BIAL R&D has announced the dosing of the first patient in the Phase 2 ACTIVATE clinical trial (NCT05819359) evaluating BIA 28-6156, an allosteric activator of beta-glucocerebrosidase (GCase), for the treatment of Parkinson's disease (PD) patients with a mutation in the glucocerebrosidase 1 (GBA1) gene (GBA-PD). The trial is currently screening patients across sites in North America, with plans to initiate a Europe-based trial in the third quarter of 2023.
ACTIVATE Trial Design
The ACTIVATE trial is a multicenter, randomized, double-blind, placebo-controlled study designed to assess the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of two fixed dose levels of BIA 28-6156 (10mg and 60mg/day). Approximately 237 genetically confirmed GBA-PD subjects will be randomized to one of three treatment arms: 10 mg, 60 mg, or placebo. The 78-week double-blind treatment period will employ a time-to-event design to evaluate the delay of meaningful clinical progression, as assessed by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts 2 and 3.
Eligible patients must have been diagnosed with PD between 1 to 7 years prior to genetic screening, have a modified Hoehn and Yahr score of at most 2.5, and a score of at least 22 on the Montreal Cognitive Assessment. Participants must also be on a stable dose of PD medication and continue the treatment throughout the study duration.
Rationale for GCase Activation
"Dosing of the first patient in our phase 2 clinical trial represents a major milestone in the clinical development of BIA 28-6156 for the treatment of Parkinson's disease patients with a genetic validated risk factor as GBA1 gene mutation. Activation of GCase enzymatic activity via allosteric modulation with BIA 28-6156 offers a novel potential treatment for patients with GBA-PD as well as a promising new approach to delay clinical motor progression," said Nuno Mendonça, MD, chief medical officer at BIAL. He added that data from nonclinical settings, including human cells, suggest that activation of GCase enzymatic activity could provide therapeutic benefit to patients with PD who carry a GBA-PD risk-associated variant in the GBA1 gene.
Phase 1b Trial Results
Data from a Phase 1b trial published in Movement Disorders showed that BIA 28-6156 (LTI-291) was safe when orally administered daily for 28 days in patients with GBA-PD. The trial demonstrated that pharmacologically active plasma and cerebrospinal fluid (CSF) concentrations were reached, and intracellular GluCer elevations were identified.
The Phase 1b trial included 40 participants with GBA-PD who were administered 28 consecutive daily doses of 10, 30, or 60 mg of BIA 28-6156, or placebo. Researchers measured levels of glycosphingolipids (glucosylceramide and lactosylceramide) in peripheral blood mononuclear cells, plasma, and CSF. They also conducted a test battery of neurocognitive tasks and assessed participants with MDS-UPDRS and the Mini-Mental State Exam.
The Phase 1b trial reported no deaths or treatment-related serious adverse effects, and no participants dropped out due to adverse events. Cmax and AUC0-6 of BIA 28-6156 increased in a dose-proportional manner, with free CSF concentrations equal to the free fraction in plasma.
GBA1 Mutations in Parkinson's Disease
According to Luís Magalhães, MD, PhD, PharmaD, director of Clinical Research & Operations at BIAL, carrying a single mutant copy of the GBA1 (glucocerebrosidase 1) gene causes moderately compromised GCase activity, resulting in decreased enzyme activity. These heterozygous mutations in the GBA1 gene are associated with a higher risk of developing Parkinson’s disease. Approximately 10% of the overall patient population in the U.S. with clinically diagnosed Parkinson’s disease carries a GBA1 mutation, with similar numbers in Europe and other countries.
BIA 28-6156 is being developed for the treatment of Parkinson’s disease in patients with a mutation in the GBA1 gene, offering a potential new approach to delay clinical motor progression in GBA-PD patients.
