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Item 1. Business

2024-02-22 compared with 2023-02-23 · 355 added, 350 removed, 734 unchanged (49% of the section changed)

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.

Our mission is to discover new medicines that improve the lives of people facing serious muscle disease .

At Edgewise, patients are at the core of everything we do.

We recognize that for patients with rare and debilitating diseases, every day without an effective treatment is a day too late and we are driven by this urgency to evolve disease knowledge with an aim to develop novel precision medicines for severe and rare disorders driven by muscle dysfunction.

Our intimate knowledge of muscle biology and biophysics along with our ability to identify and design muscle specific precision small molecules have enabled us to rapidly advance our lead product candidate into clinical development while advancing our preclinical pipeline.

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.

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.

Since our inception in 2017, our precision medicine muscle platform has generated several programs to address a variety of muscle diseases.

We are advancing two clinical-stage programs and a number of preclinical programs.

The Company’s deep expertise in muscle physiology is driving a new generation of first-in-class therapeutics.

EDG-5506 is an orally administered skeletal myosin inhibitor in multiple phase 2 clinical trials, including a pivotal cohort, in patients with either Becker, Duchenne, and Limb-Girdle muscular dystrophies or McArdle Disease.

EDG-7500, currently in a Phase 1 trial, is a novel cardiac sarcomere modulator for the treatment of hypertrophic cardiomyopathy (HCM) and other disorders of cardiac diastolic dysfunction.

We are also continuing to advance preclinical exploration, including novel cardiometabolic targets.

As a clinical-stage biopharmaceutical company we are focused on the discovery, development and commercialization of innovative treatments for severe muscle diseases 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.

Our platform utilizes custom-built high throughput and translatable systems that measure integrated muscle function in whole organ extracts to identify small molecule precision medicines regulating key proteins in muscle tissue, initially focused on addressing rare neuromuscular and cardiac diseases.

Since our inception in 2017, our precision medicine muscle platform has generated several programs to address a variety of muscle disorders.

We are advancing one clinical-stage program and two preclinical programs.

Our lead product candidate, EDG-5506, is an orally administered allosteric, selective, fast myofiber (type II) myosin small molecule inhibitor designed to address the root cause of dystrophinopathies including Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Both of these disorders are rare and often debilitating diseases, and we estimate that in the United States there are approximately 12,000 to 15,000 DMD patients and 4,000 to 5,000 BMD patients.

We have developed and

characterized a library of novel sarcomere modulators exhibiting a broad range of pharmacological and pharmacokinetic (PK) properties regulating disease-related muscle biology.

Both of these disorders are rare and often debilitating diseases, and we estimate that in the US, EU-5 and Japan there are approximately 35,000 Duchenne patients and approximately 12,000 Becker patients.

There are currently no approved therapies for individuals with Becker.

As a selective fast myosin inhibitor, EDG-5506 presents a novel mechanism of action designed to selectively limit injurious stress caused by lack of dystrophin by moderating fast skeletal muscle myosin force development and thereby compensating for the absence of functional dystrophin.

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

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.

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.

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

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 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.

We have advanced EDG-5506 through the clinic including completing a Phase 1 trial evaluating safety, tolerability, PK and pharmacodynamics of EDG-5506 in adult healthy volunteers (Phase 1a) and in adults with Becker (Phase 1b).

In ARCH, an open-label, single-center trial assessing long-term safety and PK, decreases in biomarkers of muscle damage and trends toward improvement in North Star Ambulatory Assessment (NSAA) have been observed following 12 months of treatment with EDG-5506.

We have completed enrollment of the Phase 2 trial cohorts, called CANYON, evaluating safety and effects on function and biomarkers of muscle damage in adult males with Becker, which has been expanded to include an additional 120 adult participants in a pivotal cohort called GRAND CANYON, which is currently enrolling.

The Company is also continuing to advance the fully enrolled DUNE Phase 2 exercise challenge study, to evaluate the effect of EDG-5506 on biomarkers of muscle damage following exercise in adults with LGMD2I, Becker or McArdle disease at a single site in Denmark.

In Duchenne, we are advancing our Phase 2 studies, LYNX and FOX, both assessing safety, PK and biomarkers of muscle damage in individuals with Duchenne and for the purpose to identify a dose of EDG-5506 that will reduce biomarkers of muscle damage and has the potential to provide functional benefit to patients in a Phase 3 trial.

Additionally, we added a new cohort to LYNX to include children aged four to seven years with Duchenne who are not currently treated with corticosteroids.

The FDA granted EDG-5506 Fast Track designation for the treatment of Duchenne in February 2024, and Orphan Drug Designation (ODD) for the treatment of Duchenne and Becker and Rare Pediatric Disease Designation (RPDD) for the treatment of Duchenne in November 2023.

The FDA previously granted Fast Track designation for EDG-5506 for the treatment of Becker.

The FDA previously granted Fast Track designation for the investigation and development of EDG-5506 for the treatment of Becker.

We have also evolved a second muscle-targeted initiative that focuses on the identification of novel cardiac muscle modulators.

We are initially pursuing our lead product candidate, EDG-7500, for the treatment of HCM in addition to exploring the potential of its novel mechanism in the treatment of disorders of diastolic dysfunction.

In September 2023, we announced initial dosing in a Phase 1 trial of EDG-7500 which is assessing the tolerability, PK, and pharmacodynamics of EDG-7500 in healthy adults.

The Company is also planning to begin single dose and multiple dose Phase 2 studies of EDG-7500 in individuals with obstructive HCM in the first half of 2024, as well as initiating an open-label extension trial in the fourth quarter of 2024 evaluating the long-term safety, tolerability, and treatment effects of EDG-7500.

Additionally, our EDG-003 discovery program is exploring the potential of other unique and novel mechanisms to address a variety of disorders, including cardiometabolic disease.

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

We have retained global development and commercialization rights to all of our programs.

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We have assembled an experienced and highly motivated management team with a strong track record in the biotechnology and pharmaceutical industry.

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, Biogen and MyoKardia.

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

Members of our team have extensive expertise in muscle diseases, 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, Biogen and MyoKardia.

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.

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

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.

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.

Additionally, we 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.

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

We also raised $186.1 million in net proceeds from our initial public offering in March 2021, $129.2 million in net proceeds from our follow-on public offering in September 2022 (the September 2022 Offering) and $240 million in gross proceeds from our underwritten registered direct offering in January 2024 (the January 2024 Offering).

Our vision is to improve the lives of patients and families suffering from severe muscle diseases by building the world’s leading muscle-focused, biopharmaceutical company.

Key components of our strategy to achieve this vision include:

● Engaging comprehensively with patients and their families and physicians to develop trusted relationships, transparent communications, and become a leader in the muscular dystrophy stakeholder community.

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.

● Engaging comprehensively with patients, their families and their physicians to develop trusted relationships, transparent communications, and become a leader in the rare muscle disease communities.

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, EDG-7500 and other programs for severe muscle diseases.

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 .

Our lead product candidate, EDG-5506, is a modulator of fast (type II) skeletal muscle myosin designed to selectively limit injurious stress caused by lack of dystrophin.

We plan to prioritize the development of EDG-5506 in DMD and BMD given the limited or lack of approved treatments and significant unmet medical need.

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 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.

● Leveraging clinical and regulatory precedents and our extensive experience in severe muscle diseases to rapidly advance EDG-5506 through clinical development in muscular dystrophies.

EDG-5506 is an orally administered small molecule designed to prevent contraction-induced muscle damage in dystrophinopathies including Duchenne and Becker.

EDG-5506 presents a novel mechanism of action designed to selectively limit the exaggerated muscle damage caused by the absence or loss of functional dystrophin.

By minimizing the progressive muscle damage that leads to functional impairment, EDG-5506 has the potential to benefit a broad range of patients suffering from debilitating neuromuscular disorders.

Its unique mechanism of action provides the potential to establish EDG-5506 as a foundational therapy in dystrophinopathies, either as a single agent therapy or in combination with available therapies and those in development.

We are advancing EDG-5506 through the clinic including completing enrollment of Phase 2 trial cohorts, called CANYON, evaluating safety and effects on function and biomarkers of muscle damage in adult males with Becker, which has been expanded to include an additional 120 adult participants in a pivotal cohort called GRAND CANYON, which is currently enrolling.

In Duchenne, we are advancing our Phase 2 clinical trials, LYNX, assessing safety, PK and biomarkers of muscle damage, and FOX, which includes children and adolescents previously treated with gene therapy.

We are also exploring the impact that fast skeletal myosin regulation may have on other skeletal muscle disorders common in adults, including slower-onset forms of muscle myopathies such as Limb-girdle muscular dystrophy (LGMD).

● Investing in our precision medicine drug discovery platform to fuel the development of novel targeted therapies to expand our pipeline into additional skeletal and cardiac muscle disorders.

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

● Leveraging our deep expertise in muscle-disease therapeutics to expand our pipeline, advancing EDG-7500 into the clinic for the treatment of HCM and other diseases of diastolic dysfunction .

EDG-7500 is a first-in-class oral, selective, cardiac sarcomere modulator intended for the treatment of HCM and other diseases of cardiac diastolic dysfunction.

The compound is designed to slow early contraction velocity and improve impaired cardiac relaxation.

This novel mechanism is anticipated to have a broad therapeutic index that may facilitate fixed dosing and minimize monitoring during treatment.

Preclinical data of EDG-7500 support beneficial activity in animal models of both obstructive and non-obstructive HCM with diastolic benefit and minimal changes in left ventricular systolic performance in a range of preclinical experiments.

We are currently enrolling a randomized, double-blind, placebo-controlled, single and multiple ascending dose Phase 1 trial evaluating safety, tolerability, PK and pharmacodynamics in healthy adults.

Further, we are planning to begin a Phase 2 trial of EDG-7500 in individuals with obstructive HCM in the first half of 2024 and expect Phase 1 data in healthy volunteers and individuals with obstructive HCM in the third quarter of 2024.

● Investing in our precision medicine drug discovery platform to fuel the development of novel targeted therapies to expand our pipeline into additional skeletal and cardiac muscle diseases.

In addition to EDG-5506 and EDG-7500, we are also advancing our preclinical program, EDG-003, directed to cardiometabolic targets.

● 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.

Our company was founded based on an in-depth understanding of skeletal muscle disease and integrative physiology, coupled with our strong drug discovery capabilities and a desire to improve the lives of patients with rare muscle diseases.

In addition to this expertise, we have established a growing network of key stakeholders, including patient advocacy groups, healthcare professionals, key opinion leaders, research institutions, regulators and payors, to ensure our efforts remain guided by the needs of patients suffering from rare muscle diseases.

Our company was founded based on an in-depth understanding of muscle disease and integrative physiology, coupled with our strong drug discovery capabilities and a desire to improve the lives of patients with severe muscle diseases.

We will continue to work closely with these collaborators to inform our development programs and strategies to potentially bring transformational therapies to these communities as we build a patient-centric organization.

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In addition to being critical for the regulation of contraction driving the production of force, skeletal muscle also serves as an endocrine organ regulating metabolism and neuronal activities as well as the production of systemic mediators of growth, inflammation and regeneration.

Skeletal muscle’s physiological role impacts multiple organ systems and is a complex mix of redundancies and feedback loops that require an intricate knowledge of muscle at a whole-body level in order to successfully develop drugs for muscle diseases.

Skeletal muscle’s physiological role impacts multiple organ systems and is a

complex mix of redundancies and feedback loops that require an intricate knowledge of muscle at a whole-body level in order to successfully develop drugs for muscle diseases.

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.

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We have coupled our deep understanding of the complexities of muscle physiology with cutting-edge drug discovery expertise to create a new generation of small molecule precision medicines for the treatment of severe and debilitating muscle conditions arising from defects in the skeletal and cardiac muscle systems.

EDG-5506 for Treatment of Patients with DMD and BMD

EDG-5506 for Treatment of Patients with Duchenne and Becker

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.

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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 activity.

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).

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

Our Phase 1b data in Becker 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 Becker in July 2022, a potentially registrational cohort in September 2023, a Phase 2 dose-finding clinical trial in children with Duchenne in October 2022 and a Phase 2 clinical trial in children and adolescents with Duchenne who have been previously treated with gene therapy in October 2023.

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.

Absence of dystrophin in Duchenne 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 Duchenne 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.

Disease Background

DMD and BMD are marked by an absence (DMD) or truncation (BMD) of the dystrophin protein resulting from mutations in the dystrophin gene.

Approximately 65% of mutations of the DMD gene are deletions of one or several exons, the coding sections of an RNA transcript, or the DNA encoding it, that are ultimately translated into dystrophin protein.

Duchenne and Becker are marked by an absence (Duchenne) or truncation (Becker) of the dystrophin protein resulting from mutations in the dystrophin gene.

Approximately 65% of mutations of the Duchenne gene are deletions of one or several exons, the coding sections of an RNA transcript, or the DNA encoding it, that are ultimately translated into dystrophin protein.

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

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Absence of dystrophin leads to myofiber membrane stress during normal sarcomere contraction resulting in an influx of calcium through the myofiber membrane resulting in hypercontraction, irreversible sarcomeric collapse and myofiber degeneration.

Myofiber regeneration is possible but appears to fail over time as DMD/BMD patients get older and the muscle stem cell (satellite cell) machinery is exhausted.

Myofiber regeneration is possible but appears to fail over time as Duchenne/Becker patients get older and the muscle stem cell (satellite cell) machinery is exhausted.

Fatty and fibrotic tissue then accumulate and replace normal muscle contractile tissue thus compromising function such that patients have progressive and permanent muscle weakness.

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

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

We estimate that DMD occurs in approximately one in every 3,500 to 5,000 live male births and that the patient population is approximately 12,000 to 15,000 in the United States and approximately 25,000 in Europe.

BMD has a much lower incidence of approximately 1 in every 18,450 live male births.

We estimate there are between 4,000 and 5,000 patients with BMD in the United States, with similar numbers estimated in Europe.

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

Duchenne and Becker are classified as orphan diseases in the United States and Europe.

We estimate that Duchenne occurs in approximately one in every 3,500 to 5,000 live male births and that the patient population is approximately 12,000 to 15,000 in the United States and approximately 25,000 in Europe.

Becker has a much lower incidence of approximately 1 in every 18,450 live male births.

We estimate there are about 5,000 patients with Becker in the United States, with similar numbers estimated in Europe.

Duchenne Muscular Dystrophy

DMD is a monogenic, X-linked muscle disease secondary to mutations in the dystrophin gene with mortality at a median age of approximately 30 years.

DMD pathophysiology is driven by the absence of dystrophin which normally functions as a structural protein in muscle.

Duchenne is a monogenic, X-linked muscle disease secondary to mutations in the dystrophin gene with mortality at a median age of approximately 30 years.

Duchenne pathophysiology is driven by the absence of dystrophin which

normally functions as a structural protein in muscle.

Once myofiber degeneration is initiated, regeneration typically follows.

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.

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.

However, in Duchenne, 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.

Duchenne 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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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 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.

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

Impacts on Upper Limb Function

Even while ambulant, loss of upper limb function begins around age eight and continues to decline, with DMD patients struggling to raise their arms above their head in their early teens, which impairs daily activities such as getting clothes on over their head independently or reaching for an object overhead.

Even while ambulant, loss of upper limb function begins around age eight and continues to decline, with Duchenne patients struggling to raise their arms above their head in their early teens, which impairs daily activities such as getting clothes on over their head independently or reaching for an object overhead.

Loss of upper limb muscle function continues with disease progression, and in their teens patients may lose the ability to independently lift objects to their face, self-feed, use a phone/computer or control a motorized wheelchair.

The serious disability due to the loss of key upper limb functions dramatically impacts activities of daily living in DMD patients still in their early teenage years.

The serious disability due to the loss of key upper limb functions dramatically impacts activities of daily living in Duchenne patients still in their early teenage years.

Effects on Respiratory Function

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Cardiac Complications

The loss of dystrophin leads to cardiovascular disease in most DMD patients.

The loss of dystrophin leads to cardiovascular disease in most Duchenne patients.

These patients typically develop cardiac features between the ages of 10 and 15 years.

The cardiac disease is generally progressive and as cardiac function worsens, patients present with dilated cardiomyopathy (DCM) and clinical heart failure.

Since DMD patients in their teens are non-ambulatory, identification of traditional heart failure symptoms is challenging due to relative physical inactivity.

Patients with DMD and DCM often report a history of chest pain, palpitations, dyspnea, dizziness, and syncope.

Improved care in other specialties, especially respiratory support, has reduced morbidity related to other aspects of DMD but elevated cardiomyopathy as a key driver of mortality.

The Real-World Burden of DMD

Family members and caregivers view DMD not just as a fatal disorder, but a disorder characterized by repeated “ little deaths ”.

Since Duchenne patients in their teens are non-ambulatory, identification of traditional heart failure symptoms is challenging due to relative physical inactivity.

Patients with Duchenne and DCM often report a history of chest pain, palpitations, dyspnea, dizziness, and syncope.

Improved care in other specialties, especially respiratory support, has reduced morbidity related to other aspects of Duchenne but elevated cardiomyopathy as a key driver of mortality.

The Real-World Burden of Duchenne

Family members and caregivers view Duchenne not just as a fatal disorder, but a disorder characterized by repeated “ little deaths ”.

Each loss of a functional milestone is excruciating as it represents not a clinical data point to track progression, but one more conversation a parent must have with their child, explaining why they are not allowed to play on the soccer team with their peers, or if they will ever be able to hop, or skip or go to the prom.

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contractions, pressure sores, constipation, numbness in legs and feet, and scoliosis.

Parents and caregivers devote much of their resources and time to caring for their sons with DMD.

Parents and caregivers devote much of their resources and time to caring for their sons with Duchenne.

All told, these “ little deaths ” create a family disease with lifelong impacts for all.

Perhaps the hardest moment in the life of a DMD family comes in deciding when to tell their young boy that he has this fatal disease.

DMD represents a significant societal and economic burden.

Perhaps the hardest moment in the life of a Duchenne family comes in deciding when to tell their young boy that he has this fatal disease.

Duchenne represents a significant societal and economic burden.

The economic burden associated with hospital admissions, medication, frequent doctor visits and investment in assistive devices, as well as indirect costs related to productivity losses for the caregivers and costs due to pain, anxiety and social handicap are estimated at $278 million in Germany, $154 million in Italy, $200 million in the United Kingdom, and $1.2 billion in the United States annually.

The impact on parents of children with DMD is also quite dramatic and often requires them to stop working altogether to care for their children who progressively require more help with everyday tasks.

The impact on parents of children with Duchenne is also quite dramatic and often requires them to stop working altogether to care for their children who progressively require more help with everyday tasks.

Becker Muscular Dystrophy

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.

Progression can be variable and often slower than DMD with mean age of loss of ambulation in the late 30’s and a select few remaining ambulatory into their 50’s or beyond.

While certain BMD patients with have a mild or minimal lower limb weakness and remain relatively stable over time as measured by the North Star Ambulatory Assessment (NSAA), other BMD patients have a typical BMD disease course with progressive loss of lower limb function, measurable with the NSAA over a 12-month period with the majority losing ambulation at some point in their lifetime.

Compared to DMD, BMD patients’ skeletal myopathy occurs later in childhood, and they maintain ambulation through age 16.

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

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

Current Treatments for DMD and BMD and their Limitations

There is no cure for DMD and for most patients, there are no satisfactory symptomatic or disease-modifying treatments.

Standard of care in DMD includes physical therapy to maintain mobility and prevent contractures, bracing and surgery for scoliosis, medical treatment for cardiomyopathy and heart failure, respiratory therapies for ventilatory impairment, psychosocial management to support behavior and learning, glucocorticoid regimens and exon skipping therapies.

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

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

Progression can be variable and often slower than Duchenne with mean age of loss of ambulation in the late 30’s and a select few remaining ambulatory into their 50’s or beyond.

While certain Becker patients with have a mild or minimal lower limb weakness and remain relatively stable over time as measured by the NSAA, other Becker patients have a typical Becker disease course with progressive loss of lower limb function, measurable with the NSAA over a 12-month period with the majority losing ambulation at some point in their lifetime.

Compared to Duchenne, Becker patients’ skeletal myopathy occurs later in childhood, and they maintain ambulation through age 16.

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

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

Current Treatments for Duchenne and Becker and their Limitations

There is no cure for Becker and no approved therapies on the market to treat the disease.

For Duchenne there is also no cure and for most patients, there are no satisfactory symptomatic or disease-modifying treatments.

Standard of care in Duchenne includes physical therapy to maintain mobility and prevent contractures, bracing and surgery for scoliosis, medical treatment for cardiomyopathy and heart failure, respiratory therapies for ventilatory impairment, psychosocial management to support behavior and learning, glucocorticoid regimens and exon skipping therapies.

Glucocorticoids

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

Glucocorticoid treatment with either prednisone or EMFLAZA (deflazacort), the current standard-of-care for Duchenne, 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 Duchenne, 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.

Sustained glucocorticoid dosing in young Duchenne 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 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.

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

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

An aggregate of approximately 29% of Duchenne 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 Duchenne, was granted approval by the UK, Iceland, Liechtenstein, Norway, Israel, South Korea and conditional approval granted by the EMA within the European Union (EU) Member States to treat Duchenne 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 Duchenne in the United States.

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).

Moreover, a significant limitation of exon skipping approaches for Duchenne 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 Duchenne patients (e.g., exon 51 skipping is feasible in only up to 13% of all Duchenne patients).

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.

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

The lack of dystrophin in patients with DMD has long been a target for adeno-associated virus (AAV) based gene therapy but the limited packaging capacity of AAV vectors (4.7 kilo-bases) and the large size of the dystrophin gene (2.2 mega-bases, >400 times bigger than the AAV vector itself) remain a challenge to delivering a fully functional dystrophin protein to patients.

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 Duchenne subsets.

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

Gene Therapy for Duchenne

The lack of dystrophin in patients with Duchenne has long been a target for adeno-associated virus (AAV) based gene therapy but the limited packaging capacity of AAV vectors (4.7 kilo-bases) and the large size of the dystrophin gene (2.2 mega-bases, >400 times bigger than the AAV vector itself) remain a challenge to delivering a fully functional dystrophin protein to patients.

As such, the field has shifted to the use of miniaturized dystrophin or microdystrophin expression cassettes that yield a smaller, less complete version of the dystrophin protein as the therapeutic payload;

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

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.

In June 2023, the FDA approved Sarepta’s Biologics License Application seeking accelerated approval of their microdystrophin gene therapy, Elevidys (delandistrogene moxeparvovec), for the treatment of ambulant individuals with Duchenne four to five years of age.

In October 2023, Sarepta released topline data from their Phase 3 EMBARK trial announcing the trial failed to reach its primary endpoint.

Despite the miss on the primary endpoint, Sarepta filed for sBLA in December 2023 seeking label expansion for Elevidys without restrictions on age or ambulation status.

Other companies focused on developing genetic based therapies for Duchenne 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.

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 Duchenne 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.

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.

Delivery of minidystrophin or microdystrophin to muscles in Duchenne 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.

We believe that each of the therapeutic approaches outlined above currently have significant limitations, and that there continues to be a high unmet medical need for new disease-modifying therapies for the treatment of patients with DMD.

Moreover, with the biotechnology and pharmaceutical industry’s almost exclusive focus on DMD, little attention has been paid to drug development in BMD where there are no approved therapies for patients.

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

Moreover, with the biotechnology and pharmaceutical industry’s almost exclusive focus on Duchenne, little attention has been paid to drug development in Becker where there are no approved therapies for patients.

Our Solution:

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 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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We believe EDG-5506 has the potential to overcome many of the obstacles facing other therapeutics in development for the treatment of dystrophinopathies based on the following key characteristics:

● Offers a novel, potentially disease modifying approach for the treatment of rare muscle diseases by blocking the structural destabilization of skeletal myofibers.

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.

● Offers a novel, potentially disease modifying approach for the treatment of severe muscle diseases by blocking the structural destabilization of skeletal myofibers.

By protecting dystrophin deficient myofibers from degeneration, EDG-5506’s mechanism of action is directed towards the underlying cause of muscle degeneration in Duchenne and Becker 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.

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● 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 .

EDG-5506 can potentially be used to treat all populations of Duchenne and Becker, 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 Duchenne that may provide additional functional benefits over genetic based therapeutics .

DNA based gene therapies or RNA based exon skipping therapeutics are designed to produce a mini- or micro-dystrophin but not a full-length dystrophin protein;

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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.

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

An illustration of EDG-5506’s novel mechanism of action

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Human skeletal muscle consists of three fiber types, “slow” type I and “fast” types IIa or IIx/d, defined by the specific myosin isoform that they express.

Studies have shown that fast muscle fibers are more susceptible to injury in both healthy individuals and in DMD.

Histological studies of young DMD patients document distinct fiber-type imbalances in the co-localization of fast and embryonic myosin, a marker of regenerating muscle fibers.

Similar observations have also been made in all known mammalian models of DMD.

Studies have shown that fast muscle fibers are more susceptible to injury in both healthy individuals and in Duchenne.

Histological studies of young Duchenne patients document distinct fiber-type

imbalances in the co-localization of fast and embryonic myosin, a marker of regenerating muscle fibers.

Similar observations have also been made in all known mammalian models of Duchenne.

The control and coordination of these fiber populations is a complex process, designed to maintain physical performance even under conditions of extreme environmental and metabolic stress.

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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 are higher than slow myofiber TnI (TnI1) levels, suggesting that fast myofibers are more susceptible to loss of dystrophin function during muscle contraction.

We evaluated Duchenne and Becker 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

Biomarkers of fast fiber turnover are elevated in Becker and Duchenne

Using high-throughput screens of type II fast skeletal muscle myofibrils, we identified a novel structural class of myosin ATPase inhibitors that we optimized for potency, selectivity, physiochemical properties and PK, leading to the synthesis of EDG-5506.

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Our goal is to reduce contraction of susceptible muscle fibers by five to twenty percent.

We believe that the reduced muscle breakdown will result in potential preservation or enhancement of physical function in DMD patients.

Regulating myofiber contraction in DMD patients is not a novel concept.

Dantrolene, an inhibitor of the ryanodine receptor that modulates both fast and slow skeletal myofiber contraction was used in a small clinical trial in 1991 in DMD patients.

We believe that the reduced muscle breakdown will result in potential preservation or enhancement of physical function in Duchenne patients.

Regulating myofiber contraction in Duchenne patients is not a novel concept.

Dantrolene, an inhibitor of the ryanodine receptor that modulates both fast and slow skeletal myofiber contraction was used in a small clinical trial in 1991 in Duchenne patients.

Treatment was associated with a 3-fold reduction in CK and a trend favoring attenuation of decreases in function.

While it is approved for treatment of malignant hyperthermia and chronic spasticity, it is not approved or used in DMD.

While it is approved for treatment of malignant hyperthermia and chronic spasticity, it is not approved or used in Duchenne.

Chronic treatment with dantrolene has been associated with drowsiness and the potentially serious side effect of idiosyncratic fatal hepatotoxicity, limiting its broad use.

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Another corollary to our approach of selectively targeting type II fast skeletal muscle myofibrils with EDG-5506 is mavacamten (MYK461), a selective allosteric inhibitor of cardiac type I myosin ATPase.

Mavacamten was approved by the FDA 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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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.

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.

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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.

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.

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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Mice were then sacrificed 24 hours later, and blue fibers visualized after removal of the skin (C).

We observed that EDG-5506 dramatically lowered the appearance of blue muscle fibers (examples marked with red arrows), close to that observed in healthy normal mice.

We observed that EDG-5506 dramatically lowered the appearance of blue

muscle fibers (examples marked with red arrows), close to that observed in healthy normal mice.

We believe these observations further support EDG-5506’s ability to protect muscles from membrane disruption and edema.

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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.

While Duchenne 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.

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

Unlike DMD patients, the dystrophin-deficient mdx mouse on the C57BL/10 genetic background (B10.

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

Unlike Duchenne patients, the dystrophin-deficient mdx mouse on the C57BL/10 genetic background (B10.

mdx ) is mildly affected by disease with limited muscle fibrosis.

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We observed that treatment with EDG-5506 for 14 months dramatically prevented muscle loss and kyphosis (green arrows).

This observation is particularly meaningful as scoliosis can be observed in older DMD patients following loss of ambulation.

Scoliosis coupled with diaphragm fibrosis drives respiratory failure and is a significant cause of death in DMD patients.

This observation is particularly meaningful as scoliosis can be observed in older Duchenne patients following loss of ambulation.

Scoliosis coupled with diaphragm fibrosis drives respiratory failure and is a significant cause of death in Duchenne patients.

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

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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.

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

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

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As the heart is not a direct target of EDG-5506, we believe the mechanism of this benefit is indirect via improvement of skeletal muscles, including the diaphragm.

Given that cardiac myopathy is a common driver of mortality in both DMD and BMD, we believe that this is a significant and clinically relevant finding.

Given that cardiac myopathy is a common driver of mortality in both Duchenne and Becker, we believe that this is a significant and clinically relevant finding.

Reduced cardiac fibrosis and hypertrophy in DBA/2J mdx mice following treatment with EDG-5506

Reversible decreases in circulating muscle injury biomarkers following EDG-5506 administration in Golden Retriever muscular dystrophy (GRMD) dogs

Mouse models of DMD recapitulate many features of disease but they are enriched for fast fibers, develop only localized muscle fibrosis and do not exhibit functional deficits until relatively late in life.

In contrast, dogs have muscle that has similar proportions of fast and slow fibers (approximately 50/50) compared to humans and weakness/functional deficits with age that more closely resemble DMD patients.

Amongst the dog models of DMD, the GRMD dogs are the largest and most severely affected.

Mouse models of Duchenne recapitulate many features of disease but they are enriched for fast fibers, develop only localized muscle fibrosis and do not exhibit functional deficits until relatively late in life.

Amongst the dog models of Duchenne, the GRMD dogs are the largest and most severely affected.

GRMD dogs tend to be weak at birth and then stabilize at two weeks of age before progressive muscle damage, inflammation and pseudo-hypertrophy, particularly of the flexor muscles of the limbs causing physical weakness.

Unlike DMD patients, GRMD dogs remain ambulatory and disease symptoms stabilize at six months of age, at which age their muscle histology is similar to that of a 10-year-old DMD patient.

Unlike Duchenne patients, GRMD dogs remain ambulatory and disease symptoms stabilize at six months of age, at which age their muscle histology is similar to that of a 10-year-old Duchenne patient.

Four disease-stable dystrophin deficient female GRMD dogs (seven months old) were dosed daily with vehicle for one week and then with EDG-5506 (3 mg/kg loading dose for two to three days, then 1 mg/kg daily) for two weeks before a six-day washout period.

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EDG-5506 decreased circulating injury biomarkers and improved activity in GRMD dogs

EDG-5506 lowered disease biomarkers in DMD dogs as measured by SOMAscan

EDG-5506 lowered disease biomarkers in Duchenne dogs as measured by SOMAscan

We used a SOMAscan aptamer-based high-throughput proteomics platform to determine if other proteins, beyond CK, change in plasma in response to treatment with EDG-5506.

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Gene ontology (GO) term analysis also revealed decreases in cellular pathways commonly associated with dystrophic muscle including apoptotic, cellular signaling, metabolic and immune responses.

SOMAscan analysis of patient plasma has previously been used to generate a common serum protein signature for DMD.

As such, we compared EDG-5506’s response fingerprint in GRMD to DMD patient data.

Comparison with GRMD baseline samples revealed a set of 40 elevated and nine depleted proteins overlapping with the DMD patient signature.

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

SOMAscan analysis of patient plasma has previously been used to generate a common serum protein signature for Duchenne.

As such, we compared EDG-5506’s response fingerprint in GRMD to Duchenne patient data.

Comparison with GRMD baseline samples revealed a set of 40 elevated and nine depleted proteins overlapping with the Duchenne patient signature.

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

Preclinical Pharmacokinetics and Metabolism of EDG-5506

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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.

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

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.

EDG-5506 Clinical Plan

An updated overview of our near-term clinical development plan for EDG-5506 in DMD and BMD is shown below.

An updated overview of our near-term clinical development plan for EDG-5506 in Duchenne and Becker is shown below.

EDG-5506 Phase 1 Clinical Trial

In October 2020, we initiated a Phase 1 randomized, placebo-controlled, double-blind, single and multiple ascending-dose clinical trial to evaluate the safety, tolerability and PK of EDG-5506 in adult HVs (Phase 1a) and adults with BMD (Phase 1b), to address potential differences in safety, tolerability and PK in the background of dystrophic muscle.

In October 2020, we initiated a Phase 1 randomized, placebo-controlled, double-blind, single and multiple ascending-dose clinical trial to evaluate the safety, tolerability and PK of EDG-5506 in adult HVs (Phase 1a) and adults with Becker (Phase 1b), to address potential differences in safety, tolerability and PK in the background of dystrophic muscle.

The starting dose in the SAD was informed by the no observed adverse effect levels (NOAELs) from the 13-week GLP toxicology study.

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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 of DMD .

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

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).

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

EDG-5506 was administered at a dose of 20 mg once daily, in solid dosage form taken with food for 14 days.

The primary endpoint was safety and tolerability, and secondary endpoints were PK, including tissue concentrations, and, importantly, multiple biomarkers of muscle damage in the setting of dystrophic muscle.

BMD patients in the Phase 1b were required to be ambulatory with no exclusions based on functional criteria.

An overview of the BMD patient demographics is shown below.

Becker patients in the Phase 1b were required to be ambulatory with no exclusions based on functional criteria.

An overview of the Becker patient demographics is shown below.

For the functional measures the median value for the 10 m walk run was over double the age normative value and the median rise from floor was 20 seconds with three participants being unable to complete the test (unaffected adults typically have a value of <3 seconds).

Serum creatinine was approximately half of the expected range, consistent with decreased muscle mass, while serum CK was a multiple of normal values consistent with ongoing muscle damage in these individuals.

BMD Phase 1b Patient Demographics

EDG-5506 was well tolerated in BMD subjects.

Becker Phase 1b Patient Demographics

EDG-5506 was well tolerated in Becker subjects.

Seven of the seven subjects enrolled in the Phase 1b cohort experienced TEAEs and all were Grade 1.

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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.

EDG-5506 muscle concentrations in BMD patients were adjusted to reflect the approximately 60% fat fraction in the quadriceps of these individuals, which was further corroborated by reduced overall protein content, as measured by a standard Bradford protein assay, as well as the cohort’s overall reduced functional status.

Relatedly, EDG-5506 plasma concentrations in BMD subjects were approximately two-fold higher than those in healthy volunteers at the same 20 mg dose.

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

EDG-5506 muscle concentrations in Becker patients were adjusted to reflect the approximately 60% fat fraction in the quadriceps of these individuals, which was further corroborated by reduced overall protein content, as measured by a standard Bradford protein assay, as well as the cohort’s overall reduced functional status.

Relatedly, EDG-5506 plasma concentrations in Becker subjects were approximately two-fold higher than those in healthy volunteers at the same 20 mg dose.

This observation is consistent with EDG-5506 being highly targeted to muscle, and reflective of these patient’s overall reduced muscle mass as evidenced by a mean serum creatinine level of 0.58 mg/dL, significantly below a mean value of 1.15 for an age- and sex-matched population.

Dystrophic muscle in BMD patients showed adjusted EDG-5506 levels in the range previously observed in the MAD, demonstrating a similar, high-affinity binding to myosin in fast twitch dystrophic muscles.

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.

Dystrophic muscle in Becker patients showed adjusted EDG-5506 levels in the range previously observed in the MAD, demonstrating a similar, high-affinity binding to myosin in fast twitch dystrophic muscles.

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

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.

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.

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.

Serial blood samples were taken from Becker 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 Becker disease biomarker fingerprint.

After 14 days of treatment with EDG-5506, Becker 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.

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

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.

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).

Leveraging the SOMAscan 7,000 analyte set, baseline Becker 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).

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

Interestingly, and similar to individuals with DMD, the most significant elevated proteins are from muscle and metabolic pathways enriched in muscle, consistent with leaky damaged muscles.

Baseline BMD vs.

with Becker, 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 Becker.

Interestingly, and similar to individuals with Duchenne, the most significant elevated proteins are from muscle and metabolic pathways enriched in muscle, consistent with leaky damaged muscles.

Baseline Becker vs.

Healthy Biomarker Fingerprint Analysis with SOMAscan

Subsequently, the impact of EDG-5506 treatment on the BMD proteomic fingerprint, was examined.

As anticipated, treatment of healthy individuals with 20 mg of EDG-5506 had no impact on the BMD protein signature.

In comparison, BMD individuals exhibited a robust, significant and time-dependent decrease in elevated BMD biomarkers compared to placebo after only two weeks of dosing.

Baseline BMD vs.

Subsequently, the impact of EDG-5506 treatment on the Becker proteomic fingerprint, was examined.

As anticipated, treatment of healthy individuals with 20 mg of EDG-5506 had no impact on the Becker protein signature.

In comparison, Becker individuals exhibited a robust, significant and time-dependent decrease in elevated Becker biomarkers compared to placebo after only two weeks of dosing.

Baseline Becker vs.

Healthy Biomarker Fingerprint Analysis with SOMAscan

The BMD SOMAscan signature showed that CK and TNNI2 both exhibited a robust decrease in response to EDG-5506 treatment compared to placebo treated individuals.

The Becker SOMAscan signature showed that CK and TNNI2 both exhibited a robust decrease in response to EDG-5506 treatment compared to placebo treated individuals.

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

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 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.

In fact, a comparison of the consensus SOMAscan signature of consistently elevated proteins in DMD showed substantial overlap with those responsive to EDG-5506 treatment in BMD patients after only 14-days of dosing.

As such, the positive observations in BMD are likely translatable to DMD based on EDG-5506’s unique mechanism of action.

SOMAscan Comparison of BMD and DMD Fingerprints

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

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

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

In fact, a comparison of the consensus SOMAscan signature of consistently elevated proteins in Duchenne showed substantial overlap with those responsive to EDG-5506 treatment in Becker patients after only 14-days of dosing.

As such, the positive observations in Becker are likely translatable to Duchenne based on EDG-5506’s unique mechanism of action.

SOMAscan Comparison of Becker and Duchenne Fingerprints

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 of DMD.

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

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 EDG-5506 dosing.

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).

In December 2021, we initiated our ARCH open label, single-center trial of EDG-5506 in 12 adults with Becker, including all seven participants from our Phase 1b first-in-human trial (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

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

ARCH Trial Design – 24 Months

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.

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 Becker 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.

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.

Baseline characteristics are summarized below, highlighting significant functional impairment and decreased muscle mass.

Becker Patient Baseline Characteristics in ARCH

At 12 months, EDG-5506 continued to be well tolerated following escalation to the 20 mg dose, after initially receiving a 10 mg and 15 mg doses.

An overview of the adverse events observed up to the 12-month timepoint can be seen in the table below.

Summary Table of AEs Observed in ARCH (at the 12 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.

Consistent with prior observations, treatment with EDG-5506 led to significant decreases in key biomarkers of muscle damage.

Importantly, CK and TNNI2 were reduced by an average of 37% (p=0.001) and 79% (p<0.0001) from baseline, respectively, at the participants 12-month visit.

EDG-5506 Leads to Sustained Decrease in Key Biomarkers of Muscle Damage After 12 Months of Treatment

After 12 months of EDG-5506 dosing, NSAA scores continued to trend in a positive direction.

Nine of the twelve participants showed either a functional improvement (n=6) or exhibited stable disease (n=3) on NSAA relative to their baselines.

As seen below, the NSAA scores show a consistent positive trend that diverges from trajectories observed in the natural history studies reported by Bello et al.

(2016)1 and van de Velde et al.

(2021)2 in which the yearly decline was -1.2 NSAA points.

Overall, one-year functional results were observed to have a +0.4-point improvement on the NSAA compared to the -1.2-point anticipated natural history decline in a population of Becker patients predicted to have a relentless course of disease progression.

NSAA Stabilization Observed with EDG-5506 Treatment with Trends Toward Improvement at 12 Months

The positive results from the 12-month ARCH trial support the hypothesis that a reduction in contraction-induced muscle damage in muscular dystrophies, associated with EDG-5506 administration, has the potential to preserve and improve muscle function while preventing disease progression in dystrophinopathies.

Observations from ARCH identified key factors, including the optimal dosing strategy of EDG-5506, for the design of a potentially registrational trial in Becker.

Phase 2 Clinical Trial in Becker (CANYON and GRAND CANYON Trial)

In July 2022, we initiated our CANYON Phase 2 clinical trial of EDG-5506, 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 Becker aged 12 years and above.

This placebo-controlled trial successfully recruited 69 individuals at approximately 14 sites in the United States, United Kingdom, and the Netherlands.

In September 2023, based on the positive observations from the ARCH trial, we amended the CANYON trial and initiated GRAND CANYON, a potentially registrational cohort in individuals with Becker.

GRAND CANYON is a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of EDG-5506 in adults with Becker.

Data from GRAND CANYON, if positive, could support a marketing application.

The primary endpoint of GRAND CANYON is the NSAA.

In addition, other functional assessments, biomarkers of muscle damage and safety will be assessed.

GRAND CANYON is anticipated to recruit approximately 120 individuals with Becker, aged between 18 and 50 years old, at up to 50 sites in 10 countries.

The treatment period for participants will be 18 months.

Exercise Challenge Study (DUNE Study)

In November 2022, we initiated a Phase 2 Exercise Challenge Study (DUNE), to investigate the effect of EDG-5506 on muscle injury biomarkers following exercise in individuals with LGMD2I, Becker and McArdle disease at a single site in Denmark.

Dune is fully enrolled with the aim of bringing further insights into how EDG-5506 can potentially be used to treat other individuals with severe muscle diseases such as LGMD2I and McArdle disease.

Phase 2 Open-Label Extension in Becker (MESA)

In November 2023, we initiated our MESA Phase 2 open-label extension that will assess the long-term effect of EDG-5506 on safety, biomarkers and functional measures in adults and adolescents with Becker.

MESA will provide continued access to EDG-5506 treatment to participants who were previously enrolled in ARCH, CANYON, GRAND CANYON and DUNE.

Phase 2 Clinical Trials in Duchenne (LYNX and FOX Studies)

In October 2023, we announced the expansion of our EDG-5506 program in Duchenne.

The LYNX trial in children with Duchenne rapidly enrolled at 14 sites across the United States, with the first three cohorts over-enrolled.

Based on the safety profile observed to date, we added additional cohorts to continue dose escalation of EDG-5506.

LYNX is designed to identify a dose of EDG-5506 that will reduce biomarkers of muscle damage and has the potential to provide functional benefit to patients in a Phase 3 trial.

Additionally, we added a new cohort to LYNX to include children aged four to seven years with Duchenne who are not currently treated with corticosteroids.

Patients within the LYNX trial are initially dosed in placebo controlled cohorts over 12 weeks, then continue on to the open label portion of the trial for an additional 21 months.

We initiated the FOX trial, a new Phase 2 placebo-controlled trial in children and adolescents with Duchenne who have been previously treated with gene therapy.

The FOX trial will assess the effect of EDG-5506 over 12 weeks on safety, PK and biomarkers of muscle damage.

The trial will also explore changes in functional measures, such as the NSAA and self-reported/caregiver-reported outcomes.

Approximately 24 participants, aged six to 14 years, are expected to be enrolled in the trial at multiple sites across the United States.

Participants will then continue in an open-label extension portion of the trial for a total of 56 weeks to gain further insights into safety, PK, function and biomarker measures.

Natural History Study

In 2022, we commenced an observational natural history study being conducted in collaboration with the GRASP-LGMD Consortium.

A Novel Molecule for the Treatment of Patients with HCM and Other Diseases of Diastolic Dysfunction with Significant Unmet Needs

In the course of our EDG-003 cardiometabolic discovery 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).

However, there are differences 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

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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.

In April 2022, the 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.

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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.

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

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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.

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.

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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

EDG-7500 Leads to Rapid Improvement 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.

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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.

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, and in non-GLP exploratory and dose range studies.

EDG-7500 Phase 1 Clinical Plan

In September 2023, we announced initial dosing in a Phase 1 trial of EDG-7500 which is assessing the tolerability , PK, and pharmacodynamics of EDG-7500 in healthy adults.

The Company is also planning to begin a Phase 2 trial of EDG-7500 in individuals with obstructive HCM in the first half of 2024.

Manufacturing

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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 and fourteen steps for EDG-5506 and EDG-7500 respectively, and 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.

We do not currently have arrangements in place for redundant supply.

For all of our product candidates, we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.

For all of our product

candidates, we intend to identify and qualify additional manufacturers to provide the active pharmaceutical ingredient and fill-and-finish services prior to seeking regulatory approval.

Sales and Marketing

If any of our product candidates are approved, we currently intend to market and commercialize them in the United States and select international markets, either alone or in collaboration with others.

Currently, approximately 70% of patients with DMD are treated with corticosteroids to manage the inflammatory component of the disease.

Approximately 70% of patients with Duchenne are treated with corticosteroids to manage the inflammatory component of the disease.

EMFLAZA (deflazacort) is an FDA-approved corticosteroid marketed by PTC Therapeutics, Inc.

and prednisone is also FDA-approved and is marketed by multiple companies.

In addition, there are four FDA-approved exon skipping drugs:

EXONDYS 51 (eteplirsen), AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen), which are naked PMOs approved for the treatment of DMD patients amenable to Exon 51, Exon 45 and Exon 53 skipping, respectively, and are marketed by Sarepta Therapeutics, Inc., and VILTEPSO (vitolarsen), a naked PMO approved for the treatment of DMD patients amenable to Exon 53 skipping, which is marketed by Nippon Shinyaku Co.

Companies focused on developing treatments for DMD that target dystrophin mechanisms include Sarepta Therapeutics with SRP-5051, a peptide-linked PMO currently being evaluated in a Phase 2 clinical trial for patients amenable to Exon 51 skipping, PTC Therapeutics with ataluren, a small molecule targeting nonsense mutations in a Phase 3 clinical trial, Avidity Biosciences, Inc., which is in preclinical development with an antibody oligonucleotide conjugate that targets dystrophin production and Dyne Therapeutics which is also in preclinical development with its proprietary antigen-binding oligonucleotide linker technology that targets dystrophin production.

In addition, several companies are in clinical trials to develop gene therapies to treat DMD, including Genethon Company (GNT-0004), Pfizer Inc.

(PF-06939926), Sarepta Therapeutics (SRP-9001 and Galgt2 gene therapy program), and Solid Biosciences Inc.

In March 2022, Santhera Pharmaceuticals in collaboration with ReveraGen Biopharma, commenced the new drug application (NDA) filing as a rolling submission for vamorolone, a steroid therapy for Duchenne.

In October 2023, the FDA granted Agamree (vomorolone) approval in Duchenne patients 2 years and older and Catalyst Pharmaceuticals, Inc.

will be commercializing this product in the US following its North America exclusive license deal with Santhera.

In addition, there are four FDA conditionally approved exon skipping drugs:

EXONDYS 51 (eteplirsen), AMONDYS 45 (casimersen) and VYONDYS 53 (golodirsen), which are naked PMOs approved for the treatment of Duchenne patients amenable to Exon 51, Exon 45 and Exon 53 skipping, respectively, and are marketed by Sarepta Therapeutics, Inc., and VILTEPSO (vitolarsen), a naked PMO approved for the treatment of Duchenne patients amenable to Exon 53 skipping, which is marketed by Nippon Shinyaku Co.

In June 2022, PTC Therapeutics presented new topline results with Translarna (ataluren) for patients with nonsense mutation Duchenne, a subset of the disease that impacts between 10% and 15% of patients.

It remains unclear if the data will lead to FDA approval of Translarna, for which the company plans to engage with the FDA and submit an NDA in the future.

Translarna has been conditionally approved in the European Union and Brazil for ambulatory patients aged 2 years and older with Duchenne resulting from a nonsense mutation in the dystrophin gene.

However, in January 2024, the Committee for Medicinal Products for Human Use (CHMP) of the EMA delivered a negative opinion on the re-examination procedure for the conditional marketing authorization of Translarna.

This is expected to result in the withdrawal of Translarna from the EMA markets.

In September 2023, Sarepta released the topline data from the Elevidys confirmatory study that missed its primary endpoint of NSAA change from baseline vs.

Despite the miss on the primary endpoint, Sarepta filed for sBLA in December 2023 seeking label expansion for Elevidys without restrictions on age or ambulation status.

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

We are also aware of several companies targeting non-dystrophin mechanisms for the treatment of DMD.

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.

We are also aware of several companies targeting non-dystrophin mechanisms for the treatment of Duchenne.

In June 2022, Italfarmaco announced positive topline data from its completed Phase 3 trial with Givinostat, a histone deacetylase (HDAC) inhibitor, in boys with Duchenne.

Italfarmico has filed for an NDA for Duchenne and has a PDUFA date of March 21, 2024.

Moreover, in June 2021, Italfarmaco released top line Phase 2 data for Givinostat in Becker.

Givinostat did not show a significant difference in the primary endpoint compared to placebo.

The future of this program in Becker is uncertain.

Current pharmaceutical treatment is intended to improve diastolic filling in both oHCM and nHCM and reduce LVOT in oHCM patients only.

The goal of current therapies is to achieve meaningful symptom relief.

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

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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).

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.

In April 2023, LianBio announced positive topline results from the Phase 3 EXPLORER-CN trial investigating mavacamten for the treatment of Chinese patients with symptomatic oHCM.

To date, Camzyos (mavacamten) has secured marketing approvals in the US, Europe, and other countries across five continents.

Cytokinetics is also developing a CMI, aficamten (CK-274), for which topline Phase 3 oHCM trial results were recently reported in December 2023.

In June 2023, Cytokinetics initiated another Phase 3 active-comparator clinical trial of aficamten compared to metoprolol in symptomatic oHCM patients.

BMS and Cytokinetics are also exploring their respective CMIs in ongoing Phase 3 nHCM clinical trials.

Cytokinetics and BMS are also developing next generation CMIs for the treatment of symptomatic HCM, CK-271 and MYK-224, respectively.

A Phase 2 oHCM clinical trial of MYK-224 is currently ongoing.

Non-CMI targeting drugs in development include IMB-101(Imbria Pharmaceuticals), a free fatty acid receptor antagonist, CT-G20 (Celltrion), an anti-arrhythmic cibenzoline succinate, and trientine dihydrochloride (Univar Solutions), a selective copper II chelator.

In November 2023, Imbria announced Phase 2 nHCM topline results of IMB-101.

We have limited knowledge of CT-G20’s Phase 1 oHCM trial status, while the trientine Phase 2 oHCM clinical trial is ongoing.

A gene therapy approach, TN-201, a myosin binding protein C3-targeting gene therapy candidate being developed by Tenaya Therapeutics for genetic HCM, is currently in Phase 1b.

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;

HTX-001, an antisense oligonucleotide approach being developed by Haya Therapeutics;

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).

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), both are gene therapy approaches for genetic HCM.

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 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 patents and patent applications that cover compositions of matter, methods of treating diseases such as Duchenne, Becker, LGMD and muscle spasticity disorders and combination therapies.

As of February 4, 2024, we own a patent portfolio consisting of 16 patent families.

We own 3 issued U.S.

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.

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.

patents, 2 issued European patents, 3 issued Japanese patents, 1 issued Indian patent, 2 issued South African patents, 2 issued Singaporean patents, 2 issued Hong Kong patents, 11 pending non-provisional U.S.

patent applications, 3 pending PCT applications and 39 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., one European, one South African, one Hong Kong and one Japanese patent that covers compositions of matter of EDG-5506 and methods of treatment using EDG-5506 that are expected to expire in 2039, excluding any patent term extensions.

We own one PCT 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 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.

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Third Party Agreements

2020 Exclusive License Agreement with The Ohio State Innovation Foundation

We have exclusively licensed intellectual property from The Ohio State Innovation Foundation (OSIF) in a license agreement effective November 20, 2020.

We entered into the agreement with OSIF for an exclusive worldwide license to develop and commercialize products covered by the OSIF licensed intellectual property for the treatment, prevention or palliation of muscular dystrophies and disorders.

The product candidates under development by the Company are not based on the intellectual property licensed from OSIF.

The patent applications licensed from OSIF may, in the future, provide additional patent coverage for certain aspects of the Company’s product candidates currently under development, depending on the eventual scope of any OSIF patents if and when issued, which scope and likelihood of issuance are uncertain.

Under the license agreement, we are obligated to make payments to OSIF aggregating up to $1.3 million per product covered by the OSIF licensed patent rights upon the achievement of specified development and regulatory approval milestones and approximately $2.3 million per product covered by the OSIF licensed patent rights upon the achievement of specified sales milestones.

We are also obligated to pay low single-digit royalties to OSIF based on net sales by us and our affiliates and sublicensees of each product covered by the OSIF licensed patent rights.

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.

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.

The latest possible expiration of patents licensed under the agreement is 2039 in all applicable countries, in the absence of any patent extensions that may be available for such patents.

Under the license agreement, we are obligated to use a certain level of effort to develop and commercialize at least one product covered by the OSIF licensed patents or derived from the material provided by OSIF and to achieve certain milestones within set times, subject to certain extensions.

OSIF has the right to terminate the license agreement for our uncured material breach of the license agreement, including if we fail to achieve specified development, regulatory approval and sales milestones within specified timeframes, or for certain events related to our bankruptcy.

We have the right to terminate the agreement at any time.

2020 Terminated License Agreement with The Ohio State Innovation Foundation

We exclusively licensed intellectual property from The Ohio State Innovation Foundation (OSIF) in a license agreement that was made effective November 20, 2020.

Under the license agreement, we were granted an exclusive worldwide license to develop and commercialize products covered by the OSIF licensed intellectual property for the treatment, prevention or palliation of muscular dystrophies and disorders.

We were obligated to make payments to OSIF aggregating up to $1.3 million per product covered by the OSIF licensed patent rights upon the achievement of specified development and regulatory approval milestones and approximately $2.3 million per product covered by the OSIF licensed patent rights upon the achievement of specified sales milestones.

We were also obligated to pay low single-digit royalties to OSIF based on net sales by us and our affiliates and sublicensees of each product covered by the OSIF licensed patent rights.

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

On July 27, 2023, we provided notice to OSIF to terminate the license agreement because the licensed technology is no longer relevant to the Company’s business.

The license agreement was terminated, effective October 25, 2023, and as a result we no longer have any payment obligations to OSIF.

As of December 31, 2023, the Company has paid $0.7 million for license fees and milestones achieved in connection with the license agreement.

Government Regulations

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The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies.

The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product;

The IND also includes results of animal and in vitro studies assessing the toxicology, PK, pharmacology, and pharmacodynamic characteristics of the product;

chemistry, manufacturing, and controls information;

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

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 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.

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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This review typically takes 12 months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.

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

The FDA may request additional information rather than accept an NDA for filing.

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

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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.

The Food and Drug Omnibus Reform Act (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.

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.

Under the Orphan Drug Act, the FDA may grant 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.

In view of the court decision 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.

2021), in January 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.

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

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.

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.

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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Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in revisions to the approved labeling to add new safety information;

imposition of post-market studies or clinical studies to assess new safety risks;

of post-market studies or clinical studies to assess new safety risks;

or imposition of distribution restrictions or other restrictions under a REMS program.

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The USPTO, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may apply for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

In the future, we may apply

for restoration of patent term for our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

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

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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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Also, we may be subject to private “qui tam” actions brought by individual whistleblowers on behalf of the federal or state governments.

Actual or alleged violation of any such laws or regulations may lead to investigations and other claims and proceedings by regulatory authorities and in certain cases, private actors, and violation of any of such laws or any other governmental regulations that apply may result in penalties, including, without limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, imprisonment, additional reporting obligations, and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, the curtailment or restructuring of operations, exclusion from participation in government healthcare programs and imprisonment.

limitation, significant administrative, civil and criminal penalties, damages, fines, disgorgement, imprisonment, additional reporting obligations, and oversight if we become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these laws, the curtailment or restructuring of operations, exclusion from participation in government healthcare programs and imprisonment.

Coverage and Reimbursement

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and it established a Center for Medicare Innovation at the Centers for Medicare & Medicaid Services (CMS), to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending.

Since its enactment, there have been executive, judicial and congressional challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.

Since its enactment, there have been

executive, judicial and congressional challenges to certain aspects of the ACA, and we expect there will be additional challenges and amendments to the ACA in the future.

The ACA continues to significantly impact the United States’ pharmaceutical industry.

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

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, effective April 1, 2013, which will stay in effect through 2031, with the exception of a temporary suspension implemented under various COVID-19 relief legislation from May 1, 2020 through March 31, 2022, unless additional congressional action is taken.

Under current legislation, the actual reduction in Medicare payments will vary from 1% in 2022 to up to 4% in the final fiscal year of this sequester.

These changes include aggregate reductions to Medicare payments to providers of up to 2% per fiscal year, effective April 1, 2013, which will stay in effect through 2032, unless additional congressional action is taken.

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, 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, Medicaid statutory rebates are no longer capped at 100% of the average manufacturer price.

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.

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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.

Various industry stakeholders have initiated lawsuits against the federal government asserting that the price negotiation provisions of the Inflation Reduction Act are unconstitutional.

The impact of these judicial challenges and future regulations, healthcare measures and agency rules by the government 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.

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.

FDA recently authorized the state of Florida to import certain prescription drugs from Canada for a period of two years to help reduce drug costs, provided that Florida’s Agency for Health Care Administration meets the requirements set forth by the FDA.

Other states may follow Florida.

We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate, if approved, is prescribed or used.

It is possible that additional governmental action may be taken to address the COVID-19 pandemic.

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The competent authority of the RMS prepares a draft assessment report, a draft summary of the product characteristics (SOPC) and a draft of the labeling and package leaflet, which are sent to the other Member States (referred to as the Member States Concerned) for their approval.

If the Member States Concerned raise no objections, based on a potential serious risk to public health, to the assessment, SOPC, labeling or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Member States Concerned).

If the Member States Concerned raise

no objections, based on a potential serious risk to public health, to the assessment, SOPC, labeling or packaging proposed by the RMS, the product is subsequently granted a national MA in all the Member States (i.e., in the RMS and the Member States Concerned).

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

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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