LB: Effects of Sevasemten on LVEF and NT-proBNP in Adults with Becker muscular dystrophy in CANYON

Topic:

Clinical Trials

Poster Number: 470 LBM

Author(s):

Ben Barthel, PhD, Edgewise Therapeutics, Luuli Tran, PhD, Edgewise Therapeutics, Craig McDonald, MD, University of California (UC) Davis Medical Center, Hani Kushlaf, MD, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA, Katherine Mathews, MD, University of Iowa, Iowa City, Iowa, USA, Diana Castro, MD, Neurology Rare Disease Center, Denton, Texas, USA, Arun Varadhachary, MD, PhD, Washington University School of Medicine, Anne Connolly, MD, Nationwide Children’s Hospital, Columbus, Ohio, USA , Michela Guglieri, MD, Newcastle University, Newcastle upon Tyne, England, UK , Doris Leung, MD, PhD, Kennedy Krieger Institute, Baltimore, Maryland, USA , Jeffrey Statland, MD, University of Kansas Medical Center, Kansas City, Kansas, USA, Erik Niks, MD, PhD, Leiden University Medical Center, Leiden, Netherlands, Rosaline Quinlivan, MD, National Hospital for Neurology and Neurosurgery, London, England, UK , Varun Sreenivasan, MD, University of Colorado – Denver, Denver, Colorado, USA , Aravindhan Veerapandiyan, MD, Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US, Nicholas Johnson, MD, Virginia Commonwealth University, Richmond, Virginia, USA , Han Phan, MD, Rare Disease Research, Atlanta, Georgia, USA, Brenda Wong, MD, University of Massachusetts Medical Center, Worcester, Massachusetts, USA , Roxana Donisa Dreghici, MD, Edgewise Therapeutics, James MacDougall, PhD, Edgewise Therapeutics, Joanne Donovan, MD, PhD, Edgewise Therapeutics, Alan Russell, PhD, Edgewise Therapeutics

Becker muscular dystrophy (BMD) is an inherited myopathy marked by progressive skeletal muscle degeneration and development of dilated cardiomyopathy, a major contributor of morbidity and mortality, which manifests clinically with reduced cardiac output and elevated natriuretic peptides such as NT-proBNP. Sevasemten, an investigational fast skeletal myosin inhibitor, has shown robust attenuation of proteomic markers of skeletal muscle injury and trends toward preservation of function in BMD in early clinical trials. Given sevasemten’s lack of direct activity against cardiac myosin, this work aimed to investigate sevasemten’s cardiovascular safety in adults with BMD.

In the 12-month CANYON phase 2 study (NCT05291091), plasma samples from 28 adults receiving sevasemten and 12 receiving placebo were analyzed by SOMAscan proteomics at baseline and study completion, focusing on data for NT-proBNP (somamer ID 7655-11). Left ventricular ejection fraction (LVEF) was assessed by centrally read echocardiography.

Baseline LVEF correlated with NT-proBNP (r = –0.576, p < 0.001). Participants were stratified into normal LVEF (≥55%, n=21) and below-normal LVEF (<55%, n=14) groups; the latter had higher baseline NT-proBNP but similar ages, baseline creatine kinase, and North Star Ambulatory Assessment scores . After 12 months of sevasemten treatment, LVEF was preserved in those with normal LVEF and trended towards improvement in the below-normal LVEF group. NT-proBNP was unchanged from baseline in sevasemten -treated participants and trended lower compared to placebo participants.

In conclusion, LVEF was maintained or trended towards improvement during twelve months of sevasemten treatment, while NT-proBNP was stable and trended lower than placebo. These results support the cardiovascular safety profile of sevasemten and may indicate a potentially cardioprotective role for sevasemten in adults in BMD.