Effects of long-term treatment and combination therapeutics for neuromuscular disorders

As the medical community is engaging in more novel drug/biologic development and clinical testing for therapies for inherited neuromuscular disorders, new paradigms for decisions making in therapy development are being explored. A concerted effort is needed between the relevant stakeholders to share information, optimize efforts, minimize repeat of the same mistakes, and thereby move novel therapies along more quickly. In addition, multiple therapeutic approaches are now in, or approaching, clinical trials, all competing for a limited number of patients and requiring a clear way forward to understand the spectrum of safety and side effects. Thus, a coordinated approach towards clinical trial development and conduct is crucial. Here, we present a strategy to facilitate long term therapeutic trials for neuromuscular disorders, for monitoring of potential side effects and avoiding pitfalls. Inherited neuromuscular disorders are an important cause of disability in man. However, there are over a hundred different diseases, which are caused by mutations in different (parts of) genes (see the gene table of Neuromuscular Disorders at www.musclegenetable.org). Even the most common ones (Duchenne muscular dystrophy, myotonic dystrophy, spinal muscular atrophy) are relatively rare diseases when compared to acquired conditions. It has been over two decades since the first genes involved in inherited neuromuscular disorders were reported [1]. However, the advancement from molecular mechanisms to drugs entering clinical trials has been initiated only recently and only for a subset of these disorders [2]. The majority of drugs currently in trials aim to slow down disease progression and address the progressive pathology rather than correcting the underlying genetic defect. However, since many of these genetic neuromuscular diseases can be identified before the development of weakness, the arrest of the disease would be tantamount to cure. Thus, perhaps a realistic goal for the next decade would be that of slowing down or arresting disease progression in several conditions rather than aiming to improve the condition of affected individuals especially if already significantly compromised. Notably, for only a single disorder (Pompe disease) has a drug been registered that does treat the underlying detect by replacing the a-glucosidase enzyme (myozyme ), which normally is lacking in these patients [3]. In this disease treatment appears to arrest the disease in at least some patients [4–6]. Since in most neuromuscular disorder cases life-long treatment will be required, treatments that do not improve function but only slow disease progression pose challenges for clinical development. Complicating this is the lack of data on natural disease course for many NMDs, which impedes assessment of short and long term benefit (or detriment) of treatment. Thus, a consolidated approach to set up clinical trials with an eye to long term surveillance is crucial to advance the development of treatments for these diseases.