Eteplirsen 500mg/10ml solution for injection vials

Duchenne muscular dystrophy is a fatal neuromuscular disorder affecting around one in 3,500–5,000 male births that is characterized by progressive muscular deterioration. It is inherited in an X-linked recessive fashion and is caused by loss-of-function mutations in the DMD gene coding for dystrophin, a cytoskeletal protein that stabilizes the plasma membrane of muscle fibers. In September 2016, the US Food and Drug Administration granted accelerated approval for eteplirsen (or Exondys 51), a drug that acts to promote dystrophin production by restoring the translational reading frame of DMD through specific skipping of exon 51 in defective gene variants. Eteplirsen is applicable for approximately 14% of patients with DMD mutations. This article extensively reviews and discusses the available information on eteplirsen to date, focusing on pharmacological, efficacy, safety, and tolerability data from preclinical and clinical trials. Issues faced by eteplirsen, particularly those relating to its efficacy, will be identified. Finally, the place of eteplirsen and exon skipping as a general therapeutic strategy in Duchenne muscular dystrophy treatment will be discussed.

Abstract licence: CC BY-NC 3.0

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. Ann Neurol 2016;79:257–271

Abstract licence: CC BY-NC 4.0

Eteplirsen, a phosphorodiamidate morpholino antisense oligonucleotide (PMO) that modulates splicing to treat Duchenne muscular dystrophy (DMD) patients, received accelerated approval by Food and Drug Administration (FDA) on September 19, 2016 [1]. This heralded a number of firsts: it is the first drug that is approved for DMD in the United States, the first approved oligonucleotide that modulates splicing, the first approved PMO, and also the first oligonucleotide to be approved based on very limited data. Although its approval was shrouded in controversy, eteplirsen could also become the first oligonucleotide to be a commercial success. This brief commentary reviews the disease, the therapy, the clinical data, and what eteplirsen’s approval means for the oligonucleotide therapeutics field. DMD is an X-linked progressive disease by which patients lose muscle function from an early age, resulting in wheelchair dependency generally around the age of 12, the need for assisted ventilation around the age of 20, and premature death in the third–fourth decade of life. Apart from symptomatic care, there is no treatment; while their peers gain skills and become independent, DMD patients will lose one function after another until they rely on around-the-clock care before they die prematurely. Given the severe and progressive nature and the unmet medical need, the disease clearly qualifies for the FDA-accelerated approval pathway. DMD is caused by mutations in the dystrophin gene. Normally, dystrophin stabilizes muscle fibers during contraction by connecting the actin cytoskeleton within muscle fibers to the extracellular matrix surrounding muscle fibers. DMD patients have mutations that disrupt the reading frame and/or cause premature truncation of protein translation. Interestingly, mutations that maintain the reading frame allow the production of an internally deleted protein that is partially functional, owing to the fact that the crucial domains of dystrophin are located at the very beginning and end of the protein, whereas the middle is largely redundant. These internally deleted dystrophins are found in the later onset and less progressive Becker muscular dystrophy. The exon skipping approach stems from the fact that most DMD patients have in theory the genetic capacity to produce Becker-like dystrophins. Using antisense oligonucleotides (AONs) to interfere with the splicing process, the reading frame can be restored to allow the production of a partially functional Becker-type dystrophin rather than a nonfunctional DMD-type dystrophin. Depending on the mutation present in any individual patient, one or more different exons may need to be skipped to restore the reading frame. However, because mutations cluster, skipping certain exons is expected to be therapeutic in larger groups of patients, with most notably exon 51 skipping applying to 13%–14% of patients. Ultimately, exon skipping of various exons may be an effective therapy in more DMD patients. After obtaining proof of concept in patient-derived cell models and animal models, two AON chemistries were clinically developed for exon skipping in DMD. The 2¢-O-methyl phosphorothioate exon 51 skipper drisapersen was developed by Prosensa/GSK/BioMarin. After a first dose-finding study, 12 DMD patients were treated on and off with 6 mg/kg for more than 6 years in an open-label study. Eight of the 10 ambulant patients were stable in the distance walked in 6 min for the duration of the study, whereas 2 patients lost ambulation [2]. Drisapersen was then tested in two phase 2 and one phase 3 placebo-controlled trials in more than 300 DMD patients. The primary endpoint in these trials was the 6-min walk test. Although there was a tendency of drisapersen-treated patients to walk further than placebo-treated patients, the difference was small and not statistically or clinically significant. Post hoc analysis suggested that treatment may have had a therapeutic effect on younger patients and a marketing approval application was filed. FDA did not grant this, based on

Abstract licence: CC BY-NC 4.0

Background Eteplirsen received accelerated FDA approval for treatment of Duchenne muscular dystrophy (DMD) with mutations amenable to exon 51 skipping, based on demonstrated dystrophin production. Objective To report results from PROMOVI, a phase 3, multicenter, open-label study evaluating efficacy and safety of eteplirsen in a larger cohort. Methods Ambulatory patients aged 7–16 years, with confirmed mutations amenable to exon 51 skipping, received eteplirsen 30 mg/kg/week intravenously for 96 weeks. An untreated cohort with DMD not amenable to exon 51 skipping was also enrolled. Results 78/79 eteplirsen-treated patients completed 96 weeks of treatment. 15/30 untreated patients completed the study; this cohort was considered an inappropriate control group because of genotype-driven differences in clinical trajectory. At Week 96, eteplirsen-treated patients showed increased exon skipping (18.7-fold) and dystrophin protein (7-fold) versus baseline. Post-hoc comparisons with patients from eteplirsen phase 2 studies (4658-201/202) and mutation-matched external natural history controls confirmed previous results, suggesting clinically notable attenuation of decline on the 6-minute walk test over 96 weeks (PROMOVI: –68.9 m; phase 2 studies: –67.3 m; external controls: –133.8 m) and significant attenuation of percent predicted forced vital capacity annual decline (PROMOVI: –3.3%, phase 2 studies: –2.2%, external controls: –6.0%; p < 0.001). Adverse events were generally mild to moderate and unrelated to eteplirsen. Most frequent treatment-related adverse events were headache and vomiting; none led to treatment discontinuation. Conclusions This large, multicenter study contributes to the growing body of evidence for eteplirsen, confirming a positive treatment effect, favorable safety profile, and slowing of disease progression versus natural history.

Abstract licence: CC BY-NC 4.0

Background: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. Objective: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. Methods: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients ( n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. Results: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P 0.004; and – 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts ( P < 0.05, all comparisons). Conclusions: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Abstract licence: CC BY-NC 4.0