Drug development progress in duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive, and incurable X-linked disorder caused by mutations in the dystrophin gene. Patients with DMD have an absence of functional dystrophin protein, which results in chronic damage of muscle fibers during contraction, thus leading to deterioration of muscle quality and loss of muscle mass over time. Although there is currently no cure for DMD, improvements in treatment care and management could delay disease progression and improve quality of life, thereby prolonging life expectancy for these patients. Furthermore, active research efforts are ongoing to develop therapeutic strategies that target dystrophin deficiency, such as gene replacement therapies, exon skipping, and readthrough therapy, as well as strategies that target secondary pathology of DMD, such as novel anti-inflammatory compounds, myostatin inhibitors, and cardioprotective compounds. Furthermore, longitudinal modeling approaches have been used to characterize the progression of MRI and functional endpoints for predictive purposes to inform Go/No Go decisions in drug development. This review showcases approved drugs or drug candidates along their development paths and also provides information on primary endpoints and enrollment size of Ph2/3 and Ph3 trials in the DMD space.

Keywords: clinical trial; drug developement; duchenne muscular dystrophy (DMD); research and development; therapeutic strategies.

FIGURE 1

Histograms showing enrollment sizes for Ph2/3 and Ph3 trials of therapeutic strategies for the treatment of DMD. Red dashed lines indicate medium enrollment size for trials within each therapeutic strategy. For study start and anticipated study end date of the trials please refer to Supplementary Table S2. In cell therapy, there was a pivotal Ph3 study (HOPE-3, NCT05126758) with an expected completion in 2024 to evaluate the safety and efficacy of CAP-1002 in 68 DMD patients. The smaller than expected sample size may be based on the anticipated effect size and variability in the primary endpoint, change in full Performance of the Upper Limb test version 2 (PUL 2.0) at Month 12, which achieved significance in 20 participants (12 placebo and 8 treated) enrolled in the Ph2 trial (HOPE-2, NCT03406780) (Capricor, 2021).

FIGURE 2

(A) Schematic for full length dystrophin protein (Hoffman et al., 1987): the actin-binding domains (ABD1-ABD3) bind to the intracellular cytoskeleton network of muscle cells, and the cysteine-rich (Cys) domain binds to β-dystroglycan, which is connected to the extracellular matrix protein laminin. The amino terminal and Cys domain are connected by 24 spectrin-like repeats (S1-S24) and 4 hinge domains (H1-H4). (B) Schematics for microdystrophin gene therapy candidates, which are truncated versions of the full length dystrophin, that are currently under development (Wang et al., 2000; Harper et al., 2002; Schneider et al., 2017).