Neurology · Medical Literature
Safety, Tolerability, Pharmacokinetics, Food Effect of Ribitol, and Its Effect on QTcF in Healthy Adults: First-in-Human, Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Studies.
Abstract
Limb-girdle muscle dystrophy Type R9 (LGMDR9), also known as LGMD Type 2I, is a rare genetic disease caused by partial loss of function of fukutin-related protein (FKRP) enzyme which glycosylates alpha-dystroglycan, thereby stabilizing myocytes during contraction. Hypoglycosylation leads to progressive muscle injury and impaired function including loss of ambulation. Ribitol is an endogenous pentose alcohol and precursor to CDP-ribitol, the substrate of FKRP. This first-in-human study demonstrated that ribitol was well tolerated when administered as single or multiple oral doses over 6 days to healthy adults. PK demonstrated dose-proportional increases in exposure from 0.5 to 15 g (therapeutic dose 9 and 12 g BID for patients weighing >30 to ≤50 kg and >50 kg, respectively); t½ was 9-13 h. A high-fat meal did not affect overall oral bioavailability; indicating ribitol may be taken without regard to food intake. A dedicated QT study using ribitol 21 g revealed no concentration-dependent QTcF prolongation and clinically significant QTcF prolongation was excluded over the entire range of exposures in the study, up to 351.9 µg/mL. Assay sensitivity was demonstrated with the expected effect of moxifloxacin. These results support further development of ribitol for the treatment of LGMDR9.
Clinical relevance
LGMD Type R9 (LGMDR9/LGMD2I) is a rare, progressive muscular dystrophy caused by partial loss-of-function mutations in the FKRP enzyme, leading to alpha-dystroglycan hypoglycosylation, myocyte instability, and eventual loss of ambulation — a population with no approved disease-modifying therapies. Ribitol, an endogenous pentose alcohol, serves as a precursor to CDP-ribitol (the FKRP substrate), offering a rational biochemical strategy to augment residual FKRP activity and restore glycosylation. This first-in-human trial establishes the foundational safety, pharmacokinetic, and cardiac safety profile required to advance ribitol into patient-facing efficacy trials.
Key findings
1. Safety & Tolerability: Ribitol was well tolerated across all single and multiple oral dose cohorts (0.5–15 g) administered over 6 days to healthy adults, with no dose-limiting toxicities reported in this first-in-human study. 2. Pharmacokinetics — Dose Proportionality: Systemic exposure demonstrated dose-proportional increases across the full tested range of 0.5 g to 15 g, supporting predictable PK scaling into the therapeutic dose range. 3. Proposed Therapeutic Dosing: Weight-based dosing was defined as 9 g BID for patients >30 to ≤50 kg and 12 g BID for patients >50 kg, derived from the PK profile observed in healthy adults. 4. Elimination Half-Life: The terminal half-life (t½) was 9–13 hours across dose levels, consistent with a twice-daily dosing regimen and adequate steady-state attainment. 5. Food Effect: A high-fat meal did not meaningfully alter overall oral bioavailability, indicating ribitol can be administered without regard to food intake — an important adherence-relevant finding for a chronic, high-gram-load regimen. 6. Cardiac Safety (QTcF): A dedicated thorough QT study at a supratherapeutic dose of 21 g revealed no concentration-dependent QTcF prolongation; clinically significant QTcF prolongation was excluded across the full exposure range up to 351.9 µg/mL, with assay sensitivity confirmed by the expected moxifloxacin effect.
Practice implications
These data support advancing ribitol into Phase 2/3 efficacy trials in LGMDR9 patients using weight-stratified BID dosing (9 g BID for ≤50 kg; 12 g BID for >50 kg), with no requirement for cardiac monitoring related to QTc prolongation at therapeutic or supratherapeutic exposures. The absence of a clinically meaningful food effect simplifies dosing instructions and is expected to improve adherence in pediatric and adult patients managing a complex chronic disease regimen. Clinicians involved in rare neuromuscular disease trials should anticipate enrollment opportunities and note that the favorable first-in-human safety profile de-risks cardiac and PK-related trial discontinuation.