A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI‐291 is an allosteric modulator of GCase, enhancing its activity. These first‐in‐human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI‐291 in healthy volunteers.

In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI‐291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle‐aged or elderly volunteers were randomly assigned to LTI‐291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI‐291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.

LTI‐291 was generally well tolerated and no deaths or treatment‐related SAEs occurred and no subject withdrew from a study due to AEs. C_max, AUC_0–24 and AUC_0‐inf increased in a dose proportional manner. The median half‐life was 28.0 hours after multiple dosing. No dose‐dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.

These first‐in‐human studies demonstrated that LTI‐291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI‐291 effects in a GBA1‐mutated Parkinson population.