Stakeholder cooperation to overcome challenges in orphan medicine development: the example of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is a rare, progressive, muscle-wasting disease leading to severe disability and premature death. Treatment is currently symptomatic, but several experimental therapies are in development. Implemented care standards, validated outcome measures correlating with clinical benefit, and comprehensive information about the natural history of the disease are essential for regulatory approval of any treatment. However, for Duchenne muscular dystrophy and other rare diseases, these requirements are not always in place when potential therapies enter the clinical trial phase. A cooperative effort of stakeholders in Duchenne muscular dystrophy-including representatives from patients' groups, academia, industry, and regulatory agencies-is aimed at addressing this shortfall by identifying strategies to overcome challenges, developing the tools needed, and collecting relevant data. An open and constructive dialogue among European stakeholders has positively affected development of treatments for Duchenne muscular dystrophy; this approach could serve as a paradigm for development of treatments for rare diseases in general.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy

“…There is a growing need for reliable biomarkers to follow-up patients as the development of novel therapeutics for many muscular dystrophies progresses 40. Changes in fat replacement over short periods of time are not detectable with T1-weighted muscle MRI in slowly progressive muscle dystrophies.…”

GAA Deficiency in Pompe Disease Is Alleviated by Exon Inclusion in iPSC-Derived Skeletal Muscle Cells

“…A combination of two AONs that have a larger effect than individual AONs at the same total AON dose may offer the possibility to lower the dose, which should be confirmed in animal and clinical studies. Encouraging progress toward clinical implementation has been reported for other neuromuscular disorders including SMA41, 42 and DMD43, 44 (reviewed by Havens et al 45 …”

Eteplirsen in the treatment of Duchenne muscular dystrophy

“…While the following trial, NCT02255552, has addressed this by planning to enroll 160 patients (Table 1), other steps can be taken to increase sample size further. One way would be to consider enrolling nonambulant patients into trials, as the majority of DMD patients are nonambulant 47. This prevents patients from dropping out due to ambulation loss, provides the opportunity for nonambulant patients to participate in trials, and potentially facilitates the creation of more homogeneous cohorts 47,48.…”

“…One way would be to consider enrolling nonambulant patients into trials, as the majority of DMD patients are nonambulant 47. This prevents patients from dropping out due to ambulation loss, provides the opportunity for nonambulant patients to participate in trials, and potentially facilitates the creation of more homogeneous cohorts 47,48. This would, however, entail the development and/or use of appropriate outcome measures to assess efficacy.…”

“…After being subjected to rigorous examination, these methods likely have been improved and validated according to FDA standards for NCT02255552. Nevertheless, it would be helpful to use an additional highly reproducible outcome measure, such as the quantification of muscle–fat conversion through magnetic resonance imaging and spectroscopy,47,52,53 to further strengthen the surrogate end point.…”