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.

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.