Introduction: Limb-girdle Muscular Dystrophy (LGMD) Type 2I, also called LGMDR9 FKRP-related, is caused by bi-allelic partial loss-of-function of the fukutin-related protein (FKRP) gene, which results in hypoglycosylation of alpha-dystroglycan (αDG). BBP-418 is an orally administered substrate supplementation intended to saturate the partially functional FKRP enzyme, driving increased glycosylation of αDG, and potentially ameliorating the root cause of LGMD2I.
Objectives: The MLB-01-003 Phase 2 study is intended to explore the safety and tolerability of BBP-418. Additionally, the feasibility and usefulness of clinical efficacy and pharmacodynamic (PD) assessments in patients with LGMD2I receiving ascending doses of BBP-418 will be investigated.
Methods: MLB-01-003 is an open label dose escalation study of patients with LGMD2I. Part 1 of the study involved three dose cohorts (6 g QD, 6 g BID and 12 g BID) treated for 3 months. During Parts 2 and 3 (ongoing OLE), all patients received 12 g BID, dose adjusted for lower weight.
Results: 14 patients with LGMD2I (aged 12-53, 8/14 homozygous for the L276I mutation) were enrolled. After 90 days of treatment, participants showed an average of +0.21 in the glycosylated αDG / total αDG ratio. A sustained reduction in Creatine kinase (CK) of >75% was observed over 12 months. Following 12+ months of treatment, increases in NSAD (0.95) and 10MWT velocity (0.09 m/s) were observed. This compares favorably to data for the same patients showing decline over the 12-month interval prior to treatment with BBP-418. BBP-418 was well-tolerated across a range of dose levels with no observed treatment-related serious adverse events, dose limiting toxicities or discontinuations. Updated data will be provided at the time of the meeting.
Conclusions: Preliminary MLB-01-003 data from patients with LGMD2I suggest a positive effect of BBP-418 on αDG glycosylation, CK, NSAD and 10MWT velocity. A global, double-blind placebo-controlled Phase 3 study is planned.