The FDA has recently made key decisions impacting the development of therapies for neurological and neuromuscular disorders. These include a clinical hold on PepGen's Duchenne muscular dystrophy (DMD) trial, a breakthrough therapy designation for Sanofi's multiple sclerosis (MS) drug, and positive results for Edgewise Therapeutics' Becker muscular dystrophy treatment. Here's a detailed look at each development.
FDA Pauses PepGen's PGN-EDO51 Trial for Duchenne Muscular Dystrophy
The FDA has placed a clinical hold on PepGen's Investigational New Drug (IND) application for the Phase 2 CONNECT2-EDO51 trial of PGN-EDO51 in patients with Duchenne muscular dystrophy (DMD). The trial, designed as a 25-week, multinational, double-blind, placebo-controlled study with multiple ascending doses, is currently active in the United Kingdom. The FDA's decision stems from questions raised during the regulatory review process. PepGen anticipates receiving an official clinical hold letter within 30 days and is collaborating with the agency to address their concerns.
PGN-EDO51 is an investigational phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 51 in dystrophin transcripts. Exon 51 skipping is a therapeutic target for approximately 13% of DMD patients, aiming to restore the open reading frame and enable the production of a truncated, yet functional dystrophin protein. The FDA had previously granted PGN-EDO51 both Orphan Drug and Rare Pediatric Disease Designations.
Earlier data from the Phase 2 CONNECT1-EDO51 trial, an open-label study in Canada, showed promising results. The 5 mg/kg dose cohort demonstrated a mean exon skipping level of 2.15% in biceps tissue and a mean muscle-adjusted dystrophin level of 1.49% of normal after 13 weeks. The trial continues in Canada, with the 10 mg/kg cohort fully enrolled. However, Health Canada has requested additional information regarding safety before further dose escalation or enrollment. Specifically, magnesium levels in two participants in the 10 mg/kg cohort decreased, though supplementation corrected this. Additionally, one participant experienced a reduction in estimated glomerular filtration rate (eGFR), which is now improving after a pause in dosing.
Tolebrutinib Granted Breakthrough Therapy Designation for Multiple Sclerosis
Sanofi's tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, has received breakthrough therapy designation from the FDA for patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This designation is based on findings from the Phase 3 HERCULES study (NCT04411641), where tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026). Secondary endpoints also showed that tolebrutinib nearly doubled the number of patients experiencing confirmed disability improvement (10% vs. 5% in the placebo group; HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021). Regulatory submissions for tolebrutinib are being finalized for the United States and prepared for Europe.
Sevasemten Shows Positive Results in Becker Muscular Dystrophy Trial
Edgewise Therapeutics announced positive topline data from its Phase 2 CANYON trial (NCT05291091) of sevasemten, formerly known as EDG-5506, in patients with Becker muscular dystrophy. The trial met its primary endpoint, demonstrating a statistically significant change in creatine kinase (CK) levels. Over months 6 through 12, sevasemten-treated patients showed a 28% average difference in CK decrease compared to those on placebo (P = .02). The placebo-controlled, double-blind study included 40 adults and 29 adolescents randomized to sevasemten or placebo for 12 months, followed by a 4-week follow-up. Edgewise plans to collaborate with the FDA and European Medicines Agency to pursue authorization filing strategies for sevasemten in Becker muscular dystrophy. According to Edgewise, this was the largest interventional trial to date in Becker and the first to achieve its primary end point.
