Assessment of Cardiac Outcomes in Delandistrogene Moxeparvovec Clinical Trials for Duchenne Muscular Dystrophy

Topic:

Clinical Trials

Poster Number: P73

Author(s):

Aravindhan Veerapandiyan, MD, Arkansas Children’s Hospital, University of Arkansas for Medical Sciences, Little Rock, Arkansas, US, John Bourke, NUTH NHS Hospitals Foundation Trust, Newcastle upon Tyne, UK, John Day, MD, PhD, Stanford School of Medicine, Craig M McDonald, MD, University of California, Davis Health, Jerry Mendell, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Jon Soslow, MD, Vanderbuilt, Craig Zaidman, MD, Washington University in Saint Louis, Saint Louis, MO, USA, Stefanie Mason, MD, MPH, Sarepta Therapeutics, Inc, Cambridge, MA, USA, Jianfeng Meng, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Mark Vivien, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Tao Niu, Sarepta Therapeutics, Inc., Cambridge, MA, USA, Alexander P Murphy, MD, PhD, Roche Products Ltd, Welwyn Garden City, UK, Christoph Wandel, F. Hoffmann-La Roche Ltd, Basel, Switzerland, James Richardson, MD, Sarepta Therapeutics, Inc., Cambridge, MA, USA

Delandistrogene moxeparvovec, an rAAVrh74 gene therapy, delivers a transgene encoding a functional form of dystrophin shown to stabilize or slow the progression of Duchenne muscular dystrophy (DMD). Here we assess pooled cardiac safety outcomes from delandistrogene moxeparvovec studies with 1-5 years of follow-up.

Data from 156 patients (mean age [range], 6.7 [3.2-20.2] years; baseline left ventricular ejection fraction [LVEF] range, 48.9%-77.0%; ambulatory, 148 [95%]) were collected from 4 studies (101 [NCT03375164; n=4], 102 [NCT03769116; n=41], ENDEAVOR Cohorts 1-5b [NCT04626674; n=48], and EMBARK Part 1 at 52 weeks [NCT05096221; n=63]); all excluded patients with LVEF <40%. Troponin-I (TnI) was assessed regularly in ENDEAVOR and EMBARK. Two cases of myocarditis were reported within days of delandistrogene moxeparvovec infusion; both resolved within 3 weeks (1 with sequelae). One patient experienced a recurrence of immune-mediated myositis with concurrent cardiac injury during immunosuppressant weaning and stabilized with 2 weeks of treatment. Except in the 2 myocarditis cases, TnI fluctuations were asymptomatic and compatible with fluctuations observed in DMD. In ENDEAVOR Cohorts 1-3 (n=32), there was no apparent relationship between total capsid load and peak TnI levels 1-2 weeks post-infusion. In ENDEAVOR and EMBARK, 12 patients with available baseline and post-baseline ECHO data had elevated baseline Tnl levels; 1 year post-infusion, only 1 of these patients had LVEF <50% (48% by ECHO). Five years post-infusion, LVEF (via ECHO) in all 4 patients from Study 101 remained normal (>50%). At week 52, cardiac MRI performed in a subset of patients from EMBARK revealed no relevant differences in cardiac function (including LVEF), volume, or mass between patients treated with delandistrogene moxeparvovec or placebo. Overall, LVEF values were stable across all studies.

Results of delandistrogene moxeparvovec studies to date, with 1-5 years of follow-up, indicate a manageable cardiac safety profile in this population of patients with DMD. Therapy is generally well tolerated and safe, with no signs of persistent treatment-related cardiac injury.