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Item 1. Business

2023-02-23 compared with 2022-02-24 · 344 added, 317 removed, 740 unchanged (47% of the section changed)

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From this foundation, we continue to build a leading, global biopharmaceutical company focused on rare diseases involving muscle in order to develop transformative precision medicines to treat and possibly cure these disorders.

In less than five years, we have matured into a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of innovative treatments for severe, rare muscle disorders for which there is significant unmet medical need.

We are a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of innovative treatments for severe, rare muscle disorders for which there is significant unmet medical need.

Guided by our holistic drug discovery approach to targeting the muscle as an organ, we have combined our foundational expertise in muscle biology and small molecule engineering to build our proprietary, muscle-focused drug discovery platform.

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A unique observation from our preclinical work is that EDG-5506 led to pronounced prevention of cardiac fibrosis.

This is a highly relevant finding, particularly if replicated in clinical observations, since cardiac myopathy is a major driver of mortality in both DMD and BMD.

a highly relevant finding, particularly if replicated in clinical observations, since cardiac myopathy is a major driver of mortality in both DMD and BMD.

EDG-5506 was evaluated in a Phase 1 clinical trial designed to assess the safety, tolerability and pharmacokinetics (PK) of EDG-5506 in adult healthy volunteers (HVs) (Phase 1a) and in adults with BMD (Phase 1b).

Our Phase 1a data in HVs demonstrated that EDG-5506 was generally well-tolerated and amenable to daily dosing.

Our Phase 1b data in

BMD patients demonstrated proof of concept by showing a significant reduction in key biomarkers of muscle damage.

Our Phase 1b data in BMD patients demonstrated proof of concept by showing a significant reduction in key biomarkers of muscle damage.

Following completion of our Phase 1b study, we initiated and completed enrollment in the ARCH open label study evaluating EDG-5506 in 12 adult males with BMD.

All those who participated in the Phase 1b first-in-human study of EDG-5506 also enrolled in the study.

The study evaluated multiple doses of EDG-5506 administered daily over 12 months.

Safety, PK, changes in biomarkers of muscle damage such as creatine kinase (CK) and fast skeletal muscle troponin (TNNI2), measures of function with North Star Ambulatory Assessments/ North Star Ambulatory Assessments Limb Girdle Type Muscular Dystrophies (NSAA/NSAD), time function tests and patient-reported outcomes, were evaluated.

We reported data at the end of two months, four months and six months of treatment.

Consistent with prior observations, treatment with EDG-5506 led to a significant decrease in key biomarkers of muscle damage when assessed by laboratory assays.

EDG-5506 dosing led to a positive trend in NSAA scores.

Of note, a similar trend was observed with the NSAD scores.

EDG-5506 was well-tolerated in all participants with no discontinuations or dose reductions.

The most common adverse events observed to date were dizziness, drowsiness, and headache.

All participants have been dose escalated to daily 20 mg oral doses of EDG-5506.

The 6-month ARCH study data with EDG-5506 provided further support that reducing contraction-induced damage in dystrophic muscle has the potential to preserve and improve muscle function while preventing disease progression in dystrophinopathies.

We believe EDG-5506 has potential therapeutic utility as either a standalone or combination therapy for patients suffering from rare muscular dystrophies, if approved.

We also intend to advance two other muscle-focused precision medicines into clinical development.

Our second program, EDG-5440, is a next generation myosin ATPase modulator designed to target skeletal muscle in a specific set of rare neuromuscular diseases.

Our third program, EDG-002, focuses on identification of novel mechanism cardiac modulators.

We are initially pursuing a new target for inherited hypertrophic cardiomyopathy (HCM) in addition to exploring the potential of this novel mechanism across other cardiac disorders.

Our preliminary preclinical studies offer evidence that our EDG-002 program has the potential to yield molecules that could become a new therapeutic option for the treatment of HCM as well as other cardiac disorders.

We anticipate candidate selection of a novel cardiac modulator for inherited hypertrophic cardiomyopathy from our EDG-002 cardiac muscle program in the second half of 2022.

We believe our programs also offer substantial opportunities for us to expand into related rare diseases for which there are limited or no approved treatments.

We are currently focusing on the development of EDG-5506 and anticipate advancing our preclinical programs into the next stage of development in the near term.

While EDG-5440 and EDG-002 are important preclinical programs to us, we have not needed to devote significant financial resources to these programs to date since they are still in preclinical development and have not yet advanced into clinical trials.

We have also identified a second muscle-focused potential precision medicine that focuses on identification of novel mechanism cardiac modulators.

We are initially pursuing a new target with our lead product candidate for cardiomyopathy, EDG-7500, for inherited hypertrophic cardiomyopathy (HCM) in addition to exploring the potential of this novel mechanism across other cardiac disorders.

Our preliminary preclinical studies have generated promising data.

We have initiated IND-enabling studies and plan to file an IND in the third quarter of 2023.

Our EDG-003 cardiovascular discovery program also has the potential to yield novel molecules that could become new therapeutic options for a variety of other cardiac disorders.

While EDG-003 is an important preclinical program to us, we have not needed to devote significant financial resources to this program to date since it is still in early discovery and has not advanced into clinical trials.

Using our proprietary drug discovery platform, we are developing a pipeline of precision medicine product candidates that target key muscle proteins and modulators to address a broad array of genetically defined muscle disorders.

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We are focused on building a leading, patient-centric, fully integrated global rare disease company.

Members of our team have extensive expertise in muscle disorders, small molecule drug discovery and development and patient advocacy with proven track records at organizations including Alexion, Amgen, Array Biopharma, Catabasis, Cytokinetics, Genzyme, GlaxoSmithKline, Parent Project Muscular Dystrophy, Pfizer and Biogen.

We were co-founded in 2017 by our Chief Scientific Officer, Alan Russell, Ph.D., Peter Thompson, M.D., who is currently a Partner at OrbiMed and Badreddin Edris, Ph.D., who is currently the Chief Operating Officer at SpringWorks Therapeutics, Inc.

through funding provided by OrbiMed.

Russell has extensive experience in developing novel therapeutics for diseases involving skeletal muscle, having previously served as Vice President and Head of the Muscle

Metabolism Discovery Performance Unit at GlaxoSmithKline from 2010 to 2017 and as Associate Director, Muscle Biology and Therapeutics at Cytokinetics from 2002 to 2010, where he was the co-inventor of tirasemtiv and reldesemtiv, direct muscle sensitizers for Amyotrophic Lateral Sclerosis (ALS).

Russell has extensive experience in developing novel therapeutics for diseases involving skeletal muscle, having previously served as Vice President and Head of the Muscle Metabolism Discovery Performance Unit at GlaxoSmithKline from 2010 to 2017 and as Associate Director, Muscle Biology and Therapeutics at Cytokinetics from 2002 to 2010, where he was the co-inventor of tirasemtiv and reldesemtiv, direct muscle sensitizers for Amyotrophic Lateral Sclerosis (ALS).

We are led by Kevin Koch, Ph.D., who has been in the life science industry for over 30 years with a focus on drug discovery, translational medicine and clinical development.

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Additionally, our Chief Business Officer, Behrad Derakhshan, Ph.D., our Chief Financial Officer, R.

Michael Carruthers, our Chief Medical Officer, Joanne Donovan, M.D., Ph.D., and our General Counsel, John Moore, each have more than 15 years of experience in drug research, clinical development, regulatory affairs, manufacturing, business development and commercialization of novel medicines, particularly in a range of devastating rare diseases.

business development and commercialization of novel medicines, particularly in a range of devastating rare diseases.

Additionally, we have recently appointed Marc Semigran, M.D., as Chief Development Officer.

Semigran previously served as Chief Medical Officer and Senior Vice President of medical science at MyoKardia and as Chief Medical Officer of Renovacor.

Semigran brings considerable clinical development and translational medicine experience as we prepare to advance our novel cardiac program into clinical development.

Further, we have built a scientific advisory board with experts in the field of muscle diseases affecting both children and adults.

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Venture Partners (USVP), Deerfield Management, Viking Global Investors, New Leaf Ventures, Janus Henderson Investors, RA Capital Management, Cormorant Asset Management, Logos Capital, Wellington Management, CureDuchenne Ventures and an undisclosed institutional investor.

We also raised $186.1 million in net proceeds from our initial public offering in March 2021.

We also raised $186.1 million in net proceeds from our initial public offering in March 2021 and $129.2 in net proceeds from our follow-on public offering in September 2022 (the September 2022 Offering).

Our vision is to improve the lives of patients and families suffering from rare muscle disorders by building the world’s leading muscle-focused, precision medicine company.

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By positioning ourselves as a trusted partner that moves with thoughtful urgency, we will continue to work to understand the needs of patients in order to inform our development of EDG-5506 and other programs for neuromuscular and other diseases.

We will seek to better appreciate the burden of disease from the patient perspective, understand the current standard of care and unmet needs in managing the disease and learn what is most meaningful to patients.

We continue to seek to better appreciate the burden of disease from the patient perspective, understand the current standard of care and unmet needs in managing the disease and learn what is most meaningful to patients.

● Leveraging clinical and regulatory precedents and our extensive experience in rare diseases to rapidly advance EDG-5506 through clinical development in DMD, BMD and other muscle diseases .

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In October 2020, we initiated our first Phase 1 clinical trial to evaluate the safety and tolerability of EDG-5506 in adult HVs (Phase 1a) and in adults with BMD (Phase 1b).

Leveraging the aggregated Phase 1 safety and tolerability and exposure data, we plan to initiate two Phase 2 clinical trials in 2022.

The first clinical trial will be in BMD and will assess longer duration safety and tolerability, exposure levels, changes to biomarkers of muscle breakdown and functional observations in an adolescent and adult patient population.

The second clinical trial will be a Phase 2 dose-ranging clinical trial in pediatric DMD patients.

Assuming positive results,

we also plan to explore the potential for breakthrough designation and/or an accelerated approval pathway.

Leveraging the aggregated Phase 1 safety and tolerability and exposure data, we initiated two Phase 2 clinical trials in 2022.

The first clinical trial in BMD assesses longer duration safety and tolerability, exposure levels, changes to biomarkers of muscle breakdown and functional observations in an adolescent and adult patient population.

The second clinical trial is a Phase 2 dose-ranging clinical trial in children with DMD.

Assuming positive results, we also plan to explore the potential for breakthrough designation and/or an accelerated approval pathway.

We believe EDG-5506 has a clear and predictable mechanism of action that will allow us to define objective clinical endpoints and leverage charted regulatory pathways to increase the likelihood of success of drug development and commercialization.

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Building upon our success in designing small molecule inhibitors of fast skeletal myosin, we are leveraging our proprietary drug discovery platform and capabilities to create precision medicines for muscle disorders with high levels of unmet need.

In addition to EDG-5506, we have characterized a second fast skeletal myosin inhibitor product candidate selected from our pool of diverse myosin inhibitors for the treatment of additional fast muscle-mediated movement disorders.

We are also advancing EDG-002, our research program directed to cardiac disorders.

In addition to EDG-5506, we are also advancing EDG-7500, and our preclinical program directed to cardiac disorders.

● Integrating our scientific expertise, development capabilities and growing network of patient advocacy groups and collaborators to develop novel therapies addressing muscle diseases with the highest unmet need.

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We believe that our approach can overcome many of the obstacles facing skeletal and cardiac muscle drug discovery and development that have resulted in a lack of disease modifying therapies for inherited muscle disorders.

proprietary drug discovery platform leverages our expertise in the following areas to facilitate the efficient discovery of novel therapies for neglected muscle disorders:

Our proprietary drug discovery platform leverages our expertise in the following areas to facilitate the efficient discovery of novel therapies for neglected muscle disorders:

intimate familiarity with skeletal and cardiac muscle biophysics and integrated physiology providing a unique understanding of the complex integrative relationship between skeletal and cardiac muscle contraction, transcriptional regulation and vascular/nervous/metabolic system feedback in disease;

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EDG-5506 for Treatment of Patients with DMD and BMD

We are developing a myofiber stabilizing therapy that represents a novel mechanistic approach designed to address the root cause of dystrophin deficient muscular dystrophies.

EDG-5506, our most advanced product candidate, is an orally administered, allosteric, selective, fast myofiber (type II) myosin modulator that is designed to be inactive against slow myofiber (type I) myosin present in both skeletal muscle and the heart.

Our preclinical data for EDG-5506 in animal models with muscular dystrophy demonstrated that selective regulation of fast (type II) myofiber contraction protected muscle from damage, decreased systemic fibrosis and improved measures of muscle function including strength and physical activities.

We are developing a muscle fiber stabilizing therapy that represents a novel mechanistic approach designed to address the root cause of dystrophin deficient muscular dystrophies.

EDG-5506, our most advanced product candidate, is an orally administered, allosteric, selective, fast myofiber (type II) myosin inhibitor that is designed to be inactive against slow myofiber (type I) myosin present in both skeletal muscle and the heart.

EDG-5506 was evaluated in a Phase 1 clinical trial designed to assess the safety, tolerability, and pharmacokinetics (PK) of EDG-5506 in adult HVs (Phase 1a) and in adults with BMD (Phase 1b).

Our Phase 1a data in HVs demonstrated that EDG-5506 was generally well-tolerated and amenable to daily dosing.

Our Phase 1b data in BMD patients demonstrated proof of concept by showing a significant reduction in key biomarkers of muscle damage.

Type II myosin modulation prevents muscle damage via a blockade of the biophysical stress response during normal muscle contractile activity thus stabilizing the muscle and protecting the muscle from damage.

As such, it is a potentially complementary approach to dystrophin replacement strategies which also stabilize muscle through the re-expression of truncated dystrophin.

Loss of dystrophin in DMD causes myofiber membrane stress associated myofiber damage when muscles contract.

By enhancing muscle stability and decreasing muscle damage, we believe EDG-5506 can potentially improve outcomes across a broader range of DMD patients, vis-à-vis dystrophin replacement gene therapies, when used as a single agent.

Our Phase 1b data in BMD individuals demonstrated proof of concept by showing a significant reduction in key biomarkers of muscle damage.

We also initiated a Phase 2 clinical trial in individuals with BMD in July 2022 and initiated a Phase 2 clinical trial in children with DMD in October 2022.

Type II myosin inhibition prevents muscle damage via a blockade of the biophysical stress response during normal muscle contractile activity thus stabilizing the muscle and protecting the muscle from damage.

As such, it is a potentially complementary approach to dystrophin replacement strategies which stabilize muscle through the re-expression of a truncated but not fully functional dystrophin.

Absence of dystrophin in DMD causes muscle fiber membrane stress when muscles contract, leading to myofiber damage.

By enhancing muscle stability and decreasing muscle damage, we believe EDG-5506 has the potential to improve outcomes across a broad range of DMD patients when used as a single agent.

EDG-5506 may also provide a synergistic or additive effect in combination with available therapies and therapies currently in development, including dystrophin replacement gene therapies.

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Approximately 10% of mutations are duplications of exons and approximately 15% are single point mutations.

Depending on whether the specific mutations in the DMD gene maintain the reading frame, dystrophin will or will not be present such that in-frame mutations result in truncated dystrophin and BMD phenotype while out-of-frame or early stop mutations result in no dystrophin and DMD phenotype.

Dystrophin provides a structural link between the contractile elements (actin and myosin filaments) of the sarcomere and the basement membrane of the myofibers (muscle cell).

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Circumventing the loss of dystrophin’s structural function may prevent myofiber damage and preserve skeletal muscle function in DMD/BMD.

Illustrative mutations in the dystrophin gene and their impact on dystrophin production

DMD and BMD are classified as orphan diseases in the United States and Europe.

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However, in DMD, the regenerative process appears to fail over time as patients get older leading to fibrosis and progressive loss of muscle function with severe disability and early death.

Fibrotic tissue and fatty and inflammatory infiltrate replace myofibers in dystrophic muscle

DMD predominantly occurs in boys and typically presents at three to five years of age through observation of missed functional milestones and Gowers’ sign (a finding from a medical examination that identifies weakness of the proximal hip muscles) due to symmetrical, proximal weakness in selective muscle groups in combination with calf hypertrophy and creatine kinase (CK), a plasma protein biomarker linked to muscle damage, >10 times normal.

DMD predominantly occurs in boys and typically presents at three to five years of age through observation of missed functional milestones and Gowers’ sign (a finding from a medical examination that identifies weakness of the proximal hip muscles) due to symmetrical, proximal weakness in selective muscle groups in combination with calf hypertrophy and CK, a plasma protein biomarker linked to muscle damage, >10 times normal.

Systemically circulating biomarkers of myofiber degeneration, such as CK and troponin I are significantly elevated from birth with maximal levels at approximately two years of age.

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ability to rise from the floor, ability to climb stairs, ability to walk, upper limb function and respiratory function.

Typically, boys begin to lose the ability to rise from the floor between the ages of seven and nine, with the loss of the ability to climb stairs shortly thereafter and loss of ambulation often as early as 10 years of age.

Nearly all boys with DMD will require the use of a wheelchair by the time they are young teens.

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Becker Muscular Dystrophy

In contrast to DMD, BMD results from an in-frame mutation in the dystrophin gene yielding a partially functional protein.

In contrast to DMD, BMD results from a mutation in the dystrophin gene yielding a partially functional protein.

BMD patients often are diagnosed at a later age in childhood (approximately 11 years old) with similar symptoms to DMD of symmetrical, proximal limb weakness, notable in the quadriceps, with calf hypertrophy and elevated CK.

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However, BMD patients develop cardiomyopathy at a similar mean age to DMD (14.4 years DMD and 14.6 years BMD).

BMD patients may experience worse cardiomyopathy symptoms than DMD patients because BMD patients are ambulatory longer and can perform more motor function such that symptoms of cardiomyopathy may be more readily detectable with exertion, while DMD patients will uniformly be non-ambulatory in the teenage years.

BMD patients with cardiac failure commonly have mean life expectancy of 40 to 65 years old.

Comparison of DMD and BMD

Current Treatments for DMD and BMD and their Limitations

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The chronic and ongoing damage state seen in DMD is one of the targets of glucocorticoids.

Glucocorticoid treatment with either prednisone or EMFLAZA (deflazacort), the current standard-of-care for DMD, has been shown to temporarily improve muscle strength, prolong the period of ambulation and slow the functional decline, including upper limb and respiratory function, characteristic of the disease.

The modest chronic benefit of steroids, weighed against the risks, limits utilization to a relatively narrow age range since initiation of treatment prior to age four is not recommended and treatment is discontinued after loss of ambulation.

Glucocorticoid treatment with either prednisone or EMFLAZA (deflazacort), the current standard-of-care for DMD, has been shown to temporarily improve muscle strength, prolong the period of ambulation, and slow functional decline, including upper limb and respiratory function, characteristic of the disease.

In January 2023, Santhera in collaboration with ReveraGen Biopharma, announced the acceptance of the NDA for vamorolone, a novel steroid therapy for DMD, by the FDA.

The modest chronic benefit of steroids is weighed against the risks, and treatment is often discontinued after loss of ambulation.

Sustained glucocorticoid dosing in young DMD patients is associated with side effects including weight gain which could lead to obesity, Cushingoid features, excessive growth of hair on the body, adverse behavior changes, growth impairment, delayed puberty, immune suppression, adrenal suppression, fractures and cataracts.

Exon Skipping Therapies

There are four FDA conditionally-approved antisense oligonucleotide (AO) therapies, each limited to a specific mutation and a subset of the patient population:

There are four FDA conditionally-approved antisense oligonucleotide (AO) therapies approved under the accelerated approval pathway, each limited to a specific mutation and a subset of the patient population:

EXONDYS 51 (eteplirsen), approved for the treatment of DMD patients amenable to Exon 51 skipping, AMONDYS 45 (casimersen), approved for the treatment of DMD patients amenable to Exon 45 skipping and VYONDYS 53 (golodirsen) and VILTEPSO (vitolarsen), both approved for the treatment of DMD patients amenable to Exon 53 skipping.

An aggregate of approximately 29% of DMD patients are amenable to treatment with these therapies.

The FDA labels for all four drugs state that a clinical benefit has not yet been established and that continued approval may be contingent upon the verification of such clinical benefit in confirmatory clinical trials.

In addition, Translarna® (ataluren), a small molecule intended to promote ribosomal read-through to overcome the

nonsense (stop) pathogenic mutations in DMD, was granted approval by Iceland, Liechtenstein, Norway, Israel, South Korea and conditional approval granted by the EMA within the European Union (EU) Member States to treat DMD caused by a nonsense variant in ambulatory patients aged five years and older.

The FDA labels for all four drugs state that a clinical benefit has not yet been established and that continued approval may be contingent upon the

verification of such clinical benefit in confirmatory clinical trials.

In addition, Translarna® (ataluren), a small molecule intended to promote ribosomal read-through to overcome the nonsense (stop) pathogenic mutations in DMD, was granted approval by Iceland, Liechtenstein, Norway, Israel, South Korea and conditional approval granted by the EMA within the European Union (EU) Member States to treat DMD caused by a nonsense variant in ambulatory patients aged five years and older.

However, Phase 3 trials have not confirmed clinical efficacy and Translarna® is not approved for treating DMD in the United States.

All five of these approved products seek to address DMD through exon skipping, but we believe their limited observed efficacy is due to poor muscle penetration and biodistribution.

EXONDYS 51, VYONDYS 53 and AMONDYS 45, in addition to requiring weekly intravenous infusions, have demonstrated a less than 1% mean increase in dystrophin in clinical trials, which we believe is a function of poor and inefficient muscle transduction.

Moreover, a significant limitation of exon skipping approaches for DMD is the fact that each AO has been developed for skipping of a specific exon and their use is limited to a sub-set of mutations and hence only used in a subpopulation of DMD patients (e.g., exon 51 skipping is feasible in only up to 13% of all DMD patients).

Other companies, such as Avidity Biosciences, Inc., Dyne Therapeutics, Inc.

and Entrada Therapeutics, Inc.

Other companies, such as Avidity Biosciences, Inc., Dyne Therapeutics, Inc., REGENXBIO, Inc., and Entrada Therapeutics, Inc.

are working to improve on the muscle delivery aspects of AOs but suffer from the same limitations of first-generation AOs in that they will be restricted to specific, genetically defined DMD subsets.

Data suggests that with all exon skipping approaches, the best treatment outcome that DMD patients can expect is a Becker-like disease phenotype.

As all AO therapies result in the re-expression of a truncated dystrophin protein, the best treatment outcome that DMD patients can expect is a Becker-like disease phenotype.

Gene Therapy for DMD

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current constructs express truncated dystrophin proteins that are 20% to 30% of the normal size of the full-length dystrophin protein.

Recently, a number of gene therapies designed to produce a minidystrophin or microdystrophin have progressed into clinical development.

Recently, several gene therapies designed to produce a minidystrophin or microdystrophin have progressed into clinical development.

However, it is estimated that between 20% to 60% of patients have antibodies against AAV due to naturally acquired infections.

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The question around whether gene expression can persist lifelong after a single vector administration is an area of debate across many disorders including dystrophinopathies.

The long-term persistence of transgene expression is exacerbated by preexisting or recall immune responses to the AAV vector capsid and/or to the transgene product itself, which can interfere with therapeutic efficacy.

The long-term persistence of transgene expression is exacerbated by growth/turnover of skeletal muscle and preexisting or recall immune responses to the AAV vector capsid and/or to the transgene product itself, which can interfere with therapeutic efficacy.

Furthermore, this limited durability is problematic because re-administration after the first dose is currently not possible.

The current gene therapies for DMD also have strict age cut offs for patient eligibility.

Both Pfizer and Sarepta Therapeutics have limited their Phase 3 patient enrollment to children aged four to seven years old, thus excluding a significant proportion of DMD children and adolescents.

In November 2022, Sarepta announced that the U.S.

FDA accepted their Biologics License Application seeking accelerated approval of their microdystrophin gene therapy, SRP-9001 (delandistrogene moxeparvovec), for the treatment of ambulant individuals with DMD.

SRP-9001 has been granted Priority Review by the FDA, with a regulatory action date of May 29, 2023.

Other companies focused on developing genetic based therapies for DMD that target dystrophin mechanisms include Pfizer Inc., Solid Biosciences Inc., Genethon, PepGen, Dyne Therapeutics, Avidity Biosciences, REGENXBIO, and Entrada Therapeutics.

Gene editing treatments that are in preclinical development are also being pursued by Vertex and Sarepta Therapeutics.

Both Pfizer and Sarepta Therapeutics limited their Phase 3 patient enrollment to children aged four to seven years old, thus excluding a significant proportion of DMD children and adolescents.

Due to weight-based dosing regimens, for older patients in particular, who are generally heavier, scaling up to produce enough AAV-based viral vector genomic particles or vector genomes, remains a potentially significant encumbrance and even if feasible, raises concerns relating to safety of administering higher viral loads to patients.

It is important to note that multiple clinical trials have reported significant adverse events associated with systemic administration of higher doses of AAV to treat muscle diseases.

Vector dilution will also be an important consideration that we believe will limit the current class of AAV-based gene therapies to the age groups studied in their respective trials.

Vector dilution will also be an important consideration that we believe will limit the current class of AAV-based gene

therapies to the age groups studied in their respective trials.

We anticipate that treatment with AAVs engineered to deliver mini or micro dystrophin in younger patients will lead to a dilution of the transcript with age and normal growth;

thus, children are unlikely to express dystrophin as their disease progresses and they become symptomatic and non-ambulatory.

Even if minidystrophin or microdystrophin gene therapy for DMD is successful, we believe that the best potential therapeutic outcome is inducing a Becker-like phenotype where patients would still have significant residual skeletal

muscle impairment and will thus continue to have a high degree of unmet need.

Delivery of minidystrophin or microdystrophin to muscles in DMD has been shown to be sufficient to reform the larger complex of proteins that make up the dystroglycan complex.

However, the truncated nature of the shortened dystrophin protein is not capable of providing complete protection against contraction injury.

As a result, we believe that the best potential therapeutic outcome is inducing a severe Becker-like phenotype (the shortest documented dystrophin protein in Becker is 50% of normal) where patients would still have significant residual skeletal muscle impairment and will thus continue to have a high degree of unmet need.

What is clear is that gene therapies currently in development for DMD do not represent a cure for the disease.

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Since the cloning of the dystrophin gene in 1986, researchers, clinicians, and pharmaceutical and biotechnology companies have worked relentlessly to advance the scientific and clinical understanding of DMD to accelerate finding a cure.

At Edgewise, we have built on top of this foundational work through applying our understanding of muscle physiology to develop EDG-5506, a molecule that we believe has the potential to change the devastating course of DMD.

At Edgewise, we have built on this foundational work through applying our understanding of muscle physiology to develop EDG-5506, a molecule that we believe has the potential to change the devastating course of DMD.

While many of our competitors are targeting dystrophin, our orthogonal approach is focused on protecting muscle damage induced by contractions from activities of daily living.

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By protecting dystrophin deficient myofibers from degeneration, EDG-5506’s mechanism of action is directed towards the underlying cause of muscle degeneration in DMD and BMD to reduce muscle damage, prevent downstream fibrosis, allow healthy muscle contraction, and enhance physical function.

Moreover, since muscle damage induced by excessive exercise in normal volunteers can reduce muscle strength through the generation of edema and fiber disruption by up to 30%, we believe that elimination of muscle damage could increase muscle strength and ultimately function in a muscular dystrophy populations where continuous muscle damage is the driver of disease progression.

● Highly selective for all fast type II myofibers, thus limiting the potential for serious off-target side effects.

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This reduces exposure of the compound to other organs such as the liver and kidney, limiting the chances of unexpected adverse effects.

● Offers a mutation agnostic approach with the potential to be used for disorders resulting from genetic lesions in dystrophin or the sarcoglycan complex.

EDG-5506 can potentially be used to treat all populations of DMD and BMD, as well as LGMD, a progressive, lethal myopathy that results from mutations of key proteins in the sarcoglycan complex.

● Offers a mutation agnostic approach with the potential to be used for disorders resulting from genetic lesions in dystrophin or the dystroglycan complex.

EDG-5506 can potentially be used to treat all populations of DMD and BMD, as well as many forms of LGMD, a progressive, lethal myopathy that results from mutations of key proteins in the dystroglycan complex.

● Provides a mechanistic approach to treat DMD that may provide additional functional benefits over genetic based therapeutics .

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We are developing EDG-5506 to be used as a single agent therapy but it may also provide a synergistic or additive effect in combination with available therapies and therapies currently in development.

Moreover, EDG-5506 may offer a disease modifying option for patients currently excluded from Phase 3

minidystrophin or microdystrophin gene therapy trials due to age (four to seven year old children) and those who have antibodies against AAV due to naturally acquired infections.

Moreover, EDG-5506 may offer a disease modifying option for patients currently excluded from Phase 3 minidystrophin or microdystrophin gene therapy trials due to age (four to seven year old children) and those who have antibodies against AAV due to naturally acquired infections.

We believe these characteristics uniquely position EDG-5506 as a potentially new standard of care for patients with DMD and BMD, either as a standalone or in combination with other therapies.

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We have taken advantage of this flexibility to explore an alternative therapeutic strategy to protect susceptible type II skeletal muscle fibers.

Properties of skeletal muscle fiber types:

slow (type I) and fast (type II) fibers

When muscle fibers undergo damage, they release internal proteins such as CK (A) and troponin into the blood.

When muscle fibers undergo damage, they release internal proteins such as CK and troponin into the blood.

One of the troponin subunits, TnI has a different isoform for each type of striated muscle (fast, slow and cardiac) and can be used to explore the fiber-specific source of these proteins.

We evaluated DMD and BMD patient plasma samples using high specificity assays for fast and slow myofiber TnI and observed that fast myofiber TnI (TnI2) plasma levels (B) are higher than slow myofiber TnI (TnI1) levels (C), suggesting that fast myofibers are more susceptible to loss of dystrophin function during muscle contraction.

Conversely, we observed that HVs had virtually no leak from fast muscles (B).

We evaluated DMD and BMD patient plasma samples using high specificity assays for fast and slow myofiber TnI and observed that fast myofiber TnI (TnI2) plasma levels are higher than slow myofiber TnI (TnI1) levels, suggesting that fast myofibers are more susceptible to loss of dystrophin function during muscle contraction.

Conversely, we observed that HVs had virtually no leak from fast muscles.

Biomarkers of fast fiber turnover are elevated in BMD and DMD

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We anticipate that the high potency, fast fiber targeting and low projected dose of EDG-5506 will limit unwanted side effects.

Moreover, stabilization of the sarcomere for the most damage-susceptible muscle fibers in DMD with EDG-5506 potentially provides greater muscle protection than inhibition of calcium release via the ryanodine receptor.

Moreover, stabilization of the sarcomere with EDG-5506 via direct decreases in contractile stress potentially provides greater muscle protection than secondary inhibition of calcium release via the ryanodine receptor.

Another corollary to our approach of selectively targeting type II fast skeletal muscle myofibrils with EDG-5506 is mavacamten (MYK-461), a selective allosteric inhibitor of cardiac type I myosin ATPase.

Mavacamten is currently under review by the FDA for possible approval for HCM, a disorder characterized by excessive contractility and impaired relaxation of cardiomyocytes.

Mavacamten was approved by the FDA for HCM, a disorder characterized by excessive contractility and impaired relaxation of cardiomyocytes.

Through selective targeting of cardiac type I myosin ATPase, mavacamten is designed to reduce cardiac muscle hypercontractility in HCM.

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Interestingly, nature has carried out one of the more critical experiments to help us understand the impact of inhibiting fast fiber myosin selectively.

There are several reports describing the human phenotype of people born with genetic loss of function (LOF) of the myosin heavy chain 2 gene, MYH2.

Muscle biopsies in these patients show a heavy skewing towards slow type I muscle fibers as a result of complete lack of fast type II muscle fibers.

There are several reports describing the human phenotype of people born with genetic loss of function (LOF) of the myosin heavy chain 2 gene, MYH2 which encodes Type IIa myosin and makes up approximately 85% of the body’s fast fibers.

Muscle biopsies in these patients show a heavy skewing towards slow type

I muscle fibers as a result of complete lack of fast type IIa muscle fibers.

These patients have mild, proximal muscle weakness with ocular muscle involvement but remain ambulatory throughout life.

The observations in these patients demonstrate an ability of the body to maintain function despite complete loss of one myofiber type.

Given that our goal is to only partially inhibit type II fast skeletal muscle myofibrils in order to modulate force development and not completely inhibit them, as is the case in the LOF patients, it is our belief that selective fast fiber regulation with EDG-5506 will likely be well-tolerated and may protect dystrophic myofibers from degeneration and subsequently improve and/or preserve physical function.

Given that our goal is to partially inhibit type II fast skeletal muscle myofibrils in order to modulate force development and not completely inhibit them, as is the case in the LOF patients, it is our belief that selective fast fiber regulation with EDG-5506 will likely be well-tolerated and may protect dystrophic myofibers from degeneration and subsequently improve and/or preserve physical function.

Preclinical Data

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The inhibitory activity of EDG-5506 in live skeletal muscle ex vivo was measured in wild type (WT) mouse EDL muscle, a predominantly fast skeletal muscle in the hindlimb.

We observed that the addition of EDG-5506 to isolated muscle resulted in concentration- and time-dependent decreases in maximal force (A).

We observed that the addition of EDG-5506 to isolated muscle resulted in concentration- and time-dependent decreases in maximal force.

EDL muscles from dystrophic mdx mice exhibited enhanced force run-down with eccentric (lengthening) contraction.

We also observed that the addition of 5 µM EDG-5506 to mdx EDL muscle for 60 minutes (enough to decrease pre-injury maximal force by 50%) decreased peak force decline closer to that observed in WT mouse muscle (B).

Protection with EDG-5506 exhibited a concentration dependent response with 50% of maximal protection at approximately 1 µM, associated with an approximately 10% decrease in force at the time of the injury (C).

EDG-5506 protected dystrophic skeletal muscle from contraction-induced functional decline ex vivo

Protection with EDG-5506 exhibited a concentration

dependent response with 50% of maximal protection at approximately 1 µM, associated with an approximately 10% decrease in force at the time of the injury.

In situ muscle tests were next performed on intact mdx mouse TA muscle, with contraction elicited via sciatic nerve stimulation and force measured from a tendon at the ankle of the mouse under anesthesia.

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Longer term effects of EDG-5506 were assessed in young mdx mice after eight weeks of administration.

EDG-5506 treated mice exhibited higher grip strength compared to vehicle treated mice (A).

EDG-5506 treated mice exhibited higher grip strength compared to vehicle treated mice.

At the end of the study, continued muscle protection was observed with a rotarod exercise challenge.

There was no observed difference in rotarod performance (B), but CK was observed to be lower in the treated groups compared to vehicle, consistent with single-dose results (C).

There was no observed difference in rotarod performance, but CK was observed to be lower in the treated groups compared to vehicle, consistent with single-dose results.

While DMD patients exhibit extensive muscle fibrosis with age, collagen accumulation in mdx mice is generally limited to the diaphragm.

Histological examination of the diaphragm using a collagen stain (picrosirius red) revealed lower staining in EDG-5506 treated mice (example images D, calculated area E).

EDG-5506 improved strength and diaphragm fibrosis after 8 weeks treatment of dystrophic mdx mice

Histological examination of the diaphragm using a collagen stain (picrosirius red) revealed lower staining in EDG-5506 treated mice.

Improvements in fibrosis, cardiac hypertrophy and kyphosis in the DBA/2J mdx mouse model of DMD

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EDG-5506 dramatically prevents kyphosis in DBA/2J mdx mice

Consistent with shorter term studies, we also observed significant reductions in gastrocnemius muscle fibrosis along with significant improvements in muscle weight (A).

Diaphragm fibrosis was not observed to be lowered with longer term treatment (B), but the incidence of lipid vacuole deposition (red arrows) was observed to be significantly lowered with treatment.

Consistent with shorter term studies, we also observed significant reductions in gastrocnemius muscle fibrosis along with significant improvements in muscle weight.

Diaphragm fibrosis was not observed to be lowered with longer term treatment, but the incidence of lipid vacuole deposition was observed to be significantly lowered with treatment.

Fatty tissue deposition is common in older DMD patients, in conjunction with fibrosis.

EDG-5506 improved skeletal muscle fibrosis and atrophy in DBA/2J mdx long-term studies

Improvements in cardiac fibrosis and hypertrophy in DBA/2J mdx long-term studies

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The SOMAscan analysis showed that EDG-5506 significantly and reversibly altered blood concentrations away from the DMD patient signature profile during the dosing period.

EDG-5506 positively altered GRMD proteins identified as being associated with the dystrophic state in DMD patients

Preclinical Pharmacokinetics and Metabolism of EDG-5506

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The compound distributes to skeletal muscle, its intended therapeutic target, with high skeletal tissue to plasma ratios.

Distribution to cardiac muscle is minimal and tends to be on the order of 2-fold plasma levels.

Distribution to cardiac muscle is minimal and tends to be on the order of 2-fold

plasma levels.

High absolute oral bioavailability was observed across species when presented as a solution or highly dispersed suspension.

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13-week repeated dose toxicity studies were performed in rat and dog to support the Phase 1 first-in-human clinical trial.

Additionally, a 26-week oral GLP toxicity study of EDG-5506 in rats and a 39-week oral GLP toxicity study of EDG-5506 in dogs were performed to support longterm dosing in humans.

Additionally, a 26-week oral GLP toxicity study of EDG-5506 in rats and a 39-week oral GLP toxicity study of EDG-5506 in dogs were performed to support long-term dosing in humans.

All toxicities noted were ascribed to EDG-5506 and were consistent with the known mechanism of EDG-5506 and exaggerated primary PD activity (i.e., regulation of type II fast skeletal muscle myosin).

There were no unanticipated off-target toxicities noted in either rats or dogs administered EDG-5506 for up to 39 weeks.

We expect to receive the results of a 7-week oral juvenile toxicity study in 2022.

We also completed a 7-week oral juvenile toxicity study in 2022 with no unanticipated off-target toxicities noted.

EDG-5506 Formulation

EDG-5506 is formulated as a powder for suspension in a commercially available compounding agent, SyrSpend® SF (sugar free), for once daily oral administration.

This allows EDG-5506 to be administered to young children.

In our Phase 1 clinical trial for EDG-5506, we utilized a formulation of powder for suspension in a commercially available compounding agent, SyrSpend® SF (sugar free), for once daily oral administration.

SyrSpend® SF is a sweetened, suspending vehicle for use in compounded oral liquid preparations.

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All ingredients are “Generally Recognized as Safe” (GRAS) or classified as “inactive ingredients” by the FDA when used in accordance with their intended purpose.

We have also developed an immediate release tablet formulation for the Phase 2 trials in BMD and DMD.

As EDG-5506 is a biopharmaceutics classification system (BCS) Class 1 molecule, it can be readily formulated into solid dosage forms including tablets and capsules.

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The most common AEs were dizziness and somnolence, which was seen at Grade 1 (on the Division of AIDS AE Grading Scale) except in the single dose cohort of 135 mg, where Grade II somnolence and dizziness were observed.

Phase 1a Even ts

Our SAD demonstrated rapid absorption of EDG-5506 following a single oral dose.

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Exposures were observed to be dose proportional up to the 45 mg dose.

PK modeling utilizing the SAD dataset projected that once-daily doses of 10-15 mg will achieve steady-state Ctrough drug concentrations at or above the efficacy exposure levels achieved in preclinical dystrophic models.

Phase 1a single dose PKs in HVs

As part of the first in human clinical trial, we also explored EDG-5506’s ability to inhibit involuntary quadriceps twitch force, a direct marker of target engagement.

Using a trans-magnetic device to stimulate involuntary leg contraction via a probe placed over the top of the leg, muscle force was then measured via a force transducer connected to the ankle.

This novel experimental measure has not been used previously in an interventional trial.

Our goal was to derive a relationship between dose, plasma exposure and involuntary twitch force inhibition after administration of EDG-5506 in healthy volunteers.

Proof of mechanism was demonstrated by dose dependent PD activity at doses of 45 mg and above, with each dose cohort clearly differentiated from placebo.

EDG-5506’s robust PD effect in humans was observed at exposures similar to those seen at efficacious levels in preclinical disease models.

The time course of peak PD activity (10 hours post dosing) was substantially separated from the onset of somnolence (approximately 30 minutes post dosing).

The effect was reversed within 48 hours post dosing.

Onset of the PD effect was consistent with preclinical observations of steady-state redistribution to the gastrocnemius muscle in rodents.

Importantly, EDG-5506 was not found to affect voluntary skeletal muscle function, as assessed by handgrip strength testing, nor was it found to negatively impact alternate forms of myosin elsewhere in the body (e.g., cardiac or slow muscle).

These observations provide preliminary evidence of a dose dependent change in a biomarker of fast myosin regulation following a single dose of EDG-5506.

The magnitude of the effect was in line with force reductions required to prevent muscle degeneration in preclinical experiments with dystrophic mice.

Moreover, human exposures at 10 hours were consistent with steady state concentrations observed in preclinical efficacy studies.

PK modeling utilizing the SAD dataset projected that once-daily doses of 10-15 mg will achieve steady-state C trough drug concentrations at or above the efficacy exposure levels achieved in preclinical models of Duchenne muscular dystrophy .

Multiple Ascending Dose (MAD) Cohorts

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20 mg/10 mg).

Generally, cohorts B3 to B5 did not receive a loading dose and were administered a 20 mg suspension (B3) or a solid dosage form at doses of 20 mg (B4) and 40 mg (B5) daily for 14 days.

C ohorts B3 to B5 did not receive a loading dose and were administered a 20 mg suspension (B3) or a solid dosage form at doses of 20 mg (B4) and 40 mg (B5) daily for 14 days.

The study drug was well tolerated in all multi-dose cohorts (5 to 40 mg EDG-5506 given once daily for 14 days).

Overall, 30 of 40 (75%) enrolled subjects experienced treatment emergent adverse events (TEAEs) which were all Grade 1.

Dizziness and somnolence were the most common AEs experienced and in all cases were mild and transient.

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There were no AEs of special interest, no SAEs, and no discontinuations due to AEs.

There were no AEs due to clinically significant abnormal vital signs, ECG or laboratory assessments.

Hand grip strength testing was serially measured with no significant change seen in any MAD participants.

In the MAD, the PKs on Day 1 were consistent with the PKs observed in the SAD part of the study with rapid absorption for the suspension formulation (Cohorts B1-B3).

Variability observed in exposure parameters tends to decrease over time as drug accumulates with moderate variability on Day 14 consistent with filling of the muscle compartment.

Cohorts B3 and B4 (20 mg once-daily for 14 days) allowed for the direct PK comparison of the suspension (SS) formulation and the solid dosage form (SD).

The AUC0-24 and C24 PK parameters were similar between the two cohorts on Days 1 and 14.

Accumulation ratios were also similar between the cohorts indicating similar absorption of drug.

However, Cmax was lower in the solid dosage form by approximately 50-75% on each of the 3 days on which extensive PK sampling was done (1, 4, and 14).

Mean EDG-5506 Trough Plasma Concentration Versus Time Following

Multiple Oral once-daily Doses for 14 Days in Healthy Volunteers

As already outlined in the preclinical section, we have made significant efforts to understand the pharmacology of EDG 5506, its general tolerability and its ability to improve symptoms of disease in a variety of models of muscular dystrophy.

An additional and important goal was to also provide a range of compound concentrations required to achieve efficacy and translate those levels to meaningful target muscle exposures in humans.

To achieve this, we focused on measuring absolute muscle concentrations in preclinical studies and then calculated a human target equivalent muscle exposure, based on relative proportions of fast muscle fibers (see figure below).

EDG-5506 Target Human Muscle Exposure Range

As shown, EDG-5506 human muscle levels of 1,000 to 4,100 ng/g were projected to provide meaningful clinical benefit in humans based on experiments in mdx , DBA/2J mdx and GRMD.

Of note, muscle concentrations in mouse studies were those required for maximal efficacy, essentially returning dystrophic muscle to a normal state.

In the MAD cohorts, muscle biopsy samples were taken at Day 14 to measure EDG-5506 levels in muscle.

In Cohorts B1-B5, EDG-5506 concentrates in muscle at or above levels predicted to provide meaningful clinical benefit in humans (summarized below).

Mean EDG-5506 concentration was two orders of magnitude higher concentrations in the muscle tissue versus plasma, which we believe reflects the known high-affinity binding to myosin in fast muscle fibers.

This observation was key as it demonstrated EDG-5506 achieves muscle concentrations believed to be needed in the clinic in order to demonstrate efficacy.

Muscle EDG-5506 Concentrations in Cohorts B1-B5

The pharmacodynamic effect of EDG-5506 was once again measured using the Magstim trans-magnetic device.

Findings from the MAD cohorts showed that not only is EDG-5506 reaching the fast muscle fibers but that EDG-5506 also leads to a dose dependent and highly statistically significant inhibition of involuntary fast muscle fiber twitch, the precise target of EDG-5506.

Importantly there was no impact on voluntary muscle function.

In the MAD, the PKs on Day 1 were consistent with the PKs observed in the SAD part of the study.

In summary, the Phase 1a SAD/MAD demonstrated that EDG-5506 was generally well tolerated with no serious adverse events observed.

PK data supports robust target engagement with achievement of muscle concentrations well above the efficacious levels observed in preclinical disease models.

Moreover, EDG-5506 PD data showed a dose-dependent effect on involuntary twitch response in healthy volunteers, reflecting robust target engagement.

Based on these observations, a 20 mg solid dosage form was selected for the Becker muscular dystrophy patients in the Phase 1b trial.

Becker Muscular Dystrophy Cohort (Part C)

PK data supports robust target engagement with achievement of muscle concentrations well above the efficacious levels observed in preclinical disease models of DMD .

Becker Muscular Dystrophy Cohort (Cohort C1)

Cohort C1 enrolled seven adult males with BMD who were randomized to active (n=5) or placebo (n=2).

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BMD Phase 1b Patient Demographics

Unsurprisingly, the quadriceps in the BMD patients demonstrated significant damage as determined by the lack of a detectable signal in response to Magstim and thus an inability to measure a change in twitch response with EDG-5506.

Moreover, the grip strength in BMD patients was also impaired to approximately 60% of normal grip strength.

Baseline Magstim and Hand Grip Strength in BMD Cohort

EDG-5506 was well tolerated in BMD subjects.

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There were no AEs due to clinically significant abnormal vital signs, ECG or laboratory assessments.

All participants that received EDG-5506 experienced Grade 1 dizziness with 2 of 5 participants reporting somnolence (summary below).

Hand grip strength testing was serially measured with no significant change seen in BMD participants.

Phase 1b Individuals with BMD - Adverse Events

All participants that received either EDG-5506 or placebo experienced Grade 1 dizziness with 2 of 5 participants that received EDG-5506 reporting somnolence.

Muscle Concentrations of EDG-5506 in MAD and Becker Muscular Dystrophy Cohorts

An important goal in Phase 1 was to provide a range of compound concentrations required to achieve efficacy and translate those levels to meaningful target muscle exposures in humans.

EDG-5506 Target Human Muscle Exposure Range

As shown, EDG-5506 human muscle levels of 1,000 to 4,100 ng/g were projected to provide meaningful clinical benefit in humans based on experiments in mdx , DBA/2J mdx and GRMD.

Of note, muscle concentrations in mouse studies were those required for maximal efficacy, essentially returning dystrophic muscle to a normal state.

In the MAD and Becker muscular dystrophy cohorts, muscle biopsy samples were taken at Day 14 to measure EDG-5506 levels in muscle.

In Cohorts B1-B5, EDG-5506 concentrates in muscle at or above levels predicted to provide meaningful clinical benefit in humans (summarized below).

Mean EDG-5506 concentration was 100-fold higher concentrations in the muscle tissue versus plasma, which we believe reflects the known high-affinity binding to myosin

in fast muscle fibers.

This observation was key as it demonstrated EDG-5506 achieves muscle concentrations believed to be needed in the clinic in order to demonstrate efficacy.

Muscle EDG-5506 Concentrations in Cohorts B1-B5 and C1

Similar to the MAD cohorts, biopsy samples were taken from the quadriceps of BMD patients at Day 14 to measure EDG-5506 levels in muscle.

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The muscle levels reached in BMD patients were in the range where multiple preclinical studies with EDG-5506 have shown pharmacological activity in models of DMD.

EDG-5506 Muscle and Plasma Concentration in BMD Patients

Muscle injury in muscular dystrophies leads to leaking of several muscle proteins into the circulation, including CK, myoglobin and TNNI2 (see overview of biomarkers below).

Biomarkers of Muscle Damage in Becker Muscular Dystrophy Cohort (Cohort C1)

Muscle injury in muscular dystrophies leads to leaking of several muscle proteins into the circulation, including CK, myoglobin and TNNI2.

Serial blood samples were taken from BMD participants for both biochemical analysis of biomarkers of muscle damage and proteomics using the SOMAscan to enable unbiased profiling of elevated plasma proteins and establish a unique BMD disease biomarker fingerprint.

Biomarkers of Muscle Damage in Muscular Dystrophies

After 14 days of treatment with EDG-5506, BMD participants had a significant and rapid decrease in circulating CK of 66%, reflecting a reduction from 5X to 1.6X of the upper limit of normal by the second week of dosing.

The low absolute CK levels observed following treatment with EDG-5506 are unprecedented for BMD patients and have not been previously reported for any therapeutics targeting BMD patients.

There was also a modest, non-significant and anticipated CK decrease in the placebo group, consistent with BMD patients being confined to a phase 1 clinical study unit and exhibiting an overall reduced level of physical activity – this “natural” reduction in CK has previously been reported for DMD children confined to an in-patient setting.

Importantly, following a 4-week washout, CK values rebound back to baseline levels further supporting a strong drug effect.

CK Reduction Following EDG-5506 Treatment

Additionally, myoglobin levels similarly decreased to near normal levels and aspartate transaminase (AST) dropped to within the normal range in all subjects who received EDG-5506.

Reduction in Myoglobin and AST Following EDG-5506 Treatment

Leveraging the SOMAscan 7,000 analyte set, baseline BMD patient plasma samples (n=7) were compared to baseline samples taken from healthy volunteers (n=25).

To establish a unique proteomic signature for individuals with BMD, elevated proteins were filtered by those exhibiting a magnitude of change ≥1.5X and an adjusted p value of <0.05 relative to healthy volunteers (illustrated in red box below).

To establish a unique proteomic signature for individuals

with BMD, elevated proteins were filtered by those exhibiting a magnitude of change ≥1.5X and an adjusted p value of <0.05 relative to healthy volunteers (illustrated in red box below).

This analysis is the first of its kind to characterize a unique proteomic fingerprint for individuals with BMD.

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Specifically, CK decreased by 71%, similar to the decrease observed in biochemical activity assays, while TNNI2 decreased by 83% with treatment.

Both muscle damage biomarkers returned to normal levels observed in healthy individuals following 14-days of treatment with EDG-5506 (see below).

Individual SOMAscan measures of CK and TNNI2 showed a tight correlation, as would be expected for proteins that similarly leak from damaged muscles.

CK and TNNI2 are Reduced to Levels Observed in HVs Following Treatment with EDG-5506

Interestingly, proteins that were most elevated in the BMD signature set were also those that decreased following treatment with EDG-5506.

This observation suggests a broad normalization of the proteomic signature of BMD towards a more normal state with EDG-5506 treatment.

Correlation Between Elevation of Biomarkers and Response to EDG-5506

This observation suggests a broad normalization of the proteomic signature of BMD towards a more normal state following treatment with EDG-5506.

The robust reduction in muscle damage biomarkers observed in BMD suggests that EDG-5506 may normalize the excessive stress observed in dystrophic muscle, ultimately preserving muscle function and preventing disease progression in muscular dystrophies.

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Overall, the findings for the Phase 1 clinical trial with EDG-5506 provide compelling evidence for EDG-5506 as a potentially disease modifying treatment for muscular dystrophies.

Both in HVs and BMD patients, EDG-5506 was well tolerated and achieved muscle concentrations well above those predicted to demonstrate efficacy based on preclinical disease models.

Moreover, EDG-5506 led to a robust, significant reduction in key biomarkers of muscle damage, driving CK, TNNI2, myoglobin and AST to either normal or near normal levels observed in healthy volunteers after only two weeks of dosing.

Planned Future Clinical Trials

Following successful completion of the Phase 1 clinical trial in HVs and BMD patients, a summary of the on-going and planned clinical studies with EDG-5506 in 2022 is provided in the table below.

Summary Table of Upcoming Clinical Trials

Open Label Study in BMD Patients (ARCH Study)

We are currently enrolling the ARCH study, which is an open-label, single-center study that will assess the safety and PK of EDG-5506 over one year in adults with BMD.

This study will also investigate the effect of EDG-5506 on biomarkers of muscle fiber damage.

We are enrolling participants diagnosed with BMD, who completed the Phase 1b trial, as well as participants who are treatment naïve to EDG-5506.

A 10 mg dose will be administered once-daily at night prior to bedtime.

We anticipate interim data in the first half of 2022.

Phase 2 Clinical Trial in BMD

The Phase 2 clinical trial in BMD is projected to commence in the first half of 2022 and will assess safety, PK, functional measures and upper leg fat fraction over one year as measured by MRI in BMD adults and adolescents.

Assessments in the Phase 2 clinical trial will include muscle performance measures, such as a modified-NSAA (NSAD) and timed function tests, in addition to serum biomarkers of myofiber degeneration (e.g., CK, troponins, myoglobin).

Natural History Study and Exercise Challenge Study

In 2022, we expect to commence both an observational natural history study, being conducted in collaboration with the GRASP-LGMD Consortium, and a Phase 2 Exercise Challenge Study, to investigate the effect of EDG-5506 on muscle injury biomarkers following exercise in individuals with LGMD2I, BMD or McArdle disease at a single site in Denmark.

Phase 2 Clinical Trial in DMD

We plan to initiate a Phase 2 clinical trial in pediatric DMD patients in the second half of 2022.

Rationale for Studying Adult Becker Muscular Dystrophy Patients

The typical BMD disease course is associated with progressive limb weakness resulting in severe disability and loss of ambulation as well as increased risk of early mortality from cardiac failure.

No therapies have been approved for the treatment of BMD.

In 2016, a comprehensive, longitudinal one-year academic study was published of 69 BMD patients aged between six and 69 years.

Patients were classified accordingly:

deletions ending on exon 45 (del 45-x;

n=28), deletions ending on exon 51 (del x-51;

n=10), isolated exon 48 deletions (del 48;

n=10) and other mutations (n=21).

90% of the del 48 and del x-51 had a mild or asymptomatic BMD disease course as is well known regarding the del x-51 genotype.

Interestingly, the del 45-x patients presented with a more pronounced and severe BMD course with significant lower limb weakness measurable with the NSAA over a 12-month period, with the majority losing ambulation at some point in their lifetime.

Patient and Caregiver Engagement Strategy

The muscular dystrophy patient community is highly knowledgeable and active, having been heavily engaged with many of the innovations in the rare disease regulatory and drug development landscape and with strong relationships with KOLs, regulators, the research community and payors.

We have and plan to continue to engage comprehensively with patients and physicians to develop positive relationships and transparent communication and become a valued partner in the muscular dystrophy stakeholder community.

Through a variety of engagement efforts, we will seek to more fully appreciate the burden of disease from the patient perspective, understand the current standard of care and unmet needs in managing disease, and better learn what is most meaningful to patients.

This patient insight will inform our preclinical, clinical development and commercial strategies and we expect it will facilitate more effective execution when recruiting for and conducting trials.

We plan to support the key patient advocacy organizations in the United States and the European Union in their research, care, advocacy and educational initiatives to help improve the quality of life of individuals with muscular dystrophy and other diseases.

By positioning ourselves as a trusted partner who moves with thoughtful urgency, we believe we will have a voice with the patients that will continue to serve us as we develop EDG-5506 and other programs for neuromuscular and other diseases.

Evolution of Newborn Screening for Muscular Dystrophy

There is typically is a diagnostic delay between when muscular dystrophy symptoms are first noticed by parents and brought to the attention of their primary care physicians, and when a genetic diagnosis is made.

Unless there is a known family history, muscular dystrophy has not widely been screened for in infancy.

To fill this gap, a newborn screening initiative was put into place led by muscular dystrophy patient advocacy organizations and community leaders in the mid 2000’s with the goal of identifying and providing care for every child born with muscular dystrophy and achieving Recommended Uniform Screening Panel (RUSP) status.

A critical step in this effort was developing a scalable and cost-effective algorithm for accurately detecting muscular dystrophy that could be implemented at a national level.

An Ohio NBS pilot from 2007 to 2011 developed a two-tiered process using CK measured from dried blood spot (DBS) and establishing a threshold level at which a second CK from venous blood was necessary to determine who should have genetic testing.

Currently, a newborn screening pilot program in New York State is testing this and other aspects of a comprehensive newborn screening program at a large scale.

A Steering Committee is compiling other evidence necessary to support a nomination package to the Advisory Committee for Heritable Disorders in Newborns and Children (ACHDNC) to add muscular dystrophy to the RUSP.

Once the requirements are met and accepted at a national level, implementation then takes place at the state level.

State based universal NBS would allow more infants with muscular dystrophy to be identified earlier in life, giving them a greater chance of receiving benefit from optimal care and disease modifying treatments before symptoms manifest and functional milestones are lost.

Progress in NBS for muscular dystrophy and future implementation at a national level through inclusion of muscular dystrophy on the RUSP will allow potentially disease modifying therapies, such as EDG-5506, to be initiated early on allowing the possibility to completely alter the devastating natural history of the disease.

Additional Indications

LGMD is a general term for muscular dystrophies that are not X-linked and are non-congenital.

They are a group of disorders of skeletal muscles that results in progressive limb, shoulder, and hip girdle weakness and wasting, significantly impairing daily function with resultant disability.

Collectively, they are the fourth most common genetic cause of muscle weakness.

The approximate global prevalence of LGMD as a group is estimated to be from 0.56 to 5.75 per 100,000.

Males and females are affected in equal numbers.

Onset may occur in childhood, adolescence, young adulthood, or even later.

LGMD leads to a variable shortened lifespan;

however, problems can arise in individuals who have problems in heart muscles and the respiratory system.

LGMD is caused by mutations of genes that result in abnormalities in dystrophin-glycoprotein complex, the sarcomere, glycosylation of dystroglycan, vesicle and molecular trafficking, signal transduction pathways, and nuclear functions.

There are at least 30 different subtypes of LGMD.

The inheritance pattern of LGMD varies and different genetic defects may result in the same clinical symptoms in different patients.

Several rare forms are inherited in an autosomal dominant pattern (LGMD type 1).

Most forms of LGMD are inherited in an autosomal recessive manner (LGMD type 2).

LGMD type 1 follows a slower and more variable disease course whereas LGMD type 2 tends to have an earlier onset and progresses more quickly.

Like DMD and BMD, most LGMD mutations destabilize the dystrophin/dystroglycan complex, resulting in muscle breakdown with normal muscle contraction and elevated serum CK levels.

Treatment of LGMD is exclusively symptomatic involving physical therapy, surgery, and care of the lungs and heart.

There are no disease modifying therapies approved to halt disease progression.

Because EDG-5506 stabilizes muscle independently from the functional integrity of the dystrophin complex, we anticipate that our approach could also improve muscle health in LGMD patients.

McArdle Disease

McArdle disease, also known as glycogen storage disease type V (GSDV), is an autosomal recessive disease caused by mutations in the gene encoding for the muscle isoform of glycogen phosphorylase (PYGM).

It is an ultra-rare disease, and the exact prevalence is not known, but is estimated to be one in 100,000-140,000 patients.

It is a pure myopathy characterized by high serum CK activity, exercise intolerance, the second wind phenomenon, acute crises of early fatigue, and contractures, sometimes (50% of cases) with rhabdomyolysis and myoglobinuria, triggered by static muscle contractions or vigorous exercise.

The diagnosis of McArdle’s disease is based on biological findings that reveal a lack of elevation of blood lactate levels during the forearm ischemic exercise test, excess of glycogen, and deficit of myophosphorylase in muscle biopsy or white blood cells.

There is currently no specific treatment for McArdle’s disease.

Treatment is mostly symptomatic as well as avoiding the performance of intense physical exercise.

Healthy lifestyle interventions, such as following a diet rich in complex carbohydrates, are the most effective means of preventing and managing exercise intolerance in McArdle’s disease and require a proactive attitude of clinicians, exercise professionals, patients and caregivers.

In light of the lack of approved therapies and the negative impact of excessive muscle contractures on the pathophysiology of McArdle’s disease, we plan to explore the potential role of EDG-5506 in preserving muscle integrity and function.

Our Research Programs

Our muscle screening platforms have identified small molecule modulators of muscle function with alternative targets and mechanisms beyond those described for EDG-5506.

We intend to take maximal advantage of these additional programs to expand our research and development pipeline into therapeutic areas of considerable unmet need.

Novel Molecules for Inherited HCM and Other Devastating Cardiac Disorders

Our EDG-002 program represents a unique series of novel-mechanism cardiac modulators.

This series of compounds exhibit a distinct cardiac desensitizing profile with some overlapping characteristics to cardiac myosin inhibitors such as BMS/Myokardia’s mavacamten and Cytokinetics’ CK-274.

However, this series of compounds also offer important mechanistic and phenotypic differences to both BMS/Myokardia’s and Cytokinetics’ molecules, which we believe have the potential to yield improved target product profiles for the treatment of HCM and heart failure with preserved ejection fraction (HFpEF).

Both in HVs and BMD patients, EDG-5506 was well tolerated and achieved muscle concentrations well above those predicted to demonstrate efficacy based on preclinical disease models of DMD.

EDG-5506 ARCH Open Label Data

In December 2021, we initiated our ARCH open label, single-center study of EDG-5506 in 12 adults with BMD, including all seven participants from our Phase 1b first-in-human study (following a 3-month washout).

ARCH was designed to evaluate the safety, PK, changes in biomarkers of muscle damage such CK and fast skeletal muscle troponin I, measures of function with NSAA/NSAD, time function tests and patient-reported outcomes.

The schematic below outlines the overall trial design.

ARCH will continue to monitor patients for two years and is scheduled to complete in April 2024.

ARCH Trial Design

The patients in ARCH had significant functional impairment and evidence of decreased muscle mass at baseline.

All individuals had a decreased ability to perform functional measures such as the 10-meter walk-run or rise from floor – only half of the BMD patients were able to perform the rise from the floor at baseline.

Their creatinine, which is derived directly from muscle, was decreased.

Their CK was elevated, consistent with ongoing muscle damage, and the DXA lean body mass was also decreased, consistent with the overall decreased function and decreased muscle mass.

North Star scores for these individuals ranged from 4 to 31.

Baseline characteristics are summarized below.

BMD Patient Baseline Characteristics in ARCH

At six months, EDG-5506 continued to be well tolerated following escalation to the 15 mg dose for four months, after initially receiving a 10 mg dose for 2 months.

The most common adverse events were dizziness, somnolence, and headache.

There were no dose reductions, dose adjustments or patient discontinuations due to adverse events.

All patients have since been dose escalated to the 20 mg dose of EDG-5506.

An overview of the adverse events observed up to the 6-month timepoint can be seen in the table below.

Summary Table of AEs Observed in ARCH (at the 6 Month Timepoint)

At six months, target exposure levels of EDG-5506 were maintained.

Additionally, BMD patients showed an increased level of activity compared to in Phase 1b as assessed by daily step counts.

EDG-5506 led to a sustained decrease in CK and a profound suppression of fast skeletal muscle troponin, demonstrating robust target engagement.

CK showed a highly statistically significant decrease of 40% over six months.

Fast skeletal muscle troponin showed a mean 75% decrease with a median decrease of 90% after the participant’s most recent available visit at four or six months.

Interestingly, individuals with the highest baseline biomarker values showed the greatest biomarker declines, suggesting protection against activity-induced damage.

Collectively, these biomarker observations support that muscle damage is decreased following treatment with EDG-5506.

EDG-5506 Leads to Sustained Decrease in CK and a Profound Suppression of TNNI2

We previously reported a SOMAscan signature of rapidly changing biomarkers of muscle injury, including CK and fast skeletal muscle troponin, following 14 days of treatment with EDG-5506.

At six months, we examined biomarker changes following continued EDG-5506 treatment.

SOMAscan revealed an 84% decrease from baseline in TNNI2 (p=0.013), and a 38% decrease in mean CK vs baseline (p<0.01) at six months.

In addition to changes in biomarkers of muscle injury, that were observed to change as early as one month, a set of 660 increased and 337 decreased proteins displayed progressive changes from month one to month six of dosing.

Analysis of average signals revealed a reversion of each signature towards those in healthy individuals in response to EDG-5506 treatment.

Furthermore, cluster analysis of these signatures revealed an enrichment of proteins implicated in inflammatory pathways.

Specifically, we observed a progressive change in inflammatory proteins toward a profile of unaffected individuals.

Comparison Bar Plot of Late-Decreasing Proteins (N=337)

After six months of EDG-5506 dosing, NSAA scores continued to trend in a positive direction.

Of note, a similar trend was observed with the NSAD scores.

Eight of the twelve participants showed either a functional improvement or exhibited no decline on NSAA relative to their baselines.

The positive NSAA trends in the BMD patients in ARCH diverged from trajectories observed in natural history studies from Bello et al.

(2016) and data reported at MDA 2022 Conference, showing a yearly decline of 1.22 NSAA points, and van de Velde et al.

(2021), who reported a 2.5 point NSAA decrease over two years – NSAA in BMD patients treated with EDG-5506 increased from baseline (4-31) by a mean +0.5 versus an expected decline of -0.6 points.

EDG-5506 Effect on Functional Measures in BMD Patients

Acute contraction-induced muscle injury causes pain, edema and loss of strength in healthy people.

These features are also prominent in DMD and BMD and are present prior to the onset of fibrosis.

As such, during ARCH, we asked patients to report outcomes about their general symptoms.

Interestingly, at six months, self-reported pain scores trended better (e.g., a decrease in muscle cramps).

These observations are consistent with preclinical observations in GRMDs and mdx mice showing improvements in activity and decreased edema.

We also observed a positive trend in mental health, fatigue, and sleep.

While ARCH is not a placebo-controlled trial, we believe these collective observations are encouraging.

Protection against contraction-induced injury with EDG-5506 in BMD patients has the potential to improve function by reducing acute injury and should protect against long term functional loss due to fibrosis, an observation that should potentially translate to functional improvements in DMD.

In summary, at six months, EDG-5506 continues to be well tolerated following an increase to 15 mg daily dosing for four months.

This dose led to target exposures achieved and the BMD individuals treated with EDG-5506 continued to exhibit increased activity compared to their baseline.

CK and fast skeletal muscle troponin I showed a sustained decrease through six months, despite participants’ continuing to exhibit full daily activity levels.

We also observed positive trends in patient reported outcomes (PROs), including pain and trends towards functional benefit in North Star that are remarkably divergent from the natural history reported for BMD patients.

We believe the six-month ARCH study data with EDG-5506 provides further support that reducing contraction-induced damage in dystrophic muscle has the potential to preserve and improve muscle function while preventing disease progression in dystrophinopathies.

We plan to report 12-month ARCH open label data in the second quarter of 2023.

EDG-5506’s tolerability and efficacy observations to date have allowed us to explore accelerated ways to advance EDG-5506 into potential registrational trials.

Phase 2 Clinical Trial in BMD (CANYON Study)

In July 2022, we initiated our CANYON Phase 2 clinical trial of EDG-5506.

CANYON is assessing the effect of EDG-5506 over a 12-month period on safety, PK, biomarkers of muscle damage (e.g., CK, troponins, myoglobin), and functional measures in individuals with BMD aged 12 years and above.

We are also evaluating upper leg fat fraction over one year as measured by MRI in BMD adults and adolescents.

This placebo-controlled trial is anticipated to recruit approximately 66 individuals at approximately 14 sites in the United States, United Kingdom, and the Netherlands.

Based on the positive observations from ARCH, the Company expects to amend the CANYON study to include a potentially registration-enabling cohort in the second half of 2023.

Phase 2 Clinical Trial in DMD (LYNX Study)

In October 2022, we announced initiation of our LYNX Phase 2 clinical trial of EDG-5506 for the treatment of DMD.

LYNX is a placebo-controlled trial to assess the effect of three doses of EDG-5506 over 12 weeks on safety, PK, and biomarkers of muscle damage.

After the initial 12 weeks, LYNX participants will then continue on open-label EDG-5506 for an additional 9 months to gain further insights into safety and functional measures.

Approximately 27 children with DMD aged 4 to 9 years on stable corticosteroids or approved exon-skipping agents are expected to be enrolled in this 12-month trial.

Importantly, this trial is designed to identify the doses of EDG-5506 that have the potential to reduce biomarkers of muscle damage and provide functional benefit to patients in a Phase 3 trial.

Approximately 14 investigative sites across the United States are expected to participate in the trial.

Natural History Study and Exercise Challenge Study (DUNE Study)

In 2022, we also commenced both an observational natural history study, being conducted in collaboration with the GRASP-LGMD Consortium, and a Phase 2 Exercise Challenge Study (DUNE), to investigate the effect of EDG-5506 on muscle injury biomarkers following exercise in individuals with LGMD2I, BMD and McArdle disease at a single site in Denmark.

A Novel Molecule for the Treatment of Patients with HCM and Other Severe Cardiac Disorders with Significant Unmet Needs

In the course of our EDG 002 program, a unique series of cardiac modulators with novel mechanisms of action have been identified.

One of these agents, the small molecule EDG-7500, has unique properties that may lead to a novel therapeutic approach for patients with HCM.

The effects of EDG-7500 on cardiac function overlap with some of the desirable attributes of the cardiac myosin inhibitors (CMIs) such as BMS’s CAMZYOS ® (mavacamten) and Cytokinetics’ CK-274 (aficamten).

However, there are improvements in EDG-7500's effects on cardiac function from those of CMIs that we believe have the potential to yield a potentially superior target product profile for the treatment of multiple phenotypes of HCM and may also have therapeutic benefit in sub-populations of patients with heart failure with preserved ejection fraction (HFpEF).

Disease Background and Current Treatment Limitations

HCM is the most common form of genetic heart disease, affecting one in 500 individuals and is caused by abnormal proteins in the heart, including cardiac myosin, that lead to excessive cardiac contraction.

HCM is the most common form of genetic heart disease, affecting approximately one in 500 individuals.

HCM is caused by abnormal proteins in the heart, including cardiac myosin, that lead to excessive cardiac contraction.

Estimates suggest there are as many as 630,000 people in the United States suffering from different forms of HCM.

Over time, the disruptions in cardiac muscle contraction leads to cardiac stress and thickening of the inner chambers of the heart which become stiffer and less able to pump blood.

HCM patients encounter increased risk of heart failure, stroke, atrial fibrillation and sudden cardiac arrest.

There are currently no approved therapies specifically indicated for the treatment of HCM.

Patients are typically treated with drugs that are indicated for broader cardiovascular disorders and do not address the underlying cause of the disease.

As the disease progresses, patients have limited treatment options, such as surgical or other invasive interventions and heart transplant.

More recently, the cardiac myosin inhibitor mavacamten has demonstrated significant benefit in obstructive HCM with reductions in cardiac and patient symptoms.

However, despite mavacamten’s efficacy, there are still limitations of this approach including a narrow therapeutic index, long terminal half-life (seven to nine days) and limited ability to rescue excessive pharmacology if it develops.

Our EDG-002 program has identified compounds that directly inhibit the cardiac sarcomere but via an alternative mechanism, independent of myosin.

In an initial set of studies that we conducted, a tool compound from the EDG-002 program, EDG-6036, was compared to Compound A, a clinical-stage type I myosin inhibitor (synthesized in-house in accordance with its published structure) in head-to-head experiments.

First, myosin inhibitory activity was explored by measuring the actin-activated ATPase of purified cardiac S1 myosin motor sub-fragment.

Compound A, inhibited cardiac S1 ATPase in a concentration-dependent manner while EDG-6036 was inactive in this preparation (A).

In contrast, both compounds were potent inhibitors of force development in intact slow skeletal muscle fibers, which share many protein components with cardiac muscle (B and C).

EDG-6036 targets cardiac contractility through an entirely novel MOA from myosin inhibitors

In subsequent experiments, we observed that oral administration of EDG-6036 led to a reduction in cardiac ejection fraction in healthy rats (A) with a similar exposure relationship to Compound A (B).

However, due to PK and mechanistic differences between these compounds (beyond oral availability), the observed dose/exposure relationship is considerably broader for EDG-6036 compared to Compound A (C), allowing for better dose titration.

EDG-6036 decreased cardiac contractility in healthy rats

Cardiac myosin inhibition with either mavacamten or CK274 represents a primary block of muscle contraction that can be difficult to override in situations of excessive pharmacology.

Since our EDG-002 series of compounds work through desensitization of cardiac muscle, we sought to understand how these molecules might lead to an improved pharmacological rescue of cardiac inhibition using the beta-adrenergic receptor agonist, isoproterenol (ISO).

inhibitory doses of Compound A (2 mg/kg) and EDG-6036 (10 mg/kg) were given to healthy rats via oral gavage and then rescue of inhibition was attempted with intravenous infusion of ISO.

We observed that rescue of ejection fraction was only partial for Compound A (A) but complete for EDG-6036 (B), highlighting the mechanistic differences between these two approaches.

In vivo cardiac inhibition with EDG-6036 can be reversed

We used an in vitro reconstituted cell system to measure compound efficacy in a model of HCM carrying a common myosin mutation (MYH7 R403Q).

Induced Pluripotent Stem Cells (iPSC), derived from a HCM patient were differentiated into cardiomyocytes, seeded into a hydrogel and reconstituted into a contractile myofiber.

Muscle contraction was then quantified in the presence of increasing amounts of compound and compared to iPSC-derived myofibers where the R403Q mutation had been corrected by CRISPR.

As expected, MYH7 R403Q myofibers exhibited increased contractile behavior compared to corrected myofibers and both Compound A (A) and EDG-6036 (B) demonstrated potent inhibition of hyper-contraction in these patient-derived cells.

EDG-6036 decreased contraction in reconstituted human myofibers with a HCM mutation

Our cardiac inhibitors have demonstrated activity in models of HCM.

In these models, our lead candidate to date, EDG-6036, showed equivalent inhibition of ejection fraction but improved effects on relaxation and rescue of excessive pharmacology relative to Compound A.

We believe the results from these preliminary preclinical studies support the potential of (i) our EDG-002 program to yield a lead molecule that could become a new therapeutic standard for

treatment of HCM and (ii) our proprietary drug discovery platform to identify novel and compelling molecules across a variety of muscle tissues and organs implicated in disease.

We are aiming to build a rare cardiac disease franchise by initially focusing on the development of a therapeutic for patients with HCM.

We are also characterizing a second therapeutic candidate coming out of our EDG-002 program specifically targeted at patients with HFpEF.

Over time, abnormal proteins in the heart, many of which are inherited, lead to excessive cardiac contraction, referred to as hypercontractility.

This disruption in cardiac muscle contractility leads to increased stress and thickening of the walls of the major pumping chamber of the heart, the left ventricle (LV).

The LV becomes less compliant and therefore less able to fill with and pump blood.

This results in a decrease in the LV chamber volume.

HCM patients can become extremely limited in their functional capacity and ability to perform the activities of daily living.

They may also have episodic lightheadedness and loss of consciousness (syncope).

In addition, these patients are at increased risk of heart failure, stroke, atrial fibrillation, and sudden cardiac arrest.

HCM can be divided into patients with obstructive disease, known as obstructive HCM (oHCM) and those with non-obstructive disease (nHCM).

The pathophysiologic feature of obstruction is present in two thirds of patients with HCM, as the mitral valve comes into contact with the thickened muscle of the interventricular septum during the ejection of oxygenated blood from the heart to the systemic circulation.

This creates an obstruction to blood flow exiting the heart through the LV outflow tract (LVOT) which results in a pressure gradient between the LV cavity and the systemic circulation.

As a result, higher pressures are generated in the left ventricle than normal, and a pressure gradient develops between the LV cavity and the systemic circulation.

This pressure gradient can be quantitatively measured by a routine clinical examination using Doppler echocardiography, the most common way oHCM is diagnosed and severity assessed.

Patients with nHCM do not develop LVOT obstruction and have normal left ventricular pressures during contraction.

They are characterized by the absence of a pressure gradient both at rest and following a variety of physiologic challenges, such as exertion, and non-physiologic maneuvers.

Heart failure in nHCM results from diminished filling of the heart due to impaired myocardial relaxation that results from abnormal function of the same proteins that cause hypercontractility.

This abnormal cardiac physiology, termed diastolic dysfunction leads to a decrease in cardiac output that is particularly severe when an HCM patient exerts themselves.

oHCM patients also have LV diastolic dysfunction in addition to obstruction of blood flow in the LVOT.

The clinical manifestations of oHCM and nHCM are generally similar though oHCM patients may experience more symptoms of lightheadedness and syncope.

Abnormalities in Heart Muscle Structure and Function Lead to Severe Abnormalities in HCM

Current Management of HCM

To determine the appropriate treatment approach, physicians use the New York Heart Association (NYHA) functional classification system to classify both obstructive and non-obstructive HCM patients into one of four categories;

NYHA Class I-IV (least to most severe symptoms, respectively).

The NYHA classification system is based on the degree of disease impact to the patient’s physical activity and is used to guide the physician’s choice of therapy.

The majority of diagnosed HCM patients are symptomatic and are classified as NYHA class II-IV which requires active treatment.

NYHA class I HCM patients generally do not require therapeutic intervention unless they meet established guideline criteria placing them at a high risk of sudden cardiac death, in which case implantation of a cardiac defibrillator may be advised.

Class I HCM patients are generally under physician surveillance consisting of annual follow-up visits with their cardiologist.

Current pharmaceutical treatment is intended to decrease hypercontractility and improve diastolic filling in both oHCM and nHCM and to reduce LVOT obstruction in oHCM patients in order to achieve meaningful symptom relief.

Non-vasodilating beta blockers and non-dihydropyridine calcium channel blockers, drugs that are indicated for broader cardiovascular disorders and do not address the underlying cause of the disease, are the first-line therapies for symptomatic oHCM and nHCM patients.

Commonly prescribed beta-blockers are atenolol, propranolol, and metoprolol.

Verapamil and diltiazem are calcium channel blockers used in the treatment of symptomatic oHCM and nHCM.

For oHCM patients who remain symptomatic, a sodium channel blocker may also be added, typically disopyramide.

In April 2022, the U.S.

FDA approved CAMZYOS ™ (mavacamten), a CMI, for the treatment of adults with symptomatic New York Heart Association (NYHA) Class II-III oHCM to improve functional capacity and symptoms.

Despite CAMZYOS ™ efficacy, there are still limitations of this approach including a narrow therapeutic index, long terminal half-life (seven to nine days) and limited ability to rescue excessive pharmacology if it develops.

As oHCM or nHCM progresses, patients have limited treatment options often requiring surgical or other invasive interventions including heart transplant.

Unmet Need in HCM

CMIs have complex pharmacology which results in potentially excessive reduction in cardiac function.

CMIs largely only address excessive contractility, which can limit their efficacy in a disease where both contractility and diastolic function are abnormal.

These factors lead CMIs to be difficult to dose to an efficacious maintenance dose.

These factors lead to patients requiring frequent and indefinite follow-up at expert centers accompanied by specialized cardiac imaging.

In addition, a significant percentage of oHCM patients do not respond to CMI and other therapies.

The efficacy of CMIs in patients with nHCM, who have impaired relaxation and diastolic dysfunction, also remains unproven.

Limited Efficacy of Current Therapeutic Approaches to Treat oHCM

EDG-7500 is a novel small molecule discovered by our company’s scientific research efforts.

Unlike CMIs, EDG-7500 does not bind to the myosin motor head but instead exerts its effects independently of myosin through direct interaction with a distinct sarcomeric protein.

EDG-7500 was purposefully designed to modulate the complex protein-protein interactions that control both contraction and relaxation processes within the sarcomere.

Specifically, EDG-7500 is designed to speed the rate of crossbridge detachment and slows the rate of crossbridge attachment leading to the reduction of excessive residual cross-bridges during diastole, potentially enhancing relaxation and facilitating ventricular filling.

In preclinical models, EDG-7500 has demonstrated improvement in a variety of the clinical manifestations in oHCM and nHCM.

A summary table of key preclinical studies is shown below.

Summary of Key Preclinical Studies with EDG-7500

MYBPC3 A31P Feline Model of oHCM

To evaluate the role of EDG-7500 in oHCM, we used an established feline model with a MYBPC3 A31P mutation.

Felines with this mutation exhibit a HCM phenotype with LVOT obstruction.

Treating MYBPC3 A31P felines with dobutamine induces a significant LVOT pressure gradient.

Subsequent treatment with a single 1 mg/kg dose of EDG-7500 resulted in LVOT gradient relief and improved contractility.

All treated animals saw their LVOT gradient reduced below the level of veterinary clinical significance with an average reduction of >60% following a single, 1 mg/kg dose.

EDG-7500 Improves Contractility and Alleviates LVOT Gradient

We next evaluated gradient reduction relative to EDG-7500 free fraction concentration in the feline model of oHCM by increasing exposures using doses ranging from 0.3 – 4.0 mg/kg.

Treatment with EDG-7500 is associated with a modest effect on contractility with free drug levels of ~55 to 140 ng/mL, a range in which reduction of LVOT gradient below clinical significance was observed.

To the best of our knowledge, the ability to remove a substantial portion of the gradient at levels that preserve normal systolic function is a feature that has not been observed before for an HCM drug.

This data suggests the mechanism of gradient removal is decoupled from changes in LVEF.

We have also observed that there is only a modest reduction in systolic contractility even at doses that are multiple folds higher than the predicted target dose.

Relationship of EDG-7500 Free Fraction Concentration and LVOT Gradient Relief

Myosin Heavy Chain R403Q Porcine Model of nHCM

To evaluate the role of EDG-7500 in nHCM, we used an established, genetically engineered porcine model with an MYH7 R403Q HCM mutation.

The MYH7 R403Q pigs exhibit cardiac structural and functional abnormalities, including left ventricular hypertrophy, small cavity, and increased filling pressure leading to increased left atrial size, which are consistent with the nHCM phenotype observed in humans.

In the MYH7 R403Q porcine model of nHCM, EDG-7500 was observed to reduce hypercontractility to near wild type levels.

Next, we evaluated EDG-7500’s effect on parameters of diastolic dysfunction.

EDG-7500 led to an improvement in left ventricular filling and a reduction in left atrial size, both consistent with reduced filling pressures in the heart.

Single doses of EDG-7500 also led to a dramatic, statistically significant improvement in diastolic relaxation, a decrease in left ventricular wall thickness at end-diastole, a measure of diastolic crossbridge engagement, and a reduction in left atrial size, a surrogate of chronic LV filling pressure.

EDG-7500 Leads to Rapid Normalization of nHCM Cardiac Structure and Function After a Single Dose

In summary, we have observed that EDG-7500 is a first-in-class cardiac sarcomeric protein modulator that targets the underlying pathophysiology of HCM.

Preclinical data in models of both obstructed and non-obstructed HCM suggest the ability to drive a broadly effective clinical response at a low risk of decreasing left ventricular ejection fraction below normal at all doses tested.

Due to EDG-7500’s self-limiting mechanism on systolic contraction, we plan to investigate fixed-dose regimens of EDG-7500 thus potentially eliminating the echo-mediated dose titration and intense follow-up requirements of current therapies.

As part of our IND-enabling work, we are completing the toxicity and safety pharmacology profile of EDG-7500 in standard GLP safety pharmacology studies, in non-GLP exploratory and dose range studies.

We plan to file an IND for EDG-7500 in the third quarter of 2023.

EDG-7500 Phase 1 Clinical Development Plan

Subject to clearance of the IND, we plan to initiate a Phase 1 double-blind, randomized, placebo-controlled, single and multiple ascending dose clinical trial in the second half of 2023 to assess the safety and tolerability, PK/PD of EDG-7500 in healthy subjects and patients with HCM.

The trial will evaluate the safety and tolerability of EDG-7500 in humans and is designed to demonstrate proof of mechanism by its conclusion.

Manufacturing

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We maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to our product candidates.

We have engaged CDMOs to manufacture EDG-5506 for preclinical and clinical use.

We have engaged CDMOs to manufacture EDG-5506 and EDG-7500 for preclinical and clinical use.

All of our product candidates are small molecules and are manufactured in synthetic processes from readily available starting materials.

Our chemistry is a convergent synthesis of under five steps, appears amenable to scale up and does not currently require unusual equipment in the manufacturing process.

Our chemistry is a convergent synthesis of under five steps, appears amenable to scale up and does not

currently require unusual equipment in the manufacturing process.

We obtain our supplies from these CDMOs on a purchase order basis and do not have a long-term supply arrangement in place.

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Moreover, Epirium Bio is developing a synthetic compound that targets cellular energetics and muscle regeneration as a potential therapeutic for BMD and Italfarmaco is also evaluating the use of Givinostat, an HDAC inhibitor, in BMD patients.

Non-vasodilating beta blockers and non-dihydropyridine calcium channel blockers are the first-line therapies for symptomatic oHCM and nHCM patients.

Commonly prescribed beta-blockers are atenolol, propranolol, and metoprolol.

Verapamil and diltiazem are calcium channel blockers used in the treatment of symptomatic oHCM and nHCM.

For oHCM patients who remain symptomatic, a sodium channel blocker with negative ionotropic drug properties may also be added, typically disopyramide (either Pfizer’s Norpace, marketed by Pfizer, or a generic form marketed by several companies).

In the field of targeted precision medicines intended to address the molecular underpinnings of HCM, competitors include Bristol-Myers Squibb (BMS), LianBio, Cytokinetics, Imbria Pharmaceuticals, and Celltrion.

BMS markets Camzyos (mavacamten), a CMI intended for the treatment of adults with symptomatic NYHA class II-III oHCM.

LianBio is currently conducting a Phase 3 study of mavacamten in patients with oHCM in China.

Cytokinetics is also developing a CMI, aficamten (CK-274), which is currently in a Phase 3 study in oHCM patients.

BMS and Cytokinetics are also exploring their respective CMIs in ongoing Phase 3 and Phase 2 nHCM studies, respectively.

Cytokinetics and BMS are also developing next generation CMIs, CK-271 and MYK-224, respectively.

Non-CMI targeting drugs in development include IMB-101(Imbria Pharmaceuticals), a free fatty acid receptor antagonist currently in Phase 2 and CT-G20 (Celltrion), an anti-arrhythmic cibenzoline succinate currently in a Phase 1 oHCM study.

We are aware of several preclinical HCM programs including:

TN-201, myosin binding protein MYBP-C3-targeting gene therapy approach being developed by Tenaya Therapeutics for genetic HCM;

JN-210, a microRNA activating gene therapy approach being developed by Jaan Biotherapeutics;

AVB-601, a gene therapy approach being developed by Solid Bio for genetic HCM;

CDR348T and CDR641L, both are non-coding RNA-based therapies being developed by Cardior Pharmaceuticals.

We are also aware of several early-stage preclinical HCM assets being developed by DiNAQOR in collaboration with BioMarin Pharmaceuticals (BMN-293/DINA-001) and Lexeo Therapeutics (LX2022).

Intellectual Property

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We currently, and expect that we will continue to, own or in-license patents and patent applications related to our key drug candidates.

We own patents and patent applications that cover compositions of matter, methods of treating diseasessuch as DMD, BMD, LGMD and muscle spasticity disorders and combination therapies.

As of January 21, 2022, we own a patent portfolio consisting of 10 patent families and in-license one patent family from OSIF.

We own patents and patent applications that cover compositions of matter, methods of treating diseases such as DMD, BMD, LGMD and muscle spasticity disorders and combination therapies.

As of February 4, 2023, we own a patent portfolio consisting of 13 patent families and in-license one patent family from OSIF.

We own 3 issued U.S.

patents, 4 pending U.S.

patent applications, 5 pending PCT applications, and 41 pending foreign applications filed in 15 different countrites and regions including Europe, Australia, Brazil, Canada, China, Eurasia, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, South Africa, and Hong Kong.

patents, 2 issued Japanese patents, 9 pending non-provisional U.S.

patent applications, 1 pending PCT application, and 48 pending foreign applications filed in 15 different countries and regions including Europe, Australia, Brazil, Canada, China, Eurasia, Israel, India, Japan, South Korea, Mexico, New Zealand, Singapore, South Africa, and Hong Kong.

We own one issued U.S.

patent that covers compositions of matter of EDG-5506 and methods of treatment using EDG-5506 that is expected to expire in 2039, excluding any patent term extensions.

and one Japanese patent that covers compositions of matter of EDG-5506 and methods of treatment using EDG-5506 that is expected to expire in 2039, excluding any patent term extensions.

We own one provisional patent application that covers composition of matter of EDG-7500 and methods of treatment using EDG-7500.

For our drug candidates, we generally pursue multilayered patent protection covering compositions of matter, methods of use and methods of manufacture.

We also intend to pursue patent protection, if available, with respect to biomarkers that may be useful in selecting a patient population for use of our drug candidates.We intend to strengthen the patent protection of our drug candidates and technologies through additional patent application filings.

We also intend to pursue patent protection, if available, with respect to biomarkers that may be useful in selecting a patient population for use of our drug candidates.

We intend to strengthen the patent protection of our drug candidates and technologies through additional patent application filings.

The term of individual patents depends upon the legal term for patents in the countries in which they are granted.

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Thus, we may not be able to meaningfully protect our trade secrets.

It is our policy to require

our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us.

It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us.

These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances.

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In addition, in the event we sublicense the OSIF licensed patent rights, we are obligated to pay OSIF a specified portion of income we receive from sublicensing.

To date, we have paid OSIF $235,000 in connection with the license agreement.

As of December 31, 2022, we have paid OSIF $0.5 million for license fees and milestones achieved in connection with the license agreement.

Our royalty obligations with respect to each product covered by OSIF licensed patent rights in a country extend until the last-to-expire patent claim licensed from OSIF covering the product in the country.

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We may be required to develop and implement additional clinical trial policies and procedures designed to help protect subjects from the novel coronavirus disease (COVID- 19).

For example, in March 2020, the FDA issued a guidance, which FDA subsequently updated, on conducting clinical trials during the pandemic, which describes a number of considerations for sponsors of clinical trials impacted by the pandemic, including the requirement to include in the clinical trial report contingency measures implemented to manage the trial, and any disruption of the trial as a result of the COVID-19 pandemic;

a list of all subjects affected by the COVID-19- pandemic related study disruption by unique subject identifier and by investigational site and a description of how the individual’s participation was altered;

and analyses and corresponding discussions that address the impact of implemented contingency measures (e.g., participant discontinuation from investigational product and/or study, alternative procedures used to collect critical safety and/or efficacy data) on the safety and efficacy results reported for the trial.

In 2020 and 2021, FDA published a number of industry guidance documents, including updates to previous guidance, related to Good Manufacturing Practices, remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities, and drug product manufacturing and supply chain inspections, among others.

For example, in 2020 and 2021, FDA published a number of industry guidance documents, including updates to previous guidance, related to Good Manufacturing Practices, remote interactive evaluations of drug manufacturing and bioresearch monitoring facilities, and drug product manufacturing and supply chain inspections, among others.

The extent to which the COVID-19 pandemic impacts our business, preclinical studies and clinical trials will depend on future developments, which are highly uncertain and cannot be predicted with confidence.

Recently, President Biden announced that the administration intends to end the COVID-19 national and public health emergencies on May 11, 2023.

The full impact of the termination of the public health emergencies on FDA and other regulatory policies and operations are unclear.

NDA Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are

submitted to the FDA as part of an NDA requesting approval to market the product.

The submission of an NDA is subject to the payment of substantial user fees;

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It could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries, and other risk minimization tools.

The FDA also may offer accelerated approval with postmarketing confirmatory trial requirements or approvals subject to other postmarketing requirements, including among other things, changes to proposed labeling or the development of adequate controls and specifications.

The FDA also may offer accelerated approval with postmarketing confirmatory trial requirements or approvals subject to other postmarketing requirements, including among other things, changes to

proposed labeling or the development of adequate controls and specifications.

Once approved, the FDA may withdraw the product approval if compliance with pre- and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace.

The FDA may also require one or more Phase 4 post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization and may limit further marketing of the product based on the results of these post-marketing studies.

In addition, new government

requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could impact the timeline for regulatory approval or otherwise impact ongoing development programs.

In addition, new government requirements, including those resulting from new legislation, may be established, or the FDA’s policies may change, which could impact the timeline for regulatory approval or otherwise impact ongoing development programs.

Expedited Development and Review Programs

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

In December 2022, the Consolidated Appropriations Act, 2023, including the Food and Drug Omnibus Reform Act (FDORA), was signed into law.

FDORA made several changes to the FDA’s authorities and its regulatory framework, including, among other changes, reforms to the accelerated approval pathway, such as requiring the FDA to specify conditions for post-approval study requirements and setting forth procedures for the FDA to withdraw a product on an expedited basis for non-compliance with post-approval requirements.

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

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

there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States of that drug or biologic.

Under the Orphan Drug Act, the FDA may grant orphan drug designation (ODD), to a drug or biologic intended to treat a rare disease or condition, defined as a disease or condition with either a patient population of fewer than 200,000 individuals in the United States, or a patient population greater of than 200,000 individuals in the United States when there is no reasonable expectation that the cost of developing and making available the drug or biologic in the United States will be recovered from sales in the United States of that drug or biologic.

ODD must be requested before submitting a NDA.

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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 if the manufacturer is unable to assure sufficient quantities of the product to meet the needs of patients with the rare disease or condition.

In Catalyst Pharms., Inc.

Becerra , 14 F.4th 1299 (11th Cir.

2021), the court disagreed with the FDA’s longstanding position that the orphan drug exclusivity only applies to the approved use or indication within an eligible disease, and not to all uses or indications within the entire disease or condition.

In particular, the circuit court held that the orphan-drug exclusivity for Catalyst’s drug blocked FDA’s approval of another drug for all uses or indications within the same orphan-designated disease, or Lambert-Eaton myasthenic syndrome (LEMS), even though Catalyst’s drug was approved at that time only for use in the treatment of LEMS in adults.

Accordingly, the court ordered the FDA to set aside the approval of a drug indicated for LEMS in children.

This decision created uncertainty in the application of the orphan drug exclusivity.

On January 24, 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst , FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved.

It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

Post-Approval Requirements

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There are continuing, annual program fees for any marketed products.

Drug manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon us and our third-party manufacturers.

Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented.

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However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement.

The FDCA also provides three years of marketing exclusivity for a NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an

existing drug.

This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent.

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

state and local laws which require the tracking of gifts and other remuneration and any transfer of value provided to physicians, other healthcare providers and entities;

state and local

laws which require the tracking of gifts and other remuneration and any transfer 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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One third-party payor’s decision to cover a particular product does not ensure that other payors will also provide coverage for the product.

As a result, the coverage determination process can require manufacturers to provide scientific details, information on cost-

effectiveness, and clinical support for the use of a product to each payor separately.

As a result, the coverage determination process can require manufacturers to provide scientific details, information on cost-effectiveness, and clinical support for the use of a product to each payor separately.

This can be a time-consuming process, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

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

There remain judicial and Congressional challenges to certain aspects of the ACA.

Concurrently, Congress has considered legislation that would repeal or repeal and replace all or part of the ACA.

While Congress has not passed comprehensive repeal legislation, several bills affecting the implementation of certain taxes under the ACA have passed.

For example, in 2017, Congress enacted the Tax Act, which eliminated 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, a process that is commonly referred to as the “individual mandate.” In addition, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac” tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminated the health insurer tax.

On December 14, 2018, a Texas U.S.

District Court Judge 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 ruled that the individual mandate was unconstitutional and remanded the case back to the District Court to determine whether the remaining provisions of the ACA are invalid as well.

In June 2021, the United States Supreme Court held that Texas and other challengers had no legal standing to challenge the ACA, dismissing the case without specifically ruling on the constitutionality of the ACA.

Accordingly, the ACA remains in effect in its current form.

It is unclear how this Supreme Court decision, future litigation, or healthcare measures promulgated by the Biden administration will impact our business, financial condition and results of operations.

It is unclear how future litigation or healthcare measures promulgated by the Biden administration will impact our business, financial condition and results of operations.

Complying with any new legislation or changes in healthcare regulation could be time-intensive and expensive, resulting in a material adverse effect on our business.

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Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several congressional inquiries and proposed and enacted legislation designed, among other things, to bring more transparency to product pricing, to review the relationship between pricing and manufacturer patient programs, and to reform government program reimbursement methodologies for pharmaceutical products.

For example, in 2020, HHS and CMS issued various rules that are expected to impact, among others, price reductions from pharmaceutical manufacturers to plan sponsors under Part D, fee arrangements between pharmacy benefit managers and manufacturers, manufacturer price reporting requirements under the Medicaid Drug Rebate Program, including regulations that affect manufacturersponsored patient assistance programs subject to pharmacy benefit manager accumulator programs and Best Price reporting related to certain value-based purchasing arrangements, and manufacturer price reporting under Medicare Part B.

Multiple lawsuits have been brought against HHS challenging various aspects of the rules.

Under the American Rescue Plan Act of 2021, effective January 1, 2024, the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs will be eliminated.

For example, under the American Rescue Plan Act of 2021, effective January 1, 2024, the statutory cap on Medicaid Drug Rebate Program rebates that manufacturers pay to state Medicaid programs will be eliminated.

Elimination of this cap may require pharmaceutical manufacturers to pay more in rebates than it receives on the sale of products, which could have a material impact on our business.

In addition, Congress is considering legislation that, if passed, could have significant impact on prices of prescription drugs covered by Medicare, including limitations on drug price increases and allowing Medicare to negotiate pricing for certain covered drug products.

In August 2022, Congress passed the Inflation Reduction Act of 2022, which includes prescription drug provisions that have significant implications for the pharmaceutical industry and Medicare beneficiaries, including allowing the federal government to negotiate a maximum fair price for certain high-priced single source Medicare drugs, imposing penalties and excise tax for manufacturers that fail to comply with the drug price negotiation requirements, requiring inflation rebates for all Medicare Part B and Part D drugs, with limited exceptions, if their drug prices increase faster than inflation, and redesigning Medicare Part D to reduce out-of-pocket prescription drug costs for beneficiaries, among other changes.

The impact of these legislative, executive, and administrative actions and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is unclear.

The impact of these regulations and any future healthcare measures and agency rules implemented by the Biden administration on us and the pharmaceutical industry as a whole is currently unknown.

The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability, or commercialize our product candidates if approved.

Complying with any new legislation and regulatory changes could be time-intensive and expensive, resulting in a material adverse effect on our business.At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

Complying with any new legislation and regulatory changes could be time-intensive and expensive, resulting in a material adverse effect on our business.

At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including

price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

For example, a number of states are considering or have recently enacted state drug price transparency and reporting laws that could substantially increase our compliance burdens and expose us to greater liability under such state laws once we begin commercialization after obtaining regulatory approval for any of our products.

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In addition to regulations in the United States, we will be subject to a variety of foreign regulations governing clinical trials and commercial sales and distribution of our product candidates to the extent we choose to develop or sell any product candidates outside of the United States.

The approval process varies from country to country and the time

may be longer or shorter than that required to obtain FDA approval.

The approval process varies from country to country and the time may be longer or shorter than that required to obtain FDA approval.

The requirements governing the conduct of clinical trials, regulatory approval for our products, pricing and reimbursement vary greatly from country to country.

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We were incorporated in Delaware in May 2017.

Our principal executive offices are located at 3415 Colorado Ave., Boulder, Colorado 80303.

Our principal executive offices are located at 1715 38 th Street, Boulder, Colorado 80301.

Our telephone number is (720) 262-7002.

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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