Improving clinical trial design for Duchenne muscular dystrophy

Abstract

BackgroundCurrently, the most promising therapies for Duchenne muscular dystrophy (DMD) are exon skipping and stop codon read-through, two strategies aimed at restoring the expression of dystrophin. A phase 3 clinical trial with drisapersen, a drug designed to induce exon 51-skipping, has failed to show significant improvement of the primary outcome measure, the six-minute walk test.DiscussionHere, we review some key points that should be considered when designing clinical trials for these new therapies. First, younger patients have more functional abilities and more muscle fibers to preserve than older patients and therefore are better subjects for trials designed to demonstrate the success of new treatments. Second, the inclusion of patients on corticosteroids both in the treatment and placebo groups is of concern because the positive effect of corticosteroids might mask the effect of the treatment being tested. Additionally, the reasonable expectation from these therapies is the slowing of disease progression rather than improvement. Therefore, the appropriate clinical endpoints are the prolongation of the ability to stand from the floor, climb stairs, and walk, not an increase in muscle strength or function. Hence, the time frames for the detection of new dystrophin, which occurs within months, and the ability to demonstrate a slowing of disease progression, which requires years, are strikingly different. Finally, placebo-controlled trials are difficult to manage if years of blindness are required to demonstrate a slowing of disease progression. Thus, accelerated/conditional approval for new therapies should be based on surrogate biochemical outcomes: the demonstration of de novo dystrophin production and of its beneficial effect on the functional recovery of muscle fiber.SummaryThese data suggest that clinical trials for DMD patients must be adapted to the particular characteristics of the disease in order to demonstrate the expected positive effect of new treatments.

Non-invasive evaluation of muscle disease in the canine model of Duchenne muscular dystrophy by electrical impedance myography

“…Collectively, it appears that muscle disease was relatively stable from ~7 to ~17 months in affected dogs evaluated in this study. Although large-scale population studies are needed to validate this intriguing finding, our observations in affected dogs seems to mirror the so-called “honeymoon phase” in DMD patients [4, 58–61]. Hence, the lack of difference in the EIM assay agreed well with the relatively stationary disease course.…”

Intérêt des traitements pharmacologiques symptomatiques des maladies neuromusculaires de l’enfant

“…Ainsi, dans la dystrophie musculaire de Duchenne (DMD), les essais thé-rapeutiques relevant du saut d'exons ou de la translecture d'un codon stop se heurtent à des âges d'inclusion hétérogènes, à des co-médications imposées (corticoïdes), et à des critères d'efficacité insuffisamment pertinents (performances motrices plutôt que quantité de dystrophine produite de novo) [20]. De même dans l'amyotrophie spinale typique (SMA), les essais procédant d'une correction d'épis-sage du gène SMN2 par oligonucléotides anti-sens sont confrontés à une fenêtre temporelle d'efficacité thérapeutique étroite et à la nécessité d'une diffusion systémique en raison d'une atteinte multiorgane [21].…”

Oligonucleotide therapies for disorders of the nervous system

“…For both these drugs, the time frames required to observe statistically significant accumulation of their target protein (months) and to demonstrate slowing of disease progression (years) are strikingly different from those commonly used in the trials for small-molecule compounds. At the same time, the clinical trials for ODNs cannot be simply extended to the required duration without modifying the current trial requirements and rules optimized for small molecules 82 . As study duration is extended, placebo controls, and especially sham controls common in cases of IT injections, become less feasible because of difficulties with maintaining blinding of the trial.…”