A Phase 1, Double‐Blind, Placebo‐Controlled Trial of Sevasemten (EDG‐5506), a Selective Modulator of Fast Skeletal Muscle Contraction, in Healthy Volunteers and Adults With Becker Muscular Dystrophy

ABSTRACT

Introduction/Aims

Sevasemten (EDG‐5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fiber contraction by inhibiting fast myosin ATPase. This study assessed the safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics (PD) of sevasemten in healthy adult volunteers (HVs) and adults with Becker muscular dystrophy (BMD).

Methods

This randomized, double‐blind, placebo‐controlled phase 1 study was conducted at a single site. Eligible participants were 18–55 years of age with a body mass index < 30 kg/m²; adults with BMD were required to have a confirmed diagnosis based on documentation of pathogenic variant(s) in the dystrophin gene and a BMD phenotype. Participants were randomized 3:1 to receive sevasemten or placebo for up to 14 days. Endpoints included adverse events (AEs), sevasemten PK and muscle concentration, and changes in biomarkers of muscle injury.

Results

The study enrolled 97 HVs in 7 single‐dose cohorts (N = 57) and 5 multiple‐dose cohorts (N = 40). Seven adults with BMD were enrolled in a multiple‐dose cohort. There were no serious AEs or AEs leading to trial discontinuation; the most common AEs were dizziness and somnolence. For adults with BMD, serum biomarkers of muscle injury trended down progressively with sevasemten treatment (average maximal reductions of 70% for creatine kinase, 98% for fast skeletal muscle troponin I, and 45% for myoglobin). Plasma proteomic analysis identified a signature of 125 elevated proteins characteristic of BMD that was reversibly lowered with sevasemten treatment.

Discussion

Sevasemten was generally well tolerated. Preliminary observations of decreases in biomarkers of muscle damage in adults with BMD support further clinical development.

Trial Registration: NCT04585464

Abbreviations

AE

adverse event

AUC_0‐tau

area under the curve from time 0 to tau

BMD

Becker muscular dystrophy

BQL

below the limit of quantification

BMI

body mass index

C₂₄

plasma concentration at the end of the dosing interval

C_max

maximum observed plasma concentration

CK

creatine kinase

DMD

Duchenne muscular dystrophy

EC

enteric capsule

ECG

electrocardiogram

FVC

forced vital capacity

GH

globally higher

GL

globally lower

HGS

hand grip strength

HV

healthy volunteer

MAD

multiple ascending dose

PD

pharmacodynamic

PK

pharmacokinetic

PMS

peripheral magnetic stimulation

QD

once daily

SAD

single ascending dose

SRC

safety review committee

TEAE

treatment‐emergent adverse event

t_max

time to maximum concentration

TNNI2

fast skeletal muscle troponin I

VL

vastus lateralis

1. Introduction

In patients with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), the dystrophin glycoprotein complex is compromised by the absence of fully functional dystrophin, which leads to increased contraction‐induced injury along muscle fibers, activation of stress channels, calcium influx, and muscle damage [1, 2, 3, 4]. Fast muscle fibers (types IIa and IId/x) are more susceptible than slow (type I) muscle fibers to this type of contraction stress [5, 6], and fast fibers are the first to degrade in individuals with DMD [7]. In patients with DMD and BMD, prolonged muscle damage promotes inflammation and muscle degeneration, replacement by fat and fibrosis, and ultimately, loss of muscle function [8, 9, 10, 11, 12].

Sevasemten (EDG‐5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fiber contraction by inhibiting fast myosin adenosine triphosphatase (ATPase) [13]. In preclinical studies, 10%–15% myosin inhibition with sevasemten was sufficient to prevent contraction‐induced injury to dystrophic muscles. In dystrophin‐deficient mdx mice, treatment with sevasemten reduced exercise‐induced creatine kinase (CK), improved grip strength, and reduced fibrosis in the diaphragm; in dystrophic golden retrievers, sevasemten treatment increased physical activity and reversed circulating protein signatures associated with disease [13]. These in vivo observations, along with preclinical data that sevasemten limited contraction of fast skeletal muscle fibers and protected them from contraction‐induced injury and fibrosis, support the hypothesis that by protecting fast muscle fibers, sevasemten may limit muscle breakdown and disease progression in individuals with dystrophic muscle [13].

The primary objective of this study was to assess the safety and tolerability of single and multiple oral doses of sevasemten compared with placebo. The secondary objective was to assess the plasma pharmacokinetics (PK) of single and multiple oral doses of sevasemten. Exploratory objectives included the evaluation of muscle contraction as measured by peripheral magnetic stimulation (PMS) to assess an evoked quadriceps response in healthy volunteers (HVs), evaluation of hand grip strength, evaluation of sevasemten concentration in muscle, and evaluation of changes in biomarkers of muscle injury after repeated dose administration.

2. Methods

2.1. Study Design

This randomized, double‐blind, placebo‐controlled study (NCT04585464) enrolled participants at a single site in the United States (Worldwide Clinical Trials, San Antonio, TX) between 14 September 2020 and 27 December 2021. The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonisation guidelines, and the study protocol and relevant study materials received institutional review board approval. All participants provided written informed consent before starting the study.

2.2. Participants

Eligible participants were 18–55 years of age with a body weight ≥ 50 kg and a body mass index (BMI) < 30 kg/m², without a history of dysphagia, diplopia, facial muscle weakness, or neoplastic disease. HVs had to demonstrate normal oculofacial and proximal muscle limb strength assessments and bedside swallowing function assessments. Adult men with BMD were required to have a confirmed diagnosis of BMD based on documentation of a pathogenic variant in the DMD gene and a BMD phenotype, i.e., ambulation past the age of 18 years. Additionally, participants with BMD were required to have a serum creatine kinase (CK) value ≥ 3 times the upper limit of normal during screening, be ambulatory, and be able to perform activities of daily living (see the Supplemental Methods for additional participant eligibility information).

2.3. Randomization and Dosing

Part A of the study consisted of 7 single ascending dose (SAD) cohorts, with 8 HVs per cohort randomized 3:1 to receive a single oral suspension dose of sevasemten (up to 135 mg) or placebo following an overnight fast (Figure S1). Two sentinel HVs per cohort were randomized 1:1 (sevasemten:placebo) ≥ 24 h before dosing of the 6 remaining participants; safety data from the sentinel participants were reviewed prior to dosing for the rest of the participants. For each of the Part B multiple ascending dose (MAD) cohorts, 8 unique HVs were randomized 3:1 (sevasemten [oral suspension or enteric capsule (EC)]:placebo) once daily (QD) for up to 14 days, in a fasted state (Figure S1). In each cohort, HVs received a loading dose up to 40 mg QD for days 1–4 followed by a maintenance dose up to 40 mg QD on days 5–14. The starting dose was chosen based on the safety and tolerability data from Part A. Two sentinel HVs per cohort were randomized 1:1 (sevasemten:placebo) 4 days prior to dosing of the 6 remaining participants. For Part B, sentinel participants were not required if the cohort received a dose that had been previously studied in Part B. For each of the SAD and MAD cohorts, safety and PK data from the current and prior cohort(s) were reviewed by the SRC to determine the dose level and frequency for the next cohort. In Part C, 7 ambulatory adults with BMD were randomized 3:1 to receive sevasemten 20 mg QD or placebo orally (as an EC) for 14 days, in the fed state as sevasemten absorption is not changed meaningfully by food (results not shown) (Figure S1). The sevasemten dose for Part C was selected by the SRC following their review of the safety data from Part B.

2.4. Assessments and Procedures

Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (v23.1). Treatment‐emergent adverse events (TEAEs) were defined as any AE that emerged on or after administration of the study drug or any pre‐existing AE that worsened upon treatment. AEs of special interest included safety assessments of oculofacial muscle function and proximal limb strength, assessment of extraocular muscle weakness or ophthalmoplegia, and assessment of potential effects of sevasemten on swallowing and respiratory muscle weakness (see Supplemental Methods).

Blood samples for PK/pharmacodynamic (PD) analyses were collected before and after dosing (see Supplemental Methods); needle muscle biopsies of the vastus lateralis (VL) were collected after the day 15 plasma PK sample using the RD MAGNUM Biopsy Instrument (Becton, Dickenson and Company, Franklin Lakes, NJ). To derive a comprehensive view of sevasemten effects on skeletal muscle function, muscle strength was assessed at specific timepoints before and after dosing via both involuntary electrical stimulation (PMS) and voluntary measures of strength (hand grip strength [HGS]) (see Supplemental Methods). Biomarker analyses in adults with BMD evaluated the circulating levels of 3 proteins associated with muscle injury (CK, fast skeletal muscle troponin I [TNNI2], and myoglobin). Analysis of plasma proteomics used the SomaScan version 4.1 assay (SomaLogic Inc., Boulder, CO) [14] to evaluate levels of approximately 7000 proteins in the blood plasma samples of participants from Parts B and C (see Supplemental Methods). Plasma samples were collected from 24 HVs in Part B and from 7 adults with BMD in Part C.

2.5. Statistical Analyses

All statistical analyses were performed using SAS v9.4 or higher (SAS Institute, Cary, NC). No formal sample size calculations were performed in this exploratory study. Safety data and continuous measurements were analyzed using descriptive statistics. Phoenix WinNonlin (version 8.3 [Certara, Radnor, PA]) was used to perform PK analysis and inferential statistics. See Supplemental Methods for additional information.

3. Results

3.1. Participant Demographics

Fifty‐seven and 40 HVs were randomized into Part A and Part B, respectively (Figure S1). Participants were mostly White males with comparable ages and BMIs (Table 1). In Part C, 7 men with BMD were randomized to sevasemten (N = 5) or placebo (N = 2) (Figure S1; Table 1). Per study eligibility criteria and consistent with ongoing muscle damage, evidence of reduced muscle mass and disease progression was evident in these individuals as assessed by elevated circulating CK activity, decreased creatinine (an indirect measure of muscle mass), and compromised functional measures (Table 1). Detail regarding the pathogenic variants of the men with BMD is provided in Table S1.

TABLE 1.

Participant demographics and baseline characteristics.

Parameter	Part A	Part B	Part C
	SAD in HVs	MAD in HVs	Adults with BMD
	(N = 57)	(N = 40)	(N = 7)
Age, mean (SD), years	39.5 (9.7)	35.8 (9.3)	33.0 (6.2)
Sex, n (%)
Male	47 (82.5)	39 (97.5)	7 (100.0)
Female	10 (17.5)	1 (2.5)	0
Ethnicity, n (%)
Hispanic or Latino	30 (52.6)	17 (42.5)	1 (14.3)
Not Hispanic or Latino	27 (47.4)	23 (57.5)	6 (85.7)
Race, n (%)
White	38 (66.7)	26 (65.0)	7 (100.0)
Black or African American	18 (31.6)	12 (30.0)	0
Asian	1 (1.8)	1 (2.5)	0
Other	0	1 (2.5)	0
BMI, mean (SD), kg/m2	26.4 (2.6)	25.8 (3.0)	24.0 (2.5)
Serum chemistry data, mean (SD)
Creatinine, mg/dL	0.96 (0.2)	1.04 (0.1)	0.58 (0.1)
Creatine kinase, U/L	141.7 (72.6)	152.6 (80.7)	1347.9 (609.5)
Functional measures, median
Time to walk/run 10 m, s	N/A	N/A	8.2
Time to rise from the floor, s	N/A	N/A	20.8 a
Hand grip strength, mean (SD)	35.0 (10.0)	39.2 (9.8)	22.9 (12.3)
minimum, maximum, kg	18.1, 59.9	19.6, 68.2	3.4, 35.6

Abbreviations: BMD = Becker muscular dystrophy; BMI = body mass index; HV = healthy volunteer; MAD = multiple ascending doses; N/A = not applicable; SAD = single ascending doses; SD = standard deviation.

^a Three adults with BMD were unable to complete the rise from the floor task.

3.2. Safety

No serious AEs or AEs of special interest were reported in any group, and no TEAEs led to discontinuation from the study (Table S2). Nervous system disorders were the most commonly reported TEAEs (Table S3); most TEAEs were mild or moderate in Part A, and all TEAEs were mild in Parts B and C. Participants in Part B experienced somnolence and dizziness within a few hours of dosing that generally resolved within 2–3 h of onset (data not shown). A sentinel participant in the sevasemten 40/20 mg group developed mild AEs of eye movement disorder (mild visual changes without objective changes in extraocular movement) shortly after dosing on Days 1 and 2, resolving after several hours (loading phase, sevasemten 40 mg QD), so the loading dose was adjusted to 20 mg for the remaining participants in the cohort. AEs in adults with BMD were similar to those observed in the 20 mg QD dose group in HV, with dizziness upon initiation of dosing in both placebo and active groups (Table S3). No vertigo or postural hypotension were reported. No clinically meaningful changes in vital signs and ECG findings were observed.

3.3. Pharmacokinetic Analyses

For the HV SAD cohorts, sevasemten was rapidly absorbed, with a median time to maximum concentration (t_max) of 0.52–0.77 h (Table S4; Figure 1). Sevasemten had a long half‐life, with a mean value of 531.8 h (22 days) at the highest dose (135 mg). A shorter half‐life of 3.1 h was reported at the 1.5‐mg dose, likely due to unmeasurable concentrations at 12 h and an underestimate of the terminal elimination phase. In HVs who received multiple doses of study drug, sevasemten was rapidly absorbed when administered as either a suspension or an EC, with a biphasic plasma concentration vs. time profile for both formulations (Figure S2).

FIGURE 1.

Sevasemten plasma concentration‐time curves for single‐dose administration in healthy volunteers. Data shown as mean (SD).

In the HV MAD cohorts, median t_max on day 1 ranged from 0.35–0.58 h for the suspension formulation, and from 1.5–2.5 h for the EC formulation (data not shown). On day 14, the half‐life of sevasemten was 386–754 h (Table S5), similar to the SAD cohorts at doses of ≥ 5 mg in the fasted state. Plasma concentration at the end of the dosing interval (C₂₄) was still increasing after 14 days of dosing (Figure 2A), suggesting that steady state was not yet reached due to the long half‐life of sevasemten in HVs. This is also supported by the high accumulation index for the measure of C₂₄ of up to 10.5 in the MAD cohorts. For the MAD cohorts, dose proportionality was observed between 10 and 40 mg on days 1 and 4 (Table S6). On day 14, there was a less than dose‐proportional increase in maximum observed plasma concentration (C_max) between 5 and 40 mg. However, in the 5 and 10 mg cohorts, a loading dose was administered on days 1–4 followed by the maintenance dose administered on days 5–14, whereas at doses of 20 and 40 mg, no loading dose was administered, resulting in a longer time to achieve steady state and thus distorting dose‐proportionality assessments.

FIGURE 2.

Sevasemten trough plasma concentration‐time curves following multiple oral doses in healthy volunteers and adults with Becker muscular dystrophy. (A) Healthy volunteer MAD cohorts. (B) Healthy volunteer 20/20 mg (EC) vs. BMD 20/20 mg (EC). Data shown as mean (SD). BMD = Becker muscular dystrophy; EC = enteric capsule; HV = healthy volunteer; MAD = multiple ascending dose.

Adults with BMD had an approximately 2‐fold higher C_max and area under the plasma concentration‐time curve from time 0 to tau (AUC_0‐tau) compared with HVs receiving the same dose (Figure 2B; Table S5). Following 14 days of dosing, the t_1/2 in adults with BMD was ~168 h (~7 days) versus ~530 h (22 days) in HV at the same dose. Sevasemten concentrations in muscle were approximately 2–3‐fold higher in HVs receiving the 20‐mg dose than in adults with BMD (Table 2).

TABLE 2.

Sevasemten muscle concentrations in healthy volunteers and adults with Becker muscular dystrophy.

Participants	Daily Dose, mg	Total dose, mg	Formulation	Mean (CV%), ng/g
Healthy Volunteers	10/5 (N = 6)	90	Suspension	1266 (58.7)
	20/10 (N = 6)	180	Suspension	2379 (39.6)
	20/20 (N = 5) a	280	Suspension	4360 (36.5)
	20/20 (N = 6)	280	EC	6138 (17.9)
	40/40 (N = 6)	560	EC	6571 (44.2)
Adults with BMD	20/20 (N = 5)	280	EC	2062 (43.8)

Abbreviations: BMD = Becker muscular dystrophy; CV% = percent coefficient of variation; EC = enteric capsule.

^a Includes 1 participant assigned to 40/20 mg (total dose = 360 mg).

3.4. Pharmacodynamic Analyses

For the HV MAD cohorts, average quadriceps twitch force (PMS) and HGS were similar in all dose cohorts, although trending lower at the highest dose (40 mg) at day 14 compared to baseline (Table S7). For the individuals with BMD in Part C, quadriceps twitch force was unmeasurable, presumably due to muscle loss and tissue replacement by fat and connective tissue. Average HGS for adults with BMD was unchanged by sevasemten, even in the weakest individuals (Figure S3).

In individuals with BMD, serum CK, fast skeletal muscle troponin I (TNNI2), and myoglobin were elevated at baseline and trended downward progressively with sevasemten treatment, reaching a maximal decrease at day 15 (1 day after the last dose: average 70% decrease in CK, 98% decrease in TNNI2, 45% decrease in myoglobin) and returned to baseline by day 42 (Figure 3). CK, TNNI2, and myoglobin levels were highly variable in the low number of placebo individuals (N = 2) with a general trend downward during the dosing period and an increase upon discharge from the clinical study site.

FIGURE 3.

(A) Creatine kinase, (B) Fast skeletal muscle troponin I (TNNI2), and (C) Myoglobin over time in adults with Becker muscular dystrophy. PK replicate values included. Note that for TNNI2, 1 placebo participant did not have any value larger than 0.2 (lower limit of quantification).

3.5. Analysis of Plasma Proteomics

We sought to understand whether sevasemten treatment was associated with changes in protein concentrations outside of the three injury‐associated markers measured, using a commercially available proteomics platform. First, baseline blood samples were compared to establish a proteomic ‘signature’ of BMD vs. HV. Of 7000 proteins analyzed, 125 proteins were significantly higher, and 279 proteins were significantly lower, in the BMD baseline group compared with the HV baseline group and were defined as the globally higher (GH) and globally lower (GL) biomarker sets, respectively (Figure 4A). The GH biomarker set was enriched with muscle‐centric and metabolic proteins, including TNNI2, CK, and myoglobin. Another over‐represented group included immune and inflammatory proteins (Figure 4B; Table S8). Growth factors such as vascular endothelial growth factor, epidermal growth factor, and platelet‐derived growth factor were part of the GL set (data not shown). Significant reductions in the GH biomarker set were observed with sevasemten treatment compared to placebo in BMD (Figure 4C), which reversed upon compound removal (data not shown). Conversely, treatment with sevasemten significantly increased the GL biomarker set among sevasemten–treated participants with BMD compared with those treated with placebo (data not shown).

FIGURE 4.

Plasma proteomic analyses for healthy volunteers and adults with Becker muscular dystrophy. (A) Differences in adults with Becker muscular dystrophy (BMD) (pre‐dosing) relative to healthy volunteers (HVs) are shown as a volcano plot. Each point represents one protein in the dataset. Magnitude of change is in units of log‐2 and significance was calculated by an individual t‐test and displayed as the log‐10 transformation of the p‐value. Blue lines indicate the thresholds for selection: P < 0.05 and an increase or decrease in measured level of at least 0.585 log‐2 units (1.5‐fold). Selected increased proteins are shown in red and decreased proteins are shown in blue. (B) A pie‐chart indicating a high‐level view of the gene ontology (GO) terms associated with the baseline‐increased proteins. Percentages indicate how many proteins of the total were associated with biological processes in the indicated category. (C) Changes in the baseline‐increased proteins at study Day 15 in HVs treated with sevasemten (open squares), adults with BMD treated with placebo (gray squares), or adults with BMD treated with daily sevasemten (blue circles). Protein concentration change is shown in log‐2 units. Significance was calculated with a repeat‐measure, one way ANOVA. ***: P < 0.001.

4. Discussion

Sevasemten was generally well tolerated in both HVs and adults with BMD, and physical functioning was maintained (e.g., minimal changes in HGS), providing important insight into the tolerability of this treatment for those with low muscle mass and muscle weakness.

The genetic absence of fast skeletal muscle fibers resulting from myosin heavy chain 2 deficiency (MYH2) results in muscle weakness that is specific to ocular, facial, and proximal limb strength (distinct from pathogenic mutated forms of MYH2 that can cause severe congenital myopathy) [15]. Thus, AEs of special interest were established based on weaknesses that manifest in individuals with MYH2 deficiency, including oculofacial and proximal limb weaknesses. In addition, swallowing and pulmonary function were monitored as a safety measure. Of note, no AEs of special interest were observed at any dose (data not shown). This potentially highlights differences between acute pharmacological inhibition of fast myosin versus lifelong absence of fast myosin in MYH2 deficiency.

Sevasemten exhibited a PK profile suitable for once‐daily dosing (half‐life of ~13–22 days in HVs and ~ 7 days in patients with BMD). The long half‐life of sevasemten is in line with that of mavacamten, another myosin inhibitor that binds to myosin in the heart and slow skeletal muscle [16]. In HVs, sevasemten concentrations were approximately 100x higher in muscle than in plasma. Of note, myosin is expressed at high concentrations in skeletal muscle (100–200 μM) [17], perhaps acting as a depot, shielding sevasemten from systemic metabolism and thus contributing to the long half‐life. Mean plasma concentrations were 2–3x higher in adults with BMD than HVs, while the concentrations of sevasemten in the BMD muscle in those receiving 20 mg QD were 2–3x lower than muscles in HVs receiving the same dose. Higher plasma concentrations may be related to decreased muscle mass in the BMD participants. The lower muscle concentrations may be related to the amount of fat and fibrotic tissue in BMD muscle. More specifically, MRI studies of the VL suggest a fat content of approximately 55% in adults with BMD versus < 5% in healthy adult males [18, 19, 20], which is corroborated by the lower serum creatinine (Table 1). Therefore, actual muscle concentrations of sevasemten in BMD VL might be expected to be substantially greater than that measured if a similar proportion of the biopsy was fat. This would place BMD muscle concentrations within a range where positive benefits were documented in mice and dog models of DMD, which do not have appreciable fat infiltration [13, 21, 22].

One product of the long half‐life was accumulation over 14 days of repeat dosing. The most common TEAEs observed with sevasemten, dizziness and somnolence, were observed with both single and multiple ascending doses. The time course of the adverse events of dizziness and somnolence was notable in that they were transient, generally occurred with initial dosing, and resolved with repeat dosing, despite increases in exposures due to the long half‐life of sevasemten. One possible explanation for dizziness could be changes in proprioception due to altered neuronal firing patterns to accommodate changes in fast fiber contraction patterns due to the presence of fast myosin in muscle spindles [23, 24]. Adjusting the dosing of the agent to nighttime could potentially prevent issues with daytime sleepiness.

The goal of sevasemten treatment is to change muscle contraction to a level that decreases contraction‐induced muscle injury but not voluntary strength [13]. For HVs, average quadriceps twitch force and HGS were similar in lower dose cohorts, with a trend lower at the highest dose (40 mg) at day 14 compared to baseline. For adults with BMD, average HGS, a measure of voluntary strength, was unchanged by sevasemten, even in the weakest individuals.

While there were no apparent negative functional consequences in BMD, we did see encouraging signs of reversible decreases in circulating proteins associated with muscle injury with 20 mg daily sevasemten. This included time‐dependent trends in the general muscle injury biomarker CK, and the fast fiber‐specific sarcomeric protein, TNNI2, which is enriched in the plasma of individuals with DMD or BMD [25, 26]. Interpretation of biomarker trends with sevasemten in BMD was hampered by changes in the small BMD placebo group, although the degree of reduction and return upon compound cessation was numerically lower for placebo compared to sevasemten. Of note, plasma CK reductions have been observed in individuals with DMD after admission to an inpatient hospital setting [27], even in the absence of physical activity restriction, indicating that this could be specific to the environmental change associated with this study.

Proteomic analysis of plasma from individuals with BMD identified a proteomic signature of elevated proteins characteristic of BMD. This unbiased protein set was enriched for a larger set of proteins that are exclusively expressed or enriched in skeletal muscle, such as proteins associated with contraction or metabolism. In a separate study, ≥ 20% of these proteins were also identified as elevated compared to the levels in healthy subjects and were further increased by controlled exercise in individuals with BMD, suggesting that most of these proteins are also associated with contraction‐associated injury [28].

Treatment of BMD individuals with sevasemten resulted in the lowering of this elevated protein signature with a significant reduction compared to placebo, which was reversible upon compound cessation (data not shown). Similar serum proteomic studies with boys with DMD revealed a limited overlap between elevated proteins and biomarker lowering with glucocorticoid treatment [29], highlighting the distinct mechanism of sevasemten compared to glucocorticoids. Our proteomic results are also similar to the proteomic changes measured with 2 weeks of sevasemten treatment in DMD dogs [13], illustrating the consistent biological response to the mechanism of sevasemten.

This study has several limitations, primarily associated with the small cohort sample sizes and short duration of treatment, particularly in the BMD repeat‐dose cohort. We also note that the race and ethnicity of the HVs population differed from that of the BMD population, although it is unclear how these differences may affect the generalization of our findings. Muscle injury biomarker results were also hampered by decreases in both treatment and placebo groups, most likely due to low levels of activity during the dosing period in the confined space of a residential test center. Nonetheless, these preliminary observations of decreases in biomarkers of muscle damage, along with acceptable safety and PK profiles, support further clinical development.

Additional clinical studies with sevasemten are ongoing or completed, including three phase 2 studies that aim to further define the safety, tolerability, and clinical activity of sevasemten in patients with DMD (LYNX [NCT05540860]) [30] or patients with DMD after micro‐dystrophin gene therapy (FOX [NCT06100887]) [31], as well as efficacy in patients with BMD (GRAND CANYON [NCT05291091]) [32]. By targeting fast skeletal muscle myosin to protect dystrophic muscle, sevasemten has the potential to be a novel disease‐modifying approach in DMD and BMD regardless of pathogenic variant.

Author Contributions

Joanne Donovan: conceptualization, methodology, writing – review and editing, writing – original draft, formal analysis, investigation, project administration, supervision, visualization, data curation, resources, validation. Jeffrey A. Silverman: methodology, writing – original draft, writing – review and editing, formal analysis, visualization, investigation, data curation, validation. Ben Barthel: methodology, writing – review and editing, formal analysis, writing – original draft, software, visualization, investigation, data curation, validation. Michael DuVall: methodology, writing – review and editing, formal analysis, investigation, validation. Molly Madden: methodology, writing – review and editing, formal analysis, investigation, software, data curation, validation, visualization. James MacDougall: formal analysis, methodology, writing – review and editing, data curation, software, validation, visualization, investigation. Nicole Rempel Kilburn: writing – review and editing, conceptualization. Abby Bronson: writing – review and editing. Marc Evanchik: writing – review and editing, supervision, methodology, resources, investigation, conceptualization, validation. Gilad Gordon: writing – review and editing, investigation, methodology, project administration, supervision. Kevin Koch: writing – review and editing, conceptualization, funding acquisition, project administration, supervision, resources. Alan J Russell: conceptualization, methodology, writing – review and editing, writing – original draft, formal analysis, project administration, investigation, validation, visualization, supervision, resources.

Ethics Statement

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflicts of Interest

The authors are current or prior employees or consultants of the study sponsor, Edgewise Therapeutics Inc., and may own stock and/or stock options in the company.

Supporting information

Figure S1. CONSORT diagram.

Figure S2. Sevasemten plasma concentration‐time curves for multiple‐dose administration in healthy volunteers.

Figure S3. Hand grip strength over time in adults with Becker muscular dystrophy.

Table S1. Summary of pathogenic variants for adults with Becker muscular dystrophy.

Table S2. Overall summary of adverse events.

Table S3. Summary of treatment‐emergent adverse events reported in ≥ 2 participants by system organ class and preferred term.

Table S4. Pharmacokinetic parameters of sevasemten following single‐dose administration in fasted healthy volunteers.

Table S5. Pharmacokinetic parameters of sevasemten following 2 weeks of multiple‐dose administration in healthy volunteers and adults with Becker muscular dystrophy.

Table S6. Dose‐proportionality assessment of plasma pharmacokinetic parameters of multiple‐dose sevasemten administered as a suspension formulation under fasted conditions.

Table S7. Peripheral magnetic stimulation and hand grip strength assessments over time in healthy volunteers and adults with Becker muscular dystrophy.

Table S8. Pathway enrichment table.

Donovan J., Silverman J. A., Barthel B., et al., “A Phase 1, Double‐Blind, Placebo‐Controlled Trial of Sevasemten (EDG‐5506), a Selective Modulator of Fast Skeletal Muscle Contraction, in Healthy Volunteers and Adults With Becker Muscular Dystrophy,” Muscle & Nerve 72, no. 3 (2025): 399–407, 10.1002/mus.28444.

Data Availability Statement

Individual de‐identified patient data will not be available in a publicly accessible repository to protect the interests of the trial participants, in accordance with the policies of Edgewise Therapeutics, and in line with the General Data Protection Regulation.