First Patient Dosed in Phase 2 ACTIVATE Trial of BIA 28-6156 for Parkinson Disease

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The phase 2 clinical trial ACTIVATE investigating BIA 28-6156 for Parkinson disease is currently screening for patients in North America and with the Europe-based study beginning sometime during the third quarter of 2023.

Nuno Mendonça, MD, chief medical officer at BIAL

Nuno Mendonça, MD

In recent news, BIAL R&D announced the dosing of the first patient in its phase 2 clinical trial, ACTIVATE (NCT05819359), to investigate BIA 28-6156, an allosteric activator of the enzyme beta-glucocerebrosidase (GCase), as a treatment of patients with genetically-mutated Parkinson disease (PD). The trial, which includes those with a mutation in the glucocerebrosidase 1 (GBA1) gene (GBA-PD), otherwise the most common genetic risk factor of the disease, is screening patients across sites in North America and with a Europe-based trial planned to initiate in the third quarter of 2023.

Investigators will recruit and enroll patients who were diagnosed with PD between 1 to 7 years prior to genetic screening, have a modified Hoehn and a Yahr score at most of 2.5, as well as a score of at least 22 on the Montreal Cognitive Assessment. Also, to be eligible, participants must be on stable dose of PD medication and continue the treatment throughout the duration of the study.

About the Phase 2 Trial

Trial Name: Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD (ACTIVATE)

ClinicalTrials.gov Identifier: NCT05819359

Sponsor: Bial R&D Investments, S.A.

Recruitment Contact: Luís M Magalhães, PharmD (00351229866100) luis.magalhaes@bial.com

Completion Date Estimated: 2026-03-31

"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," Nuno Mendonça, MD, chief medical officer at BIAL, said in a statement.1 “Data from nonclinical settings, including data from 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.”

ACTIVATE is a multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of 2 fixed dose levels of BIA 28-6156 (10mg and 60mg/day). The study plans to randomize approximately 237 patients who are genetically confirmed GBA-PD to 1 of the 3 treatment arms, either 10 mg, 60 mg or placebo. During the 78-week double-blind treatment period, the trial will use a time-to-event design to explore the delay of meaningful clinical progression as evaluated by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part 2 and Part 3.

"The study is designed to evaluate the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of two fixed-dose levels of BIA 28-6156 (10mg and 60mg/day). The trial will randomize approximately 237 genetically confirmed GBA-PD subjects to one of the three treatment arms, either 10mg, 60mg or placebo. The study is currently screening patients across sites in North America and in Europe," Luís Magalhães, MD, PhD, PharmaD, director of Clinical Research & Operations at BIAL told NeurologyLive®.

READ MORE: Investigational Agent ANPD001 Demonstrates Preclinical Safety and Efficacy for Parkinson Disease Treatment

"BIAL is an innovation-driven pharma. Our goal is to deliver our science to patients in need. So, the first patient dosed with BIA 28-6156 is a major milestone in the clinical development of BIA 28-6156 for the treatment of PD among patients with a genetic validated risk factor as GBA1 gene mutation. It means we are progressing in the clinical development of this compound and, hopefully, are in the path to provide clinical evidence of a once-daily GCase activator as a disease-modifying therapy for GBA-PD patients," Magalhães told.

Following this recent news, data from a phase 1b trial published in Movement Disorders investigating BIA 28-6156, formally known as LTI-291, demonstrated safety when orally administered daily for 28 days among patients with GBA-PD.2 Notably, findings showed that pharmacologically active plasma and cerebrospinal fluid (CSF) concentrations were reached and intracellular GluCer elevations were identified.

"While physiological and methodological variability should always be considered as an explanation for the observed signal in this exploratory setting, our straightforward analysis shows a clear difference in treated patients compared to placebo. Furthermore, our preclinical studies confirmed that BIA-28-6156 is a highly selective GCase activator, supporting that the observed effects derive from GCase activation,” lead author Jonas M. den Heijer MD, PhD, neurologist at Leiden University Medical Center, in Leiden, The Netherlands, and colleagues wrote.2

This randomized, double-blind, placebo-controlled 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. The levels of glycosphingolipid (glucosylceramide and lactosylceramide) were measured in peripheral blood mononuclear cells, plasma, and CSF. Researchers also conducted a test battery of neurocognitive tasks as well as assessed the participants with MDS-UPDRS and the Mini-Mental State Exam.

There were no deaths or treatment-related serious adverse effects reported using the therapy, and no participants dropped out of the study because of adverse events. Additionally, findings displayed that Cmax, and an area under the curve (AUC)0-6 of BIA 28-6156 increased in a dose-proportional manner, showing free CSF concentrations equal to the free fraction in plasma.

"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 GBA1 gene are associated with a higher risk of developing Parkinson’s disease," Magalhães told. "Recent clinical research has not only shown that GBA1 carrying PD patients progress faster in their disease course than idiopathic PD patients (PD that does not have a known genetic cause), but has revealed a strong correlation between the severity of the mutation and the rate of disease progression. Approximately 10% of the overall patient population in the U.S. with clinically diagnosed Parkinson’s disease carries a GBA1 mutation. The numbers are similar in Europe and various other countries worldwide."

"BIA 28-6156 is a novel allosteric activator of beta-glucocerebrosidase (GCase) that is being developed for the proposed indication of treatment of Parkinson’s disease in patients with a mutation in the GBA1 gene. Thus BIA 28-6156 may offer a novel potential treatment for patients with GBA-PD and a promising new approach to delay clinical motor progression," Magalhães told.

REFERENCES
1. BIAL R&D Announces First Patient Dosed in its Phase 2 Clinical Trial of BIA 28-6156 to Treat Parkinson's Disease Patients With a Pathogenic Variant in the Glucocerebrosidase (GBA1) Gene. News Release. Bial. Published May 25, 2023. Accessed August 14, 2023. https://prnmedia.prnewswire.com/news-releases/bial-rd-announces-first-patient-dosed-in-its-phase-2-clinical-trial-of-bia-28-6156-to-treat-parkinsons-disease-patients-with-a-pathogenic-variant-in-the-glucocerebrosidase-gba1-gene-301833969.html
2. den Heijer JM, Kruithof AC, Moerland M, et al. A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator. Mov Disord. 2023;38(7):1197-1208. doi:10.1002/mds.29346
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