Edgewise Therapeutics Announces Publication of Data Demonstrating the Elevation of Fast but Not Slow Skeletal Muscle Fiber Injury Biomarkers in the Circulation of Patients with Becker and Duchenne Muscular Dystrophy

– First cross-sectional, retrospective study to describe selective elevation of fast but not slow skeletal muscle fiber injury biomarkers in BMD and DMD patient samples, published in Muscle & Nerve –

– Data supports Edgewise strategy to advance EDG-5506, a small molecule drug candidate designed to protect injury-susceptible fast skeletal muscle fibers, in clinical development for BMD and DMD –

Edgewise Therapeutics, Inc., EWTX, a clinical-stage biopharmaceutical company focused on developing orally bioavailable, small molecule therapies for rare muscle disorders, today announced the publication of the first cross-sectional, retrospective study to describe selective elevation of fast but not slow skeletal muscle fiber injury biomarkers in the blood of patients with Becker and Duchenne muscular dystrophy (BMD, DMD) in the journal, Muscle & Nerve.

Human skeletal muscle is composed of fast and slow fibers in roughly equal proportion. Previous studies have demonstrated that DMD patient muscle is more prone to fast fiber injury compared to slow fiber injury. This study extends these findings to examine fiber-type specific biomarkers of muscle injury in patient blood. The results build on previous reports and suggest that slow skeletal muscle fibers do not appear to leak muscle proteins associated with muscle injury and damage in BMD and DMD. Furthermore, the study demonstrated that fast skeletal troponin I (TNNI2) may represent a more sensitive biomarker of muscle injury than creatine kinase (CK), particularly in the setting of BMD or older DMD patients where plasma CK is commonly lower than in young DMD patients. These data further support EDG-5506's unique mechanism of action aimed at protecting injury-susceptible fast skeletal muscle fibers in BMD and DMD.

"We are pleased to share our findings that elevation of fast skeletal muscle fiber injury biomarkers may be more informative, compared to slow skeletal muscle injury biomarkers, of muscle injury in patients with BMD and DMD," said Alan Russell, Ph.D., Chief Scientific Officer of Edgewise and senior author of the study. "These data guided the design of our lead clinical candidate, EDG-5506, which selectively protects injury-susceptible fast skeletal muscle fibers for BMD and DMD. Indeed, EDG-5506, in preclinical models, acts as a muscle stabilizer by protecting muscle through limiting excessive contraction. This protection reduces injury and the leak of muscle proteins that in the long term protects against fibrosis and functional declines associated with prolonged inflammation and degradation of the muscle."

Kevin Koch, Ph.D., President and Chief Executive Officer added, "These data are invaluable as we continue to advance EDG-5506 in clinical development. We are excited about the potential of EDG-5506 for patients affected by BMD and DMD, who are currently underserved with limited treatment options."

About the Skeletal Muscle Study

One of the hallmarks of injured skeletal muscle is the appearance of elevated skeletal muscle proteins in circulation. Human skeletal muscle generally consists of a mosaic of slow (type I) and fast (type IIa, IIx/d) fibers, defined by their myosin isoform expression. Recently, measurement of circulating fiber‐type specific isoforms of troponin I has been used as a biomarker to suggest that muscle injury in healthy volunteers results in the appearance of muscle proteins from fast but not slow fibers. Data from this study demonstrates that this is also the case in severe myopathy patients with Becker and Duchenne muscular dystrophy (BMD, DMD).

An ELISA test that selectively measures fast and slow skeletal troponin I (TNNI2 and TNNI1) was used to measure a cross‐section of patient plasma samples from healthy volunteers (N=50), BMD (N=49) and DMD (N=132) patients. CK activity, which is a type of protein found in skeletal and heart muscles, was also measured from the same samples for comparison.

The fast skeletal troponin, TNNI2, was elevated in BMD and DMD and correlated with the injury biomarker, CK. In contrast, the slow skeletal troponin, TNNI1, levels were indistinguishable from levels in healthy volunteers. There was an inverse relationship between CK and TNNI2 levels and age but no relationship for TNNI1. Of note, a surprising discrepancy between TNNI1 and TNNI2 in patient plasma may have implications for the interpretation of elevated muscle protein levels in BMD, DMD and other dystrophinopathies.

This is the first cross-sectional, retrospective study to describe differences between fast and slow skeletal muscle fiber biomarkers in BMD and DMD patient plasma. Findings of differential troponin levels is consistent with previous studies of muscle injury after eccentric exercise in healthy volunteers. This appears to be distinct from muscle injury via sepsis or trauma where both fast and slow TNNI are elevated. Previous studies have demonstrated preferential fast fiber injury in DMD patients. Our data extend these findings to suggest that slow fibers do no not appear to leak muscle proteins in the context of BMD/DMD. The majority of healthy volunteers (83%) had TNNI2 levels below the lower level of detection of the ELISA (<0.1 ng/ml), while only 4% of BMD and 6% of DMD patients had non-measurable levels of TNNI2. This is in marked contrast to CK where large overlap exists, particularly between healthy volunteers and patients with BMD. As a result, TNNI2 may represent a more sensitive biomarker of muscle injury than CK, particularly in the setting of BMD or older DMD patients where plasma CK is commonly lower than in young DMD patients.

About EDG-5506 for BMD and DMD

EDG-5506, is an orally administered small molecule designed to address the root cause of dystrophinopathies including DMD and BMD. EDG-5506 presents a novel mechanism of action to selectively limit injurious hypercontraction stress caused by the absence of functional dystrophin. EDG-5506 has the potential to benefit a broad range of patients suffering from debilitating rare neuromuscular disorders. It can be used as a single agent therapy but it may also provide a synergistic or additive effect in combination with available therapies and therapies currently in development.

Our Phase 1 study of EDG-5506 is designed to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of EDG-5506 in adult healthy volunteers (Phase 1a) and adults with BMD (Phase 1b). In March 2021, EDG-5506 advanced into the Multiple Ascending Dose (MAD) cohort, having successfully completed the Single Ascending Dose (SAD) portion of the study. The company expects to report topline MAD and BMD patient data, later in 2021. To learn more about this study (NCT04585464), go to clinicaltrials.gov.

About Muscular Dystrophy

Muscular dystrophies are a group of genetic disorders associated with defects in the critical muscle-associated structural protein dystrophin or the sarcomere complex and are characterized by progressive muscle degeneration and weakness. In individuals with neuromuscular conditions such as Duchenne muscular dystrophy, normal muscle use leads to continued rounds of muscle breakdown that the body struggles to repair. Over time, fibrosis and fatty tissue accumulate in the muscle portending a steep decline and permanent loss of physical function that ends with mortality. There remains an unmet need for treatments that reduce muscle breakdown in patients with neuromuscular conditions. Arresting this amplified muscle response will have a dramatic effect on disease progression.

About Edgewise Therapeutics

Edgewise Therapeutics is 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 its holistic drug discovery approach to targeting the muscle as an organ, Edgewise has combined its foundational expertise in muscle biology and small molecule engineering to build its proprietary, muscle focused drug discovery platform. Edgewise's 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. To learn more, go to: www.edgewisetx.com or follow us on LinkedIn.

Cautionary Note Regarding Forward-Looking Statements

This press release contains forward-looking statements as that term is defined in Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. Statements in this press release that are not purely historical are forward-looking statements. Such forward-looking statements include, among other things, statements regarding the potential advantages of Edgewise's product candidates and programs, including plans underlying EDG-5506 or any other programs; and statements by the company's chief executive officer. Words such as "believes," "anticipates," "plans," "expects," "intends," "will," "goal," "potential" and similar expressions are intended to identify forward-looking statements. The forward-looking statements contained herein are based upon Edgewise's current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those projected in any forward-looking statements due to numerous risks and uncertainties, including but not limited to: risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics and operating as an early clinical stage company including the potential for Edgewise's product candidates to cause serious adverse events; Edgewise's ability to develop, initiate or complete preclinical studies and clinical trials for, obtain approvals for and commercialize any of its product candidates for muscular dystrophy patients or other patient populations; the timing, progress and results of preclinical studies and clinical trials for EDG-5506 and Edgewise's other product candidates in its EDG-6289, EDG-002 and EDG-003 programs; Edgewise's ability to raise any additional funding it will need to continue to pursue its business and product development plans; negative impacts of the COVID-19 pandemic on Edgewise's operations, including preclinical and clinical trials; the timing, scope and likelihood of regulatory filings and approvals; Edgewise's ability to develop a proprietary drug discovery platform to build a pipeline of product candidates; Edgewise's manufacturing, commercialization and marketing capabilities and strategy; the size of the market opportunity for Edgewise's product candidates; the loss of key scientific or management personnel; competition in the industry in which Edgewise operates; Edgewise's reliance on third parties; Edgewise's ability to obtain and maintain intellectual property protection for its product candidates; general economic and market conditions; and other risks. Information regarding the foregoing and additional risks may be found in the section entitled "Risk Factors" in Edgewise's Registration Statement on Form S-1 filed with the Securities and Exchange Commission (the "SEC") on March 26, 2021, and Edgewise's future reports to be filed with the SEC. These forward-looking statements are made as of the date of this press release, and Edgewise assumes no obligation to update the forward-looking statements, or to update the reasons why actual results could differ from those projected in the forward-looking statements, except as required by law.

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