Long-term treatment with eteplirsen in nonambulatory patients with Duchenne muscular dystrophy

Abstract

This analysis aims to describe the outcomes of two nonambulatory patients with Duchenne muscular dystrophy (DMD) who participated in two clinical studies. The two consecutive trials of eteplirsen (studies 201 and 202) were conducted in patients with DMD (N = 12) and confirmed genetic mutations amenable to exon 51 skipping.In study 201, 12 patients were randomized to receive once-weekly, double-blind intravenous infusions of eteplirsen 30 or 50 mg/kg or placebo for 24 weeks; patients then received open-label eteplirsen during weeks 25 through 28. All 12 patients continued onto open-label extension study 202 and received long-term treatment with eteplirsen. We compared cardiac, pulmonary, and upper limb function and dystrophin production in the nonambulatory twin patients versus the 10 ambulatory patients through 240 combined treatment weeks.Ten study patients remained ambulatory through both studies, while the identical twin patients both experienced early, rapid loss of ambulation. The twin patients had greater disease severity at baseline (6-minute walk test [6MWT], 330 and 256 m) versus the other patients (n = 10; 6MWT range, 341-418 m). They maintained cardiac and upper limb function through combined week 240, with outcomes similar to those of the patients who remained ambulatory. Dystrophin production was confirmed following eteplirsen treatment.Despite the loss of ambulation, other markers of disease progression remained relatively stable in the eteplirsen-treated twin patients and were similar to those of the ambulatory patients.

Conflict of interest statement

Conflicts of interest: Medical writing and editorial support were provided by Callie Grimes, PhD, and Barbara Zeman, PhD, of Peloton Advantage, LLC, an OPEN Health company (Parsippany, NJ), and funded by Sarepta Therapeutics, Inc. L. N. Alfano, L. Cripe, R. Dracker, Z. Sahenk, and L. Lowes have no conflicts to disclose. J. S. Charleston, J. Dworzak, H. Eliopoulos, D. E. Frank, K. Lucas, J. Lynch, E. Naughton, and F.J. Schnell are employees of Sarepta Therapeutics, Inc. and may own stock or options in the company. C. Donoghue was an employee at the time of the study. A. M. Connolly has served on advisory boards for AveXis, Inc., Cytokinetics, Inc., Sanofi Genzyme, and Sarepta Therapeutics, Inc. She serves on the data management safety board for Catabasis Pharmaceuticals, Inc., and as an investigator for AveXis, Inc., Biogen, Bristol-Myers Squibb, Cytokinetics, Inc., FibroGen, Italfarmeco SpA, NS Pharma, Inc., Pfizer Inc, PTC Therapeutics, Inc., and Sarepta Therapeutics, Inc. S. Lewis is an employee of Nationwide Children's Hospital, which received funding from Sarepta Therapeutics in the form of the study budget. A. J. Milici serves as a remunerated consultant for Sarepta Therapeutics, Inc. A. Flynt is an employee of PharPoint Research, which received funding from Sarepta Therapeutics for data analysis for the study. At the time of the study, L.R. Rodino-Klapac was an employee of Nationwide Children's Hospital, which received funding from Sarepta Therapeutics in the form of a research agreement; she is currently an employee of Sarepta Therapeutics, Inc., and may own stock/options in the company. She is the inventor of technology that has been exclusively optioned to Sarepta Therapeutics. G. D. Young serves as a remunerated consultant for Sarepta Therapeutics, Inc. J. R. Mendell serves on an advisory board for Sarepta Therapeutics, Inc.

Figures

Figure 1

Six-minute walk test distance for all patients at baseline (day 1 visit). 6MWT = 6-minute walk test.

Figure 2

Rapid decline and loss of ambulation in the eteplirsen-treated twin patients. 6MWT = 6-minute walk test.

Figure 3

Measures of pulmonary and cardiac function in patients A and B versus study mean through 240 weeks of eteplirsen treatment: (A) FVC%p and (B) LVEF. FVC%p = percent predicted forced vital capacity, LVEF = left ventricular ejection fraction.

Figure 4

Measures of upper limb function in patients A and B versus study mean through 240 weeks of eteplirsen treatment: (A) 9-Hole Peg Test; (B) grip strength; (C) elbow flexion; and (D) elbow extension. All data represent the right hand, which was the dominant hand for all 12 patients.

Figure 5

Dystrophin expression following 180 weeks of eteplirsen treatment, based on Western blot analysis and immunohistochemistry (A), Western blot image (B), PDPF (C), and the intensity of dystrophin fluorescent signal in muscle fibers (D). In panels A, C, and D, standard deviations are represented by error bars. In panel B, lanes in the Western blot image are identified left to right as the standard curve (4%, 2%, 1%, 0.5%, 0.25% of normal), patient samples (treated or untreated in blinded random order in next two lanes), and negative pooled DMD control sample. Patient samples representing patient A and patient B are identified in both figures. Note that either an unrelated patient sample representing an untreated (left figure) or treated (right figure) patient was run on the adjacent lane due to the random blinded nature that samples were evaluated. DMD = Duchenne muscular dystrophy, PDPF = percent dystrophin-positive fibers, tx = treated, untx = untreated.