A Phase 1B Trial in GBA1‐Associated Parkinson's Disease of BIA‐28‐6156, a Glucocerebrosidase Activator

Abstract Background Loss‐of‐function mutations in the GBA1 gene are one of the most common genetic risk factors for onset of Parkinson's disease and subsequent progression (GBA‐PD). GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), a promising target for a possible first disease‐modifying therapy. LTI‐291 is an allosteric activator of GCase, which increases the activity of normal and mutant forms of GCase. Objectives This first‐in‐patient study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of 28 daily doses of LTI‐291 in GBA‐PD. Methods This was a randomized, double‐blind, placebo‐controlled trial in 40 GBA‐PD participants. Twenty‐eight consecutive daily doses of 10, 30, or 60 mg of LTI‐291 or placebo were administered (n = 10 per treatment allocation). Glycosphingolipid (glucosylceramide and lactosylceramide) levels were measured in peripheral blood mononuclear cells (PBMCs), plasma, and cerebrospinal fluid (CSF), and a test battery of neurocognitive tasks, the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale and the Mini‐Mental State Exam, were performed. Results LTI‐291 was generally well tolerated, no deaths or treatment‐related serious adverse events occurred, and no participants withdrew due to adverse events. C max , and AUC 0–6 of LTI‐291 increased in a dose‐proportional manner, with free CSF concentrations equal to the free fraction in plasma. A treatment‐related transient increase in intracellular glucosylceramide (GluCer) in PBMCs was measured. Conclusion These first‐in‐patient studies demonstrated that LTI‐291 was well tolerated when administered orally for 28 consecutive days to patients with GBA‐PD. Plasma and CSF concentrations that are considered pharmacologically active were reached (ie, sufficient to at least double GCase activity). Intracellular GluCer elevations were detected. Clinical benefit will be assessed in a larger long‐term trial in GBA‐PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.