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Randomized Controlled Trial
. 2014 Oct;50(4):477-87.
doi: 10.1002/mus.24332.

Ataluren treatment of patients with nonsense mutation dystrophinopathy

Katharine Bushby  1 , Richard Finkel, Brenda Wong, Richard Barohn, Craig Campbell, Giacomo P Comi, Anne M Connolly, John W Day, Kevin M Flanigan, Nathalie Goemans, Kristi J Jones, Eugenio Mercuri, Ros Quinlivan, James B Renfroe, Barry Russman, Monique M Ryan, Mar Tulinius, Thomas Voit, Steven A Moore, H Lee Sweeney, Richard T Abresch, Kim L Coleman, Michelle Eagle, Julaine Florence, Eduard Gappmaier, Allan M Glanzman, Erik Henricson, Jay Barth, Gary L Elfring, Allen Reha, Robert J Spiegel, Michael W O'donnell, Stuart W Peltz, Craig M Mcdonald; PTC124-GD-007-DMD STUDY GROUP
Collaborators, Affiliations
Randomized Controlled Trial

Ataluren treatment of patients with nonsense mutation dystrophinopathy

Katharine Bushby et al. Muscle Nerve. 2014 Oct.

Abstract

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders.

Methods: Randomized, double-blind, placebo-controlled study; males ≥ 5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48.

Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo.

Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.

Keywords: Duchenne muscular dystrophy; genetic; nonsense mutation; orphan; pediatric.

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Figures

Figure 1
Figure 1
Change in 6MWD. Mean changes in the ataluren 10, 10, 20 mg/kg and placebo arms were −12.86 and −44.14 meters, respectively, resulting in a difference of 31.28 meters.
Figure 2
Figure 2
Time to persistent ≥10% worsening in 6MWD.
Figure 3
Figure 3
Mean change in 6MWD from baseline to week 48 in the < 350 meters 6MWD subgroup.
Figure 4
Figure 4
Mean change in 6MWD from baseline to week 48 in the decline-phase subgroup.
Figure 5
Figure 5
Mean change in 6MWD by disease severity.
Figure 6
Figure 6
Timed function tests change from baseline to week 48 in Study 007 overall population versus decline-phase subgroup.
Figure 7
Figure 7
Mean change in 6MWD and timed function tests by concentration.
Figure 8
Figure 8
Difference in change from baseline and statistical significance by concentration. Note: Shaded area represents exposure range for 40 mg/kg/day ataluren.
See this image and copyright information in PMC

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