Ribitol First-in-Human Study Shows Predictable PK and QT Safety

Key Takeaways

• In healthy adults in a first-in-human ribitol program, oral dosing was generally well tolerated and showed a predictable pharmacokinetic profile across single-dose, multiple-dose, food-effect, and QT assessments.
• Exposure rose in a mostly dose-proportional pattern across the tested single-dose range, with rapid absorption and a terminal half-life of roughly half a day.
• Repeated dosing reached steady state within the first several days and did not show accumulation over the 6-day regimen.
• A high-fat meal delayed absorption and lowered peak concentration without a marked change in overall exposure.
• The dedicated QT assessment did not show a meaningful QTcF signal within the observed concentration range, and no serious adverse events or adverse-event discontinuations were reported.

Limb-girdle muscular dystrophy type R9 (LGMDR9) is a progressive neuromuscular disease caused by reduced fukutin-related protein (FKRP) activity, and the source framed it as having no approved disease-modifying therapy. Ribitol is being developed as an oral precursor intended to increase substrate availability for alpha-dystroglycan (alpha-DG) glycosylation, a pathway linked to muscle-cell stability. Before patient-focused studies can address biologic or functional effects, early development needed to define tolerability, pharmacokinetics (PK), food effect, and cardiac repolarization in healthy adults.

Healthy-adult findings were reported in the First-in-human ribitol clinical pharmacology study in Clinical Pharmacology in Drug Development. The program combined randomized placebo-controlled single-ascending-dose cohorts under fasted conditions at 0.5, 1.5, 3, 6, 9, 12, and 15 g; multiple-ascending-dose regimens of 1.5 g once daily, 3 g once daily, and 3, 6, or 9 g every 12 hours for 6 days; a separate open-label 12 g fed-versus-fasted comparison; and a dedicated 21 g QT interval corrected using the Fridericia method (QTcF) program with moxifloxacin as the assay-sensitivity control. PK analyses subtracted baseline endogenous ribitol, and the primary QT analysis used concentration-QTcF modeling. The program was built to define exposure, tolerability, food effect, and repolarization rather than efficacy.

No serious adverse events or adverse-event discontinuations were reported across the study parts, and most treatment-emergent adverse events were mild. After single doses, ribitol was rapidly absorbed, with Tmax of 1.5 hours or less, and exposure increased in a mostly dose-proportional manner across 0.5 to 15 g. The single-dose terminal half-life was about 9 to 13 hours. During repeated dosing, Day 1 PK resembled the single-dose profile, apparent steady state was reached by about Day 3, and no accumulation in Cmax or AUC0-tau was seen on Day 6, leaving the repeated-dose profile predictable over 6 days.

Meal timing changed the absorption profile more than total exposure. With a high-fat meal, Tmax shifted from about 0.5 to 1.5 hours and Cmax fell by about 50%, while fed-versus-fasted AUC confidence intervals remained within 80% to 125%, supporting the narrower claim that overall exposure was not materially changed. In the dedicated QT assessment, placebo-corrected QTcF changes ranged from -1.3 to 2.2 ms, and effects above 10 ms were excluded across observed concentrations up to about 351.9 microg/mL. Moxifloxacin produced the expected positive-control effect, supporting assay sensitivity.

These first-in-human studies were conducted in healthy adults and were designed around safety, tolerability, PK, food effect, and QTcF rather than patient efficacy, biomarker change, or functional outcomes in LGMDR9. The authors framed the observed exposure range against intended weight-based twice-daily regimens, but those regimens were not tested in patients in this program. They also reported that muscle biopsies were not pursued because healthy adults would be expected to have normal alpha-DG glycosylation.

The authors concluded that ribitol was generally well tolerated in healthy adults, showed predictable exposure across the tested program, was not meaningfully altered in overall exposure by food, and did not show concentration-dependent QTcF prolongation within the observed range. These findings support continued clinical development for LGMDR9, without establishing patient benefit in this dataset.

Clinician Questions

What did the ribitol first-in-human program evaluate before studies in LGMDR9 patients?

Oral ribitol in healthy adults was evaluated across single-ascending-dose, multiple-ascending-dose, food-effect, and dedicated QT assessments to characterize tolerability, PK, meal-related absorption effects, and QTcF behavior before patient-focused studies in LGMDR9.

Why were muscle biopsies not included in the healthy-adult ribitol program?

The authors reported that healthy adults would be expected to have normal alpha-DG glycosylation, so a detectable increase with ribitol was not expected; the program therefore emphasized safety, tolerability, and PK endpoints instead of tissue biomarker assessment.

How was the QTcF assessment for ribitol designed to show assay sensitivity?

The dedicated QT program included a placebo- and moxifloxacin-controlled crossover component, with moxifloxacin serving as the positive control to confirm that the study could detect a QTc effect when one was present.