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UNITED STATES

SECURITIES AND EXCHANGE COMMISSION

Washington, D.C. 20549

FORM 10-K

(Mark One)

☒ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES

EXCHANGE ACT OF 1934

For the fiscal year ended December 31, 2022

☐TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES

EXCHANGE ACT OF 1934

Commission File Number: 001-40236

Edgewise Therapeutics, Inc.

(Exact name of registrant as specified in its charter)

(State or other jurisdiction of (I.R.S. Employer

incorporation or organization) Identification Number)

3415 Colorado Ave.

Boulder, CO80303

(Address of Principal Executive Offices)

(720) 262-7002

(Registrant’s telephone number)

Securities registered pursuant to Section 12(b) of the Act:

Title of Each Class Trading Symbol Name of Exchange on which registered

Common stock, par value $0.0001 per share EWTX Nasdaq Global Select Market

Securities registered pursuant to Section 12(g) of the Act: None

Indicate by check mark if the registrant is a well known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐No☒

Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐No☒

Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes☒ No ☐

Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes☒ No ☐

Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.

Large accelerated filer ☐ Accelerated filer ☐

Non-accelerated filer ☒ Smaller reporting company ☒ Emerging growth company ☒

If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐

Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report.☐

If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously issued financial statements. ☐

Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐

Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒

The aggregate market value of registrant’s common equity held by non-affiliates of registrant on June 30, 2022, the last business day of the registrant’s most recently completed second fiscal quarter, was approximately $247.9 million, based upon the closing sale price of the common stock as reported on The Nasdaq Global Select Market.

As of January 31, 2023, there were 63,262,464 of the registrant’s ordinary shares outstanding.

DOCUMENTS INCORPORATED BY REFERENCE

Information required by Part III of this Form 10-K is incorporated by reference to the registrant’s proxy statement for the 2023 annual meeting of stockholders, which proxy statement will be filed with the Securities and Exchange Commission within 120 days after the end of the fiscal year covered by this Form 10-K.

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Page

PART I

Item 1. Business 5

Item 1A. Risk Factors 60

Item 1B. Unresolved Staff Comments 128

Item 2. Properties 128

Item 3. Legal Proceedings 129

Item 4. Mine Safety Disclosures 129

PART II

Item 6. [Reserved] 130

Item 7A. Quantitative and Qualitative Disclosures About Market Risk 141

Item 8. Financial Statements and Supplementary Data 141

Item 9A. Controls and Procedures 160

Item 9B. Other Information 161

PART III

Item 10. Directors, Executive Officers and Corporate Governance 161

Item 11. Executive Compensation 161

Item 14. Principal Accounting Fees and Services 161

PART IV

Item 15. Exhibit and Financial Statement Schedules 162

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SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS

This Annual Report on Form 10-K (Annual Report) contains forward-looking statements that involve risks and uncertainties. All statements other than statements of historical facts contained in this Annual Report, including statements regarding our future results of operations and financial position, business strategy, development plans, planned preclinical studies and clinical trials, future results of clinical trials, expected research and development costs, regulatory strategy, timing and likelihood of success, as well as plans and objectives of management for future operations, are forward-looking statements. In some cases, you can identify forward-looking statements by terminology such as “may”, “will”, “should”, “expects”, “intends”, “plans”, “anticipates”, “believes”, “estimates”, “predicts”, “potential”, “continue” or the negative of these terms or other comparable terminology. These forward-looking statements include, but are not limited to, statements about:

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● our financial performance;

● the impact of laws and regulations; and

We have based these forward-looking statements largely on our current expectations and projections about our business, the industry in which we operate and financial trends that we believe may affect our business, financial condition, results of operations and prospects, and these forward-looking statements are not guarantees of future performance or development. These forward-looking statements speak only as of the date of this Annual Report and are subject to a number of risks, uncertainties and assumptions described in the section titled “Risk Factors” and elsewhere in this Annual Report. Because forward-looking statements are inherently subject to risks and

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uncertainties, some of which cannot be predicted or quantified, you should not rely on these forward-looking statements as predictions of future events. The events and circumstances reflected in our forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events or otherwise.

In addition, statements that “we believe” and similar statements reflect our beliefs and opinions on the relevant subject. These statements are based upon information available to us as of the date of this Annual Report and while we believe such information forms a reasonable basis for such statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and you are cautioned not to unduly rely upon these statements.

PART I

Item 1. Business

Overview

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.

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. 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. 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. Our preclinical data with EDG-5506 in animal models of muscular dystrophy demonstrated that selective regulation of fast (type II) myofiber contraction protected muscle from damage, reduced systemic fibrosis and improved measures of muscle function including strength and ability to engage in physical activities, which we believe may provide evidence of a disease modifying effect. A unique observation from our preclinical work is that EDG-5506 led to pronounced prevention of cardiac fibrosis. This is

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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.

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.

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Our Pipeline

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 retained global development and commercialization rights to all of our programs. Our current pipeline is summarized below.

Our History and Team

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 were co-founded in 2017 by our Chief Scientific Officer, Alan Russell, Ph.D., Peter Thompson, M.D., who is currently a Partner at OrbiMed and Badreddin Edris, Ph.D., who is currently the Chief Operating Officer at SpringWorks Therapeutics, Inc. through funding provided by OrbiMed. Dr. Russell has extensive experience in developing novel therapeutics for diseases involving skeletal muscle, having previously served as Vice President and Head of the Muscle Metabolism Discovery Performance Unit at GlaxoSmithKline from 2010 to 2017 and as Associate Director, Muscle Biology and Therapeutics at Cytokinetics from 2002 to 2010, where he was the co-inventor of tirasemtiv and reldesemtiv, direct muscle sensitizers for Amyotrophic Lateral Sclerosis (ALS).

We are led by Kevin Koch, Ph.D., who has been in the life science industry for over 30 years with a focus on drug discovery, translational medicine and clinical development. Dr. Koch previously served as the Senior Vice President of Drug Discovery, Chemical and Molecular Therapeutics at Biogen where he managed global drug discovery and biomarker development. Dr. Koch was a co-founder of Array BioPharma, serving as President, Chief Scientific Officer and Board member from the company’s inception in 1998 to 2013. While there, he built a fully integrated research and development team that oversaw the invention of over 20 clinical development candidates across multiple therapeutic areas, several of which are now marketed medicines. Prior to Array, Dr. Koch held senior positions at Amgen and Pfizer Central Research. Additionally, our Chief Business Officer, Behrad Derakhshan, Ph.D., our Chief Financial Officer, R. Michael Carruthers, our Chief Medical Officer, Joanne Donovan, M.D., Ph.D., and our General Counsel, John Moore, each have more than 15 years of experience in drug research, clinical development, regulatory affairs, manufacturing,

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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. Dr. Semigran previously served as Chief Medical Officer and Senior Vice President of medical science at MyoKardia and as Chief Medical Officer of Renovacor. Dr. Semigran brings considerable clinical development and translational medicine experience as we prepare to advance our novel cardiac program into clinical development.

Further, we have built a scientific advisory board with experts in the field of muscle diseases affecting both children and adults. Our scientific advisors include researchers who publish widely-cited articles on the skeletal and cardiac aspects of muscular dystrophy as well as on inherited forms of cardiovascular disease. Moreover, some of our advisors lead clinical units at some of the leading muscle disease centers in the United States and are actively involved in our drug development process and programs.

As a private company, we raised $160.7 million from leading institutional investors which include OrbiMed, Novo Holdings A/S, U.S. 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 Strategy

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. Key components of our strategy to achieve this vision include:

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Our Proprietary Drug Discovery Platform

Our precision medicine muscle platform enables the discovery and development of therapies with disease modifying potential

Muscle is the most abundant tissue in the body. Skeletal muscle alone accounts for 40% to 50% of body mass. 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.

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

Our Programs

EDG-5506 for Treatment of Patients with DMD and BMD

Overview

We are developing a muscle fiber stabilizing therapy that represents a novel mechanistic approach designed to address the root cause of dystrophin deficient muscular dystrophies. EDG-5506, our most advanced product candidate, is an orally administered, allosteric, selective, fast myofiber (type II) myosin inhibitor that is designed to be inactive against slow myofiber (type I) myosin present in both skeletal muscle and the heart. 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). 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. 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.

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Absence of dystrophin in DMD causes muscle fiber membrane stress when muscles contract, leading to myofiber damage. By enhancing muscle stability and decreasing muscle damage, we believe EDG-5506 has the potential to improve outcomes across a broad range of DMD patients when used as a single agent. EDG-5506 may also provide a synergistic or additive effect in combination with available therapies and therapies currently in development, including dystrophin replacement gene therapies.

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. Approximately 10% of mutations are duplications of exons and approximately 15% are single point mutations. Dystrophin provides a structural link between the contractile elements (actin and myosin filaments) of the sarcomere and the basement membrane of the myofibers (muscle cell). 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. 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.

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. Once myofiber degeneration is initiated, regeneration typically follows.

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

DMD predominantly occurs in boys and typically presents at three to five years of age through observation of missed functional milestones and Gowers’ sign (a finding from a medical examination that identifies weakness of the proximal hip muscles) due to symmetrical, proximal weakness in selective muscle groups in combination with calf hypertrophy and CK, a plasma protein biomarker linked to muscle damage, >10 times normal. Systemically circulating biomarkers of myofiber degeneration, such as CK and troponin I are significantly elevated from birth with maximal levels at approximately two years of age. Levels decrease with time, presumably as muscle mass is lost.

Loss of Ambulation

Clinical manifestations occur in a predictable pattern of loss of functional milestones: ability to rise from the floor, ability to climb stairs, ability to walk, upper limb function and respiratory function. Typically, boys begin to lose the ability to rise from the floor between the ages of seven and nine, with the loss of the ability to climb stairs shortly thereafter and loss of ambulation 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.

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. 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.

Effects on Respiratory Function

Respiratory function decline, as measured by spirometry, occurs by age 12, and is generally relentlessly progressive. Progressive respiratory muscle impairment leads to cardiovascular issues and poor respiratory secretion clearance, hypoventilation and pulmonary infections putting patients at increased risk of hospitalization and need of continuous ventilatory support.

Cardiac Complications

The loss of dystrophin leads to cardiovascular disease in most DMD 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”. 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. As the disease progresses, boys lose their ability to toilet, to feed, to dress, to take a bath, all the things that represent independence in a young man’s life. And these losses lead to more symptoms: contractions, pressure sores, constipation, numbness in legs and feet, and scoliosis.

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

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.

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 modest chronic benefit of steroids is weighed against the risks, and treatment is often discontinued after loss of ambulation. Sustained glucocorticoid dosing in young DMD patients is associated with side effects including weight gain which could lead to obesity, Cushingoid features, excessive growth of hair on the body, adverse behavior changes, growth impairment, delayed puberty, immune suppression, adrenal suppression, fractures and cataracts.

Exon Skipping Therapies

There are four FDA conditionally-approved antisense oligonucleotide (AO) therapies 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

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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, VYONDYS 53 and AMONDYS 45, in addition to requiring weekly intravenous infusions, have demonstrated a less than 1% mean increase in dystrophin in clinical trials, which we believe is a function of poor and inefficient muscle transduction. Moreover, a significant limitation of exon skipping approaches for DMD is the fact that each AO has been developed for skipping of a specific exon and their use is limited to a sub-set of mutations and hence only used in a subpopulation of DMD patients (e.g., exon 51 skipping is feasible in only up to 13% of all DMD patients). Other companies, such as Avidity Biosciences, Inc., Dyne Therapeutics, Inc., 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. 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; current constructs express truncated dystrophin proteins that are 20% to 30% of the normal size of the full-length dystrophin protein.

Recently, several gene therapies designed to produce a minidystrophin or microdystrophin have progressed into clinical development. However, it is estimated that between 20% to 60% of patients have antibodies against AAV due to naturally acquired infections. These antibodies prevent them from receiving AAV gene therapy due to pre-existing AAV immunity to the capsid, the protein shell of the virus used for delivery, which can lead to severe and potentially deadly immune response. The duration of activity and utility/safety of these approaches in older patients is also an open question.

The question around whether gene expression can persist lifelong after a single vector administration is an area of debate across many disorders including dystrophinopathies. The long-term persistence of transgene expression is exacerbated by growth/turnover of skeletal muscle and preexisting or recall immune responses to the AAV vector capsid and/or to the transgene product itself, which can interfere with therapeutic efficacy. Furthermore, this limited durability is problematic because re-administration after the first dose is currently not possible.

In November 2022, Sarepta announced that the U.S. FDA accepted their Biologics License Application seeking accelerated approval of their microdystrophin gene therapy, SRP-9001 (delandistrogene moxeparvovec), for the treatment of ambulant individuals with DMD. SRP-9001 has been granted Priority Review by the FDA, with a regulatory action date of May 29, 2023. Other companies focused on developing genetic based therapies for DMD that target dystrophin mechanisms include Pfizer Inc., Solid Biosciences Inc., Genethon, PepGen, Dyne Therapeutics, Avidity Biosciences, REGENXBIO, and Entrada Therapeutics. Gene editing treatments that are in preclinical development are also being pursued by Vertex and Sarepta Therapeutics.

Both Pfizer and Sarepta Therapeutics limited their Phase 3 patient enrollment to children aged four to seven years old, thus excluding a significant proportion of DMD children and adolescents. Due to weight-based dosing regimens, for older patients in particular, who are generally heavier, scaling up to produce enough AAV-based viral vector genomic particles or vector genomes, remains a potentially significant encumbrance and even if feasible, raises concerns relating to safety of administering higher viral loads to patients. It is important to note that multiple clinical trials have reported significant adverse events associated with systemic administration of higher doses of AAV to treat muscle diseases. Vector dilution will also be an important consideration that we believe will limit the current class of AAV-based gene

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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. 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.

Our Solution: EDG-5506

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.

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

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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.

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

Background and Rationale of Our Approach

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. 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. Under normal conditions, skeletal muscle contractile demand is much lower than at the maximal output. Maximal activation of muscle is painful, damaging and unproductive to sustained function. We have taken advantage of this flexibility to explore an alternative therapeutic strategy to protect susceptible type II skeletal muscle fibers.

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When muscle fibers undergo damage, they release internal proteins such as CK and troponin into the blood. One of the troponin subunits, TnI has a different isoform for each type of striated muscle (fast, slow and cardiac) and can be used to explore the fiber-specific source of these proteins. We evaluated DMD and BMD patient plasma samples using high specificity assays for fast and slow myofiber TnI and observed that fast myofiber TnI (TnI2) plasma levels 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

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. EDG-5506 acts to protect dystrophic muscle from breakdown by modulating contraction in susceptible fast muscle fibers. 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. 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. Chronic treatment with dantrolene has been associated with drowsiness and the potentially serious side effect of idiosyncratic fatal hepatotoxicity, limiting its broad use. We anticipate that the high potency, fast fiber targeting and low projected dose of EDG-5506 will limit unwanted side effects. Moreover, stabilization of the sarcomere with EDG-5506 via direct decreases in contractile stress potentially provides greater muscle protection than secondary inhibition of calcium release via the ryanodine receptor.

Another corollary to our approach of selectively targeting type II fast skeletal muscle myofibrils with EDG-5506 is mavacamten (MYK-461), a selective allosteric inhibitor of cardiac type I myosin ATPase. Mavacamten 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. Mavacamten’s mechanism of action further validates selective allosteric regulation of myofibers as a viable therapeutic approach to treating various muscle disorders.

Interestingly, nature has carried out one of the more critical experiments to help us understand the impact of inhibiting fast fiber myosin selectively. There are several reports describing the human phenotype of people born with genetic loss of function (LOF) of the myosin heavy chain 2 gene, MYH2 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

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I muscle fibers as a result of complete lack of fast type IIa muscle fibers. These patients have mild, proximal muscle weakness with ocular muscle involvement but remain ambulatory throughout life. The observations in these patients demonstrate an ability of the body to maintain function despite complete loss of one myofiber type. Given that our goal is to partially inhibit type II fast skeletal muscle myofibrils in order to modulate force development and not completely inhibit them, as is the case in the LOF patients, it is our belief that selective fast fiber regulation with EDG-5506 will likely be well-tolerated and may protect dystrophic myofibers from degeneration and subsequently improve and/or preserve physical function.

Preclinical Data

In Vitro Biochemical and Single Muscle Fiber Assays

The inhibitory activity and specificity of EDG-5506 was measured using skeletal myofibril preparations isolated from muscle sources with uniform myosin composition. We observed that EDG-5506 inhibited fast myofibril ATPase from rabbit psoas muscle with an IC50 of 0.2 μM (A). Myosin inhibitory activity was further supported by measuring the actin-activated ATPase of purified S1 myosin motor sub-fragment. We observed that EDG-5506 inhibited the enzymatic activity of fast, but not cardiac or the more unrelated smooth muscle S1, with an IC50 of 0.11 μM and >100 μM, respectively (B and C). We also observed that EDG-5506 selectively reduced contraction in fast skeletal muscle fibers with an IC50 of 0.7 μM (D). In contrast, maximal inhibitory concentrations of EDG-5506 had no observed effect on slow skeletal or cardiac muscle fibers (E and F). In ex vivo assays using mouse muscle, we observed that EDG-5506 reduced contraction in a concentration and time-dependent manner, completely inhibiting fast extensor digitorum longus (EDL) muscle but only partially inhibiting mixed fast/slow soleus muscle.

EDG-5506 selectively inhibited fast skeletal muscle ATPase and contraction

Protection of Dystrophic Skeletal Muscle from Contraction-induced Functional Decline

The inhibitory activity of EDG-5506 in live skeletal muscle ex vivo was measured in wild type (WT) mouse EDL muscle, a predominantly fast skeletal muscle in the hindlimb. We observed that the addition of EDG-5506 to isolated muscle resulted in concentration- and time-dependent decreases in maximal force. EDL muscles from dystrophic mdx mice exhibited enhanced force run-down with eccentric (lengthening) contraction. We also observed that the addition of 5 μM EDG-5506 to mdx EDL muscle for 60 minutes (enough to decrease pre-injury maximal force by 50%) decreased peak force decline closer to that observed in WT mouse muscle. Protection with EDG-5506 exhibited a concentration

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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. In this model, contracting muscle is rapidly lengthened, resulting in excessive stress that causes an amplified decrease in the ability of the muscle to contract after the injury in mdx but not normal mice. We observed that oral doses of EDG-5506 caused dose-dependent decreases in muscle force prior to lengthening injury (A). After lengthening injury, we observed that EDG-5506 prevented exaggerated force deficits, returning the injury response in mdx mice to that of a normal mouse (B). Importantly, we observed that full protection of the muscle was possible with only small decreases in force prior to injury (<10% — compare force decrease in (A) with protection in (B)).

EDG-5506 protected dystrophic skeletal muscle from contraction-induced functional decline in situ

Protection of Dystrophic Skeletal Muscle from membrane disruption

In conjunction with exaggerated force deficits, exercise of dystrophic skeletal muscle triggers membrane disruption that results in edema, entry of extracellular calcium ions and necrosis. Fluid entry was visualized in mdx mouse muscle ex vivo and in vivo. Ex vivo imaging was performed by incubating mdx extensor digitorum longus (EDL) muscle with procion orange, a membrane impermeable dye. We observed that lengthening contraction of muscle led to increased uptake of the dye, which was visualized with immunofluorescence (A). We also observed that preincubation of muscles with EDG-5506 resulted in a concentration-dependent decrease in procion-positive fibers (B).

Muscle membrane leak was separately visualized in vivo by intravenous injection of Evans blue dye (EBD), which is only taken up by disrupted muscle fibers and marks them with a blue color. Mdx mice were administered vehicle or EDG-5506 daily for three weeks before EBD injection. 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 believe these observations further support EDG-5506’s ability to protect muscles from membrane disruption and edema.

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EDG-5506 reduced muscle membrane disruption in mdx mice

Protection of dystrophic skeletal muscle from exercise-induced injury

Exercise was next used to induce exaggerated muscle injury in mdx mice. Exercise in mdx mice yields membrane injury which causes muscle proteins, including CK, to leak from muscle into the circulation. Mdx mice were administered a single dose of vehicle or EDG-5506 and were physically challenged with a grip strength test device four hours later. We observed that EDG-5506 had no detrimental effect on grip strength performance (A) but that circulating CK activity after the exercise was significantly lower than that shown in disease controls (B). This study demonstrated that therapeutic muscle protection in vivo is possible without inhibiting myosin to a level that decreases strength. It is worth noting that this type of single-dose challenge experiment was not expected to demonstrate strength improvements but instead was used as a strength challenge to elicit muscle injury.

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EDG-5506 protected muscle from exercise-induced injury in mdx mice

Improvements in strength and diaphragm fibrosis in mdx mice after eight weeks oral administration of EDG-5506

Longer term effects of EDG-5506 were assessed in young mdx mice after eight weeks of administration. EDG-5506 treated mice exhibited higher grip strength compared to vehicle treated mice. At the end of the study, continued muscle protection was observed with a rotarod exercise challenge. There was no observed difference in rotarod performance, but CK was observed to be lower in the treated groups compared to vehicle, consistent with single-dose results. While DMD patients exhibit extensive muscle fibrosis with age, collagen accumulation in mdx mice is generally limited to the diaphragm. Histological examination of the diaphragm using a collagen stain (picrosirius red) revealed lower staining in EDG-5506 treated mice.

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.mdx) is mildly affected by disease with limited muscle fibrosis. A more severe muscle disease is observed when the mdx mutation is crossed onto the DBA/2J genetic background (D2.mdx). This model exhibits greater muscle damage, impaired muscle regeneration, muscle wasting, and exacerbated progression of intramuscular fibrosis than age matched B10.mdx mice. Given that the DBA/2J mdx mouse phenotype better recapitulates characteristics of the human disease, we evaluated the effect of EDG-5506 on skeletal muscle fibrosis in this mouse model.

We observed that twelve weeks EDG-5506 dosing via incorporated chow at 50 ppm (roughly equivalent to 1 mg/kg per day by oral administration) in DBA/2J mdx mice starting at five weeks old, reduced fibrosis in anterior tibialis (TA) muscle and diaphragm muscles (A, B) with a trend towards lower fibrosis in the left ventricle of the heart (C).

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EDG-5506 reduced muscle fibrosis in DBA/2J mdx mice after 12 weeks treatment

Unexpected trends in the reduction of cardiac fibrosis led us to examine DBA/2J mdx mice in two studies after longer term (12 to 15 months) dosing. At the end of the study in 15-month-old mice, we performed a whole-body examination of musculoskeletal anatomy after removing the skin in euthanized mice. Skeletal muscles were noticeably smaller in the fore and hindlimbs of DBA/2J mdx mice and kyphosis (spinal curvature) was visible when compared to control DBA 2/J mice (blue arrows). 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.

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

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

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

Longer term dosing of DBA/2J mdx mice also demonstrated lower cardiac fibrosis compared to vehicle controls in both long term studies (A, B). We also observed a reduction in the incidence of cardiac hypertrophy (C). Observing cardiac benefit in DBA/2J mdx mice is uncommon and has not been demonstrated in long-term studies with high level AAV micro-dystrophin transduction. 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.

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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. 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.

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. CK was reversibly decreased >50% with EDG-5506 (A).

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Circulating CK levels correlate with activity in GRMD dogs. In a follow-up study, (same dogs, 18 months of age), we tested whether administration of EDG-5506 affected activity using an activity monitor. We observed that EDG-5506 improved average daily activity by >30% (B), increased active time and decreased rest time in a reversible manner demonstrating both reduction in CK and improved physical function. To our knowledge, this is the first documented intervention to improve biomarkers and physical function in symptomatic, disease stable GRMD dogs. Our studies demonstrating consistent beneficial effects of EDG-5506 across multiple established preclinical models is differentiated and we believe speaks to the fundamental nature of our novel approach.

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

EDG-5506 lowered disease biomarkers in DMD 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. As expected, GRMD control plasma samples exhibited many protein differences compared to healthy dogs, reflecting the serious skeletal muscle pathology of these animals. EDG-5506 successfully restored the GRMD plasma protein signature closer to that of WT dogs, reversibly lowering elevated proteins and increasing downregulated proteins. A closer examination of proteins significantly lowered by treatment with EDG-5506 validated previous CK activity measures (muscle CK reversibly lowered 34%, p<0.05). 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.

Preclinical Pharmacokinetics and Metabolism of EDG-5506

In all species studied to date, concentration-time profiles resulting from bolus intravenous administration are characterized by rapid distribution phase followed by mono-exponential decay. EDG-5506 displayed a terminal half-life ranging from 21 to 69 hours across species. The compound distributes to skeletal muscle, its intended therapeutic target, with high skeletal tissue to plasma ratios. Distribution to cardiac muscle is minimal and tends to be on the order of 2-fold

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

Cytochrome P450 (CYP) reaction phenotyping studies using recombinant enzymes have identified several isoforms that are involved in EDG-5506 metabolism, including CYP3A4, 2D6, and 2C19. Drug-drug interaction studies in human liver microsomes conducted at concentrations up to 30 μM did not indicate reversible inhibition of CYPs 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4. Similarly, EDG-5506 did not display measurable inhibition in time-dependent studies in the same panel of CYPs.

EDG-5506 has been administered to mouse, rat, dog, pig and monkey by intravenous and oral administration, the intended route of administration in humans, to project human PK parameters using simple allometry.

EDG-5506 Toxicology Studies

The toxicity and safety pharmacology profile of EDG-5506 has been explored in standard good laboratory practice (GLP) safety pharmacology studies, in non-good laboratory practice exploratory and dose range studies. 13-week repeated dose toxicity studies were performed in rat and dog to support the Phase 1 first-in-human clinical trial. Additionally, a 26-week oral GLP toxicity study of EDG-5506 in rats and a 39-week oral GLP toxicity study of EDG-5506 in dogs were performed to support long-term dosing in humans. All toxicities noted were ascribed to EDG-5506 and were consistent with the known mechanism of EDG-5506 and exaggerated primary PD activity (i.e., regulation of type II fast skeletal muscle myosin). There were no unanticipated off-target toxicities noted in either rats or dogs administered EDG-5506 for up to 39 weeks. We also completed a 7-week oral juvenile toxicity study in 2022 with no unanticipated off-target toxicities noted.

EDG-5506 Formulation

In our Phase 1 clinical trial for EDG-5506, we utilized a formulation of powder for suspension in a commercially available compounding agent, SyrSpend® SF (sugar free), for once daily oral administration. SyrSpend® SF is a sweetened, suspending vehicle for use in compounded oral liquid preparations. SyrSpend® SF is composed of modified food starch, citric acid, sucralose, and sodium citrate. All ingredients are “Generally Recognized as Safe” (GRAS) or classified as “inactive ingredients” by the FDA when used in accordance with their intended purpose. We have also developed an immediate release tablet formulation for the Phase 2 trials in BMD and DMD. As EDG-5506 is a biopharmaceutics classification system (BCS) Class 1 molecule, it can be readily formulated into solid dosage forms including tablets and capsules.

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EDG-5506 Clinical Plan

An updated overview of our near-term clinical development plan for EDG-5506 in DMD and BMD 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. The starting dose in the SAD was informed by the no observed adverse effect levels (NOAELs) from the 13-week GLP toxicology study. The Phase 1 clinical trial was carried out at a single site in San Antonio, Texas.

EDG-5506 Phase 1 Clinical Trial Schematic

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Phase 1a: Single Ascending Dose (SAD) Cohorts

In the first-in-human single ascending dose (SAD) trial, oral doses of EDG-5506 (0.5, 1.5, 5, 15, 45, 90 and 135 mg) or matching placebo were administered to 57 HVs — cohorts of eight participants were randomized to six receiving EDG-5506 and two receiving a placebo for each dose group. A single dose of EDG-5506 up to 90 mg was considered generally safe and well-tolerated. The most common AEs were dizziness and somnolence, which was seen at Grade 1 (on the Division of AIDS AE Grading Scale) except in the single dose cohort of 135 mg, where Grade II somnolence and dizziness were observed.

Our SAD demonstrated rapid absorption of EDG-5506 following a single oral dose. EDG-5506 displayed a favorable human PK profile, consistent with extensive on-target muscle distribution and a half-life of approximately 15 days. Exposures were observed to be dose proportional up to the 45 mg dose. PK modeling utilizing the SAD dataset projected that once-daily doses of 10-15 mg will achieve steady-state Ctrough drug concentrations at or above the efficacy exposure levels achieved in preclinical models of Duchenne muscular dystrophy.

Phase 1a: Multiple Ascending Dose (MAD) Cohorts

The MAD enrolled 40 participants of whom 30 were randomized to EDG-5506 and 10 were randomized to placebo. Cohorts B1 and B2 received a suspension with a 4-day loading dose of EDG-5506 once-daily followed by 10 days at half of this dose (B1: 10 mg/5 mg, B2: 20 mg/10 mg). Cohorts B3 to B5 did not receive a loading dose and were administered a 20 mg suspension (B3) or a solid dosage form at doses of 20 mg (B4) and 40 mg (B5) daily for 14 days.

The study drug was well tolerated in all multi-dose cohorts (5 to 40 mg EDG-5506 given once daily for 14 days). Dizziness and somnolence were the most common AEs experienced and in all cases were mild and transient. At projected therapeutic doses, AEs generally decreased over time suggesting development of tolerance. There were no AEs of special interest, no SAEs, and no discontinuations due to AEs. In the MAD, the PKs on Day 1 were consistent with the PKs observed in the SAD part of the study.

In summary, the Phase 1a SAD/MAD demonstrated that EDG-5506 was generally well tolerated with no serious adverse events observed. PK data supports robust target engagement with achievement of muscle concentrations well above the efficacious levels observed in preclinical disease models of DMD.

Phase 1b: 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). 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. 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.

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BMD Phase 1b Patient Demographics

EDG-5506 was well tolerated in BMD subjects. Seven of the seven subjects enrolled in the Phase 1b cohort experienced TEAEs and all were Grade 1. There were no AEs of special interest, no SAEs, and no discontinuations due to AEs. There were no AEs due to clinically significant abnormal vital signs, ECG or laboratory assessments. All participants that received either EDG-5506 or placebo experienced Grade 1 dizziness with 2 of 5 participants that received EDG-5506 reporting somnolence.

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

An important goal in Phase 1 was to provide a range of compound concentrations required to achieve efficacy and translate those levels to meaningful target muscle exposures in humans. To achieve this, we focused on measuring absolute muscle concentrations in preclinical studies and then calculated a human target equivalent muscle exposure, based on relative proportions of fast muscle fibers (see figure below).

EDG-5506 Target Human Muscle Exposure Range

As shown, EDG-5506 human muscle levels of 1,000 to 4,100 ng/g were projected to provide meaningful clinical benefit in humans based on experiments in mdx, DBA/2J mdx and GRMD. Of note, muscle concentrations in mouse studies were those required for maximal efficacy, essentially returning dystrophic muscle to a normal state.

In the MAD and Becker muscular dystrophy cohorts, muscle biopsy samples were taken at Day 14 to measure EDG-5506 levels in muscle. In Cohorts B1-B5, EDG-5506 concentrates in muscle at or above levels predicted to provide meaningful clinical benefit in humans (summarized below). Mean EDG-5506 concentration was 100-fold higher concentrations in the muscle tissue versus plasma, which we believe reflects the known high-affinity binding to myosin

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

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

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

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. 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). To establish a unique proteomic signature for individuals

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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. 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.

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Baseline BMD 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. 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.

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SOMAscan Comparison of BMD and DMD 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. 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). ARCH was designed to evaluate the safety, PK, changes in biomarkers of muscle damage such CK and fast skeletal muscle troponin I, measures of function with NSAA/NSAD, time function tests and patient-reported outcomes. The schematic below outlines the overall trial design. ARCH will continue to monitor patients for two years and is scheduled to complete in April 2024.

ARCH Trial Design

The patients in ARCH had significant functional impairment and evidence of decreased muscle mass at baseline. All individuals had a decreased ability to perform functional measures such as the 10-meter walk-run or rise from floor – only half of the BMD patients were able to perform the rise from the floor at baseline. Their creatinine, which is derived directly from muscle, was decreased. Their CK was elevated, consistent with ongoing muscle damage, and the DXA lean body mass was also decreased, consistent with the overall decreased function and decreased muscle mass. North Star scores for these individuals ranged from 4 to 31. Baseline characteristics are summarized below.

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BMD Patient Baseline Characteristics in ARCH

At six months, EDG-5506 continued to be well tolerated following escalation to the 15 mg dose for four months, after initially receiving a 10 mg dose for 2 months. The most common adverse events were dizziness, somnolence, and headache. There were no dose reductions, dose adjustments or patient discontinuations due to adverse events. All patients have since been dose escalated to the 20 mg dose of EDG-5506. An overview of the adverse events observed up to the 6-month timepoint can be seen in the table below.

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

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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

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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.

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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.

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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.

EDG-7500: A Novel Molecule for the Treatment of Patients with HCM and Other Severe Cardiac Disorders with Significant Unmet Needs

Overview

In the course of our EDG 002 program, a unique series of cardiac modulators with novel mechanisms of action have been identified. One of these agents, the small molecule EDG-7500, has unique properties that may lead to a novel therapeutic approach for patients with HCM. The effects of EDG-7500 on cardiac function overlap with some of the desirable attributes of the cardiac myosin inhibitors (CMIs) such as BMS’s CAMZYOS® (mavacamten) and Cytokinetics’ CK-274 (aficamten). However, there are improvements in EDG-7500's effects on cardiac function from those of CMIs that we believe have the potential to yield a potentially superior target product profile for the treatment of multiple phenotypes of HCM and may also have therapeutic benefit in sub-populations of patients with heart failure with preserved ejection fraction (HFpEF).

Disease Background and Current Treatment Limitations

HCM is the most common form of genetic heart disease, affecting approximately one in 500 individuals. HCM is caused by abnormal proteins in the heart, including cardiac myosin, that lead to excessive cardiac contraction. Estimates suggest there are as many as 630,000 people in the United States suffering from different forms of HCM. Over time, abnormal proteins in the heart, many of which are inherited, lead to excessive cardiac contraction, referred to as hypercontractility. This disruption in cardiac muscle contractility leads to increased stress and thickening of the walls of the major pumping chamber of the heart, the left ventricle (LV). The LV becomes less compliant and therefore less able to fill with and pump blood. This results in a decrease in the LV chamber volume. HCM patients can become extremely limited in their functional capacity and ability to perform the activities of daily living. They may also have episodic lightheadedness and loss of consciousness (syncope). In addition, these patients are at increased risk of heart failure, stroke, atrial fibrillation, and sudden cardiac arrest.

HCM can be divided into patients with obstructive disease, known as obstructive HCM (oHCM) and those with non-obstructive disease (nHCM). The pathophysiologic feature of obstruction is present in two thirds of patients with HCM, as the mitral valve comes into contact with the thickened muscle of the interventricular septum during the ejection of oxygenated blood from the heart to the systemic circulation. This creates an obstruction to blood flow exiting the heart through the LV outflow tract (LVOT) which results in a pressure gradient between the LV cavity and the systemic circulation. As a result, higher pressures are generated in the left ventricle than normal, and a pressure gradient develops between the LV cavity and the systemic circulation. This pressure gradient can be quantitatively measured by a routine clinical examination using Doppler echocardiography, the most common way oHCM is diagnosed and severity assessed. Patients with nHCM do not develop LVOT obstruction and have normal left ventricular pressures during contraction.

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They are characterized by the absence of a pressure gradient both at rest and following a variety of physiologic challenges, such as exertion, and non-physiologic maneuvers. Heart failure in nHCM results from diminished filling of the heart due to impaired myocardial relaxation that results from abnormal function of the same proteins that cause hypercontractility. This abnormal cardiac physiology, termed diastolic dysfunction leads to a decrease in cardiac output that is particularly severe when an HCM patient exerts themselves. oHCM patients also have LV diastolic dysfunction in addition to obstruction of blood flow in the LVOT. The clinical manifestations of oHCM and nHCM are generally similar though oHCM patients may experience more symptoms of lightheadedness and syncope.

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

Current Management of HCM

To determine the appropriate treatment approach, physicians use the New York Heart Association (NYHA) functional classification system to classify both obstructive and non-obstructive HCM patients into one of four categories; NYHA Class I-IV (least to most severe symptoms, respectively). The NYHA classification system is based on the degree of disease impact to the patient’s physical activity and is used to guide the physician’s choice of therapy. The majority of diagnosed HCM patients are symptomatic and are classified as NYHA class II-IV which requires active treatment. NYHA class I HCM patients generally do not require therapeutic intervention unless they meet established guideline criteria placing them at a high risk of sudden cardiac death, in which case implantation of a cardiac defibrillator may be advised. Class I HCM patients are generally under physician surveillance consisting of annual follow-up visits with their cardiologist.

Current pharmaceutical treatment is intended to decrease hypercontractility and improve diastolic filling in both oHCM and nHCM and to reduce LVOT obstruction in oHCM patients in order to achieve meaningful symptom relief. Non-vasodilating beta blockers and non-dihydropyridine calcium channel blockers, drugs that are indicated for broader cardiovascular disorders and do not address the underlying cause of the disease, are the first-line therapies for symptomatic oHCM and nHCM patients. Commonly prescribed beta-blockers are atenolol, propranolol, and metoprolol. Verapamil and diltiazem are calcium channel blockers used in the treatment of symptomatic oHCM and nHCM. For oHCM patients who remain symptomatic, a sodium channel blocker may also be added, typically disopyramide.

In April 2022, the U.S. FDA approved CAMZYOSTM (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 CAMZYOSTM efficacy, there are still limitations of this approach including a narrow therapeutic index, long terminal half-life (seven to nine days) and limited ability to rescue excessive pharmacology if it develops. As oHCM or nHCM progresses, patients have limited treatment options often requiring surgical or other invasive interventions including heart transplant.

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Unmet Need in HCM

CMIs have complex pharmacology which results in potentially excessive reduction in cardiac function. CMIs largely only address excessive contractility, which can limit their efficacy in a disease where both contractility and diastolic function are abnormal. These factors lead CMIs to be difficult to dose to an efficacious maintenance dose. These factors lead to patients requiring frequent and indefinite follow-up at expert centers accompanied by specialized cardiac imaging. In addition, a significant percentage of oHCM patients do not respond to CMI and other therapies. The efficacy of CMIs in patients with nHCM, who have impaired relaxation and diastolic dysfunction, also remains unproven.

Limited Efficacy of Current Therapeutic Approaches to Treat oHCM

Our Approach

EDG-7500 is a novel small molecule discovered by our company’s scientific research efforts. Unlike CMIs, EDG-7500 does not bind to the myosin motor head but instead exerts its effects independently of myosin through direct interaction with a distinct sarcomeric protein. EDG-7500 was purposefully designed to modulate the complex protein-protein interactions that control both contraction and relaxation processes within the sarcomere. Specifically, EDG-7500 is designed to speed the rate of crossbridge detachment and slows the rate of crossbridge attachment leading to the reduction of excessive residual cross-bridges during diastole, potentially enhancing relaxation and facilitating ventricular filling.

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In preclinical models, EDG-7500 has demonstrated improvement in a variety of the clinical manifestations in oHCM and nHCM. A summary table of key preclinical studies is shown below.

Summary of Key Preclinical Studies with EDG-7500

EDG-7500: MYBPC3 A31P Feline Model of oHCM

To evaluate the role of EDG-7500 in oHCM, we used an established feline model with a MYBPC3 A31P mutation. Felines with this mutation exhibit a HCM phenotype with LVOT obstruction. Treating MYBPC3 A31P felines with dobutamine induces a significant LVOT pressure gradient. Subsequent treatment with a single 1 mg/kg dose of EDG-7500 resulted in LVOT gradient relief and improved contractility. All treated animals saw their LVOT gradient reduced below the level of veterinary clinical significance with an average reduction of >60% following a single, 1 mg/kg dose.

EDG-7500 Improves Contractility and Alleviates LVOT Gradient

We next evaluated gradient reduction relative to EDG-7500 free fraction concentration in the feline model of oHCM by increasing exposures using doses ranging from 0.3 – 4.0 mg/kg. Treatment with EDG-7500 is associated with a modest effect on contractility with free drug levels of ~55 to 140 ng/mL, a range in which reduction of LVOT gradient below clinical significance was observed. To the best of our knowledge, the ability to remove a substantial portion of the gradient at levels that preserve normal systolic function is a feature that has not been observed before for an HCM drug. This data suggests the mechanism of gradient removal is decoupled from changes in LVEF. We have also observed that there is only a modest reduction in systolic contractility even at doses that are multiple folds higher than the predicted target dose.

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

EDG-7500: Myosin Heavy Chain R403Q Porcine Model of nHCM

To evaluate the role of EDG-7500 in nHCM, we used an established, genetically engineered porcine model with an MYH7 R403Q HCM mutation. The MYH7 R403Q pigs exhibit cardiac structural and functional abnormalities, including left ventricular hypertrophy, small cavity, and increased filling pressure leading to increased left atrial size, which are consistent with the nHCM phenotype observed in humans.

In the MYH7 R403Q porcine model of nHCM, EDG-7500 was observed to reduce hypercontractility to near wild type levels. Next, we evaluated EDG-7500’s effect on parameters of diastolic dysfunction. EDG-7500 led to an improvement in left ventricular filling and a reduction in left atrial size, both consistent with reduced filling pressures in the heart. Single doses of EDG-7500 also led to a dramatic, statistically significant improvement in diastolic relaxation, a decrease in left ventricular wall thickness at end-diastole, a measure of diastolic crossbridge engagement, and a reduction in left atrial size, a surrogate of chronic LV filling pressure.

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

In summary, we have observed that EDG-7500 is a first-in-class cardiac sarcomeric protein modulator that targets the underlying pathophysiology of HCM. Preclinical data in models of both obstructed and non-obstructed HCM suggest the ability to drive a broadly effective clinical response at a low risk of decreasing left ventricular ejection fraction below normal at all doses tested. Due to EDG-7500’s self-limiting mechanism on systolic contraction, we plan to investigate fixed-dose regimens of EDG-7500 thus potentially eliminating the echo-mediated dose titration and intense follow-up requirements of current therapies.

As part of our IND-enabling work, we are completing the toxicity and safety pharmacology profile of EDG-7500 in standard GLP safety pharmacology studies, in non-GLP exploratory and dose range studies. We plan to file an IND for EDG-7500 in the third quarter of 2023.

EDG-7500 Phase 1 Clinical Development Plan

Subject to clearance of the IND, we plan to initiate a Phase 1 double-blind, randomized, placebo-controlled, single and multiple ascending dose clinical trial in the second half of 2023 to assess the safety and tolerability, PK/PD of EDG-7500 in healthy subjects and patients with HCM. The trial will evaluate the safety and tolerability of EDG-7500 in humans and is designed to demonstrate proof of mechanism by its conclusion.

Manufacturing

We currently do not own or operate any manufacturing facilities. We rely and expect to continue to rely for the foreseeable future, on third-party contract development and manufacturing organizations (CDMOs) to produce our product candidates for preclinical and clinical testing, as well as for commercial manufacture if our product candidates receive marketing approval. Our CDMOs are obligated to produce bulk drug substances and finished drug products in accordance with current Good Manufacturing Practices (cGMPs) and all other applicable laws and regulations. We maintain agreements with our manufacturers that include confidentiality and intellectual property provisions to protect our proprietary rights related to our product candidates.

We have engaged CDMOs to manufacture EDG-5506 and EDG-7500 for preclinical and clinical use. All of our product candidates are small molecules and are manufactured in synthetic processes from readily available starting materials. Our chemistry is a convergent synthesis of under five steps, appears amenable to scale up and does not

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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.

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.

Competition

EDG-5506

Currently, approximately 70% of patients with DMD 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. Ltd. 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. (SGT-001). Gene editing treatmentsthat 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.

EDG-7500

Non-vasodilating beta blockers and non-dihydropyridine calcium channel blockers are the first-line therapies for symptomatic oHCM and nHCM patients. Commonly prescribed beta-blockers are atenolol, propranolol, and metoprolol. Verapamil and diltiazem are calcium channel blockers used in the treatment of symptomatic oHCM and nHCM. For oHCM patients who remain symptomatic, a sodium channel blocker with negative ionotropic drug properties may also be added, typically disopyramide (either Pfizer’s Norpace, marketed by Pfizer, or a generic form marketed by several companies).

In the field of targeted precision medicines intended to address the molecular underpinnings of HCM, competitors include Bristol-Myers Squibb (BMS), LianBio, Cytokinetics, Imbria Pharmaceuticals, and Celltrion. BMS markets Camzyos (mavacamten), a CMI intended for the treatment of adults with symptomatic NYHA class II-III oHCM. LianBio is currently conducting a Phase 3 study of mavacamten in patients with oHCM in China. Cytokinetics is also developing a CMI, aficamten (CK-274), which is currently in a Phase 3 study in oHCM patients. BMS and Cytokinetics are also exploring their respective CMIs in ongoing Phase 3 and Phase 2 nHCM studies, respectively. Cytokinetics and BMS are also developing next generation CMIs, CK-271 and MYK-224, respectively.

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Non-CMI targeting drugs in development include IMB-101(Imbria Pharmaceuticals), a free fatty acid receptor antagonist currently in Phase 2 and CT-G20 (Celltrion), an anti-arrhythmic cibenzoline succinate currently in a Phase 1 oHCM study. We are aware of several preclinical HCM programs including: TN-201, myosin binding protein MYBP-C3-targeting gene therapy approach being developed by Tenaya Therapeutics for genetic HCM; JN-210, a microRNA activating gene therapy approach being developed by Jaan Biotherapeutics; AVB-601, a gene therapy approach being developed by Solid Bio for genetic HCM; CDR348T and CDR641L, both are non-coding RNA-based therapies being developed by Cardior Pharmaceuticals. We are also aware of several early-stage preclinical HCM assets being developed by DiNAQOR in collaboration with BioMarin Pharmaceuticals (BMN-293/DINA-001) and Lexeo Therapeutics (LX2022).

Intellectual Property

Our commercial success depends in part on our ability to obtain and maintain proprietary or intellectual property protection for our drug candidates, technology and know-how, to operate without infringing the proprietary or intellectual property rights of others and to prevent others from infringing our proprietary or intellectual property rights. We expect that we will seek to protect our proprietary and intellectual property position by, among other methods, pursuing and obtaining patent protection in the United States and in jurisdictions outside of the United States related to our proprietary technology, inventions, improvements and drug candidates that are important to the development and implementation of our business. We also rely on trade secrets, know-how, trademarks, continuing technological innovation and licensing opportunities to develop and maintain our proprietary and intellectual property position.

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

The term of individual patents depends upon the legal term for patents in the countries in which they are granted. In most countries in which we file, the patent term is generally 20 years from the earliest date of filing a non-provisional patent application. In the United States, the patent term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the U.S. Patent and Trademark Office (USPTO) in examining and granting a patent or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date. Additionally, the Drug Price Competition and Patent Term Restoration Act of 1984 (the Hatch-Waxman Act) permits patent term extension of up to five years beyond the expiration date of a U.S. patent as partial compensation for the length of time a drug is under regulatory review while a patent that covers the drug is in force. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent term extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, only one patent applicable to each regulatory review period may be extended and only those claims covering the approved drug, a method for using it or a method for manufacturing it may be extended.

Similar provisions are available in the European Union and certain other foreign jurisdictions to extend the term of a patent that covers an approved drug. In the future, if and when our drug candidates receive approval by the FDA or foreign regulatory authorities, we expect to apply for patent term extensions on issued patents covering those products, if available. However, there is no guarantee that the applicable authorities, including the FDA in the United States, will agree with our assessment of whether such extensions should be granted, and, if granted, the length of such extensions.

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For more information regarding the risks related to our intellectual property, see the section titled “Risk Factors — Risks Related to Our Intellectual Property.” Expiration dates referred to above are without regard to potential patent term extension or other market exclusivity that may be available to us.

In addition to patent protection, we also rely on trade secrets, know-how, trademarks, other proprietary information and continuing technological innovation to develop and maintain our competitive position. Weseek to protect and maintain the confidentiality of proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection. Although we take steps to protect our proprietary information and trade secrets, including through contractual means with our employees and consultants, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements upon the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the course of the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. Our agreements with employees also provide that all inventions conceived by the employee in the course of employment with us or from the employee’s use of our confidential information are our exclusive property. However, such confidentiality agreements and invention assignment agreements can be breached, and we may not have adequate remedies for any such breach. For more information regarding the risks related to our intellectual property, see the section titled “Risk Factors — Risks Related to Our Intellectual Property.”

The patent positions of biotechnology companies like ours are generally uncertain and involve complex legal, scientific and factual questions. Our commercial success will also depend in part on not infringing upon the proprietary rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, alter our drugs or processes, obtain licenses or cease certain activities. Our breach of any license agreements or our failure to obtain a license to proprietary rights required to develop or commercialize our future products may have a material adverse impact on us. If third parties prepare and file patent applications in the United States that also claim technology to which we have rights, we may have to participate in interference or derivation proceedings in the USPTO to determine priority of invention. For more information, see the section titled “Risk Factors — Risks Related to Our Intellectual Property.”

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.

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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.

Government Regulations

Government authorities in the United States, at the federal, state, and local level, and other countries extensively regulate, among other things, the research, development, nonclinical and clinical testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing, and export and import of products such as those we are developing. Generally, before a new drug can be marketed, considerable data must be generated, which demonstrate the drug’s quality, safety, and efficacy. Such data must then be organized into a format specific for each regulatory authority, submitted for review and approved by the regulatory authority.

U.S. Drug Development Process

In the United States, the FDA regulates drugs under the federal Food, Drug, and Cosmetic Act (FDCA), and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, the approval process or after approval may subject an applicant to administrative or judicial sanctions. These sanctions could include the FDA’s refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement, or civil or criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

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

Prior to beginning the first clinical trial with a product candidate in the United States, we must submit an IND to the FDA. An IND is a request for authorization from the FDA to administer an investigational new drug product to humans. The central focus of an IND submission is on the general investigational planand 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; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments. Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site and must monitor the study until completed. Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the clinical trial is unlikely to meet its stated objectives. Some trials also include oversight by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board, which may review data and endpoints at designated check points, make recommendations and/or halt the clinical trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical studies and clinical trial results to public registries.

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

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Post-approval clinical trials, sometimes referred to as Phase 4 studies, may be conducted after initial marketing approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. In addition, some clinical trials are overseen by an independent group of qualifiedexperts organized by the sponsor, known as a data safety monitoring board or committee. Depending on its charter, this group may determine whether a clinical trial may move forward at designated check points based on access to certain data from the clinical trial.

During the development of a new drug, sponsors are given opportunities to meet with the FDA at certain points. These points may be prior to submission of an IND, at the end of Phase 2, and before an NDA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach agreement on the next phase of development. Sponsors typically use the meetings at the end of the Phase 2 clinical trial to discuss Phase 2 clinical results and present plans for the pivotal Phase 3 clinical trials that they believe will support approval of the new drug.

Phase I, Phase II, and Phase III clinical testing may not be completed successfully within a specified period, if any all, and there can be no assurance that the data collected will support FDA approval of a product candidate. Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality, and purity of the final drug. In addition, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

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

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.

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NDA Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development nonclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality, and purity. Under the Prescription Drug User Fee Act (PDUFA), guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission. 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. In this event, the NDA must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing.

The FDA may refer an application for a novel drug to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA will typically inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs. If the FDA determines that the application, manufacturing process, or manufacturing facilities are not acceptable, it will outline the deficiencies in the submission and often will request additional testing or information. Notwithstanding the submission of any requested additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

After the FDA evaluates an NDA, it will issue an approval letter or a Complete Response Letter. An approval letter authorizes commercial marketing of the drug with prescribing information for specific indications. A Complete Response Letter indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A Complete Response Letter usually describes the specific deficiencies in the NDA identified by the FDA and may require additional clinical data, such as an additional pivotal Phase 3 clinical trial or other significant and time-consuming requirements related to clinical trials, nonclinical studies, or manufacturing. If a Complete Response Letter is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the NDA with a risk evaluation and mitigation strategy (REMS) to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use. 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

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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.

Expedited Development and Review Programs

The FDA has a fast-track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria. Specifically, new drugs are eligible for fast-track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. With regard to a fast-track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

Any product submitted to the FDA for approval, including a product with a fast-track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval. A product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory alternative therapy exists or a significant improvement in the treatment, diagnosis, or prevention of a disease compared to marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a new drug designated for priority review in an effort to facilitate the review. The FDA endeavors to review applications with priority review designations within six months of the filing date as compared to ten months for review of new molecular entity NDAs under its current PDUFA review goals.

In addition, a product may be eligible for accelerated approval. Drug products intended to treat serious or life-threatening diseases or conditions may be eligible for accelerated approval upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of approval, the FDA may require that a sponsor of a drug receiving accelerated approval perform adequate and well-controlled post-marketing clinical trials. In addition, the FDA currently requires pre-approval of promotional materials as a condition for accelerated approval, which could adversely impact the timing of the commercial launch of the product.

The Food and Drug Administration Safety and Innovation Act established a category of drugs referred to as “breakthrough therapies” that may be eligible to receive breakthrough therapy designation. A sponsor may seek FDA designation of a product candidate as a “breakthrough therapy” if the product is intended, alone or in combination with one or more other products, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the fast-track program features, as well as more intensive FDA interaction and guidance. The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met. If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug. 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.

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

Orphan Drugs

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 Statesof that drug or biologic. ODD must be requested before submitting a NDA. After the FDA grants ODD, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

If a product that has received ODD and subsequently receives the first FDA approval for a particular active ingredient for the disease for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, including a full NDA, to market the same biologic for the same indication for seven years from the approval of the NDA, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs of patients with the disease or condition for which the drug was designated. Orphan drug exclusivity does not prevent the FDA from approving a different drug or biologic for the same disease or condition, or the same drug or biologic for a different disease or condition. Among the other benefits of ODD are tax credits for certain research and a waiver of the NDA application user fee.

A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the indication for which it received ODD. 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. v. Becerra, 14 F.4th 1299 (11th Cir. 2021), the court disagreed with the FDA’s longstanding position that the orphan drug exclusivity only applies to the approved use or indication within an eligible disease, and not to all uses or indications within the entire disease or condition. In particular, the circuit court held that the orphan-drug exclusivity for Catalyst’s drug blocked FDA’s approval of another drug for all uses or indications within the same orphan-designated disease, or Lambert-Eaton myasthenic syndrome (LEMS), even though Catalyst’s drug was approved at that time only for use in the treatment of LEMS in adults. Accordingly, the court ordered the FDA to set aside the approval of a drug indicated for LEMS in children. This decision created uncertainty in the application of the orphan drug exclusivity. On January 24, 2023, the FDA published a notice in the Federal Register to clarify that while the agency complies with the court’s order in Catalyst, FDA intends to continue to apply its longstanding interpretation of the regulations to matters outside of the scope of the Catalyst order – that is, the agency will continue tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved, which permits other sponsors to obtain approval of a drug for new uses or indications within the same orphan designated disease or condition that have not yet been approved. It is unclear how future litigation, legislation, agency decisions, and administrative actions will impact the scope of the orphan drug exclusivity.

Post-Approval Requirements

Any products manufactured or distributed by us pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There are continuing, annual program fees for any marketed products. Drug

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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. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements upon us and any third-party manufacturers that we may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. 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; or imposition of distribution restrictions or other restrictions under a REMS program. Other potential consequences include, among other things:

● fines, warning letters, or untitled letters;

● clinical holds on post-approval or Phase IV clinical studies, if applicable;

● injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising, and promotion of drug products. A company can make only those claims relating to safety and efficacy that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising, and potential civil and criminal penalties. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion. The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.

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U.S. Patent-Term Restoration and Marketing Exclusivity

Depending upon the timing, duration and specifics of FDA approval of any future product candidates, some of our U.S. patents may be eligible for limited patent term extension under the Hatch-Waxman Act. The Hatch-Waxman Act permits restoration of the patent term of up to five years as compensation for patent term lost during product development and FDA regulatory review process. Patent-term restoration, however, cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date. The patent-term restoration period is generally one-half the time between the effective date of an IND or the issue date of the patent, whichever is later, and the submission date of an NDA plus the time between the submission date of an NDA or the issue date of the patent, whichever is later, and the approval of that application, except that the review period is reduced by any time during which the applicant failed to exercise due diligence. Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. 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.

Market exclusivity provisions under the FDCA also can delay the submission or the approval of certain applications. The FDCA provides a five-year period of non-patent marketing exclusivity within the United States to the first applicant to gain approval of a NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not accept for review an abbreviated new drug application (ANDA), or a 505(b)(2) NDA submitted by another company for a generic version of such drug where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement. The FDCA also provides three years of marketing exclusivity for a NDA, 505(b)(2) NDA or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example, new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the conditions of use associated with the new clinical investigations and does not prohibit the FDA from approving ANDAs for drugs containing the original active agent. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness or generate such data themselves.

Pediatric exclusivity is another type of marketing exclusivity available in the United States and provides for an additional six months of marketing exclusivity attached to another period of exclusivity if a sponsor conducts clinical trials in children in response to a written request from the FDA. The issuance of a written request does not require the sponsor to undertake the described clinical trials.

Other U.S. Regulatory Matters

Pharmaceutical manufacturers are subject to additional healthcare laws, regulation, and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such laws include, without limitation, U.S. federal anti-kickback, anti-self-referral, false claims, transparency, including the federal Physician Payments Sunshine Act, consumer fraud, pricing reporting, data privacy, data protection, and security laws and regulations, including the Health Insurance Portability and Accountability Act of 1996 (HIPAA), as well as similar foreign laws in the jurisdictions outside the U.S. Similar state and local laws and regulations may also restrict business practices in the pharmaceutical industry, such as state anti-kickback and false claims laws, which may apply to business practices, including but not limited to, research, distribution, sales, and marketing arrangements and claims involving healthcare items or services reimbursed by nongovernmental third-party payors, including private insurers, or by patients themselves; state laws that require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government, or otherwise restrict payments that may be made to healthcare providers and other potential referral sources; state laws and regulations that require drug manufacturers to file reports relating to pricing and marketing information; state and local

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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; and state and local laws governing the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

EWTX US Equity

EWTX · 10-K · period ended 2022-12-31

Item 1. Business

EWTX US Equity☆

EWTX · 10-K · period ended 2022-12-31

Item 1. Business

EWTX US Equity