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); t ½ 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.