OP40 – 2251: Idebenone as a new therapy to treat respiratory function loss in Duchenne muscular dystrophy: from preclinical studies to phase III trial outcome

Abstract

Based on its dual mode of action (reducing oxidative stress and improving mitochondrial respiratory chain function), we hypothesized idebenone as a potential therapeutic strategy for DMD. Here we summarize the development program which was executed between 2004 and 2014. A preclinical observer-blinded and placebo-controlled study in the mdx mouse model of DMD showed a significant cardioprotective and voluntary exercise performance effect for presymptomatic-initiated and long-term idebenone treatment. Next, a phase 2 randomized placebo-controlled clinical trial (DELPHI) was performed in 21 DMD boys aged 8–16 years, demonstrating trends for beneficial effects of idebenone on early functional cardiac and respiratory parameters. An important finding was that patients treated for 12 months with idebenone stabilized in peak expiratory flow percent predicted (PEF%p, marker of expiratory muscle strength), compared to patients receiving placebo who declined. Next we investigated the efficacy and tolerability of idebenone in a multicenter phase 3 trial (DELOS) in 64 DMD patients aged 10–18 years not taking concomitant glucocorticoid steroids. The majority of patients (92%) were non-ambulatory at baseline. The primary endpoint was change in PEF%p over the 12 month treatment period. Other respiratory outcome measures included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), weekly home-based PEF measurements, peak cough flow (PCF) and maximal static airway pressures. Idebenone significantly reduced the decline in PEF%p. A significant treatment effect was also observed in PEF (L/min), weekly home-based PEF as well as analyses of FVC and FEV1. The outcomes were comparable between patients with previous glucocorticoid steroid use and steroid naive patients. Results of respiratory function analyses were supported by responder analyses and clinical observations. In conclusion, our data consistently demonstrated that Idebenone was safe and well tolerated, significantly preserved respiratory function, and represents a new treatment option for patients with DMD.