A Combined Prospective and Retrospective Comparison of Long-Term Functional Outcomes Suggests Delayed Loss of Ambulation and Pulmonary Decline with Long-Term Eteplirsen Treatment

Journal of Neuromuscular Diseases, 2022

Background

Studies 4658-201/202 (201/202) evaluated treatment effects of eteplirsen over 4 years in patients with Duchenne muscular dystrophy and confirmed exon-51 amenable genetic mutations. Chart review Study 4658-405 (405) further followed these patients while receiving eteplirsen during usual clinical care.

Objective

To compare long-term clinical outcomes of eteplirsen-treated patients from Studies 201/202/405 with those of external controls.

Methods

Median total follow-up time was approximately 6 years of eteplirsen treatment. Outcomes included loss of ambulation (LOA) and percent-predicted forced vital capacity (FVC%p). Time to LOA was compared between eteplirsen-treated patients and standard of care (SOC) external controls and was measured from eteplirsen initiation in 201/202 or, in the SOC group, from the first study visit. Comparisons were conducted using univariate Kaplan-Meier analyses and log-rank tests, and multivariate Cox proportional hazards models with regression adjustment for baseline characteristics. Annual change in FVC%p was compared between eteplirsen-treated patients and natural history study patients using linear mixed models with repeated measures.

Results

Data were included from all 12 patients in Studies 201/202 and the 10 patients with available data from 405. Median age at LOA was 15.16 years. Eteplirsen-treated patients experienced a statistically significant longer median time to LOA by 2.09 years (5.09 vs. 3.00 years, p < 0.01) and significantly attenuated rates of pulmonary decline vs. natural history patients (FVC%p change: -3.3 vs. -6.0 percentage points annually, p < 0.0001).

Conclusions

Study 405 highlights the functional benefits of eteplirsen on ambulatory and pulmonary function outcomes up to 7 years of follow-up in comparison to external controls.

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Authors

Mitelman O, Abdel-Hamid HZ, Byrne BJ, Connolly AM, Heydemann P, Proud C, Shieh PB, Wagner KR, Dugar A, Santra S, Signorovitch J, Goemans N, investigators from the LNMRC Natural History study, McDonald CM, investigators from the CINRG Duchenne National History Study, Mercuri E, investigators from The DMD Italian Group, Mendell JR