Association Between Exon-Skipping Therapy With Eteplirsen and Cardiac Outcomes in Duchenne Muscular Dystrophy

Topic:

Clinical Trials

Poster Number: P79

Author(s):

Joel Iff, PhD, Sarepta Therapeutics, Inc., Isabelle Desguerre, MD, PhD, APHP- Necker Hospital, Neuromuscular Center, FILNEMUS Network, Yunjuan Liu, PhD, Analysis Group, Inc., Francois Sarkozy, MD, FSNB Health & Care, Edward Tuttle, MA, Analysis Group, Inc., Francesco Muntoni, MD, University College London, Craig M McDonald, MD, University of California, Davis Health, MarieChristine Nougues, MD, Centre de Référence des Pathologies Neuromusculaires, Hôpital Trousseau, APHP, Helge Amthor, MD, PhD, Hôpital Raymond Poincaré, APHP Université Paris-Saclay, Yi Zhong, MD, Analysis Group, Inc., Karim Wahbi,  MD, PhD, AP-HP, Cochin Hospital, Cardiology Department

Background: Duchenne muscular dystrophy (DMD) leads to dilated cardiomyopathy and heart failure during teenage years or young adulthood. Eteplirsen promotes dystrophin production through skipping of exon 51 of the DMD gene.
Objective: This analysis compared left ventricular ejection fraction (LVEF) decline between eteplirsen-treated and matched control patients with exon 51 skip-amenable DMD.
Methods: Eteplirsen-treated patients from clinical trials were matched with control patients from natural history studies in a propensity score (PS) analysis. Each control patient could be matched up to 2 times. Baseline characteristics for this analysis included age, LVEF, exposure to prophylactic angiotensin-converting enzyme inhibitors and/or angiotensin-receptor blockers, and stable corticosteroid use. Risk of reaching LVEF thresholds (50%, 55%, 60%) was evaluated with Cox proportional hazard models. Annual rate of LVEF decline was characterized using linear mixed effects models. A sensitivity analysis and analyses for potential bias were conducted, including risk of geographic imbalance, E-value analysis, and restricted mean survival time analysis to assess impact of age.
Results: Among 141 eteplirsen-treated patients and 103 control patients available for matching, the analysis included 122 treated patients matched with 122 control patients (64 unique control patients) with a mean follow-up of 26.5 ± 9.7 and 69.3 ± 71.1 months, respectively; PS matching allowed for balanced cohorts by aligning time of eteplirsen initiation for treated patients with a point in the lifespan of the control patients when their characteristics were most comparable. No eteplirsen-treated patients and 27 control patients (22.1%) reached LVEF <50%; eteplirsen-treated patients had a lower risk of reaching <55% and <60% thresholds versus controls (hazard ratio = 0.22; 95% CI = 0.07–0.66; P<0.01 and hazard ratio = 0.40; 95% CI = 0.22–0.76; P<0.01, respectively). Annual rate of LVEF decline for eteplirsen-treated and control patients was –0.66% (95% CI = –0.96 to –0.36, P<0.01) and –1.38% (95% CI = –1.60 to –1.16; P<0.01), respectively. Results were consistent with the sensitivity analysis and the analyses for potential bias.
Conclusions: In this retrospective study, eteplirsen-treated patients were observed to have a significantly lower risk of reaching LVEF thresholds indicative of cardiac function decline and attenuation of LVEF decline compared with matched control patients.