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

Abstract

ObjectiveTo 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).MethodsAmbulatory 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.ResultsAt 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.InterpretationOver 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271

DMD genotypes and loss of ambulation in the CINRG Duchenne natural history study

“…[19][20][21] Even very small quantities of dystrophin, hardly detectable by immunohistochemistry (IHC) or Western blot (WB), might ameliorate the disease and delay LoA by several years. This is particularly relevant for the development of dystrophin-restoring treatments, such as exon skipping by antisense oligonucleotides (AONs) [22][23][24][25][26][27][28][29][30] and stop codon readthrough, [31][32][33] as variation in baseline levels of dystrophin may confound evaluations of efficacy in clinical trials.…”

From Petunias to the Present- A Review of Oligonucleotide Therapy

“…The decision of approval by FDA was based on four studies-NC T00844597, NC T01396239/ NC T01540409 [38][39][40] and NC T02255552 [32]. Though the studies showed a positive increase in the level of dystrophin they are plagued with several concerns like absence of good control, low sample size, chort heterogeneity, reproducibility and reliability [38].…”

Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy

“…DMD is caused by a lack of dystrophin protein due to mutations in the dystrophin gene (2). Exon skipping using a splice-switching oligonucleotide (SSO) is one of the most promising therapies for DMD and is currently the focus of clinical trials (3). SSO-mediated exon skipping prevents the incorporation of mutated exons and/or neighboring exons into the spliced mRNA and restores its reading frame (4).…”