties to assert claims against us.

We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful.

Accordingly, our efforts to enforce our intellectual property and proprietary rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.

Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties.

In addition, many countries limit the enforceability of patents against government agencies or government contractors.

In these countries, the patent owner may have limited remedies, which could materially diminish the value of such patent.

If we or any of our current or future licensors is forced to grant a license to third parties with respect to any patents relevant to our business, our competitive position may be impaired, and our business, financial condition, results of operations and prospects may be adversely affected.

We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.

We or our licensor may be subject to claims that former employees, collaborators or other third parties have an interest in our owned or in-licensed patents, trade secrets or other intellectual property as an inventor or co-inventor.

For example, we or our licensor may have inventorship disputes arise from conflicting obligations of employees, consultants or others who are involved in developing any product candidates.

Litigation may be necessary to defend against these and other claims challenging inventorship or our or our licensor’s ownership of our owned or in-licensed patents, trade secrets or other intellectual property.

If we or our licensor fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights, such as exclusive ownership of, or right to use, intellectual property that is important to any product candidates.

Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees.

Any of the foregoing could have a material adverse effect on our business, financial condition, results of operations and prospects.

We may be subject to claims by third parties asserting that our employees, consultants or contractors have wrongfully used or disclosed confidential information of third parties, or we have wrongfully used or disclosed alleged trade secrets of their current or former employers or claims asserting we have misappropriated their intellectual property, or claiming ownership of what we regard as our own intellectual property.

Certain of our employees, consultants and contractors were previously employed at universities or other pharmaceutical or biotechnology companies, including our competitors or potential competitors.

Although we try to ensure that our employees, consultants and contractors do not use the proprietary information or know-how of others in their work for us, we may be subject to claims that these individuals or we have used or disclosed intellectual property, including trade secrets or other proprietary information, of any such individual’s current or former employer.

Litigation may be necessary to defend against these claims.

In addition, while it is our policy to require that our employees, consultants and contractors who may be involved in the development of intellectual property to execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with each party who in fact develops intellectual property that we regard as our own.

Our intellectual property assignment agreements with them may not be self-executing or may be breached, and we may be forced to bring claims against third parties, or defend claims they may bring against us, to determine the ownership of what we regard as our intellectual property.

Such claims could have a material adverse effect on our business, financial conditions, results of operations and prospects.

If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could have a material adverse effect on our competitive business position and prospects.

Such intellectual property rights could be awarded to a third-party, and we could be required to obtain a license

from such third - party to commercialize our technology or products, which license may not be available on commercially reasonable terms, or at all, or such license may be non-exclusive.

Even if we are successful in prosecuting or defending against such claims, litigation could result in substantial costs and be a distraction to our management and employees.

If we are unable to protect the confidentiality of our trade secrets, our business and competitive position may be harmed.

In addition to seeking patents for any product candidates, we also rely on trade secrets and confidentiality agreements to protect our unpatented know-how, technology and other proprietary information, to maintain our competitive position.

We seek to protect our trade secrets and other proprietary technology, in part, by entering into non-disclosure and confidentiality agreements with parties who have access to them, such as our employees, corporate collaborators, outside scientific collaborators, contract research organizations, contract manufacturers, consultants, advisors and other third parties.

We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants, but we cannot guarantee that we have entered into such agreements with each party that may have or has had access to our trade secrets or proprietary technology.

Despite these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able to obtain adequate remedies for such breaches.

Detecting the disclosure or misappropriation of a trade secret and enforcing a claim that a party illegally disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable.

In addition, some courts inside and outside of the United States are less willing or unwilling to protect trade secrets.

If any of our trade secrets were to be lawfully obtained or independently developed by a competitor or other third-party, we would have no right to prevent them, or those to whom they communicate it, from using that technology or information to compete with us.

If any of our trade secrets were to be disclosed to or independently developed by a competitor or other third-party, our competitive position may be materially and adversely harmed.

Intellectual property rights do not necessarily address all potential threats.

The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations and may not adequately protect our business or permit us to maintain our competitive advantage.

others may be able to make product candidates that are similar to ours but that are not covered by the claims of the patents that we own;

we, or our license partners or current or future collaborators, might not have been the first to make the inventions covered by the issued patent or pending patent applications that we license or may own in the future;

we, or our license partners or current or future collaborators, might not have been the first to file patent applications covering certain of our or their inventions;

others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our owned or in-licensed intellectual property rights;

it is possible that our owned and in-licensed pending patent applications or those we may own or in-license in the future will not lead to issued patents;

issued patents that we hold rights to may be held invalid or unenforceable, including as a result of legal challenges by our competitors;

our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such activities to develop competitive products for sale in our major commercial markets;

we cannot ensure that any of our patents, or any of our pending patent applications, if issued, or those of our licensor, will include claims having a scope sufficient to protect any product candidates;

we cannot ensure that any patents issued to us or our current or future licensors will provide a basis for an exclusive market for our commercially viable product candidates or will provide us with any competitive advantages;

we cannot ensure that our commercial activities or product candidates will not infringe upon the patents of others;

we cannot ensure that we will be able to successfully commercialize any product candidates on a substantial scale, if approved, before the relevant patents that we own or license expire;

we may not develop additional proprietary technologies that are patentable;

the patents of others may harm our business;

we may choose not to file a patent in order to maintain certain technology as a trade secrets or know-how, and a third-party may subsequently file a patent application covering such technology.

Should any of these events occur, they could have a material adverse effect on our business, financial condition, results of operations and prospects.

Risks Related to Regulatory Approval of Our Product Candidates and Other Legal Compliance Matters

Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of any product candidates.

If we are not able to obtain, or if there are delays in obtaining, required regulatory approvals, we will not be able to commercialize any product candidates, and our ability to generate revenue will be materially impaired.

IMR-687 and any future product candidates we may identify and pursue and the activities associated with their development and commercialization, including design, testing, manufacture, packaging, recordkeeping, labeling, storage, approval, advertising, promotion, sale and distribution, export, import and adverse event reporting, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States and by the EMA and similar regulatory authorities outside of the United States.

In addition, regulatory agencies may not approve the labeling claims that are necessary or desirable for the successful commercialization of any such product candidates.

For example, the development of IMR-687 for the treatment of SCD in pediatric patients is an important part of our current business strategy, and if we are unable to obtain regulatory approval for the desired age ranges, our business may suffer.

Marketing approval of drugs in the United States requires the submission of a new drug application, or NDA, to the FDA and we are not permitted to market any product candidate in the United States until we obtain approval from the FDA of the NDA for that product.

An NDA must be supported by extensive clinical and preclinical data, as well as extensive information regarding pharmacology, toxicology, and chemistry, manufacturing and controls.

We have not submitted an application for or received marketing approval for IMR-687 and any other product candidates we may develop in the United States or in any other jurisdiction.

We have only limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party clinical research organizations or other third-party consultants or vendors to assist us in this process.

Securing marketing approval requires the submission of extensive preclinical and clinical data and supporting information to regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy.

Securing marketing approval also requires the submission of information about the product manufacturing processes to, and inspection of manufacturing facilities by, the regulatory authorities.

Our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may preclude our obtaining marketing approval or prevent or limit commercial use.

If any of any product candidates receives marketing approval, the accompanying label may limit the approved use of our drug, which could limit sales of the product.

The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years, if approval is obtained at all, and can vary substantially based upon a variety of factors, including the type, complexity and novelty of the product candidates involved.

Changes in marketing approval policies during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory review for each submitted product application may cause delays in the approval or rejection of an application.

Regulatory authorities have substantial discretion in the approval process and may refuse to accept any application or may decide that our data is insufficient for approval and require additional preclinical, clinical or other studies.

In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate in various countries.

Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the approved product not commercially viable.

Finally, disruptions at the FDA and other agencies may prolong the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical employees and stop critical activities.

If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse

effect on our business.

The Trump Administration also took several executive actions that could impose significant burdens on, or otherwise materially delay, the FDA’s ability to engage in routine regulatory and oversight activities.

If we experience delays in obtaining approval or if we fail to obtain approval of IMR-687 and any other product candidates we may develop, the commercial prospects for any product candidates may be harmed and our ability to generate revenues will be materially impaired.

We may not be able to obtain or maintain orphan drug designation or exclusivity for any product candidates and, even if we do, that exclusivity may not prevent the FDA or the EMA from approving other competing products.

We received orphan drug designation for IMR-687 for SCD and β-thalassemia in the United States in February 2017 and June 2020, respectively.

We also received orphan drug designation for IMR-687 for SCD in the European Union in August 2020.

We may seek orphan drug designation in other indications or for any other future product candidates.

Regulatory authorities in some jurisdictions, including the United States and the European Union, may designate drugs for relatively small patient populations as orphan drugs.

Under the Orphan Drug Act, the FDA may designate a product as an orphan drug if it is a drug intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000 individuals in the United States.

Generally, if a product with an orphan drug designation subsequently receives the first marketing approval for the indication for which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA or the EMA from approving another marketing application for the same drug for that time period.

The applicable period is seven years in the United States and ten years in the European Union.

The exclusivity period in the European Union can be reduced to six years if a drug no longer meets the criteria for orphan drug designation or if the drug is sufficiently profitable so that market exclusivity is no longer justified.

Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for designation was materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition.

Even if we obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because competing drugs containing a different active ingredient can be approved for the same condition.

In addition, even after an orphan drug is approved, the FDA can subsequently approve the same drug for the same condition if the FDA concludes that the later drug is clinically superior in that it is shown to be safer, more effective or makes a major contribution to patient care.

On August 3, 2017, the U.S.

Congress passed the FDA Reauthorization Act of 2017, or FDARA.

FDARA, among other things, codified the FDA’s pre-existing regulatory interpretation to require that a drug sponsor demonstrate the clinical superiority of an orphan drug that is otherwise the same as a previously approved drug for the same rare disease in order to receive orphan drug exclusivity.

The new legislation reverses prior precedent holding that the Orphan Drug Act unambiguously requires that the FDA recognize the orphan exclusivity period regardless of a showing of clinical superiority.

The FDA may further reevaluate the Orphan Drug Act and its regulations and policies.

We do not know if, when or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any changes might affect our business.

Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.

Although we have obtained Rare Pediatric Disease Designation, or RPDD, for IMR-687 for the treatment of SCD and β-thalassemia, we may not be eligible to receive a priority review voucher in the event that FDA approval does not occur prior to October 1, 2022.

The Rare Pediatric Disease Priority Review Voucher Program, or PRV Program, is intended to incentivize pharmaceutical sponsors to develop drugs for rare pediatric diseases.

A sponsor who obtains approval of an NDA or BLA for a rare pediatric disease may be eligible for a Priority Review Voucher, or PRV, under this program, which may be redeemed by the owner of such PRV to obtain priority review for a marketing application.

A PRV is fully transferrable and can be sold to any sponsor, who in turn can redeem the PRV for priority review of a marketing application in six months, compared to the standard timeframe of approximately 10 months.

In December 2016, extended the Rare Pediatric Disease Priority Review Voucher Program, authorizing the FDA to award vouchers through September 30, 2022, limited to drugs with rare pediatric disease designation granted by September 30, 2020.

On September 30, 2020, Congress provided a short-term extension of the Priority Review Voucher Program.

On December 27, 2020, the Rare Pediatric Disease Priority Review Voucher Program was further extended.

Under the current statutory sunset provisions, after September 30, 2024, FDA may only award a voucher for an approved rare pediatric disease

product application if the sponsor has rare pediatric disease designation for the drug, and that designation was granted by September 30, 2024.

After September 30, 2026, FDA may not award any rare pediatric disease priority review vouchers.

If we do not obtain approval of an NDA for IMR-687 for SCD or β-thalassemia by these dates, and if the PRV Program is not further extended by congressional action, we may not receive a PRV .

A Fast Track designation by the FDA may not lead to a faster development or regulatory review or approval process.

We have received Fast Track designation for IMR-687 from the FDA, and we may seek Fast Track designation for other product candidates we may develop.

If a drug is intended for the treatment of a serious or life-threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA Fast Track designation.

The FDA has broad discretion whether or not to grant this designation, so even if we believe a particular product candidate is eligible for this designation, we cannot be certain that the FDA would decide to grant it.

Even if we do receive Fast Track designation, we may not experience a faster development process, review or approval compared to conventional FDA procedures.

The FDA may withdraw Fast Track designation if it believes that the designation is no longer supported by data from our clinical development program.

Accelerated approval by the FDA, even if granted for any product candidates does not increase the likelihood that any product candidates will ultimately receive full approval.

We may seek approval of IMR-687 and any other product candidates we may develop using the FDA’s accelerated approval pathway.

A product may be eligible for accelerated approval if it treats a serious or life-threatening condition and generally provides a meaningful advantage over available therapies.

In addition, it must demonstrate an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is reasonably likely to predict an effect on IMM or other clinical benefit.

The FDA makes the determination regarding whether to accept a biomarker as a proposed surrogate endpoint.

Prior to seeking such accelerated approval, we will request feedback from the FDA regarding the eligibility of the drug product candidate for accelerated approval and otherwise evaluate our ability to seek and receive such accelerated approval.

As a condition of accelerated approval, the FDA will require that a sponsor of a drug or biologic product candidate receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

These confirmatory trials must be completed with due diligence and we may be required to evaluate different or additional endpoints in these post-marketing confirmatory trials.

In addition, the FDA currently requires as a condition for accelerated approval pre-clearance of promotional materials prior to use, which could adversely impact the timing of the commercial launch of the product.

There can be no assurance that the FDA will agree with our surrogate endpoints or intermediate clinical endpoints, including red blood cell biomarkers and adhesion/white blood cell markers, or that we will decide to pursue or submit an NDA for accelerated approval or any other form of expedited development, review or approval.

Similarly, there can be no assurance that, after feedback from FDA, we will continue to pursue or apply for accelerated approval or any other form of expedited development, review or approval, even if we initially decide to do so.

Furthermore, if we decide to submit an application for accelerated approval or under another expedited regulatory designation, there can be no assurance that such submission or application will be accepted or that any expedited review or approval will be granted on a timely basis, or at all.

Moreover, as noted above, for drugs granted accelerated approval, the FDA requires post-marketing trials to confirm the benefit of the drug.

These confirmatory trials must be completed with due diligence.

We may be required to evaluate additional or different clinical endpoints in these post-marketing confirmatory trials.

These confirmatory trials may require enrollment of more patients than we currently anticipate and will result in additional costs, which may be greater than the estimated costs we currently anticipate.

The FDA may withdraw approval of a product candidate approved under the accelerated approval pathway if, for example, the trial required to verify the predicted clinical benefit of our product candidate fails to verify such benefit or does not demonstrate sufficient clinical benefit to justify the risks associated with the drug.

The FDA may also withdraw approval if other evidence demonstrates that our product candidate is not shown to be safe or effective under the conditions of use, we fail to conduct any required post approval trial of our product candidate with due diligence or we disseminate false or misleading promotional materials relating to our product candidate.

A failure to obtain accelerated approval or any other form of expedited development, review or approval for IMR-687 and any other product candidates we may develop, or withdrawal of a product candidate, would result in a longer time period for commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our competitive position in the marketplace.

Even if we do receive accelerated approval, we may not ultimate ly be able to obtain full FDA approval.

Failure to obtain marketing approval in foreign jurisdictions would prevent any product candidates from being marketed abroad.

In order to market and sell our products in the European Union and many other foreign jurisdictions, we or our potential third-party collaborators must obtain separate marketing approvals and comply with numerous and varying regulatory requirements.

The approval procedure varies among countries and can involve additional testing.

The time required to obtain approval may differ substantially from that required to obtain FDA approval.

The regulatory approval process outside of the United States generally includes all of the risks associated with obtaining FDA approval.

In addition, in many countries outside of the United States, it is required that the product be approved for reimbursement before the product can be made available for sale in that country.

We or our potential third-party collaborators may not obtain approvals from regulatory authorities outside of the United States on a timely basis, if at all.

Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside of the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.

However, a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in other countries.

We may not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.

Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the recent withdrawal of the United Kingdom from the European Union, commonly referred to as Brexit.

Pursuant to the formal withdrawal arrangements agreed between the United Kingdom and the European Union, the United Kingdom withdrew from the European Union, effective December 31, 2020.

On December 24, 2020, the United Kingdom and the European Union entered into a Trade and Cooperation Agreement.

The agreement sets out certain procedures for approval and recognition of medical products in each jurisdiction.

Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, would prevent us from commercializing any product candidates in the United Kingdom and/or the European Union and restrict our ability to generate revenue and achieve and sustain profitability.

If any of these outcomes occur, we may be forced to restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European Union for any product candidates, which could significantly and materially harm our business.

We expect that we will be subject to additional risks in commercializing any of our product candidates that receive marketing approval outside the United States, including tariffs, trade barriers and regulatory requirements;

economic weakness, including inflation, or political instability in particular foreign economies and markets;

compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;

foreign currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to doing business in another country;

and workforce uncertainty in countries where labor unrest is more common than in the United States.

In light of the large population of patients with SCD and β-thalassemia who reside in foreign countries, our ability to generate meaningful revenues in those jurisdictions may be limited due to the strict price controls and reimbursement limitations imposed by governments outside of the United States.

In some countries, including for example countries in the European Union, the pricing of prescription pharmaceuticals is subject to governmental control.

In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a drug.

To obtain coverage and reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidate to other available therapies.

If reimbursement of our product candidates is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our business could be harmed, possibly materially, based on the large population of patients with SCD and β-thalassemia who reside in foreign countries.

Any product candidate for which we obtain marketing approval could be subject to post-marketing restrictions or withdrawal from the market and we may be subject to substantial penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our products, when and if any of them are approved.

Any product candidate for which we obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling, advertising and promotional activities for such product, will be subject to continual requirements of and review by the FDA and other regulatory authorities.

These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to manufacturing, quality control, quality assurance and corresponding maintenance of records and documents, requirements regarding the

distribution of samples to physicians and recordkeeping.

Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the conditions of approval, including the requirement to implement a REMS.

If any product candidate receives marketing approval, the accompanying label may limit the approved use of our drug, which could limit sales of the product.

The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of the product, including the adoption and implementation of REMS.

The FDA and other agencies, including the Department of Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of drugs to ensure, among other things, that they are marketed and distributed only for the approved indications and in accordance with the provisions of the approved labeling.

The FDA and other agencies impose and enforce stringent restrictions on manufacturers’ communications regarding off-label use, and if we promote our products beyond their approved indications, we may be subject to enforcement action or prosecution arising from off-label promotion.

Violations of the Federal Food, Drug and Cosmetic Act, or FDCA, and other statutes relating to the promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state healthcare fraud and abuse laws, including the False Claims Act, as well as state consumer protection laws.

In addition, later discovery of previously unknown adverse events or other problems with our products, manufacturers or manufacturing processes, or failure to comply with regulatory requirements, may have various consequences, including:

suspension of or restrictions on such products, manufacturers or manufacturing processes;

restrictions and warnings on the labeling or marketing of a product;

restrictions on product distribution or use;

requirements to conduct post-marketing studies or clinical trials;

warning letters or untitled letters;

withdrawal of the products from the market;

refusal to approve pending applications or supplements to approved applications that we submit;

recall of products;

fines, restitution or disgorgement of profits or revenues;

suspension of any ongoing clinical trials;

suspension or withdrawal of marketing approvals;

damage to relationships with any potential collaborators;

unfavorable press coverage and damage to our reputation;

refusal to permit the import or export of our products;

product seizure or detention;

injunctions or the imposition of civil or criminal penalties;

litigation involving patients using our products.

Non-compliance with European Union requirements regarding safety monitoring or pharmacovigilance, and with requirements related to the development of products for the pediatric population, can also result in significant financial penalties.

Similarly, failure to comply with the European Union’s requirements regarding the protection of personal information can also lead to significant penalties and sanctions.

In addition, manufacturers of approved products and those manufacturers’ facilities are required to comply with extensive FDA requirements, including ensuring that quality control and manufacturing procedures conform to cGMPs applicable to drug manufacturers or quality assurance standards applicable to medical device manufacturers, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and documentation and reporting requirements.

We, any contract manufacturers we may engage in the future, our future collaborators and their contract manufacturers will also be subject to other regulatory requirements, including submissions of safety and other post-marketing information and reports, registration and listing requirements, requirements regarding the

distribution of samples to clinicians, recordkeeping, and costly post-marketing studies or clinical trials and surveillance to monit

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What changed 10-K

Item 1. Business