Introduction: LGMD Type 2I/R9 is caused by bi-allelic loss-of-function of the Fukutin-Related Protein (FKRP) gene, which results in hypoglycosylation of alpha-dystroglycan (?DG). BBP-418 (Ribitol) is an oral-administered substrate supplementation therapy intended to saturate the FKRP enzyme to drive increased glycosylation of the ?DG, thus addressing the root cause of disease in LGMD Type 2I/R9.
Objectives: The MLB-01-002 Phase 1 study is intended to explore safety and tolerability of single (SAD) and multiple (MAD) ascending doses of BBP-418 following administration to healthy subjects. Investigators sought to characterize single dose and steady state pharmacokinetics (PK) of BBP-418 and evaluate the effect of a standardized high calorie meal on the PK profile of BBP-418
Methods: This is a randomized, blinded, placebo-controlled study of the administration of BBP-418 to 85 healthy subjects. The SAD part of this study includes 1 food effect (FE) cohort. Vital signs, ECGs, evaluation of AEs and blood draws for PK and safety laboratory tests were obtained serially. SAD dosing was assessed across 7 cohorts to a maximum dose of 15 g. Five MAD cohorts were enrolled to a maximum dose of 9 g BID.
Results: All studied doses were well-tolerated with no dose-limiting toxicity. PK assessment showed dose proportional exposure following both single (0.5 g to 15 g) and multiple dose administrations (1.5 g QD to 9 g BID). The geometric mean (%CV) for Cmax and AUC(0-?) following a single 15 g dose were 221 (12.6%) µg/mL and 543 (12.3%) µg*hr/mL, respectively. Effective half-life was ~4-5 hours. No clinically significant differences in exposure occurred when administered under fed conditions.
Conclusions: Phase 1 study of BBP-418 in healthy volunteers demonstrated broad tolerability across a wide range of dosing, including doses beyond expected therapeutic range. No dose limiting toxicity was observed. A phase 2 “first in patient” study is currently ongoing.