Assessment of Target Engagement in a First‐in‐Human Trial with Sinbaglustat, an Iminosugar to Treat Lysosomal Storage Disorders

In this first‐in‐human study, the tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple oral doses of sinbaglustat, a dual inhibitor of glucosylceramide synthase (GCS) and non‐lysosomal glucosyl ceramidase (GBA2), were investigated in healthy subjects. The single‐ascending dose (SAD) and multiple‐ascending dose (MAD) studies were randomized, double‐blind, and placebo‐controlled. Single doses from 10 to 2,000 mg in men and multiple doses from 30 to 1,000 mg twice daily for 7 days in male and female subjects were investigated. Tolerability, PK, and PD data were collected up to 3 days after (last) treatment administration and analyzed descriptively. Sinbaglustat was well‐tolerated in the SAD and MAD studies, however, at the highest dose of the MAD, three of the four female subjects presented a similar pattern of general symptoms. In all cohorts, sinbaglustat was rapidly absorbed. Thereafter, plasma concentrations decreased biphasically. In the MAD study, steady‐state conditions were reached on Day 2 without accumulation. During sinbaglustat treatment, plasma concentrations of glucosylceramide (GlcCer), lactosylceramide, and globotriaosylceramide decreased in a dose‐dependent manner, reflecting GCS inhibition. The more complex the glycosphingolipid, the more time was required to elicit PD changes. After treatment stop, GlcCer levels returned to baseline and increased above baseline at lowest doses, probably due to the higher potency of sinbaglustat on GBA2 compared to GCS. Overall, sinbaglustat was welltolerated up to the highest tested doses. The PK profile is compatible with b.i.d. dosing. Sinbaglustat demonstrated target engagement in the periphery for GCS and GBA2.