Lessons Learned From Translational Research in Neuromuscular Diseases: Impact on Study Design, Outcome Measures and Managing Expectation

The last 15 years have seen an impressive development of new therapeutic approaches for neuromuscular diseases, in particular in Duchenne muscular dystrophy (DMD) and Spinal muscular atrophy (SMA), with a rapid increase in the number of interventional clinical trials and the first few drugs approved and integrated as part of the care for some patients. Conversely, the field has also seen several phase III clinical trials fail due to inability to show a significant improvement on the chosen outcome measures, regardless of promising pre-clinical efficacy data. In addition, some drugs taken to regulators for evaluation for approvals were refused due to lack of evidences in demonstrating a clinical significant impact on patient underlying condition and quality of life. These failures highlight the need for strong preclinical data, rigour in clinical trial designs, ensiling the chosen endpoints are of a sufficient quality and possess clinical meaning to the individuals involved. The regulatory approval process has also demonstrated variable assessment criteria from different regulators and payers, leading to unequal access to new treatments.

Therapeutic approaches targeting the underlying cause of the disease seem to be more attractive and promising, however open new study design and ethical issues when more than one approach might be available either in clinical trial or in the form of license drugs with no comparative/superiority data available. Moreover trials targeting the primary genetic defect could jeopardise recruitment in trials aiming to impact the downstream pathogenic effects. Will these trials still play a role in neuromuscular diseases? The translational research experience in neuromuscular diseases has highlighted the importance of strong natural history data to support study design, identification of robust outcome measures and anticipated modifiers which are expected to impact the course of the disease. These include pharmacological treatment, physical interventions including physiotherapy and orthotics, and genetic modifiers.

The need to carefully select trial populations to observe a significant drug effect within a reasonable trial timeframe has led to targeting a specific disease stage and population. This can create recruitment issues and impacts the feasibility of clinical trials which do not specifically target the underlying cause of the disease, especially for interventions aiming to address co-morbidities or complications associated with the disease. Strict inclusion criteria have also highlighted regulatory and ethical concerns about extrapolation of study results and accessibility of new treatment to a wider patient population.
With a growing number of clinical trials using new advanced therapies including gene therapy, expectations will need to be carefully managed. Questions emerge regarding subject selection, psychological impacts on patients refused access to these trials or confirmed ineligible to receive disease modifier drugs, and the demand of expensive treatments on national health systems and payers. Families feel that there is still inequality in accessing clinical trials and there are concerns around inequity in accessing treatment if and when they become available.
Lessons learned on all these aspects including considerations for study designs and outcome measure selection, impact of genotype and other external intervention on disease progression and drug effect monitoring, surrogates endpoint and data extrapolation, and ethical and health economy issues should be shared to inform future studies as well as drug development in other neuromuscular and non-neuromuscular rare diseases.