BIA 28-6156 / BIAL - LARVOL DELTA

HOW THE THERAPEUTIC APPROACH TO EARLY PARKINSON'S DISEASE WILL CHANGE IN THE NEXT FUTURE (ADPD 2025) - "Levodopa remains the most efficacious drug, a better preparation of levodopa like IPX 203 can ensure more stable plasma levels of Levodopa...Tavapadon is a new dopamine agonist stimulating D1-D5 receptors which concluded the phase III. Other compounds such as CVN424 (Cerevance) orally active and selective GPR6 inverse agonist, piperamat (IRLAB 752) a cortical enhancer to improve balance, Clenbuterol/Nadolol for cognition, mesdopetam a D3 antagonist are under investigation...These include the monoclonal antibody prasinezumab, UCB0599 and buntanetap small-molecules α-synuclein aggregation inhibitor, the vaccine ACI-7104.056 by AC immune...The LRKK2 kinase inhibitor BIIB122/DNL151 is in phase IIb in PD. BIAL BIA 28-6156 activator of the GCase enzyme is under investigation in patients with GBA mutation. The combination of symptomatic and disease modifying therapy, the use of accurate biomarkers and more precise treatment will be the future in the treatment of PD."

CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

BIAL Announces First Patient Out in its Phase 2 Clinical Trial of BIA 28-6156 - a Novel Therapy for GBA1 Parkinson’s Disease (PRNewswire) - "BIAL...announced that the first patient has completed the full dose regimen in the ACTIVATE Phase 2 study....The ACTIVATE study...is a Phase 2, multicenter, randomised, double-blind, placebo-controlled study evaluating the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of two fixed-dose levels (10mg/day and 60mg/day) of BIA 28-6156. Topline data from this Phase 2 study is expected to be released in mid-2026."

P2 data • Trial status • CNS Disorders • Parkinson's Disease

ACTIVATE: Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD (clinicaltrials.gov) - P2 | N=237 | Active, not recruiting | Sponsor: Bial R&D Investments, S.A. | Recruiting ➔ Active, not recruiting

Enrollment closed • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

A Randomized, Double-Blinded, Placebo-Controlled QTc Study to Evaluate BIA 28­6156 Effect On Cardiac Repolarization (EAN 2024) - "A single dose of 60 mg or 150 mg BIA 28-6156, 400 mg moxifloxacin or placebo was administered in fed state (Table 1). BIA-28-6156 doses were well tolerated, with a favorable safety profile. These results showed no clinically relevant effects on ECG parameters, constituting a negative thorough QT/QTc study."

Clinical • CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

ACTIVATE: Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD (clinicaltrials.gov) - P2 | N=237 | Recruiting | Sponsor: Bial R&D Investments, S.A. | Trial completion date: Mar 2026 ➔ Jul 2026 | Trial primary completion date: Dec 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • CNS Disorders • Movement Disorders • Parkinson's Disease • LRRK2

A structural perspective on the interaction between glucocerebrosidase and the positive allosteric modulator BIA 28-6156 (Neuroscience 2023) - "This residue is located in an unfolded loop of GCase structure that undergoes a conformational change and is stabilized by BIA 28-6156. A model for GCase with BIA 28-6156 in complex with Sap C is reported suggesting a role played by BIA 28-6156 in the interaction between both proteins and provides insights on the mechanism underling the observed positive allosteric modulation of GCase."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Parkinson's Disease

Design of a time-to-event study in GBA Parkinson’s Disease patients: Efficacy and safety of BIA 28- 6156, an allosteric activator of beta-glucocerobridase (GCase) (MDS Congress 2023) - "This time-to-event study will evaluate the efficacy and safety of a once-daily GCase activator, BIA 28-6156, as a disease-modifying therapy for GBA-PD patients."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Parkinson's Disease

Integrated safety analysis of BIA-28-6156 phase 1 clinical trials (a novel allosteric activator of beta- glucocerebrosidase) (MDS Congress 2023) - "BIA-28-6156 was well-tolerated and presented a favorable safety profile in healthy subjects and in GBA-PD patients. No relevant safety concerns were identified in completed phase I clinical studies."

Clinical • P1 data • CNS Disorders • Parkinson's Disease • GBA

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 (PRNewswire) - "BIAL...announced the dosing of the first patient in its Phase 2 clinical trial...to evaluate the efficacy, safety, and tolerability of BIA 28-6156....The ACTIVATE study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled study 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. This is a time to event study to assess the delay of meaningful clinical progression as assessed by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III up to 78 weeks of double-blind treatment period. The ACTIVATE study is currently screening patients across sites in North America and planned to start in Q3.2023 in EU."

Trial status • CNS Disorders • Parkinson's Disease

A Phase 1B Trial in GBA1-Associated Parkinson's Disease of BIA-28-6156, a Glucocerebrosidase Activator. (PubMed, Mov Disord) - "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."

Clinical • Journal • P1 data • CNS Disorders • Movement Disorders • Parkinson's Disease

Dysregulation of β-Glucocerebrosidase-1 (GBA1) signalling in immune cells drives inflammasome activation in Parkinson’s disease (Neuroscience 2022) - "Crucially, using the small molecule GCase activator LTI-291 (BIA 28-6156), we found that pharmacological activation of GCase could effectively suppress inflammasome activation markers triggered by synuclein aggregates, demonstrating a novel role for lysosomal GCase signalling in regulating inflammasome activation in the CNS...Together, our studies provide compelling evidence for lysosomal GCase signalling in immune cells as a novel negative regulator of NLRP3 inflammasome activation in PD. Pharmacological activation of GCase in the CNS thus provides a new therapeutic avenue by which to ameliorate chronic NLRP3 activation in PD and other synucleinopathies."

CNS Disorders • Parkinson's Disease • NLRP3

A Novel Role for Glucocerebrosidase 1 (GBA1) in Parkinson's Disease. (PubMed, FASEB J) - "After overnight serum cells was primed with 200 ng/mL of ultrapure LPS for 3 hr followed by treatment with either 40 µM of LTI-291 or 200 µM of Condruitol β-epoxide (CBE) for an hour...Overall, these findings identify the potential role of NLRP3 inflammasome activation in driving GCase dysfunction, which could contribute to PD pathogenesis. Furthermore, we demonstrated that pharmacological augmentation of GCase activity was protective, reducing NLRP3 inflammasome activation in vitro and dopaminergic neuronal loss in vivo."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • IL1B • NLRP3

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. (PubMed, Br J Clin Pharmacol) - "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."

Clinical • Journal • CNS Disorders • Movement Disorders • Parkinson's Disease • GBA

BIAL Goes Global With New US Research Center and Acquisition of Promising Parkinson’s Disease Programs (Businesswire) - "BIAL...announced today that it has established a new affiliate in the United States of America, BIAL Biotech Investments Inc. (BIAL Biotech)....BIAL announced that it has acquired worldwide rights of LTI-291 and all the Parkinson’s disease research programs of Lysosomal Therapeutics Inc. (LTI) and taken on the entire R&D team....'It has successfully completed a Phase I trial program and should be ready to start Phase II studies in 2021.'"

Licensing / partnership • New P2 trial • CNS Disorders • Parkinson's Disease

Parkinson's therapies seek to stem progression (Alzforum) - "Biotech company Lysosomal Therapeutics in Cambridge, Massachusetts, developed a small-molecule activator of glucocerebrosidase, LTI-291, that unclogged the recycling pathway and appeared to benefit brain function in Phase 1b....In Phase 1 testing, about 1 percent of plasma LTI-291 entered the brain, achieving a concentration of 1 μM or better, based on the amount of free drug in CSF....In treated patients, the researchers measured a transient surge in glycosphingolipids (GSLs) downstream of ceramide, indicating an accelerating recycling rate. The surge subsided as lipid recycling stabilized, presumably at a higher level."

P1 data • CNS Disorders • Parkinson's Disease

"Data presented at @adpdnet shows a small-molecule activator of #GBA LTI-291 appears to benefit brain function by restoring lipid recycling in Phase 1b trials & TLR2 antagonist targeting #autophagy & #inflammation goes to Phase 1 @Neuropore_news. Good news for #Parkinsons & #ALS!" (@B_A_Benitez)

P1 data • CNS Disorders • Gene Therapies • Genetic Disorders • Immunology • Movement Disorders • Parkinson's Disease

[VIRTUAL] A 28 DAY DOSING TRIAL OF THE GLUCOCEREBROSIDASE ALLOSTERIC ACTIVATOR LTI-291 IN GBA-PD (AAT-ADPD 2020) - "The PK and safety profiles justify continued development. A one-year study in GBA-PD is being planned."

CNS Disorders • GBA

A Dose Ranging, Placebo-Controlled, 28-Day, Safety and Biomarker Phase 2a Study in GBA-PD Patients with the Selective GCase Activator, LTI-291 (MDS Congress 2019) - "LTI-291 was safe and well tolerated over 28 days of dosing in GBA-PD patients. Significant changes in PBMC GSLs were observed, consistent with the drug having its intended biologic effect on GCase. The GSL effects were larger in the GBA-PD patients carrying GD mutations versus mild mutations."

Biomarker • Clinical • Late-breaking abstract • P2a data