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. 2021 Sep;87(9):3561-3573.
doi: 10.1111/bcp.14772. Epub 2021 Mar 2.

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator

Jonas M den Heijer  1   2 , Annelieke C Kruithof  1   2 , Guido van Amerongen  1   2 , Marieke L de Kam  1 , Eva Thijssen  1   2 , Hendrika W Grievink  1 , Matthijs Moerland  1   2 , Mike Walker  3 , Kees Been  4 , Renato Skerlj  4 , Craig Justman  4 , Lindsay Dudgeon  4 , Peter Lansbury  4   5 , Valerie C Cullen  4 , Dana C Hilt  4 , Geert Jan Groeneveld  1   2
Affiliations

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator

Jonas M den Heijer et al. Br J Clin Pharmacol. 2021 Sep.

Abstract

Aims: 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.

Methods: 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.

Results: LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. Cmax , AUC0-24 and AUC0-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.

Conclusions: 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.

Keywords: GBA; Parkinson's disease; clinical trial; disease modification; phase 1.

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Conflict of interest statement

K.B., R.S., C.J., L.D., P.L., V.C. and D.H. were employees of Lysosomal Therapeutics, Inc. at time of execution of these studies. There are no other conflicts of interest to declare.

Figures

FIGURE 1
FIGURE 1
SAD study: Geometric mean (± geometric SD) plasma concentration of LTI‐291 against time (h) after dose following a single oral dose of 3, 10, 30 and 90 mg LTI‐291 in the fasted state and 10 mg LTI‐291 in the fed state
FIGURE 2
FIGURE 2
MAD study: Geometric mean (± geometric SD) plasma concentration of LTI‐291 against time (h) after dose following the first (top), seventh (middle) and fourteenth (bottom) oral dose of 3, 10, 30 or 60 mg LTI‐291
See this image and copyright information in PMC

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