Authors:
Sebahattin Cirak MD, Virginia Arechavala-Gomeza PhD, Michela Guglieri MD, Lucy Feng PhD, Silvia Torelli PhD, Karen Anthony PhD, Stephen Abbs PhD, Prof Maria Elena Garralda MD, John Bourke MD, Prof Dominic J Wells VetMB PhD, Prof George Dickson PhD, Matthew JA Wood MD PhD, Prof Steve D Wilton PhD, Prof Volker Straub MD, Prof Ryszard Kole PhD, Stephen B Shrewsbury MD, Prof Caroline Sewry PhD, Jennifer E Morgan PhD, Prof Kate Bushby MD, & Prof Francesco Muntoni MD
Summary:
Background - We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with Duchenne muscular dystrophy.
Method - We undertook an open-label, phase 2, dose-escalation study (0•5, 1•0, 2•0, 4•0, 10•0, and 20•0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5—15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting.
Findings - 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0•0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8•9% (95% CI 7•1—10•6) to 16•4% (10•8—22•0) of normal control after treatment (p=0•0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0•9% to 17%, and from 0% to 7•7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts.
Interpretation - The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy.
Source:
The Lancet; Vol. 378, Issue 9791, 595-605 (08/13/11)