making muscle wasting history

The absence of dystrophin does not only weaken the cell membranes but also negatively affects the mitochondria in the muscle cells of Duchenne patients. In these “power stations” of the cells, the universal biological energy carrier, adenosine triphosphate (ATP), is generated by oxidative phosphorylation. The synthetic compound Idebenone, developed by the company Santhera Pharmaceuticals in Liestal near Basel, under the direction of Dr. Thomas Meier, its Chief Scientific Officer, is chemically derived from the natural coenzyme Q10. Idebenone not only is a powerful antioxidant but, even more importantly,
it facilitates the generation of cellular energy. Moreover, Idebenone has been optimized chemically so that it can easily enter cells, including muscle cells.

The efficacy of Idebenone has previously been demonstrated for patients with Friedreich’s ataxia. In this neuromuscular disease Idebenone was shown to improve neurological function. In addition, Idebenone also could ameliorate hypertrophic cardiomyopathy (enlargement of the heart), which in this neuromuscular disease is a life-threatening complication. More recently, scientists at the University of Leuven in Belgium, lead by Prof. Gunnar Buyse in collaboration with Santhera started to determine whether Idebenone would also be beneficial in Duchenne dystrophy. First, 15 they treated dystrophin-deficient mdx mice for 10 months – from shortly after birth until adult age – with Idebenone or placebo in a double-blind study. In this study the cardiac dysfunction of these dystrophic mice was significantly improved. Particularly, the mortality due to experimentally induced cardiac stress decreased from 58% to 19%. In addition, long-term voluntary wheel running performance (an overall muscle function test) improved significantly in mdx mice upon Idebenone treatment. The detailed scientific report of this exciting and innovative study will be published soon.

These results encouraged the researchers to perform a phase-II double-blind, placebo-controlled clinical trial with 21 Duchenne boys at 8 to 16 years of age conducted at the University of Leuven, also under the direction Prof. Gunnar Buyse. Thirteen boys were treated for 12 months with a daily dose of 450 mg Idebenone, applied as 150 mg tablets, while eight patients received placebo. The primary objective of this study was to determine the effect of Idebenone on the heart muscle function measured as the change in peak systolic radial strain of the left ventricular inferolateral heart wall, the region of the heart which in DMD is affected early and most severely. Patients on Idebenone improved markedly on this functional cardiac test compared to placebo. Secondary outcome measures of this study included respiratory function tests. Patients treated with Idebenone improved in peak flow during the 52-week study period, while this respiratory function continued to deteriorate in patients on placebo. These strong indications for improvement in heart and respiratory functions with Idebenone are particularly encouraging, since those problems cause very severe complications in patients with duchenne dystrophy. Results of this study will be presented for the first time to the medical community at the 2008 annual congress of the American Academy of Neurology.

In summary, this is the first indication of clinical efficacy with Idebenone on cardiac and respiratory functions in Duchenne patients. The results provide the basis for the planning of further clinical development studies with Idebenone. After these positive results, Santhera has decided to continue the development of Idebenone, which already received orphan drug designation, to an effective therapy for Duchenne dystrophy.