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Item 1. Business

2022-03-03 compared with 2021-02-26 · 409 added, 458 removed, 545 unchanged (61% of the section changed)

We are a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutics in the disease areas of immunology, inflammation and oncology.

Our goal is to be an industry leader in each of these therapeutic areas and to enhance and extend the lives of patients suffering from such diseases.

Our goal is to be an industry

leader in each of these therapeutic areas and to enhance and extend the lives of patients suffering from such diseases.

To accomplish this goal, we have assembled a deeply experienced and highly skilled group of industry veterans, scientists, clinicians and key opinion leaders from leading biotechnology and pharmaceutical companies, as well as leading academic centers from around the world.

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We are pursuing product candidates with strong scientific rationale to address indications where there is both a high unmet need and an opportunity to develop best-in-class or first-in-class therapeutics.

We currently have four clinical-stage product candidates, in addition to six preclinical programs.

We currently have three clinical-stage product candidates, in addition to one late-stage preclinical product candidate and five additional preclinical programs.

The following table summarizes our current programs:

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Seralutinib has been generally well tolerated in completed clinical trials.

In contrast to the three classes of marketed vasodilatory therapies for PAH, we believe that seralutinib has the potential to be disease-modifying by addressing the cellular overgrowth, fibrosis and vascular remodeling which underlie PAH.

In contrast to the three classes of marketed vasodilatory therapies for PAH, we believe that seralutinib has the potential to reverse pathological remodeling by addressing mechanisms that underlie PAH.

Inhaled seralutinib, which is designed to act on both isoforms of the PDGFR, α and β, as well as the CSF1R and c-KIT pathways, inhibited and reversed cellular overgrowth in lung blood vessels in multiple animal PAH models.

In 2013, results from a Phase 3 clinical trial in PAH of imatinib (Gleevec), an oral tyrosine kinase inhibitor with known activity against PDGF and c-KIT, marketed for oncology indications, showed statistically significant improvement in its primary efficacy endpoint, however systemic toxicities were also observed.

To date, these toxicities have not been observed with seralutinib in our completed Phase 1 single-ascending dose / multiple ascending dose, or SAD / MAD, studies in healthy volunteers or in our Phase 1b study in PAH patients.

In the two-week Phase 1b clinical trial in PAH patients, seralutinib demonstrated rapid systemic clearance, target engagement via whole blood CSF1R stabilization assay and was generally well tolerated.

In 2013, results from a Phase 3 clinical trial in PAH of imatinib (Gleevec), an oral tyrosine kinase inhibitor with known activity against PDGFR and c-KIT, marketed for oncology indications, showed statistically significant improvement in its primary efficacy endpoint, however serious systemic toxicities were also observed.

To date, these serious toxicities have not been observed with seralutinib in our completed short-duration Phase 1 single-ascending dose / multiple ascending dose, or SAD / MAD, studies in healthy volunteers or in our two-week Phase 1b trial in PAH patients.

In the Phase 1b clinical trial in PAH patients, seralutinib demonstrated rapid systemic clearance, target engagement via whole blood CSF1R stabilization assay and was generally well tolerated.

We commenced the Phase 2 TORREY trial in PAH patients in December 2020.

Topline results from this trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

Topline results from this trial are expected in the second half of 2022, subject to developments in the ongoing COVID-19 pandemic.

We in-licensed seralutinib from Pulmokine, Inc.

in 2017 and retain worldwide rights.

The United States Food and Drug Administration, or FDA, and the European Medicines Agency, or EMA, have granted seralutinib orphan drug designation for the treatment of patients with PAH.

GB004 (HIF-1 α Stabilizer)

GB004 is a novel, gut-targeted, oral small molecule being developed for the treatment of inflammatory bowel disease, or IBD, including ulcerative colitis, or UC, and Crohn’s disease, or CD.

The United States Food and Drug Administration, or FDA, and the European Commission, or EC, have granted seralutinib orphan drug designation for the treatment of patients with PAH.

GB004 (Gut-Targeted HIF-1 α Stabilizer)

GB004 is a gut-targeted, oral small molecule being developed for the treatment of inflammatory bowel disease, or IBD, including ulcerative colitis, or UC, and Crohn’s disease, or CD.

GB004 stabilizes hypoxia-inducible factor 1α, or HIF-1α, through the inhibition of prolyl hydroxylase domains, or PHDs, key enzymes involved in HIF degradation.

Preclinical data from animal models of IBD demonstrated that HIF-1α stabilization restores intestinal epithelial barrier integrity and function and results in immunomodulatory effects that we believe are important in reducing inflammation and enhancing mucosal healing in IBD patients.

We have completed Phase 1 SAD and MAD studies in healthy volunteers and a Phase 1b study in patients with active UC, and GB004 has been generally well tolerated.

mucosal healing in IBD patients.

We have completed Phase 1 SAD and MAD studies in healthy volunteers and a Phase 1b trial in patients with active UC, and GB004 has been generally well tolerated.

In a 28-day Phase 1b clinical trial in patients with active UC, GB004 was well-tolerated, demonstrated a gut-targeted PK profile, showed evidence of target engagement, and initial signs of potential clinical efficacy were observed.

We commenced the Phase 2 SHIFT-UC trial in patients with active mild-to-moderate UC in October 2020.

Topline results from this trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

We in-licensed GB004 from Aerpio Pharmaceuticals, Inc., or Aerpio, in June 2018 and retain worldwide rights.

GB1275 (CD11b Modulator)

GB1275 is an oral, small molecule, CD11b modulator in clinical development for the treatment of oncology indications.

CD11b and CD18 are members of the integrin family of cell adhesion receptors that combine to form the functional adhesion receptor CD11b / CD18, also known as Mac-1, CR3 or alpha-M beta-2, on cell surfaces.

CD11b is highly expressed on myeloid cells of the immune system, including tumor-associated macrophages, or TAMs, and myeloid derived suppressor cells, or MDSCs, which play a significant role in promoting tumor growth, immune evasion and metastasis.

Increased presence of CD11b positive MDSCs in tumors is observed across multiple tumor types and is associated with poor prognosis in multiple cancers.

GB1275 is currently being tested in an ongoing Phase 1/2 clinical trial (KEYNOTE-A36) for the treatment of selected solid tumor types.

In the fourth quarter of 2019, we announced a clinical trial and supply agreement with Merck & Co., Inc., or Merck, to evaluate the combination of GB1275 and pembrolizumab (Keytruda) in advanced solid tumors, as part of the ongoing Phase 1/2 clinical trial.

In this ongoing Phase 1/2 clinical trial, oral GB1275 alone and in combination with pembrolizumab, up to 1,200 mg twice daily, or BID, has been generally well tolerated.

To date, one partial response, or PR, has been observed in a patient with microsatellite stable colorectal cancer, or MSS CRC, and biomarker data suggest that GB1275, alone or in combination with pembrolizumab, may modulate myeloid cell biology in the tumor microenvironment, or TME, inducing a more inflamed tumor phenotype.

We expect to report further data from this trial in 2021.

The FDA and the EMA have granted GB1275 orphan drug designation for the treatment of patients with pancreatic cancer.

We retain worldwide rights to GB1275.

GB001 (DP2 Antagonist)

GB001 is an oral prostaglandin D2 receptor 2, or DP2, antagonist in development for the treatment of moderate-to-severe eosinophilic asthma.

GB001 has been studied in over 800 subjects who have received at least 1 dose in completed clinical trials to date and has been generally well tolerated up to a dose of 40 mg.

In the global Phase 2b LEDA study, GB001 showed a consistent numerical reduction of 32-35% across all three dose groups in proportion of patients with asthma worsening by week 24, as compared to placebo, which was the primary endpoint of the clinical trial, but these results were not statistically significant for any of three dose groups.

Additionally, in the same clinical trial, GB001 showed a nominally statistically significant reduction in time-to-first asthma worsening for the 20 mg and the 60 mg dose groups of GB001, as compared to placebo, which was the key secondary endpoint.

The 40 mg dose of GB001 also demonstrated a numeric improvement, as compared to placebo, but this result was not statistically significant.

One adverse event of interest was a serious adverse event, or SAE, of liver chemistry elevations meeting Hy’s Law criteria in the GB001 60 mg group.

The patient was asymptomatic during the event, which was reversible and resolved without sequelae.

In a Phase 2 clinical trial conducted in Japan, GB001 showed a statistically significant improvement in time-to-first asthma worsening compared to placebo.

A single SAE, intrahepatic cholestasis, a liver disorder, deemed by the investigator likely to be related to study drug was observed in a Japanese patient who had received a 160 mg dose of GB001 in a Phase 1 clinical trial conducted by Teijin Pharma Limited, or Teijin.

The patient had GB001 exposure levels approximately three to five times higher than the other patients receiving the 160 mg dose.

We engaged with the FDA and the EMA about the clinical development path in asthma, and based off those interactions, we believe that there is a viable clinical development path for GB001, or its backup molecule, in asthma.

We do not currently plan to move forward with GB001, or its backup molecule, in further clinical trials without a partner.

As previously announced, we do not plan to continue further development of GB001 in chronic rhinosinusitis, or CRS.

We retain worldwide rights to GB001, excluding Japan.

We completed enrollment for the ongoing Phase 2 SHIFT-UC trial in patients with active mild-to-moderate UC in the fourth quarter of 2021.

Topline results for the week 12 primary endpoint for this trial are expected to be publicly reported in the second quarter of 2022, and topline results for the week 36 treat-through endpoint for this trial are expected to be publicly reported in the fourth quarter of 2022.

We in-licensed GB004 from Aadi Bioscience, Inc., or Aadi, in 2018 and retain worldwide rights.

GB5121 (CNS-Penetrant BTK Inhibitor)

GB5121 is an oral, irreversible, covalent, small molecule inhibitor of Bruton’s Tyrosine Kinase, or BTK, in clinical development for the treatment of primary central nervous system lymphoma, or PCNSL.

GB5121 was selected based on its central nervous system, or CNS, penetration and kinase selectivity.

BTK is expressed in several immune cells including B cells and myeloid cells, where it mediates signaling downstream of multiple receptors.

Inhibition of BTK results in the immediate blockade and down-regulation of several cellular activities that drive autoimmunity and inflammation.

Active BTK signaling is also present in many B cell malignancies.

BTK inhibitors are approved in the United States to treat oncology indications.

In preclinical mouse models, GB5121 has demonstrated superior CNS penetration at studied doses when compared to selected BTK inhibitors.

We believe the CNS penetration observed in these preclinical studies supports the development of GB5121 as a potential therapy for the treatment of hematologic malignancies in the CNS, including PCNSL.

GB5121 is currently being evaluated in a Phase 1 clinical study in healthy volunteers.

We expect to initiate a global Phase 1b/2 clinical trial in PCNSL patients in the first half of 2022.

GB5121 was internally developed and is wholly owned.

GB7208 (CNS-Penetrant BTK Inhibitor)

GB7208 is an oral, small molecule, BTK inhibitor in preclinical development for the treatment of multiple sclerosis, or MS.

Like GB5121, GB7208 was selected based on its CNS penetration and kinase selectivity.

Immune cells are believed to play an important role in the pathology of MS, and BTK inhibitors are in late-stage clinical development for the treatment of autoimmune indications, such as MS.

In preclinical mouse models, GB7208 has demonstrated superior CNS penetration at studied doses, when compared to selected BTK inhibitors in development for autoimmune indications, including MS.

GB7208 is currently undergoing preclinical testing, and pending the outcomes of our ongoing preclinical work, we expect to initiate a Phase 1 study in healthy volunteers in the second half of 2022.

GB7208 was internally developed and is wholly owned.

Our Research Capabilities and Preclinical Programs

We currently have multiple programs in preclinical development.

Including GB7208, we have six programs in preclinical development.

We are continuing to build our research capabilities, specifically focusing on our areas of expertise within immunology, inflammation and oncology, in order to advance new programs into the clinic, as well as to optimize our existing programs.

We have six programs in preclinical development, and we expect at least one additional product candidate to enter clinical trials within the next 12 months.

Our founders and management team have held senior positions at leading biopharmaceutical companies, including Receptos, Inc., Bristol-Myers Squibb Company, and Celgene Corporation, among others, and possess substantial experience and expertise across the spectrum of drug discovery, development and commercialization.

Our founders and management team have held senior positions at leading biopharmaceutical companies and possess substantial experience and expertise across the spectrum of drug discovery, development and commercialization.

Faheem Hasnain is our Co-Founder and has served as our Chief Executive Officer since November 2020 and as our Chairman since our inception.

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Previously, Mr.

Hasnain was the President and Chief Executive Officer and a director of Facet

Biotech Corporation, a biology-driven antibody company with a focus in multiple sclerosis and oncology.

Hasnain was the President and Chief Executive Officer and a director of Facet Biotech Corporation, a biology-driven antibody company with a focus in MS and oncology.

He held that position from December 2008 until the company's acquisition by Abbott Laboratories in April 2010.

Luisa Salter-Cid, Ph.D., our Chief Scientific Officer, was previously the Head of Immunology Discovery at Bristol-Myers Squibb, having overseen immunology and immuno-oncology discovery efforts since 2005.

Bryan Giraudo, our Chief Financial Officer, has extensive biotechnology and medical technology investment banking experience, having previously served as Senior Managing Director at Leerink Partners (now known as SVB Leerink) and Managing Director at Merrill Lynch, Pierce, Fenner & Smith Incorporated.

Christian Waage, our Executive Vice President and General Counsel, has extensive biotechnology experience, having previously held various positions at Receptos, most recently as Managing Director after its acquisition by Celgene, and served at Ardea Biosciences, Inc.

Bryan Giraudo, our Chief Financial Officer and Chief Operating Officer, has extensive biotechnology and medical technology finance experience, having previously served as Senior Managing Director at Leerink Partners (now known as SVB Leerink) and Managing Director at Merrill Lynch, Pierce, Fenner & Smith Incorporated.

Richard Aranda, M.D., our Chief Medical Officer, is an experienced clinician and drug developer with previous experience at Bristol Myers Squibb Company, Novo-Nordisk, Inc., Receptos and Celegene Corporation.

Laura Carter, Ph.D., our Chief Scientific Officer, has over 20 years of industry experience spanning target identification and validation activities through Phase 2 clinical trials in multiple

therapeutic areas having previously held positions at Lycera Corporation, Medimmune, Array Biopharma and Wyeth.

Christian Waage, our Executive Vice President, has meaningful management biotechnology experience, having previously held various positions at Receptos, most recently as Managing Director after its acquisition by Celgene, and served at Ardea Biosciences, Inc.

as Vice President, General Counsel.

Caryn Peterson, our Executive Vice President, Regulatory Affairs, has considerable experience and regulatory expertise as a Managing Director of Development & Strategic Consulting Associates, as well as management positions leading regulatory affairs at Syndax Pharmaceuticals and FeRx Incorporated.

We are a clinical-stage biopharmaceutical company focused on discovering, acquiring, developing and commercializing therapeutics in the disease areas of immunology, inflammation and oncology.

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• Create deep therapeutic centers of excellence by leveraging our immunology and translational discovery and development expertise.

We currently have four clinical-stage product candidates and six preclinical-stage programs across the areas of immunology, inflammation and oncology.

We currently have three clinical-stage product candidates, one late-stage preclinical product candidate, and an additional five preclinical-stage programs across the areas of immunology, inflammation and oncology.

We will continue to build out our portfolio, focusing on these therapeutic areas, through both internal discovery and strategic transactions to create a diversified portfolio of early and late-stage product candidates.

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We aim to focus our development efforts on product candidates that have the potential to treat multiple diseases and plan to develop them in additional indications where warranted.

For example, we plan to develop GB004 in both UC and CD, and we are evaluating GB1275 for the treatment of multiple solid tumor types.

For example, we plan to develop GB004 in both UC and CD.

We continue to evaluate potential neurological conditions for GB7208.

• Expeditiously generate proof-of-concept data from our preclinical programs to facilitate value creation and efficient capital deployment.

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As of December 31, 2021, seralutinib has been generally well tolerated in completed clinical trials.

Inhaled seralutinib, which is designed to act on both isoforms of the PDGF receptor, α and β, as well as the CSF1R and c-KIT pathways, inhibited and reversed cellular overgrowth in lung blood vessels in animal PAH models.

To date, these toxicities have not been observed with seralutinib in our completed Phase 1 SAD / MAD studies in healthy volunteers or in our Phase 1b study in PAH patients.

In the two-week Phase 1b clinical trial in PAH patients, seralutinib rapid systemic clearance, target engagement via whole blood CSF1R stabilization assay and was generally well tolerated.

To date, these serious toxicities have not been observed with seralutinib in our completed short-duration Phase 1 SAD / MAD studies in healthy volunteers or in our two-week Phase 1b trial in PAH patients.

In the Phase 1b clinical trial in PAH patients, seralutinib demonstrated rapid systemic clearance, target engagement via whole blood CSF1R stabilization assay and was generally well tolerated.

We commenced the Phase 2 TORREY trial in PAH patients in December 2020.

Topline results from this trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

We in-licensed

seralutinib from Pulmokine, Inc.

Topline results from this trial are expected in the second half of 2022, subject to developments in the ongoing COVID-19 pandemic.

We in-licensed seralutinib from Pulmokine, Inc.

in 2017 and retain worldwide rights.

The FDA and the EMA have granted seralutinib orphan drug designation for the treatment of patients with PAH.

The FDA and the EC have granted seralutinib orphan drug designation for the treatment of patients with PAH.

Mechanism of Action

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This progressive obstruction of blood flow from the right side of the heart to the lungs can cause the right ventricle to fail, thus leading to severe breathlessness, reduced exercise tolerance and death.

Seralutinib was designed to inhibit multiple kinases that play a role in the pathology of PAH, including PDGFRα/β, c-KIT and CSF1R.

Seralutinib was designed to inhibit multiple kinases that play a role in the pathology of PAH, including PDGFRα/β, CSF1R and c-KIT.

The PDGFR is a tyrosine kinase receptor which, when activated by its agonist, induces cellular proliferation.

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PDGFRs and their ligands are both upregulated in PAH.

Upregulated PDGF signaling results in endothelial cell and fibroblast dysfunction and the proliferation and migration of smooth muscle cells.

Upregulated PDGFR signaling results in endothelial cell and fibroblast dysfunction and the proliferation and migration of smooth muscle cells.

This effect results in the overgrowth and occlusion of blood vessels in the lung.

Kinase inhibitors with activity against the PDGF pathway have shown the ability to reverse PAH in animal models.

Kinase inhibitors with activity against the PDGFR pathway have shown the ability to reverse PAH in animal models.

Inhaled seralutinib is designed to act on both isoforms of the PDGFR, α and β.

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C-KIT positive endothelial cells may also secrete PDGF, and perivascular c-KIT positive mast cells have been shown to secrete pro-inflammatory cytokines and tryptase that further contribute to the inflammatory process in PAH.

Mechanistic validation of a PDGFR and c-KIT kinase inhibitor has been observed in studies of imatinib (Gleevec), an oral tyrosine kinase inhibitor with known activity against the PDGFR and c-KIT pathways, which demonstrated proof-of-concept in humans in a Phase 3 clinical trial in PAH.

Mechanistic validation of a PDGFR and c-KIT kinase inhibitor has been observed in clinical trials of imatinib (Gleevec), an oral tyrosine kinase inhibitor with known activity against the PDGFR and c-KIT pathways, which demonstrated proof-of-concept in humans in a Phase 3 clinical trial in PAH.

In preclinical models, as compared to imatinib, seralutinib was a more potent inhibitor of the PDGFRα isoform, and seralutinib was a ten-fold more potent inhibitor of the PDGFRβ isoform and c-KIT.

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Macrophages, which express the CSF1 receptor, are now recognized to play an important role in PAH pathology.

Activated CSF1R positive macrophages accumulate around pulmonary arterioles in PAH, which has been shown in vivo in PAH patients with positron emission tomography.

Activated CSF1R positive macrophages accumulate around pulmonary arterioles in PAH, which have been shown in vivo in PAH patients with positron emission tomography.

Additionally, macrophage activity in PAH is associated with bone morphogenetic protein receptor type II, or BMPR2, levels.

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Imatinib has known activity against multiple tyrosine kinases, including the PDGFR, c-KIT receptors and Abelson murine leukemia viral oncogene homolog 1, or c-ABL.

202 patients were enrolled in the IMPRES trial, of which 41% were being treated with prostanoids, oral phosphodiesterase type 5, or PDE5, inhibitors and oral endothelin receptor agonists, or

The study met its primary endpoint, improvement in six-minute walk distance, or 6MWD, versus placebo at week 24 from baseline, with statistical significance (p = 0.002).

The p-value is the probability that the difference between two data sets was due to chance.

202 patients were enrolled in the IMPRES trial, of which 41% were being treated with prostanoids, oral phosphodiesterase type 5, or PDE5, inhibitors and oral endothelin receptor agonists, or ERAs.

The trial met its primary endpoint, improvement in 6-minute walk distance, or 6MWD, versus placebo at week 24 from baseline, with statistical significance (p = 0.002).

The p-value is the probability that the difference between two data sets was

due to chance.

The smaller the p-value, the more likely the differences are not due to chance alone.

In general, if the p-value is less than or equal to 0.05, the outcome is considered statistically significant.

The FDA’s evidentiary standard of efficacy generally relies on a p-value of less than or equal to 0.05.

Patients on imatinib also demonstrated statistically significant improvements in measures of hemodynamics, including pulmonary vascular resistance, or PVR, a standard measurement in the evaluation of patients with PAH.

However, systemic adverse events such as bleeding and poor tolerability and frequent drug discontinuation led to a high drop-out rate within the active arm of the trial.

Subdural hematomas occurred in eight patients who were also being administered oral anticoagulants during the study.

Subdural hematomas occurred in eight patients who were also being administered oral anticoagulants during the trial.

Novartis withdrew its supplemental regulatory applications in PAH in 2013 and, to our knowledge, did not pursue further development of imatinib in the indication.

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Additionally, recent medical society guidelines have identified intermediate and high-risk categories of PAH based on several variables including signs of right heart failure, rate of symptom progression, functional class, 6MWD, maximum oxygen consumption, NT-proBNP, which is a biomarker for heart failure and measures of right heart function.

Despite the introduction of many new therapies over the last several years, PAH continues to have a high morbidity and mortality.

Based on registry data, newly diagnosed functional class III and IV patients have 5-year survival rates of 60% and 44%, respectively, while rates for previously diagnosed patients were even lower at 57% and 27%, respectively.

Multiple PAH-specific treatments have been introduced in the past two decades, however PAH continues to have a high morbidity and mortality.

Based on REVEAL registry data, newly diagnosed functional class III and IV patients have 5-year survival rates of 60% and 44%, respectively, while rates for previously diagnosed patients were even lower at 57% and 27%, respectively.

Overview of PAH Market

Diagnosed PAH prevalence in the United States is approximately 53,000 patients, as of 2018, and prevalence is highest among women between the ages of 30-60.

PAH most commonly affects women between the ages of 30 and 60.

The true incidence and prevalence of PAH are unknown.

The American Lung Association estimates that between 500 and 1,000 new cases are diagnosed each year in the US.

PAH has an estimated prevalence of 70,000 patients in the US and Europe.

The number of diagnosed PAH patients continues to increase, and we believe this increase is likely due to enhanced awareness and diagnosis of the disease.

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PDE5 inhibitors are often used in combination with ERAs as an early treatment strategy.

In patients who fail to respond to combination therapy of an ERA and a PDE5 inhibitor, it is common practice to add a

In patients who fail to respond to combination therapy of an ERA and a PDE5 inhibitor, it is common practice to add a prostanoid.

Prostanoids are also commonly used to treat patients with evidence of right heart failure.

While existing treatments have led to significant improvements in time to clinical worsening and other composite endpoints in PAH patients, none directly alter the underlying disease process.

While existing treatments

have led to significant improvements in time to clinical worsening and other composite endpoints in PAH patients, none directly alter the underlying disease process.

The effect of vasodilation, while improving blood flow through the lungs, may eventually be overtaken by the worsening cellular proliferation and arterial remodeling underlying the condition.

We believe an agent with disease-modifying characteristics that safely addresses the underlying cellular overgrowth could provide utility across functional classes and risk categories.

We believe an agent with the ability to safely reverse pathological remodeling could provide utility across functional classes and risk categories.

Seralutinib Product Differentiation

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Additionally, seralutinib is multiple orders more potent against CSF1R, as compared to imatinib.

We believe seralutinib has the potential to be a differentiated and disease-modifying PAH therapeutic that may provide:

We believe seralutinib has the potential to be a differentiated PAH therapeutic that may provide:

• an improved response to PDGF-driven abnormal cell proliferation in pulmonary arteries by addressing the underlying mechanism that leads to arterial wall thickening;

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Irregularities in BMPR2 expression have been linked to PAH.

Summary of Completed Phase 1a Study

Summary of Completed Phase 1a Studies

We completed Phase 1a SAD and MAD double-blind, placebo-controlled, randomized studies of orally inhaled seralutinib in 82 healthy adult volunteers.

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Seralutinib was well-tolerated, and there were no dose-limiting toxicities.

No SAEs were reported, and no reported AEs led to study drug discontinuation.

No serious adverse events, or SAEs, were reported, and no reported adverse events, or AEs, led to study drug discontinuation.

The most common AEs were throat irritation and cough, which were mild in severity and similar in incidence to placebo.

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In December 2020, we announced initial topline results from the completed Phase 1b randomized, double-blind, placebo-controlled, multi-center trial of seralutinib in functional class II and III PAH patients.

At the time of announcement, eight patients had completed the two-week blinded portion of the study.

Enrollment for this study was temporarily paused due to the ongoing COVID-19 pandemic but was reopened in the third quarter of 2020.

At the time of announcement, eight patients had completed the two-week blinded portion of the trial.

Enrollment for this trial was temporarily paused due to the COVID-19 pandemic but was reopened in the third quarter of 2020.

The primary outcome of this 2-week trial was safety and tolerability.

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There were no SAEs, and the most frequently reported AEs were mild-to-moderate cough and mild headache.

Systemic PK was characterized by low systemic exposure and rapid drug clearance in PAH patients, which was consistent with PK data from the Phase 1a trials in healthy volunteers.

Systemic PK was characterized by low systemic exposure and rapid drug clearance in PAH patients, which was consistent with PK data from the Phase 1a studies in healthy volunteers.

Target engagement in PAH patients was demonstrated via whole blood CSF1R stabilization assay across all tested dose levels.

Upon completion of the 2-week Phase 1b study, patients were given the option of entering into an open-label extension phase.

Upon completion of the two-week Phase 1b trial, two PAH patients were able to enroll and complete a six-month open label extension trial of seralutinib.

Both patients were able to titrate up to the maximum allowed dose, 90 mg twice daily.

No SAEs were reported during the extension trial.

Both patients demonstrated a decrease in NT-proBNP levels from baseline, and both patients demonstrated an increase in 6-MWD from baseline.

Summary of Ongoing Phase 2 PAH Clinical Trial (TORREY Study)

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Patients will be randomized in a 1:1 fashion to seralutinib and placebo.

Patients on the active arm will receive seralutinib at doses ranging from 45 mg twice daily to 90 mg twice daily.

Patients will remain on their background PAH therapies throughout the trial.

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We have implemented COVID-19 mitigation plans related to this trial, including opening more sites, spread regionally across the globe, and incorporating countries less impacted by the pandemic.

Upon completion of the 24-week TORREY trial, patients will have the option of entering a stand-alone open-label extension study.

Topline results from the TORREY trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

Upon completion of the 24-week TORREY trial, patients will have the option of entering a stand-alone open-label extension trial.

Topline results from the TORREY trial are expected in the second half of 2022, subject to developments in the ongoing COVID-19 pandemic.

GB004 (HIF-1 α Stabilizer)

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We have completed Phase 1 SAD and MAD studies in healthy volunteers and a Phase 1b study in patients with active UC, and GB004 was generally well tolerated.

We have completed Phase 1 SAD and MAD studies in healthy volunteers and a Phase 1b trial in patients with active UC, and GB004 was generally well tolerated.

We commenced the Phase 2 SHIFT-UC trial in patients with active mild-to-moderate UC in October 2020.

Topline results from this trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

We in-licensed GB004 from Aerpio in June 2018 and retain worldwide rights.

We commenced the Phase 2 SHIFT-UC trial in patients with active mild-to-moderate UC in October 2020, and we announced that we had completed trial enrollment in the fourth quarter of 2021.

We in-licensed GB004 from Aadi in 2018 and retain worldwide rights.

Mechanism of Action

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Gut biopsies from patients with active UC in our Phase 1b trial showed increased expression of genes associated with HIF-1α stabilization and enhanced epithelial barrier function, such as tight junction protein 1, or TJP1, and Claudin 1, or CLDN1, and evidence of reduced gut epithelial neutrophil activity in the GB004 group compared to placebo.

Modulation of HIF stability is being evaluated in other diseases contexts, including in the treatment of anemia due to chronic kidney disease.

Modulation of HIF stability is being evaluated in other disease contexts, including in the treatment of anemia due to chronic kidney disease.

The systemic PHD inhibitors being developed in this setting have on-target effects of increased erythropoietin, or EPO, and vascular endothelial growth factor, or VEGF.

As this would be an undesirable effect in patients with IBD, we have designed GB004 to be gut-targeted, with multi-fold higher concentrations in the gut than in the periphery.

In our Phase 1 healthy volunteer trials and in our Phase 1b trial in patients with active UC, no differences in plasma EPO or VEGF levels were observed for GB004 relative to placebo or with respect to GB004 dose.

In our Phase 1 healthy volunteer studies and in our Phase 1b trial in patients with active UC, no differences in plasma EPO or VEGF levels were observed for GB004 relative to placebo or with respect to GB004 dose.

In addition to promoting the expression of protective pathways, HIF-1α is also an important modulator of the innate and adaptive immune response.

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Overview of IBD

IBD refers to two conditions, UC and CD, which are characterized by chronic inflammation of the gastrointestinal, or GI, tract.

IBD includes UC and CD, which are characterized by chronic inflammation of the gastrointestinal, or GI, tract.

Global epidemiology of IBD varies greatly from region to region.

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However, as the severity of IBD increases, the potential toxicities of the medications required to manage the disease also increase.

For example, treatment of mild-to-moderate patients typically starts with topical agents, such as 5-aminosalicylic acid, or 5-ASA.

For example, treatment of mild-to-moderate patients typically starts with 5-aminosalicylic acid, or 5-ASA.

For those IBD patients who do not respond to 5-ASAs, or those with more severe disease, corticosteroids are generally used to induce clinical remission.

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Immunomodulators show a delay in onset of action of one to three months and can result in neutropenia, pancreatitis, nephrotoxicity and hepatotoxicity.

Therefore, the treatment of IBD patients with moderate-to-severe active disease is dominated by anti-TNF biologics.

This paradigm is shifting because of the approval of agents in other classes, such as an anti-integrin, an anti-IL-12 / IL-23 and a JAK inhibitor.

There is potential that the approval of biosimilar anti-TNF biologics moves the class further up in the treatment paradigm.

Additional immune suppressive therapies for the treatment of IBD are expected in the coming years with the anticipated introduction of oral S1P1 inhibitors and additional oral JAK inhibitors.

For those patients with mild-to-moderate disease who do not respond to 5-ASAs, these immunomodulatory therapies and associated toxicities and risks may not be appropriate.

There exists substantial unmet need for additional mild-to-moderate treatment options.

The treatment of moderate-to-severe patients is dominated by anti-TNF biologics, though the paradigm is shifting because of the approval of agents in other classes, such as anti-integrins, anti-IL-12 / -23s, S1P1 receptor modulators and JAK inhibitors.

GB004 Product Differentiation

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In IBD animal models, GB004 has demonstrated greater accumulation of HIF-1α than HIF-2α which may lead to restoration of epithelial barrier function and resolution of inflammation, while avoiding the potential adverse effects of increased EPO.

In the Phase 1b study in patients with active UC, GB004 showed rapid clearance from systemic circulation, suggesting gut-targeted PK, and multi-fold higher concentrations of drug in the gut as compared to the plasma after eight hours of dosing.

Additionally, in this study, GB004 continued to demonstrate no effects on systemic EPO or VEGF.

In the Phase 1b trial in patients with active UC, GB004 showed rapid clearance from systemic circulation, suggesting gut-targeted PK, and multi-fold higher concentrations of drug in the gut as compared to the plasma after eight hours of dosing.

Additionally, in this trial, GB004 continued to demonstrate no effects on systemic EPO or VEGF.

GB004 is distinct, and may have a differentiated profile, from the immunomodulatory or immunosuppressive mechanisms of approved IBD medicines and those in late-stage development.

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Summary of Completed Phase 1 Clinical Studies in Healthy Volunteers

GB004 was evaluated by Aerpio in a first-in-human Phase 1 SAD study in healthy male volunteers.

GB004 was evaluated by Aadi in a first-in-human Phase 1 SAD study in healthy male volunteers.

The primary objective of the study was to evaluate the safety and tolerability of ascending dose levels of GB004 after single oral administrations.

The secondary objective was to characterize PK.

A total of 40 subjects were randomized into five cohorts with 8 subjects each.

A total of 40 subjects were randomized into five cohorts with eight subjects each.

All subjects completed the study.

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GB004 was also evaluated in a randomized, double-blind, placebo-controlled Phase 1a study to assess the safety, tolerability, PK and PD, effects of various doses and formulations in healthy male and female volunteers.

Volunteers received daily doses of 120 mg solution or placebo, or up to 240 mg tablet, or up to 240 mg delayed-release tablet, or placebo for 7 days.

All formulations of GB004 were generally well tolerated, and in this study, the tolerability of 240 mg tablet was comparable to the 120 mg solution dose.

Volunteers received daily doses of 120 mg solution or placebo, or up to 240 mg tablet, or up to 240 mg delayed-release tablet, or placebo for seven days.

All formulations of GB004 were generally well tolerated, and in this study, the tolerability of 240 mg tablet was

comparable to the 120 mg solution dose.

No SAEs occurred.

There were no differences in systemic levels of VEGF and EPO between GB004 and placebo.

In the Phase 2 SHIFT-UC trial, Gossamer will be utilizing a tablet formulation of GB004.

In the Phase 2 SHIFT-UC trial, Gossamer is utilizing a tablet formulation of GB004.

Summary of Completed Phase 1b Clinical Trial in UC

The Phase 1b study was designed to evaluate the safety, tolerability and PK of a 120 mg once-daily dose of GB004 in a solution formulation over a 28-day treatment period in UC patients with active disease despite treatment with 5-ASA therapy.

The Phase 1b trial was designed to evaluate the safety, tolerability and PK of a 120 mg once-daily dose of GB004 in a solution formulation over a 28-day treatment period in UC patients with active disease despite treatment with 5-ASA therapy.

In addition, PD and clinical activity were studied as exploratory measures.

34 patients were randomized 2:1 to receive either GB004 (n=23) or placebo (n=11).

GB004 was generally well tolerated during the study with no effects on systemic EPO or VEGF observed, relative to placebo.

GB004 was generally well tolerated during the trial with no effects on systemic EPO or VEGF observed, relative to placebo.

The most frequent AEs experienced by patients on the GB004 group were nausea and dysgeusia, all of which were mild in severity, aside from one case of moderate nausea.

All patients completed the study, except for a single patient in the GB004 group who experienced an SAE of worsening UC, which was deemed by the investigator to be unrelated to study drug.

All patients completed the trial, except for a single patient in the GB004 group who experienced an SAE of worsening UC, which was deemed by the investigator to be unrelated to study drug.

GB004 demonstrated a gut-targeted PK profile with rapid clearance from systemic circulation and multi-fold higher concentrations of drug in the gut, as compared to the plasma after eight hours of dosing.

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Summary of Ongoing Phase 2 Clinical Trial in UC (SHIFT-UC Study)

In October 2020, we commenced the Phase 2 SHIFT-UC trial, a randomized, double-blind, placebo-controlled, multi-center clinical trial in UC patients with active mild-to-moderate UC.

We are enrolling approximately 195 patients with active mild-to-moderate UC disease despite treatment with 5-ASA therapy.

Patients will be randomized in a 1:1:1 ratio to one of two doses of GB004 in tablet form and placebo.

Patients are required to remain on stable background 5-ASA therapy throughout the study.

The primary endpoint of the SHIFT-UC study is clinical remission at week 12, with secondary endpoints including clinical response, histological remission, endoscopic improvement and mucosal healing.

The study will also evaluate these endpoints at week 36.

In October 2020, we commenced the Phase 2 SHIFT-UC trial, a randomized, double-blind, placebo-controlled, multi-center clinical trial in UC patients with active mild-to-moderate UC disease, despite treatment with 5-ASA therapy.

In the fourth quarter of 2021, we announced the completion of enrollment.

Patients are randomized in a 1:1:1 ratio to one of two doses of GB004 in tablet form and placebo.

Patients are required to remain on stable background 5-ASA therapy throughout the trial.

The 12-week primary endpoint of the SHIFT-UC study is clinical remission, with secondary endpoints including clinical response, histological remission, endoscopic improvement and mucosal healing.

The trial will also evaluate these endpoints at week 36.

We are also assessing relevant safety endpoints and exploratory endpoints.

Patients may also enter an open-label extension upon completion of the placebo-controlled period or by meeting disease activity criteria during the placebo-controlled period at or after week 12.

Topline 12-week results from the SHIFT-UC trial are expected in the first half of 2022, subject to developments in the ongoing COVID-19 pandemic.

GB1275 (CD11b Modulator)

GB1275 is an oral, small molecule, CD11b modulator in clinical development for the treatment of oncology indications.

CD11b is highly expressed on myeloid cells of the immune system, including TAMs and MDSCs, which play a significant role in promoting tumor growth, immune evasion and metastasis.

Increased presence of CD11b positive MDSCs in tumors is observed across multiple tumor types and is associated with poor prognosis in multiple cancers.

GB1275 is currently being tested in an ongoing Phase 1/2 clinical trial (KEYNOTE-A36) for the treatment of selected solid tumor types.

In the fourth quarter of 2019, we announced a clinical trial and supply agreement with Merck to evaluate the combination of GB1275 and pembrolizumab (Keytruda) in advanced solid tumors, as part of the ongoing Phase 1/2 clinical trial.

In this ongoing Phase 1/2 clinical trial, oral GB1275 alone and in combination with pembrolizumab, up to 1,200mg BID, has been generally well tolerated.

To date, one PR has been observed in a patient with MSS CRC, and biomarker data suggest that GB1275, alone or in combination with pembrolizumab, may modulate myeloid cell biology in the TME, inducing a more inflamed tumor phenotype.

We expect to report further data from this trial in 2021.

The FDA and the EMA have granted GB1275 orphan drug designation for the treatment of patients with pancreatic cancer.

We retain worldwide rights to GB1275.

Mechanism of Action

The introduction of immune checkpoint therapies has revolutionized the treatment of many cancers in recent years.

Despite this, the effectiveness of approved immunotherapies has been limited to a minority of patients in only a small number of approved indications, and many cancers show little to no response to checkpoint therapy.

In many cancers, innate immune cells, such as TAMs and MDSCs, are recruited into the TME, where they induce a suppressive state which down-

regulates the activation and infiltration of cytotoxic T lymphocyte, or CD8 + T cells.

The result is an immunologically ‘cold’ tumor state, which allows for tumor growth and metastasis, ultimately resulting in reduced survival.

GB1275 is being developed to address the immunological state leading to cold tumors, which state down-regulates the activation and infiltration of tumor-killing cytotoxic CD8 + T cells in the TME.

GB1275 binds to CD11b on TAMs and MDSCs, and preclinical data showed that GB1275 reduced tumor influx of CD11b-positive MDSCs and re-polarized immuno-suppressive (M2) TAMs towards the pro-immune M1 phenotype.

These pharmacodynamic effects have the potential to convert the TME from an immunosuppressive / cold state to an immunologically hot, or active state, which would ultimately allow the influx of activated, tumoricidal CD8 + T cells.

Preclinical studies of GB1275 have demonstrated reduced tumor burden and improved survival as a single agent and in combination with chemotherapy and immuno-oncology therapies across multiple tumor mouse models, including pancreatic, breast and colon cancer.

Preclinical studies and profile characterization of GB1275 support daily oral dosing with no significant preclinical toxicology findings.

Clinical Development Plan in Selected Solid Tumors

Summary of Ongoing Phase 1/2 Clinical Trial (KEYNOTE-A36 Study)

We commenced a Phase 1/2 open-label, multi-center trial (KEYNOTE-A36 Study) with GB1275 in the third quarter of 2019.

The Phase 1 portion of the trial is studying patients with selected tumor types, including pancreatic adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, triple negative breast cancer, castration-resistant prostate cancer and MSS CRC.

The Phase 1 portion of the trial consists of dose escalation of GB1275 monotherapy, dose escalation in combination with pembrolizumab (Keytruda), and in patients with pancreatic adenocarcinoma, dose escalation in combination with standard-of-care chemotherapy.

The dose escalation portion of the Phase 1 has been completed, and the study will enroll up to 40 patients in a Phase 1 expansion cohort, studying the recommended Phase 2 dose, in patients with gastric or esophageal cancer that have progressed after initial response to anti-PD-1 therapy and patients with advanced MSS CRC.

Subject to the results of the Phase 1 expansion cohort, the Phase 1 portion of the trial will be followed by a Phase 2 basket expansion phase in patients with specified metastatic solid tumors.

The primary endpoints of the Phase 1 portion of the trial are safety, tolerability and PK.

The primary endpoint of the Phase 2 portion of the trial is objective response rate.

Clinical safety data to date from the Phase 1 portion of the ongoing Phase 1/2 clinical trial suggest that GB1275 alone and combined with pembrolizumab, up to 1,200 mg BID, has been generally well tolerated in these clinical trials.

The maximum tolerated dose of GB1275 has not been reached, and no significant overlapping toxicities between GB1275 and pembrolizumab were observed, suggesting that GB1275 can be safely combined with pembrolizumab.

Encouraging anti-tumor activity has been observed, particularly at GB1275 doses greater than or equal to 800 mg BID in tumor types that are known to be less responsive to checkpoint inhibitors, including triple negative breast cancer, castration-resistant prostate cancer, MSS CRC or gastric cancer.

As of October 14, 2020, seven cases of prolonged stable disease (greater than 84 days) have been observed, among which one MSS CRC patient subsequently had a PR.

Five of these seven cases have occurred at doses 800mg BID or greater.

Biological activity, including the down-regulation of peripheral MDSCs, the increase in tumor-infiltrating lymphocytes, and CD8+ T cell changes in tumor tissue, was observed with GB1275 alone and in combination with pembrolizumab, supporting the mechanism of action of GB1275 in modulating myeloid cell biology in the TME, potentially to enhance anti-tumor response when it is combined with a checkpoint inhibitor.

We expect to release additional data from this trial in 2021.

Further clinical development of GB1275 in cancer indications will be informed by the results of the ongoing Phase 1/2 study.

GB001 (DP2 Antagonist)

GB001 is an oral DP2 antagonist in development for the treatment of moderate-to-severe eosinophilic asthma.

GB001 has been studied in over 800 subjects who have received at least one dose in completed clinical trials to date and has been generally well tolerated up to a dose of 40 mg.

In the global Phase 2b LEDA study, GB001 showed a consistent numeric reduction in odds of 32-35% across all three dose groups in proportion of patients with asthma worsening by week 24, as compared to placebo, which was the primary endpoint of the clinical trial, but these results were not statistically significant for any of three dose groups.

The 40 mg dose of GB001 also demonstrated a numeric improvement, as compared to placebo, but this result was not statistically significant.

One adverse event of interest was an SAE of liver chemistry elevations meeting Hy’s Law criteria in the GB001 60 mg group.

The patient was asymptomatic during the event, which was reversible and resolved without sequelae.

In a Phase 2 clinical trial conducted in Japan, GB001 showed a statistically significant improvement in time-

to-first asthma worsening compared to placebo.

The patient had GB001 exposure levels approximately three to five times higher than the other patients receiving the 160 mg dose.

We do not currently plan to move forward with GB001, or its backup molecule, in further clinical trials without a partner.

As previously announced, we do not plan to continue further development of GB001 in CRS.

We retain worldwide rights to GB001, excluding Japan.

The co-primary endpoint of the SHIFT-UC study is percentage of participants with a treatment emergent adverse event, from the first dose of the open-label extension through week 28 of the open-label extension.

Topline results for the 12-week primary endpoint for the SHIFT-UC trial are expected in the second quarter of 2022.

Topline results for the 36-week treat-through endpoint are expected in the fourth quarter of 2022.

GB5121 (CNS-Penetrant BTK Inhibitor)

GB5121 is an oral, irreversible, covalent, small molecule inhibitor of BTK, in clinical development for the treatment of PCNSL.

GB5121 was selected based on its CNS penetration and kinase selectivity.

BTK is expressed in several immune cells including B cells and myeloid cells, where it mediates signaling downstream of multiple receptors.

Inhibition of BTK results in the immediate blockade and down-regulation of several cellular activities that drive autoimmunity and inflammation.

Active BTK signaling is also present in many B cell malignancies.

BTK inhibitors are approved in the United States to treat oncology indications.

In preclinical mouse models, GB5121 has demonstrated superior CNS penetration at studied doses when compared to selected BTK inhibitors.

GB5121 is currently being evaluated in a Phase 1 clinical study in healthy volunteers.

We expect to initiate a global Phase 1b/2 clinical trial in PCNSL patients in the first half of 2022.

GB5121 was internally developed and is wholly owned.

Mechanism of Action

DP2, also known as CRTh2, is a receptor for prostaglandin D2, or PGD2, a lipid mediator produced mainly by mast cells.

DP2 is primarily responsible for mediating the pro-inflammatory effects of PGD2, including:

• the activation of T helper 2, or Th2, cells, ILC2 cells, basophils and eosinophils;

• the stimulation of type 2 cytokine production, including IL-4, IL-5 and IL-13, by Th2 cells;

• the increased expression of adhesion molecules on eosinophils and basophils.

These pro-inflammatory effects contribute to airway constriction, swelling in the walls of the airways and mucous production at sites of allergic airway inflammation, all of which are hallmarks of the airway obstruction seen in asthma.

The expression of DP2 is more common in patients with more severe disease, and, importantly, a significant proportion of severe asthma patients have eosinophilic inflammation.

Aberrant Th2 cell activation and resulting type 2 cytokine production have been shown to play a prominent role in various allergic and inflammatory disorders beyond eosinophilic asthma, including chronic rhinosinusitis, or CRS, chronic spontaneous urticaria, eosinophilic esophagitis and atopic dermatitis.

GB001 has been shown in preclinical studies to be a selective antagonist of the DP2 receptor.

GB001 binds reversibly to human DP2 with an affinity, or Ki, of 1 to 2 nanomolar, significantly greater than its affinity for the other PGD2 receptors.

No significant activity was demonstrated in a standard selectivity panel of 90 other receptors and enzymes.

In in vitro assays conducted by us, GB001 compared favorably to other DP2 antagonists, including high binding affinity, prolonged pharmacodynamics, long receptor residence time and slow receptor dissociation.

Furthermore, we believe based on these data that GB001 may be highly insurmountable, meaning high concentrations of PGD2 would not be able to overcome receptor inhibition.

Combined with our observed human plasma half-life of 10 to 15 hours, we believe these measurements support the oral, once-daily dosing regimen of GB001.

Overview of Asthma

Asthma is a complex, chronic, highly heterogeneous inflammatory condition of the airways characterized by airflow obstruction, bronchial hyperactivity and airway inflammation.

Symptoms of asthma, which can be fatal, are also called asthma exacerbations or attacks and include episodes of wheezing, breathlessness, chest tightness and coughing.

Patients are deemed to have intermittent, mild, moderate or severe disease based on the frequency and severity of their symptoms.

Asthma can also be sub-categorized by the composition of the white blood cells that are causing inflammation in and around the airway wall.

We estimate that approximately 50% of severe asthma patients have a phenotype called eosinophilic asthma, which is marked by an increase of eosinophils in the mucosal sputum that coats the airways.

Eosinophils are immune cells that have been shown to play a major role in inflammation and allergic response, and eosinophilic asthma is associated with more severe symptoms, late-onset disease and response to steroid treatment.

BTK plays a critical and multifaceted role within the immune system.

BTK is a non-receptor protein-tyrosine kinase that belongs to the TEC family of kinases.

It is present in hematopoietic cells such as B cells, macrophages, neutrophils

and mast cells.

BTK is a critical mediator of B cell receptor, or BCR, signaling and the adaptive immune response.

Upon stimulation of BCR, the BTK pathway results in an increased level of intracellular calcium and activation of transcription factors involved in B cell proliferation, differentiation and survival.

The pathway is also key for the proliferation, migration and survival of malignant B cells, and inhibition of this pathway has been effective in treating several hematological malignancies.

BTK inhibitors are approved by the FDA for the treatment of multiple B cell lymphomas.

While BTK inhibitors provide a valuable treatment option for patients with hematologic malignancies, existing treatments may be suboptimal for the treatment of CNS disease.

The blood brain barrier, or BBB, is comprised of endothelial cells that serve as a highly discriminatory boundary, separating the systemic circulation and the extracellular fluid of the CNS.

The BBB effectively protects the brain from circulating pathogens, but it also restricts the ability of pharmaceutical agents from crossing from the systemic circulation into the CNS, including most BTK inhibitors.

GB5121 demonstrated superior CNS penetration at studied doses in preclinical mouse models, when compared to other BTK inhibitors targeting oncological conditions.

Treatment with BTK inhibitors is associated with on-target and off-target AEs, such as rash, diarrhea, infection, bleeding, cytopenias and cardiovascular AEs, including atrial fibrillation.

Molecules with modest selectivity may incur increased off-target AEs through unintended interaction with off-target kinases.

Later generation BTK inhibitors have focused on minimizing off-target toxicities with increased selectivity, but limited CNS penetration makes these molecules potentially suboptimal for the treatment of CNS disease.

In pre-clinical assays, GB5121 has been observed to be highly selective for BTK, and we believe that higher selectivity has the potential to limit the adverse events associated with modestly selective BTK inhibitors.

Overview of Primary CNS Lymphoma

PCNSL is a rare, aggressive form of non-Hodgkin lymphoma that originates from the brain, eyes and cerebrospinal fluid without evidence of systemic involvement.

Standard lymphoma therapies are inadequate due to poor penetration of the BBB.

First-line PCNSL treatment typically includes polychemotherapy on backbone high-dose methotrexate, followed by consolidative whole brain radiotherapy.

Despite this treatment option, durable remission is achieved in only 50% of patients.

Treatment is associated with significant neurotoxicity, and for those patients who cannot tolerate methotrexate or for those whose cancer progresses, there is no FDA approved treatment.

In human trials, ibrutinib, a non-selective BTK inhibitor with limited ability to cross the BBB, has demonstrated efficacy at high doses in recurrent or refractory PCSNL patients.

We believe the high dose necessary to reach therapeutic levels in the CNS, as well as an affinity for other kinases, including EGFR, JAK3 and HER2, are likely responsible for some of the toxicities associated with ibrutinib therapy.

We believe that the high specificity for BTK and high CNS penetration observed in preclinical models could potentially allow GB5121 to achieve the clinical efficacy seen with ibrutinib at lower systemic doses, which could improve tolerability.

We selected GB5121 to move forward into human clinical trials based on the potency, specificity and high brain penetration observed in preclinical models.

Clinical Development History of GB5121

We acquired GB001 through our acquisition of Pulmagen Therapeutics (Asthma) Limited, or Pulmagen, a wholly-owned subsidiary of our AA BioPharma Inc.

subsidiary, in January 2018, after its partner, Teijin, completed a positive Phase 2, proof-of-concept clinical trial in Japanese patients.

We have worldwide rights, outside of Japan, to all of the data from the two Phase 2 clinical trials conducted by Pulmagen and Teijin described below.

In addition, Gossamer has completed two Phase 2 trials with GB001 for the treatment of asthma and CRS.

Over 800 subjects have received at least one dose of GB001 in completed clinical trials to date.

Summary of Pulmagen and Teijin Phase 1 Clinical Trials

In Phase 1 studies conducted by Pulmagen and Teijin, GB001 demonstrated safety and PD parameters consistent with the DP2 drug class.

Most treatment emergent adverse events, or TEAEs, were mild or moderate and were considered not related to study drug.

A single SAE deemed by the investigator likely to be related to study drug was observed in a Japanese patient who had received a 160 mg dose of GB001, which is eight times higher than the highest dose Teijin tested in its Phase 2 clinical trial conducted in Japan.

The patient experienced intrahepatic cholestasis, which resolved after treatment discontinuation.

At the time of the intrahepatic cholestasis, the patient had GB001 exposure levels approximately three to five times higher than other patients receiving the 160 mg dose.

Other than this SAE, there were no laboratory testing, physical exam or electrocardiographic findings that were considered to be clinically significant and related to GB001.

Summary of Completed Pulmagen Phase 2 Clinical Trial

In December 2014, Pulmagen completed a Phase 2 clinical trial of GB001, the primary objectives of which were (1) to evaluate the safety and efficacy of 20 mg GB001 once daily compared to placebo and an active comparator, montelukast, over a 10-week treatment period and (2) to evaluate the effect of the co-administration of 10 mg montelukast once daily with GB001 treatment in a two-week extension.

The primary endpoint was improvement in forced expiratory volume in one second, or FEV1, over 10 weeks.

The study enrolled 248 patients with mild-to-moderate asthma that were uncontrolled on low- or medium-dose ICS, randomized 1:1:1 to placebo, 20 mg GB001 once daily and 10 mg montelukast once daily.

Patients were put on a standard medium-dose of ICS with and without LABA in a four-week lead-in to the study, during which they were also removed from their LABA, if applicable.

GB001 was generally well tolerated with a TEAE incidence similar to placebo, but the study did not meet its primary endpoint.

Notably, neither the active comparator, montelukast, nor GB001, showed statistically significant differences in FEV1 improvement as compared to placebo.

We believe the lack of statistically significant differences between the active treatment arms and placebo was primarily related to study design and execution issues related to patient selection, including adherence to ICS therapy, eosinophilic phenotype thresholds and disease severity.

Summary of Completed Teijin Phase 2 Clinical Trial

In December 2016, Pulmagen and Teijin announced results from a Phase 2 clinical trial of GB001 conducted by Teijin in Japan.

The trial was a double-blind, randomized, placebo-controlled, multi-center study, enrolling 158 patients with mild-to-moderate asthma who were using LABA and/or medium-dose ICS to control their disease.

Patients on LABA discontinued its use upon entry to the trial, and all patients were brought to a standardized medium dose of ICS for a four-week lead-in period.

Patients were then randomized 1:1:1 to one of two dose arms of GB001, 5 mg or 20 mg once daily, or to placebo in combination with a low dose of ICS for four weeks.

Following this period of combination with low-dose ICS, use of ICS was discontinued, and patients continued taking GB001 or placebo for 12 weeks.

The primary endpoint of the trial was change in morning peak expiratory flow, or AM PEF, a measure of lung function, from baseline to the last visit, marked as study completion or termination from the trial.

A statistically significant difference was seen in the AM PEF between placebo and both arms of GB001 (p = 0.015, 5 mg;

p = 0.027, 20 mg).

In addition, time-to-first asthma worsening reached statistical significance for the 20 mg dose arm versus placebo (p < 0.001).

Asthma worsening in this trial was defined as a composite measure to help characterize overall uncontrolled asthma, including exacerbations.

GB001 was generally well tolerated in this trial, with adverse events consistent with placebo, including nasopharyngitis, gastrointestinal disorders and measures of blood and liver markers.

No SAEs were observed in the GB001 treatment arms.

Summary of Completed Phase 2b Eosinophilic Asthma Clinical Trial (LEDA Study)

In October 2020, we announced topline results from the completed Phase 2b clinical trial (LEDA Study) of GB001 in moderate-to-severe eosinophilic asthma.

The primary objective of this clinical trial was to evaluate the efficacy and safety of 20 mg, 40 mg, and 60 mg GB001 once daily relative to placebo when added to standard of care treatment.

The LEDA study enrolled 480 patients with uncontrolled, moderate-to-severe eosinophilic asthma and assessed the effect of oral GB001 add-on therapy to standard of care over 24 weeks, comparing three dose groups of once-daily, oral GB001 (20 mg, n=120;

40 mg, n=118;

and 60 mg, n=122) to placebo (n=120).

The primary outcome, asthma worsening, included five components and was chosen for its sensitivity in detecting deterioration in clinical outcome measures known to be correlated with exacerbations.

Asthma worsening was a

composite outcome defined as the occurrence of any one of the following at any time by Week 24:

deterioration of morning peak expiratory flow, pre-bronchodilator FEV1, or asthma control as measured by the Asthma Control Questionnaire 5, relative to baseline;

an increase in rescue medication use relative to baseline;

or the occurrence of a severe asthma exacerbation, defined as deterioration of asthma that led to the use of systemic corticosteroids for at least 3 days, hospitalization, or an Emergency Department visit.

This endpoint has previously been used in the context of steroid withdrawal studies, including a prior Phase 2 trial of GB001.

The primary endpoint of the trial was not met, though consistent and meaningful numeric reductions in the odds of asthma worsening as compared to placebo were observed across all GB001 groups:

33% (p=0.1425), 32% (p=0.1482), and 35% (p=0.1086), for the GB001 20 mg, 40 mg, and 60 mg groups, respectively.

In addition, statistically significant improvements in the key secondary endpoint of time to first asthma worsening as compared to placebo were observed for GB001 20 mg and 60 mg (28% and 30% risk reduction, p=0.0466 and p=0.0304, respectively), with GB001 40 mg also demonstrating a numeric improvement (23%, p=0.1222).

Numeric reductions for each GB001 group as compared to placebo were seen across all individual components of the asthma worsening endpoint.

In addition to asthma worsening, the expected Phase 3 registrational endpoint of annualized severe exacerbation rate, or AER, was evaluated as a secondary endpoint.

While AER is typically formally evaluated in large Phase 3 studies with a one-year duration, reductions as compared to placebo were seen for each GB001 group (GB001 20 mg:

11%), although the reductions were not statistically significant.

Numeric improvements in lung function, as measured by morning peak expiratory flow and pre-bronchodilator FEV1, and asthma control, as measured by the Asthma Control Questionnaire were also observed for all three GB001 groups compared to placebo.

The incidence of adverse events was generally comparable across treatment groups:

65.8% placebo, 65.8% GB001 20 mg, 69.5% GB001 40 mg, and 68.0% GB001 60 mg.

Adverse events of interest (liver chemistry elevations leading to study drug discontinuation) occurred more frequently in GB001 60 mg (4.1%, n=5) than placebo (0.8%, n=1), GB001 20 mg (0.8%, n=1), or GB001 40 mg (1.7%, n=2).

One adverse event of interest was a SAE of liver chemistry elevations meeting Hy’s Law criteria in the GB001 60 mg group.

The patient was asymptomatic during the event, which was reversible and resolved without sequelae.

Completed Phase 2 Chronic Rhinosinusitis Clinical Trial (TITAN Study)

The TITAN trial enrolled 97 patients with CRS with and without nasal polyps and assessed treatment with GB001 40 mg as compared to placebo over 16 weeks.

Neither the primary nor the secondary endpoints of the trial were met.

The safety and tolerability of GB001 40 mg was generally consistent with that observed in the LEDA Study.

We do not plan to continue further development of GB001 in CRS.

Summary of Ongoing Phase 1 Clinical Study

In the fourth quarter of 2021, we commenced a dose-escalating Phase 1 open-label study in healthy human volunteers to evaluate the safety, tolerability, PK and PD of GB5121 in humans.

The study includes both SAD and MAD portions as well as clinical pharmacology assessments.

Summary of Planned Phase 1b/2 Clinical Trial in PCNSL

We plan to initiate the Phase 1b portion of a global Phase 1b/2 clinical trial in the first half of 2022.

The Phase 1b portion of the trial will enroll patients with recurrent or refractory primary or secondary CNS lymphoma or with recurrent or refractory primary vitreoretinal lymphoma.

The primary endpoints of the Phase 1b will include safety and tolerability, and the secondary endpoints will include overall response rate, or ORR, and duration of response.

Phase 2 dose selection will be informed by the results from the Phase 1b.

The Phase 2 portion of the of the trial will enroll recurrent or refractory PCNSL patients and is expected to initiate in the first half of 2023.

The primary endpoint of the Phase 2 portion of the trial will be ORR, and secondary endpoints will include duration of response, overall survival, progression free survival, safety and tolerability.

GB7208 (CNS-Penetrant BTK Inhibitor)

GB7208 is an oral, small molecule, BTK inhibitor in preclinical development for the treatment of MS.

Like GB5121, GB7208 was selected based on its CNS penetration and kinase selectivity.

Immune cells are believed to play an important role in the pathology of MS, and BTK inhibitors are in late-stage clinical development for the treatment of autoimmune indications, such as MS.

In preclinical mouse models, GB7208 has demonstrated superior CNS penetration at studied doses, when compared to selected BTK inhibitors in development for autoimmune indications, including MS.

GB7208 is currently undergoing preclinical testing, and pending the outcomes of our ongoing preclinical work, we expect to initiate a Phase 1 study in healthy volunteers in the second half of 2022.

GB7208 was internally developed and is wholly owned.

Our Research Capabilities and Preclinical Programs

We currently have multiple programs in preclinical development.

Including GB7208, we have six programs in preclinical development.

We have six programs in preclinical development, and we expect at least one additional product candidate to enter clinical trials within the next 12 months.

The biotechnology and pharmaceutical industries are characterized by rapid technological advancement, significant competition and an emphasis on intellectual property.

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We expect competition in this patient set will include prostanoids, available in oral form as Orenitram (United Therapeutics Corporation, or United Therapeutics) and Uptravi (Janssen), by inhalation as Tyvaso (United Therapeutics), and by infusion as Remodulin (United Therapeutics).

We also may face some competition from products used in class I and II patients, such as the oral PDE5

inhibitors, including Revatio (Pfizer Inc.) and Adcirca (United Therapeutics);

We also may face some competition from products used in class I and II patients, such as the oral PDE5 inhibitors, including Revatio (Pfizer Inc.) and Adcirca (United Therapeutics);

the sGC stimulator Adempas (Bayer AG);

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PAH is also an active indication for investigational drugs, and we may face competition in the future from ralinepag (Arena Pharmaceuticals, Inc.

and United Therapeutics), sotatercept (Acceleron Pharma, Inc.), RVT-1201 (Altavant Sciences, Inc.), PB1046 (PhaseBio Pharmaceuticals Inc.), MK-5475 (Merck) and GMA310 (Gmax Biopharm LLC).

and United Therapeutics), sotatercept (Merck & Co., Inc.), RVT-1201 (Altavant Sciences, Inc.), MK-5475 (Merck) and GMA310 (Gmax Biopharm LLC).

Additionally, although not approved for the treatment of PAH, we may face competition from formulations of imatinib, including those from Tenax Therapeutics, Aerovate Therapeutics and Aerami Therapeutics / Vectura Group.

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Patients who have become nonresponsive or intolerant to corticosteroids may move to azathioprine and 6-mercaptopurine.

The treatment of severe patients is dominated by anti-TNF biologics, though the paradigm is shifting because of the approval of agents in other classes, such as anti-integrin, IL-12 / IL-23, and JAK inhibitors.

There is potential that the approval of biosimilar anti-TNF biologics moves the class further up in the treatment paradigm.

Further disruption is expected in the coming years through the introduction of oral S1P1 inhibitors and additional oral JAK inhibitors.

GB1275 is a CD11b modulator for the treatment of cancer indications.

To our knowledge, there are no other CD11b modulator programs in clinical development for oncology.

Our initial targeted cancer indications for GB1275 include pancreatic, gastric, esophageal, prostate, triple negative breast cancer and colorectal.

Treatment for patients in these indications has historically included chemotherapy, radiation, targeted therapy and surgery.

In recent years immune checkpoint inhibitors have received approvals, including Keytruda (pembrolizumab / Merck) and Tecentriq (atezolizumab / Bristol-Myers Squibb), for the treatment of some of these difficult to treat cancer indications, including gastric and esophageal cancers (Keytruda) and triple negative breast cancer (Tecentriq).

In addition to current standard of care, we may face competition from compounds with novel mechanisms of action that are currently in clinical development, including compounds targeting the CCR2, CCR5, CSF1R and CXCR2 pathways.

GB001, in development for the treatment of moderate-to-severe eosinophilic asthma, is an oral DP2 antagonist, a class of medicines with no currently approved agents.

However, other DP2 antagonists are currently in development by Chiesi Farmaceutici S.p.A., Merck, Sunshine Lake Pharma Co., Ltd., Idorsia Pharmaceuticals Ltd., ZAI Lab Ltd.

and CSPC ZhongQi Pharmaceutical Technology Co., Ltd.

If approved, we will also face branded competition from existing biologics, including Xolair (omalizumab / anti-IgE, marketed by Genentech and Novartis) and Dupixent (dupilumab / anti-IL-4 / IL-13, marketed by Regeneron Pharmaceuticals, Inc.

and Sanofi S.A.), for moderate-to-severe asthma, and Nucala (mepolizumab / anti-IL-5, marketed by GlaxoSmithKline), Cinqair (reslizumab / anti-IL-5, marketed by Teva Pharmaceutical Industries Ltd.), and Fasenra (benralizumab / anti-IL-5R, marketed by AstraZeneca Pharmaceuticals LP) for severe eosinophilic asthma.

We will also face competition from generic montelukast, which is utilized in mild-to-moderate patients.

Several other agents are advancing in clinical trials for moderate and / or severe asthma, including tezepelumab (anti-TSLP;

/ AstraZeneca), REGN3500 (anti-IL-33R;

Regeneron), masitinib (anti-c-kit / PDGF;

AB Science S.A.) and Dexpramipexole (dopamine receptor agonist, Knopp Biosciences LLC).

GB5121 and GB7208 are BTK inhibitors for the treatment of oncological and immunological indications, including PCNSL and MS.

There are no FDA or EMA approved therapies for refractory or recurrent PCNSL.

If approved in MS, GB7208 may face competition from existing approved and investigational therapies.

While no BTK inhibitors are FDA or EMA approved for the treatment of either PCNSL or MS, we believe that if approved, GB5121 and / or GB7208 may face competition from currently FDA and EMA approved BTK inhibitors Imbruvica (AbbVie Inc.

/ Janssen), Calquence (AstraZeneca plc) and / or Brukinsa (BeiGene, Ltd.).

Our BTK inhibitors may also face competition from BTK inhibitor Velexbru (Ono Pharmaceutical Co., Ltd.), which is approved in Japan, South Korea and Taiwan for the treatment of recurrent or refractory primary central nervous system lymphoma.

We may also face competition from early and late-stage investigational BTK inhibitors, including, but not limited to, evobrutinib, tolebrutinib, fenebrutinib, orelabrutinib, pirtobrutinib, rilzabrutinib and remibrutinib.

There may be other earlier stage clinical programs that, if approved, would compete with our product candidates.

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Upon termination of the Pulmokine Agreement for any reason, all rights and licenses granted to us under the agreement will terminate and revert to Pulmokine, and in the event of certain termination events, we would grant Pulmokine worldwide rights to the terminated program.

Aerpio Pharmaceuticals

In June 2018, we entered into a license agreement, or the Aerpio Agreement, with Aerpio Pharmaceuticals, Inc., under which we were granted an exclusive worldwide license to certain intellectual property rights owned or controlled by Aerpio to develop and commercialize GB004 and certain other related compounds for all applications.

We also have the right to sublicense our rights under the Aerpio Agreement, subject to certain conditions.

Aadi Bioscience

In June 2018, we entered into a license agreement, or the Aadi Agreement, with Aerpio Pharmaceuticals, Inc., now known as Aadi, under which we were granted an exclusive worldwide license to certain intellectual property rights owned or controlled by Aadi to develop and commercialize GB004 and certain other related compounds for all applications.

We also have the right to sublicense our rights under the Aadi Agreement, subject to certain conditions.

We are required to use commercially reasonable efforts to develop and commercialize at least one licensed product in the United States, in at least two countries in the European Union, and in Japan, in each case for at least one of the initial indications of UC or CD.

The Aerpio Agreement also includes a sublicense to a patent concerning methods for treating inflammatory bowel disease owned by The Regents of the University of Colorado, or UC Regents, and licensed to Aerpio in a nonexclusive license agreement, or the UC Regents License.

If Aerpio breaches the UC Regents License and the UC Regents terminate the license, our sublicense under the Aerpio Agreement will also terminate.

Under the terms of the Aerpio Agreement, we made an upfront payment of $20 million to Aerpio in June 2018, which represented the purchase consideration for an asset acquisition.

On May 11, 2020, we entered into an amendment to the license agreement with Aerpio pursuant to which we made an upfront payment of $15.0 million to Aerpio for a reduction in future milestone payments and royalties.

The Aadi Agreement also includes a sublicense to a patent concerning methods for treating inflammatory bowel disease owned by The Regents of the University of Colorado, or UC Regents, and licensed to Aadi in a nonexclusive license agreement, or the UC Regents License.

If Aadi breaches the UC Regents License and the UC Regents terminate the license, our sublicense under the Aadi Agreement will also terminate.

Under the terms of the Aadi Agreement, we made an upfront payment of $20 million to Aadi in June 2018, which represented the purchase consideration for an asset acquisition.

On May 11, 2020, we entered into an amendment to the license agreement with Aadi pursuant to which we made an upfront payment of $15.0 million to Aadi for a reduction in future milestone payments and royalties.

Under the amended license agreement, we are obligated to make future approval milestone payments of up to $40.0 million and a sales milestone payment of $50.0 million.

We are also obligated to pay tiered royalties on sales for each licensed product, at percentages ranging from a low- to mid-single-digits, subject to certain customary reductions.

In addition, if we choose to sublicense or assign to any third parties our rights under the Aerpio Agreement with respect to any licensed product or if our GB004 operating subsidiary undergoes a change of control and the value of such transaction exceeds a specified value, we have an option to pay a specified percentage of all revenue to be

received in connection with such transaction, and if we exercise the option Aerpio will no longer be paid the development, regulatory, commercial or sales milestones or royalties on the sales of licensed products under the agreement.

If we do not exercise our buy-down option with respect to a sublicense or assignment of our rights under the Aerpio Agreement or with respect to a change of control of our GB004 operating subsidiary, Aerpio will have an option to receive a specified percentage of all revenue received in connection with such transaction, and if Aerpio exercises the option Aerpio will no longer be paid the development, regulatory, commercial or sales milestones or royalties on sales of licensed products under the agreement.

Our royalty obligations and the Aerpio Agreement will expire on a licensed product-by-licensed product and country-by-country basis on the later of fifteen years from the date of first commercial sale or when there is no longer a valid patent claim covering such licensed product in such country.

The agreement may be terminated either by Aerpio or by us in the event of an uncured material breach by the other party or in the event the other party becomes subject to specified bankruptcy, insolvency or similar circumstances.

In the event we commence a legal action challenging the validity or enforceability of any licensed patents, Aerpio will have the right to terminate the agreement or elect to increase milestone and royalty payments by a specified percentage.

In addition, if we choose to sublicense or assign to any third parties our rights under the Aadi Agreement with respect to any licensed product or if our GB004 operating subsidiary undergoes a change of control and the value of such transaction exceeds a specified value, we have an option to pay a specified percentage of all revenue to be received in connection with such transaction, and if we exercise the option Aadi will no longer be paid the development, regulatory, commercial or sales milestones or royalties on the sales of licensed products under the agreement.

If we do not exercise our buy-down option with respect to a sublicense or assignment of our rights under the Aadi Agreement or with respect to a change of control of our GB004 operating subsidiary, Aadi will have an option to receive a specified percentage of all revenue received in connection with such transaction, and if Aadi exercises the option Aadi will no longer be paid the development, regulatory, commercial or sales milestones or royalties on sales of licensed products under the agreement.

Our royalty obligations and the Aadi Agreement will expire on a licensed product-by-licensed product and country-by-country basis on the later of fifteen years from the date of first commercial sale or when there is no longer a valid patent claim covering such licensed product in such country.

The agreement may be terminated either by Aadi or by us in the event of an uncured material breach by the other party or in the event the other party becomes subject to specified bankruptcy, insolvency or similar circumstances.

In the event we commence a legal action challenging the validity or enforceability of any licensed patents, Aadi will have the right to terminate the agreement or elect to increase milestone and royalty payments by a specified percentage.

We may terminate the agreement in the event of potential safety or efficacy concerns affecting a licensed product.

Upon termination of the agreement for any reason all rights and licenses granted to us under the agreement will terminate, and in the event of certain termination events, we would grant Aerpio worldwide rights to the terminated program.

Manufacturing

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These patents and patent applications are directed to seralutinib compound, formulation and method of use claims.

As of December 31, 2020, with respect to GB004, we have exclusively licensed from Aerpio ten issued U.S.

As of December 31, 2021, with respect to GB004, we have exclusively licensed from Aadi ten issued U.S.

patents directed to compound, pharmaceutical composition and method of use claims, eight of which are not due to expire before 2030, and one, directed to synthetic method claims, is not due to expire before 2035, excluding any additional term for patent term extension;

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and a number of patents and pending patent applications in other jurisdictions.

patents in Australia, Canada, China, the European Patent Convention, India, Japan, Mexico, New Zealand and South Korea, and pending patent applications in Brazil, the European Patent Convention, India, Mexico and South Korea.

The patents and pending patent applications directed to compound, pharmaceutical composition and method of use claims in other jurisdictions, and which are not due to expire before 2030, include issued patents in Australia, Canada, China, the European Patent Convention, India, Japan, Mexico, New Zealand and South Korea, and pending patent applications in Brazil, the European Patent Convention, India, Mexico and South Korea.

The patents and pending patent applications directed to synthetic method claims in other jurisdictions, and which are not due to expire before 2035, include pending patent applications in China, the European Patent Convention, India and Japan.

As of December 31, 2020, we owned one issued U.S.

patent directed to compound, pharmaceutical composition and method of use claims for GB1275, which, if issued, is not due to expire before 2036, excluding any additional term for patent term extension, and a number of corresponding patent applications pending in other jurisdictions, including Australia, Brazil, Canada, China, the European Patent Convention, Israel, Japan, Mexico, New Zealand, Singapore and South Korea, also directed to compound, pharmaceutical composition and method of use claims for GB1275.

As of December 31, 2020, with respect to GB001, we owned one issued U.S.

patent directed to compound and pharmaceutical composition claims, which is not due to expire before 2026, excluding any additional term for patent term extension, and a number of patents in other jurisdictions, including issued patents in Australia, Canada, China, the European Patent Convention, India, Mexico, New Zealand, Russia, and Brazil directed to compound and pharmaceutical composition claims.

As of December 31, 2020, we owned one U.S.

patent directed to compound claims, which is not due to expire before 2037, excluding any additional term for patent term adjustment or extension, and a number of pending patent applications in other jurisdictions, including pending applications in Australia, Brazil, Canada, China, the European Patent Convention, India, South Korea, Mexico, New Zealand, Russia, and Taiwan directed to compound claims.

As of December 31, 2020, with respect to a backup DP2 molecule, we owned three issued U.S.

patent directed to compound and pharmaceutical composition claims, which are not due to expire before 2032, excluding any additional patent term extension, and a number of patents and pending patent applications in other jurisdictions, including issued patents in UK, France, Germany, China, Japan, Korea, Australia, Canada, New Zealand, Mexico and Israel, and pending patent applications in India and Brazil.

With respect to our product candidates and processes we intend to develop and commercialize in the normal course of business, we intend to pursue patent protection covering, when possible, compositions, methods of use, dosing and formulations.

We may also pursue patent protection with respect to manufacturing and drug development processes and technologies.

Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment, and other requirements imposed by governmental patent agencies.

We may not be able to obtain patent protections for our compositions, methods of use, dosing and formulations, manufacturing and drug development processes and technologies throughout the world.

Issued patents can provide protection for varying periods of time, depending upon the date of filing of the patent application, the date of patent issuance and the legal term of patents in the countries in which they are obtained.

In general, patents issued for applications filed in the United States can provide exclusionary rights for 20 years from the earliest effective filing date.

In addition, in certain instances, the term of an issued U.S.

patent that covers or claims an FDA approved product can be extended to recapture a portion of the term effectively lost as a result of the FDA regulatory review period, which is called patent term extension.

The restoration period cannot be longer than five years and the total patent term, including the restoration period, must not exceed 14 years following FDA approval.

The term of patents outside of the United States varies in accordance with the laws of the foreign jurisdiction, but typically is also 20 years from the earliest effective filing date.

However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country, and the validity and enforceability of the patent.

Patent term may be inadequate to protect our competitive position on our products for an adequate amount of time.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions.

No consistent policy regarding the scope of claims allowable in patents in the field of biopharmaceuticals has emerged in the United States.

The relevant patent laws and their interpretation outside of the United States is also uncertain.

Changes in either the patent laws or their interpretation in the United States and other countries may diminish our ability to protect our technology or product candidates and could affect the value of such intellectual property.

In particular, our ability to stop third parties from making, using, selling, offering to sell or importing products that infringe our intellectual property will depend in part on our success in obtaining and enforcing patent claims that cover our technology, inventions and improvements.

We cannot guarantee that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may file in the future, nor can we be sure that any patents that may be granted to us in the future will be commercially useful in protecting our products, the methods of use or manufacture of those products.

Moreover, even our issued patents do not guarantee us the right to practice our technology in relation to the commercialization of our products.

Patent and other intellectual property rights in the pharmaceutical and biotechnology space are evolving and involve many risks and uncertainties.

For example, third parties may have blocking patents that could be used to prevent us from commercializing

our product candidates and practicing our proprietary technology, and our issued patents may be challenged, invalidated or circumvented, which could limit our ability to stop competitors from marketing related products or could limit the term of patent protection that otherwise may exist for our product candidates.

In addition, the scope of the rights granted under any issued patents may not provide us with protection or competitive advantages against competitors with similar technology.

Furthermore, our competitors may independently develop similar technologies that are outside the scope of the rights granted under any issued patents.

For these reasons, we may face competition with respect to our product candidates.

Moreover, because of the extensive time required for development, testing and regulatory review of a potential product, it is possible that, before any particular product candidate can be commercialized, any patent protection for such product may expire or remain in force for only a short period following commercialization, thereby reducing the commercial advantage the patent provides.

Additionally, as of December 31, 2021, with respect to GB004, we owned one pending US patent application and three pending international patent applications directed to formulations and solid forms of GB004, which, if issued, are not due to expire before 2040, excluding any additional term for patent term extension.

As of December 31, 2021, with respect to GB5121, we owned one pending U.S.

patent application, and a corresponding international patent application, directed to GB5121 compound, formulation and method of use claims, which, if issued, is not due to expire before 2041, excluding any additional term for patent term extension.

As of December 31, 2021, with respect to GB7208, we owned one pending U.S.

patent application, and a corresponding international patent application, directed to GB7208 compound, formulation and method of use claims, which, if issued, is not due to expire before 2042, excluding any additional term for patent term extension.

Government Regulation

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• submission to the FDA of an IND, which must become effective before human clinical trials may begin;

• approval by an independent institutional review board, or IRB, at each clinical site before each trial may be initiated;

• approval by an independent institutional review board, or IRB, or ethics committee at each clinical site before each trial may be initiated;

• performance of adequate and well-controlled human clinical trials in accordance with Good Clinical Practice, or GCP, regulations to establish the safety and efficacy of the proposed drug for its intended use;

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• satisfactory completion of an FDA advisory committee review, if applicable;

• satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current GMP, or cGMP, requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.

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An IND sponsor must submit the results of the preclinical tests, together with manufacturing information and analytical data, to the FDA as part of the IND.

An IND is a request for authorization from the FDA to administer an investigational new drug product to humans.

The sponsor will also include a protocol detailing, among other things, the objectives of the first phase of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the first phase lends itself to an efficacy evaluation.

An IND is a request for authorization from the FDA to administer an investigational drug product to humans.

The sponsor will also include a protocol detailing, among other things, the objectives of the clinical trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated, if the clinical trial lends itself to an efficacy evaluation.

Some preclinical testing may continue even after the IND is submitted.

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Each protocol must be submitted to the FDA as part of the IND as well as any subsequent protocol amendments, and timely safety reports must be submitted to the FDA and the investigators for serious and unexpected adverse events.

An IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations.

An IRB at each institution participating in the clinical trial must review and approve each protocol before a clinical trial commences at that

institution and must also approve the information regarding the trial and the consent form that must be provided to each trial subject or his or her legal representative, monitor the study until completed and otherwise comply with IRB regulations.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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In the case of some products for severe or life-threatening diseases, such as cancer, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

Sponsors sometimes designate their Phase 1 clinical trials as Phase 1a or Phase 1b.

Phase 1b clinical trials are typically aimed at confirming dosing, pharmacokinetics and safety in larger number of patients.

Some Phase 1b studies evaluate biomarkers or surrogate markers that may be associated with efficacy in patients with specific types of diseases.

This phase involves clinical trials in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and appropriate dosage.

Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population, generally at geographically dispersed clinical study sites.

These clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide, if appropriate, an adequate basis for product labeling.

These clinical trials are intended to establish the overall risk-benefit ratio of the product candidate and provide an adequate basis for product labeling.

Post-approval trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval.

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The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate

approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

In addition, some clinical trials are overseen by an independent group of qualified experts organized by the sponsor, known as a data safety monitoring board or committee.

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In addition, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

While the IND is active and before approval, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

There are also requirements governing the reporting of ongoing clinical trials and completed trial results to public registries.

Sponsors of certain clinical trials of FDA-regulated products are required to register and disclose specified clinical trial information, which is publicly available at www.clinicaltrials.gov.

Information related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial is then made public as part of the registration.

Sponsors are also obligated to discuss the results of their clinical trials after completion.

Information related to the product, patient population, phase of investigation, trial sites and investigators and other aspects of the clinical trial is then made public as part

of the registration.

Sponsors are also obligated to disclose the results of their clinical trials after completion.

Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved.

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In reviewing the NDA application for such a product, however, FDA reviewers in the drug center could consult with their counterparts in the device center to ensure that the device component of the combination product met applicable requirements regarding safety, effectiveness, durability and performance.

In addition, under FDA regulations, combination products are subject to cGMP requirements applicable to both drugs and devices, including the Quality System, or QS, regulations applicable to medical devices.

In addition, under FDA regulations, combination products are subject to cGMP requirements applicable to both drugs and devices, including the Quality System, regulations applicable to medical devices.

NDA Review and Approval Process

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a waiver of such fees may be obtained under certain limited circumstances.

The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.

Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity.

Under the Prescription Drug User Fee Act, or PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

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The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review The FDA may request additional information rather than accept an NDA for filing.

In this event, the NDA must be resubmitted with the additional information.

In this event,

the NDA must be resubmitted with the additional information.

The resubmitted application also is subject to review before the FDA accepts it for filing.

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A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional pivotal Phase 3 trial or other significant and time consuming requirements related to clinical trials, nonclinical studies or manufacturing.

A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional clinical trial or other significant and time consuming requirements related to clinical trials, nonclinical studies or manufacturing.

If a Complete Response Letter is issued, the sponsor must resubmit the NDA or, addressing all of the deficiencies identified in the letter, or withdraw the application.

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The FDA may also place other conditions on approval including the requirement for a risk evaluation and mitigation strategy, or REMS, to assure the safe use of the drug.

If the FDA concludes a

REMS is needed, the sponsor of the NDA must submit a proposed REMS.

If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS.

The FDA will not approve the NDA without an approved REMS, if required.

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Marketing approval may be withdrawn for non-compliance with regulatory requirements or if problems occur following initial marketing.

The Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

In addition, the Pediatric Research Equity Act, or PREA, requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

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Orphan designation does not convey any advantage in or shorten the duration of the regulatory review and approval process.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities.

If a product that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same drug for the same disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan exclusivity or inability to manufacture the product in sufficient quantities.

The designation of such drug also entitles a party to financial incentives such as opportunities for grant funding toward clinical trial costs, tax advantages and user-fee waivers.

However, competitors, may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

Orphan exclusivity also could block the approval of one of our product candidates for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

However, competitors, may

receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

In addition, if an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if the second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

seralutinib has received orphan drug designation for the treatment of patients with PAH, and GB1275 has received orphan drug designation for the treatment of pancreatic cancer.

Expedited Development and Review Programs

A sponsor may seek approval of its product candidate under programs designed to accelerate FDA’s review and approval of new drugs and biological products that meet certain criteria.

The FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.

Specifically, new drugs are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Unique to a fast track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Any product submitted to the FDA for approval, including a product with a fast track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and

accelerated approval.

A product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the safety or effectiveness of the treatment, diagnosis or prevention of a serious disease or condition.

The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review.

For example, the FDA has a fast track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.

Specifically, a product candidate is eligible for fast track designation if it is intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Fast track designation applies to the combination of the product and the specific indication for which it is being studied.

The sponsor of a fast track product candidate has opportunities for more frequent interactions with the applicable FDA review team during development.

With regard to a fast track product, the FDA may also consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review.

A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

Any NDA for a product candidate submitted to the FDA for approval, including for a product candidate with a fast track designation or breakthrough designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

An NDA is eligible for priority review if the product candidate is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition.

The FDA will attempt to direct additional resources to the evaluation of an application designated for priority review in an effort to facilitate the review.

The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

Priority review designation does not change the scientific/medical standard for approval or the quality of evidence necessary to support approval.

In addition, a product may be eligible for accelerated approval.

In addition, a product candidate may be eligible for accelerated approval.

Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has 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, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

As a condition of approval, the FDA will generally require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials.

In addition, the FDA currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

FDA may withdraw approval of a drug or indication approved under accelerated approval if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product.

The FDA Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies” that may be eligible to receive breakthrough therapy designation.

A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

If the FDA designates a breakthrough therapy, it may take actions appropriate to expedite the development and review of the application, which may include holding meetings with the sponsor and the review team throughout the development of the therapy;

providing timely advice to, and interactive communication with, the sponsor regarding the development of the drug to ensure that the development program to gather the nonclinical and clinical data necessary for approval is as efficient as practicable;

involving senior managers and experienced review staff, as appropriate, in a collaborative, cross-disciplinary review;

assigning a cross-disciplinary project lead for the FDA review team to facilitate an efficient review of the development program and to serve as a scientific liaison between the review team and the sponsor;

and considering alternative clinical trial designs when scientifically appropriate, which may result in smaller trials or more efficient trials that require less time to complete and may minimize the number of patients exposed to a potentially less efficacious treatment.

The designation includes all of the fast track program features, which means that the sponsor may file sections of the NDA for review on a rolling basis if certain conditions are satisfied, including an agreement with FDA on the proposed schedule for submission of portions of the application and the payment of applicable user fees before the FDA may initiate a review.

The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.

Fast track designation, priority review and breakthrough therapy designation do not change the standards for approval but may expedite the development or approval process.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

We may explore some of these opportunities for our product candidates as appropriate.

FDA may withdraw approval of a drug or indication approved under accelerated approval on an expedited basis if, for example, the confirmatory trial fails to verify the predicted clinical benefit of the product or if the sponsor fails to conduct such trials in a timely manner.

Fast track designation, breakthrough therapy designation, priority review and accelerated approval do not change the standards for approval but may expedite the development or approval process.

Even if a product candidate qualifies for one or more of these programs, the FDA may later decide that the product candidate no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Post-Approval Requirements

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For example, the FDA may require post-marketing testing, including Phase 4 clinical trials, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

Any drug products manufactured or distributed by us or our partners pursuant to FDA approvals will be subject to pervasive and continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the drug, providing the FDA with updated safety and efficacy information, drug sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements.

Any drug products manufactured or distributed pursuant to FDA approvals will be subject to pervasive and continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the drug, providing the FDA with updated safety and efficacy information, drug sampling and distribution requirements, complying with certain electronic records and signature requirements, and complying with FDA promotion and advertising requirements.

The FDA strictly regulates labeling, advertising, promotion and other types of information on products that are placed on the market and imposes requirements and restrictions on drug manufacturers, such as those related to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional activities involving the internet.

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Market exclusivity provisions under the FDCA can delay the submission or the approval of certain marketing applications.

The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity.

The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity.

A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance.

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Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA.

The issuance of a written request does not require the sponsor to undertake the described clinical trials.

The issuance of a written request does not

require the sponsor to undertake the described clinical trials.

In addition, orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

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The process for determining whether a third-party payor will provide coverage for a product is typically separate from the process for setting the reimbursement rate that the payor will pay for the product.

A third-party payor’s

decision to provide coverage for a product does not imply that an adequate reimbursement rate will be available.

A third-party payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be available.

Additionally, in the United States there is no uniform policy among payors for coverage or reimbursement.

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Since its enactment, there have been judicial and political challenges to certain aspects of the ACA.

For example, the Tax Cuts and Jobs Act of 2017, or Tax Act, included a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the ACA on certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual mandate.” On December 14, 2018, a U.S.

District Court Judge in the Northern District of Texas ruled that the individual mandate is a critical and inseverable feature of the ACA, and therefore, because it was repealed as part of the Tax Act, the remaining provisions of the ACA are invalid as well.

On December 18, 2019, the U.S.

Court of Appeals for the 5th Circuit affirmed the District Court’s decision that the individual mandate was unconstitutional but remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

Supreme Court is currently reviewing the case, although it is unclear when a decision will be made or how the Supreme Court will rule.

In addition, there may be other efforts to challenge, repeal or replace the ACA.

On June 17, 2021, the U.S.

Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without

specifically ruling on the constitutionality of the ACA.

Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.

The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare, including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA.

Other legislative changes have been proposed and adopted since the ACA was enacted.

On August 2, 2011, the Budget Control Act of 2011 was signed into law, which, among other things, resulted in aggregate reductions of Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2030, with the exception of a temporary suspension from May 1, 2020

through March 31, 2021, unless additional Congressional action is taken.

On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, reduced Medicare payments to several providers, including hospitals, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, created additional federal civil and criminal statutes that prohibit, among other things, knowingly and willfully executing a scheme to defraud any healthcare benefit program.

The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain other health care professionals beginning in 2022, and teaching hospitals, and applicable manufacturers and applicable group purchasing organizations to report annually to CMS ownership and investment interests held by physicians (as defined by statute) and their immediate family members.

report annually to CMS ownership and investment interests held by physicians (as defined by statute) and their immediate family members.

Similar state and local laws and regulations may also restrict business practices in the biopharmaceutical industry, such as state anti-kickback and false claims laws, which may apply to business practices, including but not limited to, research, distribution, sales and marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors, including private insurers, or by patients themselves;

state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources;

state laws and regulations that require drug manufacturers to file reports relating to pricing and

marketing information or which require tracking gifts and other remuneration and items of value provided to physicians, other healthcare providers and entities;

state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information or which require tracking gifts and other remuneration and items of value provided to physicians, other healthcare providers and entities;

and state and local laws that require the registration of pharmaceutical sales representatives.

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healthcare programs, integrity oversight and reporting obligations, contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of operations.

Data Privacy & Security

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including HIPAA, and federal and state consumer protection laws and regulations (e.g., Section 5 of the FTC Act), that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners.

In addition, certain state laws, such as the California Consumer Privacy Act, or the CCPA, and the California Privacy Rights Act, or the CPRA, govern the privacy and security of personal information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Data Privacy and Security Laws

Numerous state and federal laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information, and could apply now or in the future to our operations or the operations of our partners.

In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws, including HIPAA, and federal and state consumer protection laws and regulations (e.g., Section 5 of the Federal Trade Commission Act) that govern the collection, use, disclosure, and protection of health-related and other personal information could apply to our operations or the operations of our partners.

In addition, certain state laws, such as the California Consumer Privacy Act, or CCPA, the California Privacy Rights Act, or CPRA, govern the privacy and security of personal information, including health-related information in certain circumstances, some of which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

Failure to comply with these laws, where applicable, can result in the imposition of significant civil and/or criminal penalties and private litigation.

Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to make compliance efforts more challenging, and can result in investigations, proceedings, or actions that lead to significant penalties and restrictions on data processing.

Foreign Regulation

In order to market any product outside of the United States, we would need to 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 our products.

In order to market any product outside of the United States, we need to 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 our products.

Whether or not we obtain FDA approval for a product, we would need to obtain the necessary approvals by the comparable foreign regulatory authorities before we can commence clinical trials or marketing of the product in foreign countries and jurisdictions.

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Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others.

To market a medicinal product in the European Economic Area, or EEA (which is comprised of the 28 Member States of the EU plus Norway, Iceland and Liechtenstein), we must obtain a Marketing Authorization, or MA.

There are two types of marketing authorizations:

• the Community MA, which is issued by the European Commission through the Centralized Procedure, based on the opinion of the Committee for Medicinal Products for Human Use of the European Medicines Agency, or EMA, and which is valid throughout the entire territory of the EEA.

The Centralized Procedure is mandatory for certain types of products, such as biotechnology medicinal products, orphan medicinal products, advanced therapy products, and medicinal products containing a new active substance indicated for the treatment certain diseases, such as AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and viral diseases.

The Centralized Procedure is optional for products containing a new active substance not yet authorized in the EEA, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU;

• National MAs, which are issued by the competent authorities of the Member States of the EEA and only cover their respective territory, are available for products not falling within the mandatory scope of the Centralized Procedure.

Where a product has already been authorized for marketing in a Member State of the EEA, this National MA can be recognized in another Member State through the Mutual Recognition Procedure.

Failure to comply with applicable foreign regulatory requirements, may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Non-clinical studies and clinical trials

Similar to the U.S., the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls.

Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances.

Non-clinical studies must be conducted in compliance with the principles of good laboratory practice, or GLP, as set forth in EU Directive 2004/10/EC.

In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies.

These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Certain countries outside of the United States have a similar process that requires the submission of a clinical study application much like the IND prior to the commencement of human clinical studies.

Clinical studies of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization, or ICH, guidelines on GCP as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki.

If the sponsor of the clinical trial is not established within the EU, it must appoint an EU entity to act as its legal representative.

The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

The regulatory landscape related to clinical trials in the EU has been subject to recent changes.

The EU Clinical Trials Regulation, or CTR, which was adopted in April 2014 and repeals the EU Clinical Trials Directive, became applicable on January 31, 2022.

Unlike directives, the CTR is directly applicable in all EU member states without the need for member states to further implement it into national law.

The CTR notably harmonizes the assessment and supervision processes for clinical trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

While the Clinical Trials Directive required a separate clinical trial application, or CTA, to be submitted in each member state, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application to all member states concerned.

The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state.

The CTA must include, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation.

The assessment procedure of the CTA has been harmonized as well, including a joint assessment by all member states concerned, and a separate assessment by each member state with respect to specific requirements related to its own territory, including ethics rules.

Each member state’s decision is communicated to the sponsor via the centralized EU portal.

Once the CTA is approved, clinical study development may proceed.

The CTR foresees a three-year transition period.

The extent to which ongoing and new clinical trials will be governed by the CTR varies.

For clinical trials whose CTA was made under the Clinical Trials Directive before January 31, 2022, the Clinical Trials Directive will continue to apply on a transitional basis for three years.

Additionally, sponsors may still choose to submit a CTA under either the Clinical Trials Directive or the CTR until January 31, 2023 and, if authorised, those will be governed by the Clinical Trials Directive until January 31, 2025.

By that date, all ongoing trials will become subject to the provisions of the CTR.

Medicines used in clinical trials must be manufactured in accordance with Good Manufacturing Practices , or GMP.

Other national and EU-wide regulatory requirements may also apply.

Marketing Authorization

To market a medicinal product in the EU, we must obtain a marketing authorization, or MA.

To obtain regulatory approval of an investigational medicinal product under EU regulatory systems, we must submit a marketing authorization application, or MAA.

The process for doing this depends, among other things, on the nature of the medicinal product.

There are two types of MAs:

• ”Centralized MAs” are is issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use, or CHMP, of the European Medicines Agency, or EMA, and are valid throughout the EU.

The centralized procedure is mandatory for certain types of products, such as:

(i) medicinal products derived from biotechnology medicinal products, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products, or ATMPs, and (iv) medicinal products containing a new active substance indicated for the treatment certain diseases, such as HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other dysfunctions and viral diseases.

The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products

that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.

• “National MAs” are issued by the competent authorities of the EU member states, only cover their respective territory, and are available for products not falling within the mandatory scope of the centralized procedure.

Where a product has already been authorized for marketing in an EU member state, this national MA can be recognized in another member state through the mutual recognition procedure.

If the product has not received a national MA in any member state at the time of application, it can be approved simultaneously in various member states through the decentralized procedure.

Under the above described procedures, before granting the MA, the EMA or the competent authorities of the Member States of the EEA make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the reference member state.

Under the above described procedures, before granting the MA, the regulatory authorities make an assessment of the risk-benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy.

Under the centralized procedure the maximum timeframe for the evaluation of a MAA by the EMA is 210 days.

In exceptional cases, the CHMP might perform an accelerated review of a MAA in no more than 150 days (not including clock stops).

Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the Priority Medicines, or PRIME, scheme, which provides incentives similar to the breakthrough therapy designation in the U.S.

In March 2016, the EMA launched an initiative, the PRIME scheme, a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs.

It is based on increased interaction and early dialogue with companies developing promising medicines, to optimize their product development plans and speed up their evaluation to help them reach patients earlier.

Product developers that benefit from PRIME designation can expect to be eligible for accelerated assessment but this is not guaranteed.

Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated MAA assessment once a dossier has been submitted.

Importantly, a dedicated contact and rapporteur from the CHMP is appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level.

An initial meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

MAs have an initial duration of five years.

After these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the risk-benefit balance.

Data and marketing exclusivity

In the EEA, new products authorized for marketing, or reference products, qualify for eight years of data exclusivity and an additional two years of market exclusivity upon marketing authorization.

The data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial authorization of the reference product in the EU.

The 10-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Pediatric investigation plan

In the EEA, marketing authorization applications for new medicinal products not authorized have to include the results of studies conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

In the EU, new products authorized for marketing, or reference products, generally receive eight years of data exclusivity and an additional two years of market exclusivity upon MA.

If granted, the data exclusivity period prevents generic or biosimilar applicants from relying on the preclinical and clinical trial data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU.

During the additional two‑year period of market exclusivity, a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced, but no generic or biosimilar product can be marketed until 10 years have elapsed from the initial MA of the reference product in the EU.

The overall 10-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical entity, and products may not qualify for data exclusivity.

Pediatric development

In the EU, MAAs for new medicinal products have to include the results of trials conducted in the pediatric population, in compliance with a pediatric investigation plan, or PIP, agreed with the EMA’s Pediatric Committee, or PDCO.

The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the drug for which marketing authorization is being sought.

The PDCO can grant a deferral of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults.

Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data is not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients.

Once the marketing authorization is obtained in all Member States of the EU and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension.

treatments for pediatric patients.

Once the MA is obtained in all EU member states and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of approval) or, in the case of orphan pharmaceutical products, a two year extension of the orphan market exclusivity is granted.

Orphan drug designation

In the EEA, a medicinal product can be designated as an orphan drug if its sponsor can establish that the product is intended for the diagnosis, prevention or treatment of 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 that the product is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the European Community 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.

In the EEA, an application for designation as an orphan product can be made any time prior to the filing of an application for approval to market the product.

Marketing authorization for an orphan drug leads to a ten-year period of market exclusivity.

During this market exclusivity period, the EMA or the member state competent authorities, cannot accept another application for a marketing authorization, or grant a marketing authorization, for a similar medicinal product for the same indication.

The period of market exclusivity is extended by two years for medicines that have also complied with an agreed PIP.

This period may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, for example because the product is sufficiently profitable not to justify market exclusivity.

Market exclusivity can be revoked only in very selected cases, such as consent from the marketing authorization holder, inability to supply sufficient quantities of the product, demonstration of “clinical superiority” by a similar medicinal product, or, after a review by the Committee for Orphan Medicinal Products, requested by a member state in the fifth year of the marketing exclusivity period (if the designation criteria are believed to no longer apply).

Medicinal products designated as orphan drugs pursuant are eligible for incentives made available by the EU and its Member States to support research into, and the development and availability of, orphan drugs.

Clinical trials

Clinical trials of medicinal products in the European Union must be conducted in accordance with European Union and national regulations and the International Conference on Harmonization, or ICH, guidelines on GCPs.

Additional GCP guidelines from the European Commission, focusing in particular on traceability, apply to clinical trials of advanced therapy medicinal products.

If the sponsor of the clinical trial is not established within the European Union, it must appoint an entity within the European Union to act as its legal representative.

The sponsor must take out a clinical trial insurance policy, and in most EU countries, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical trial.

Prior to commencing a clinical trial, the sponsor must obtain a clinical trial authorization from the competent authority, and a positive opinion from an independent ethics committee.

The application for a clinical trial authorization must include, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation.

Currently, clinical trial authorization applications must be submitted to the competent authority in each EU Member State in which the trial will be conducted.

Under the new Regulation on Clinical Trials, which is currently expected to take effect in 2019, there will be a centralized application procedure where one national authority takes the lead in reviewing the application and the other national authorities have only a limited involvement.

Any substantial changes to the trial protocol or other information submitted with the clinical trial applications must be notified to or approved by the relevant competent authorities and ethics committees.

Medicines used in clinical trials must be manufactured in accordance with cGMP.

Other national and European Union-wide regulatory requirements also apply.

Privacy and data protection laws

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States.

A medicinal product may be designated as orphan if its sponsor can establish that (1) the product is intended for the diagnosis, prevention or treatment of a life threatening or chronically debilitating condition (2) either (a) such condition affects not more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from the orphan status, would not generate sufficient return in the EU to justify the necessary investment;

and (3) there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized for marketing in the EU or, if such method exists, the product will be of significant benefit to those affected by that condition.

In the EU, an application for designation as an orphan product can be made any time prior to the filing of an MAA.

Orphan drug designation entitles a party to incentives such fee reductions or fee waivers, protocol assistance, and access to the centralized procedure.

Upon grant of a MA, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA cannot accept another MAA, or grant a MA, or accept an application to extend a MA for a similar product for the same indication for a period of ten years.

The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed PIP.

No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications.

Orphan drug designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The orphan exclusivity period may, however, be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan drug designation, for example because the product is sufficiently profitable not to justify market exclusivity, or where the prevalence of the condition has increased above the threshold.

Granting of an authorization for another similar orphan medicinal product can happen at any time if:

(i) the second applicant can establish that its product, although similar to the authorized product, is safer, more effective or otherwise clinically superior, (ii) inability of the applicant to supply sufficient quantities of the orphan medicinal product or (iii) where the applicant consents to a second orphan medicinal product application.

A company may voluntarily remove a product from the orphan register.

Post-Approval Requirements

Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the member states.

The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system.

Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, or PSURs.

All new MAA must include a risk management plan, or RMP describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product.

The regulatory authorities may also impose specific obligations as a condition of the MA.

Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies.

The advertising and promotion of medicinal products is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising and unfair commercial practices.

All advertising and promotional activities for the product must be consistent with the approved summary of product characteristics, and therefore all off-label promotion is prohibited.

Direct-to-consumer advertising of prescription medicines is also prohibited in the EU.

Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each member state and can differ from one country to another.

The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the 27 EU member states plus Norway, Liechtenstein and Iceland.

Failure to comply with EU and member state laws that apply to the conduct of clinical trials, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of

pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties.

These penalties could include delays or refusal to authorize the conduct of clinical trials, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

Brexit and the Regulatory Framework in the United Kingdom

The United Kingdom, or UK, left the EU on January 31, 2020, following which existing EU medicinal product legislation continued to apply in the UK during the transition period under the terms of the EU-UK Withdrawal Agreement.

The transition period, which ended on December 31, 2020, maintained access to the EU single market and to the global trade deals negotiated by the EU on behalf of its members.

The transition period provided time for the UK and EU to negotiate a framework for partnership for the future, which was then crystallized in the Trade and Cooperation Agreement, or TCA, and became effective on the January 1, 2021.

The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not foresee wholesale mutual recognition of UK and EU pharmaceutical regulations.

EU laws which have been transposed into UK law through secondary legislation continue to be applicable as “retained EU law”.

However, new legislation such as the EU CTR will not be applicable.

The UK government has passed a new Medicines and Medical Devices Act 2021, which introduces delegated powers in favor of the Secretary of State or an ‘appropriate authority’ to amend or supplement existing regulations in the area of medicinal products and medical devices.

This allows new rules to be introduced in the future by way of secondary legislation, which aims to allow flexibility in addressing regulatory gaps and future changes in the fields of human medicines, clinical trials and medical devices.

As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, is the UK’s standalone medicines and medical devices regulator.

As a result of the Northern Ireland protocol, different rules will apply in Northern Ireland than in England, Wales, and Scotland, together, Great Britain, or GB;

broadly, Northern Ireland will continue to follow the EU regulatory regime, but its national competent authority will remain the MHRA.

The MHRA has published a guidance on how various aspects of the UK regulatory regime for medicines will operate in GB and in Northern Ireland following the expiry of the Brexit transition period on December 31, 2020.

The guidance includes clinical trials, importing, exporting, and pharmacovigilance and is relevant to any business involved in the research, development, or commercialization of medicines in the UK.

The new guidance was given effect via the Human Medicines Regulations (Amendment etc.) (EU Exit) Regulations 2019, or the “Exit Regulations”.

The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicines that will benefit patients, including a 150-day assessment and a rolling review procedure.

All existing EU MAs for centrally authorized products were automatically converted or grandfathered into UK MAs, effective in GB (only), free of charge on January 1, 2021, unless the MA holder chooses to opt-out.

In order to use the centralized procedure to obtain a MA that will be valid throughout the EEA, companies must be established in the EEA.

Therefore after Brexit, companies established in the UK can no longer cannot use the EU centralized procedure and instead an EEA entity must hold any centralized MAs.

In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures to obtain an MA to commercialize products in the UK.

The MHRA may rely on a decision taken by the European Commission on the approval of a new (centralized procedure) MA when determining an application for a GB authorization;

or use the MHRA’s decentralized or mutual recognition procedures which enable MAs approved in EU member states (or Iceland, Liechtenstein, Norway) to be granted in GB.

There will be no pre-MA orphan designation.

Instead, the MHRA will review applications for orphan designation in parallel to the corresponding MA application.

The criteria are essentially the same, but have been tailored for the market, i.e., the prevalence of the condition in GB, rather than the EU, must not be more than five in 10,000.

Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in GB.

Regulation of Combination Products in the EU

The EU regulates medical devices and medicinal products separately, through different legislative instruments, and the applicable requirements will vary depending on the type of drug-device combination product.

EU guidance has been published to help manufacturers select the right regulatory framework.

Drug-delivery products intended to administer a medicinal product where the medicinal product and the device form a single integral product are regulated as medicinal products in the EU.

The EMA is responsible for evaluating the

quality, safety and efficacy of MAAs submitted through the centralized procedure, including the safety and performance of the medical device in relation to its use with the medicinal product.

The EMA or the EU member state national competent authority will assess the product in accordance with the rules for medicinal products described above but the device part must comply with the Medical Devices Regulation (including the general safety and performance requirements provided in Annex I).

MAA must include – where available – the results of the assessment of the conformity of the device part with the Medical Devices Regulation contained in the manufacturer’s EU declaration of conformity of the device or the relevant certificate issued by a notified body.

If the MAA does not include the results of the conformity assessment and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required, the competent authority must require the applicant to provide a notified body opinion on the conformity of the device.

By contrast, in case of drug-delivery products intended to administer a medicinal product where the device and the medicinal product do not form a single integral product (but are e.g.

co-packaged), the medicinal product is regulated in accordance with the rules for medicinal products described above while the device part is regulated as a medical device and will have to comply with all the requirements set forth by the Medical Devices Regulation.

The characteristics of non-integral devices used for the administration of medicinal products may impact the quality, safety and efficacy profile of the medicinal products.

To the extent that administration devices are co-packaged with the medicinal product or, in exceptional cases, where the use of a specific type of administration device is specifically provided for in the product information of the medicinal product, additional information may need to be provided in the MAA for the medicinal product on the characteristics of the medical device(s) that may impact on the quality, safety and/or efficacy of the medicinal product.

The requirements regarding quality documentation for medicinal products when used with a medical device, including single integral products, co-packaged and referenced products, are outlined in the EMA guideline of July 22, 2021, which became applicable as of January 1, 2022.

The aforementioned EU rules are generally applicable in the EEA.

Data privacy and security laws

We are also subject to laws and regulations in non-U.S.

countries covering data privacy and the protection of health-related and other personal data.

EU member states and other jurisdictions have adopted data protection laws and regulations, which impose significant compliance obligations.

Laws and regulations in these jurisdictions apply broadly to the collection, use, storage, disclosure, processing and security of personal data that identifies or may be used to identify an individual, such as names, contact information, and sensitive personal data such as health data.

These laws and regulations are subject to frequent revisions and differing interpretations, and have generally become more stringent over time.

The General Data Protection Regulation, or GDPR, went into effect in May 2018.

The GDPR imposes many requirements for controllers and processors of personal data of individuals within the EEA, including, for example, higher standards for obtaining consent from individuals to process their personal data, more robust disclosures to individuals and a strengthened individual data rights regime, shortened timelines for data breach notifications, limitations on retention and secondary use of information, increased requirements pertaining to health data and pseudonymized (i.e., key-coded) data and additional obligations when we contract third-party processors in connection with the processing of the personal data.

The GDPR allows EU and EEA Member States to make additional laws and regulations further limiting the processing of genetic, biometric or health data.

Failure to comply with the requirements of GDPR and the applicable national data protection laws of the EU member states may result in fines of up to €20,000,000 or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, and other administrative penalties.

Among other requirements, the GDPR regulates transfers of personal data subject to the GDPR to third countries that have not been found to provide adequate protection to such personal data, including the United States, and the efficacy and longevity of current transfer mechanisms between the EU and the United States remains uncertain.

For example, in 2016, the EU and United States agreed to a transfer framework for data transferred from the EU to the United States, called the Privacy Shield, but the Privacy Shield was invalidated in July 2020 by the Court of Justice of the European Union.

Further, from January 1, 2021, companies have to comply with the GDPR and also the United Kingdom GDPR (UK GDPR), which, together with the amended UK Data Protection Act 2018, retains the GDPR in UK national law.

The UK GDPR mirrors the fines under the GDPR, e.g.

fines up to the greater of €20 million (£17.5 million) or 4% of global turnover.

The relationship between the United Kingdom and the European Union in relation to certain aspects of data protection law remains unclear, and it is unclear how United Kingdom data protection laws and regulations will develop in the medium to longer term, and how data transfers to and from the United Kingdom will be regulated in the long term.

Currently there is a four to six-month grace period agreed in the EU and United Kingdom Trade and Cooperation Agreement, ending June 30, 2021 at the latest, whilst the parties discuss an adequacy decision.

However, it is not clear whether (and when) an adequacy decision may be granted by the European Commission enabling data transfers from EU member states to the United Kingdom long term without additional measures.

These changes may lead to additional costs and increase our overall risk exposure.

countries governing data privacy and the protection of personal data, including health-related data.

Laws and regulations in the EU and other jurisdictions apply broadly to the collection, use, storage, disclosure, processing and security of personal data, and have generally become more stringent over time.

For example, the General Data Protection Regulation, or GDPR, imposes strict requirements for processing the personal data of individuals within the EEA.

Failure to comply with the requirements of GDPR and the applicable national data protection laws of the EU member states may result in fines of up to €20 million or up to 4% of the total worldwide annual turnover of the preceding financial year, whichever is higher, and other administrative penalties.

Additionally, following the United Kingdom’s withdrawal from the European Union, from January 1, 2021, companies have had to comply with the GDPR and the United Kingdom GDPR, or UK GDPR, each regime having the ability to fine up to the greater of €20 million/ £17.5 million or 4% of global turnover.

The relationship between the United Kingdom and the European Union in relation to certain aspects of data protection law remains unclear, for example around how data can lawfully be transferred between each jurisdiction, which exposes us to further compliance risk.

Human Capital

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The principal purposes of our equity and cash incentive plans are to attract, retain and motivate personnel through the granting of stock-based and cash-based compensation awards, in order to align our interests and the interests of our stockholders with those of our employees and consultants.

As of February 19, 2021, we had 195 full-time employees and one part-time employee.

As of February 25, 2022, we had 185 full-time employees and no part-time employees.

Of those 185 employees, 58, or 31%, have a Ph.D.

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and changed our name to Gossamer Bio, Inc.

Our principal executive offices are located at 3013 Science Park Road, Suite 200, San Diego, California 92121, and our telephone number is (858) 684-1300.

Our principal executive offices are located at 3013 Science Park Road, San Diego, California 92121, and our telephone number is (858) 684-1300.

Available Information

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They are also available for free on the SEC’s website at www.sec.gov.

We use our investor relations website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD.

Investors should monitor such website, in addition to following our press releases, SEC filings and public conference calls and webcasts.

Information relating to our corporate governance is also included on our investor relations website.

The information in or accessible through the SEC and our website are not incorporated into, and are not considered part of, this filing.

Further, our references to the URLs for these websites are intended to be inactive textual references only.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business