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Background  Lucerastat, an inhibitor of glucosylceramide synthase, has the potential to restore the balance between synthesis and degradation of glycosphingolipids in glycolipid storage disorders such as Gaucher disease and Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat were evaluated in two separate randomized, double-blind, placebo-controlled, single- and multiple-ascending dose studies (SAD and MAD, respectively) in healthy male subjects.    Methods  In the SAD study, 31 subjects received placebo or a single oral dose of 100, 300, 500, or 1000 mg lucerastat. Eight additional subjects received two doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study, 37 subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7 consecutive days. Six subjects in the 500 mg cohort received lucerastat in both absence and presence of food.    Results  In the SAD study, 15 adverse events (AEs) were reported in ten subjects. Eighteen AEs were reported in 15 subjects in the MAD study, in which the 500 mg dose cohort was repeated because of elevated alanine aminotransferase (ALT) values in 4 subjects, not observed in other dose cohorts. No severe or serious AE was observed. No clinically relevant abnormalities regarding vital signs and 12–lead electrocardiograms were observed. Lucerastat C max  values were comparable between studies, with geometric mean C max  10.5 (95% CI: 7.5, 14.7) and 11.1 (95% CI: 8.7, 14.2) μg/mL in the SAD and MAD study, respectively, after 1000 mg lucerastat b.i.d. t max  (0.5 – 4 h) and t 1/2  (3.6 – 8.1 h) were also within the same range across dose groups in both studies. Using the Gough power model, dose proportionality was confirmed in the SAD study for C max  and AUC 0–∞ , and for AUC 0–12  in the MAD study. Fed-to-fasted geometric mean ratio for AUC 0–12  was 0.93 (90% CI: 0.80, 1.07) and t max  was the same with or without food, indicating no food effect.    Conclusions  Incidence of drug-related AEs did not increase with dose. No serious AEs were reported for any subject. Overall, lucerastat was well tolerated. These results warrant further investigation of substrate reduction therapy with lucerastat in patients with glycolipid storage disorders.  SAD study was registered on clinicaltrials.gov under the identifier NCT02944487 on the 24 th  of October 2016 (retrospectively registered). MAD study was registered on clinicaltrials.gov under the identifier NCT02944474 on the 25 th  of October 2016 (retrospectively registered).    Trial registration  A Study to Assess the Safety and Tolerability of Lucerastat in Subjects With Fabry Disease. Clinicaltrials.gov:  NCT02930655 .

orphanet journal of rare diseases

Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects