On 20 September 2013, GlaxoSmithKline (GSK) and Prosensa announced that GSK’s Phase III clinical trial (NCT01254019) of Drisapersen, an exon skipping drug for Duchenne muscular dystrophy (DMD), failed to meet the primary endpoint of a statistically significant improvement in the 6 Minute Walking Distance Test (6MWT) compared to placebo. 1 On 12 November 2013, Sarepta Therapeutics announced that the US Food and Drug Administration (FDA) has considered its application for accelerated approval of Eteplirsen as a DMD drug to be premature. 2 The news came as a great disappointment to the scientific community and more specifically to the families and foundations that had followed the trail of research articles and press announcements. Moreover, the clinical trial results and the FDA’s view of the relationship between the dystrophin biomarker and functional endpoint of 6MWT in clinic will have a far reaching impact beyond exon skipping therapy in DMD. Currently, the most promising therapies for DMD are arguably gene therapy and exon skipping, both aiming to restore the expression of dystrophin. For exon skipping, the general strategy of restoring expression of the mutated dystrophin gene by excluding frame-disrupting mutations was vindicated by early experiments in dystrophic animal models. 3–6 This principle has been substantiated for DMD by clinical trials over the last 7 years with two chemistries, the 2’O-methyl phosphorothioate backbone (2OMePS, named PRO051/Drisapersen initiated by Prosensa/GSK) and the morpholino backbone (PMO, named Eteplirsen initiated by AVI Biopharma, now Sarepta Therapeutics). 7–10 Both drugs target dystrophin exon 51 and both elicited the expected skipping of exon 51 and production of dystrophin protein following intramuscular injections.

In a subsequent open-label, dose-escalation systemic study, five weekly subcutaneous injections of Prosensa/GSK’s PRO051 at 0.5, 2, 4, or 6 mg/kg induced skipping of exon 51 accompanied by low levels of dystrophin in 12 DMD boys. But, importantly, this data lacked pretreatment controls. 10 This lack of pretreatment controls in combination with the use of the highly sensitive dystrophin antibody MANDYS106 led to reports of expansion of dystrophin positive fibre counts to up to 100%. The follow-up extension for 12-weeks at 6 mg/kg of the PRO051 reported stabilisation of motor function in the boys. 10 However, the study included