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.

Using a State-of-the-Art Toolbox to Evaluate Molecular and Functional Readouts of Antisense Oligonucleotide-Induced Exon Skipping in mdx Mice

“…While it is encouraging that a relatively low amount of dystrophin may already be sufficient to restore muscle leakiness and improve motor function in mdx mice, it remains to be seen to what extent this can be extrapolated to the human situation in DMD. So far, in clinical trials applying exon skipping AONs, reported dystrophin levels have been low, but in some patients a functional improvement was observed [55,56]. However, in the absence of more robust dystrophin levels and functional outcome, it is not justified to make an accurate statement on how much dystrophin restoration in DMD patients is necessary for a specific functional benefit.…”

Developments in reading frame restoring therapy approaches for Duchenne muscular dystrophy

“…progression for eteplirsen-treated patients [20][21][22][23]. In September 2016 FDA granted eteplirsen accelerated marketing authorization based on increases in dystrophin expression, stating on the label that functional effects have not yet been confirmed.…”

A well‐tolerated core needle muscle biopsy process suitable for children and adults

“…5 Despite the decreased reliance on muscle biopsy for clinical diagnosis, clinical trials for investigational new drugs for DMD are increasingly mandating muscle biopsies to obtain target tissue, especially in the case of therapeutic interventions intended to induce dystrophin expression in DMD skeletal muscle, such as exon skipping, nonsense readthrough, or microdystrophin replacement or dystrophin correction. [6][7][8] Successful observation of dystrophin induction in humans thus far has relied on open muscle biopsies in clinical trials, because of the need for sufficient material of high quality. 2,7 Core needle biopsies have not been used substantially in clinical trials because there is a perceived risk that these muscle biopsies may be too small or dis- 8,9 We should seek to minimize risks of these necessary samplings especially in the context of therapies of unknown benefit.…”

“…[6][7][8] Successful observation of dystrophin induction in humans thus far has relied on open muscle biopsies in clinical trials, because of the need for sufficient material of high quality. 2,7 Core needle biopsies have not been used substantially in clinical trials because there is a perceived risk that these muscle biopsies may be too small or dis- 8,9 We should seek to minimize risks of these necessary samplings especially in the context of therapies of unknown benefit. Thus, there is ample reason to develop, and to evaluate the safety and success, of less invasive means for serial muscle sampling in adults and children with muscle disease.…”

“…Thus, sampling the same muscle group on the same side of the body is more challenging with open biopsy and may introduce unknown variations from comparison of dominant versus non‐dominant muscle. As an example of the need for biopsy, most pediatric patients enrolled in the phase II trial for eteplirsen underwent four open muscle biopsies 8,9 . We should seek to minimize risks of these necessary samplings especially in the context of therapies of unknown benefit.…”