Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Jerry R Mendell, Nathalie Goemans, Linda P Lowes, Lindsay N Alfano, Katherine Berry, James Shao, Edward M Kaye, Eugenio Mercuri, Eteplirsen Study Group and Telethon Foundation DMD Italian Network, M Pane, E Mazzone, S Messina, G L Vita, A D Amico, Bertini, A Berardinelli, Y Torrente, F Magri, G P Comi, G Baranello, T Mongini, A Pini, R Battini, E Pegoraro, C Bruno, L Politano, S Previtali, Hoda Abdel Hamid, Barry J Byrne, Anne M Connolly, Robert A Dracker, L Matthew Frank, Peter T Heydemann, Kevin C O'Brien, Susan E Sparks, Linda A Specht, Louise Rodino-Klapac, Zarife Sahenk, Samiah Al-Zaidy, Linda H Cripe, Sarah Lewis, Jerry R Mendell, Nathalie Goemans, Linda P Lowes, Lindsay N Alfano, Katherine Berry, James Shao, Edward M Kaye, Eugenio Mercuri, Eteplirsen Study Group and Telethon Foundation DMD Italian Network, M Pane, E Mazzone, S Messina, G L Vita, A D Amico, Bertini, A Berardinelli, Y Torrente, F Magri, G P Comi, G Baranello, T Mongini, A Pini, R Battini, E Pegoraro, C Bruno, L Politano, S Previtali, Hoda Abdel Hamid, Barry J Byrne, Anne M Connolly, Robert A Dracker, L Matthew Frank, Peter T Heydemann, Kevin C O'Brien, Susan E Sparks, Linda A Specht, Louise Rodino-Klapac, Zarife Sahenk, Samiah Al-Zaidy, Linda H Cripe, Sarah Lewis

Abstract

Objective: To continue evaluation of the long-term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three-year progression of eteplirsen-treated patients was compared to matched historical controls (HC).

Methods: Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open-label basis. The primary functional assessment in this study was the 6-Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.

Results: At 36 months, eteplirsen-treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen-treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.

Interpretation: Over 3 years of follow-up, eteplirsen-treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC.

Trial registration: ClinicalTrials.gov NCT01396239 NCT01540409.

© 2016 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Figures

Figure 1
Figure 1
Study design: 4658‐201 and 4658‐202. Twelve patients with Duchenne muscular dystrophy were randomly assigned to 1 of 3 cohorts receiving weekly intravenous (IV) infusions in a 24‐week, double‐blind, placebo‐controlled study (study 201): eteplirsen 30mg/kg (solid line), eteplirsen 50mg/kg (dashed line), or placebo (dotted line). At week 25, eteplirsen‐treated patients continued the same weekly dose open‐label and placebo patients were randomized to open‐label treatment with eteplirsen 30mg/kg or 50mg/kg weekly IV (study 202). Functional clinical assessments including the 6‐Minute Walk Test and pulmonary function tests were performed at each week shown on the time axis. Muscle biopsies for evaluation of dystrophin were obtained from the upper arm at the time points specified; data reported elsewhere.1 BL = baseline.
Figure 2
Figure 2
Subgroup identification. The hierarchical chart shows the predefined filters by which patients were evaluated to select the most appropriate subgroups for comparison, as well as the most appropriate matched cohorts for comparison to eteplirsen‐treated patients. 6MWT = 6‐Minute Walk Test.
Figure 3
Figure 3
Historical control longitudinal 6‐minute walk distance over 3 years (mean ± standard error of the mean). (A) Age dichotomy predicts a change in disease trajectory at age 7 years. Disease progression trajectory is shown for steroid‐treated Duchenne muscular dystrophy historical controls who were older and younger than 7 years and amenable to skipping any exon. (B) 6‐Minute Walk Test (6MWT) performance declines more rapidly in patients with mutations amenable to exon skipping compared to those not amenable to exon skipping. Disease progression trajectory is compared in steroid‐treated patients ≥7 years of age with genotypes amenable or not amenable to exon skipping therapy. (C) 6MWT performance declines more rapidly in patients amenable to exon 51 skipping versus patients amenable to skipping other exons. Disease progression trajectory is shown in steroid‐treated patients ≥7 years of age with genotypes amenable to exon 51 skipping or amenable to skipping other exons. y.o. = years old.
Figure 4
Figure 4
Longitudinal 6‐minute walk distance (mean ± standard error of the mean) and loss of ambulation over 3 years. (A) Eteplirsen‐treated patients experience slower disease progression than matched historical controls. Disease progression trajectory is shown for steroid‐treated historical controls, ≥7 years old amenable to exon 51 skipping (n = 13) and eteplirsen‐treated patients (n = 12). Baseline characteristics for eteplirsen‐treated patients and those of the matched historical controls amenable to exon 51 skipping were comparable on mean age (difference of

Figure 5

Stability of respiratory muscle function…

Figure 5

Stability of respiratory muscle function as assessed by pulmonary function testing (mean ±…

Figure 5
Stability of respiratory muscle function as assessed by pulmonary function testing (mean ± standard error of the mean). Observed percentage of predicted (% Pred) maximum expiratory pressure (MEP), maximum inspiratory pressure (MIP), and forced vital capacity (FVC) demonstrate relative stability of respiratory muscle strength in all patients over >3 years of treatment with eteplirsen. % Pred MEP, MIP, and FVC at month 36 were 74.3, 89.5, and 91.9, respectively. BL = baseline.
Figure 5
Figure 5
Stability of respiratory muscle function as assessed by pulmonary function testing (mean ± standard error of the mean). Observed percentage of predicted (% Pred) maximum expiratory pressure (MEP), maximum inspiratory pressure (MIP), and forced vital capacity (FVC) demonstrate relative stability of respiratory muscle strength in all patients over >3 years of treatment with eteplirsen. % Pred MEP, MIP, and FVC at month 36 were 74.3, 89.5, and 91.9, respectively. BL = baseline.

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