Background

LTI-291 is a small-molecule activator of glucocerebrosidase (GCase), a lysosomal enzyme involved in the breakdown of glycosphingolipids. Mutations in GBA1, the gene encoding GCase, are the leading genetic risk factor for the synucleinopathies Parkinson’s disease and dementia with Lewy bodies. GBA1 mutations that lower enzyme activity are associated with a higher risk of developing PD, more severe disease, and faster progressing disease.

No preclinical data have been published for this drug.

Findings

In 2017, Lysosomal Therapeutics completed two Phase 1 studies in the Netherlands. One trial examined safety and pharmacokinetics of single ascending doses in 40 healthy adults. A second trial analyzed 14 days of multiple dosing in 39 healthy older volunteers, age 50 to 75. According to results presented at the 2020 AAT-AD/PD Focus Meeting, LTI-291 was safe after single or multiple dosing. Its pharmacokinetics were dose-proportional, with a half-life in blood of 30 hours. The drug accumulated in the brain to about 1 percent of plasma levels, or enough to double GCase activity, based on its in vitro potency (Apr 2020 conference news).

At the same meeting, the company presented results of a Phase 1b study in PD patients with GBA1 mutations. Run from 2017 to 2018, it randomized 40 participants to 10, 30, or 60 mg LTI-291 or placebo daily for 28 days. The drug appeared safe. Treatment transiently increased the abundance of glycosphingolipid pathway intermediates measured in peripheral blood cells, which the authors equate to increased GCase activity.

A separate imaging study treated 14 GBA-PD patients with placebo, 10, or 60 mg LTI daily for 26 days, and analyzed changes in brain blood flow, FDG-PET glucose uptake, and fMRI functional connectivity. Treated patients consistently showed higher blood flow and glucose uptake; functional connectivity in their default mode networks returned toward normal. Group differences were not statistically significant in this small sample.