Biohaven Ltd. has initiated a pivotal Phase II/III clinical trial of BHV-8000, a novel brain-penetrant TYK2/JAK1 inhibitor, for the treatment of early Parkinson's disease. The global, randomized, double-blind, placebo-controlled study represents a significant milestone in addressing the critical unmet need for disease-modifying therapies in Parkinson's disease, which currently affects more than 10 million people worldwide.
Trial Design and Scope
The Phase II/III study will evaluate the safety and efficacy of BHV-8000 at two dose levels (10mg and 20mg) compared to placebo in 550 patients with early Parkinson's disease. The trial will be conducted across approximately 185 sites in 13 countries, including the United States, Canada, and 11 European nations.
The study features an innovative design with a time-to-event primary endpoint analysis based on significant changes in the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II, which is recognized by the US Food and Drug Administration (FDA) to support registration. Additionally, the trial incorporates first-in-clinic Parkinson's disease composite scales (PARCOMS), designed to enhance sensitivity in detecting meaningful functional changes in early Parkinson's disease patients.
Mechanism and Rationale
BHV-8000 is a first-in-clinic, orally-administered, brain-penetrant, and highly selective inhibitor of tyrosine kinase 2 (TYK2) and Janus Kinase 1 (JAK1). The drug targets neuroinflammation and immune dysregulation that drives disease progression in Parkinson's disease.
"Collectively, genetic, epidemiological, preclinical, and emerging clinical data demonstrate the key role immune dysregulation plays in PD pathophysiology," stated Pete Ackerman, M.D., Senior Vice President of Clinical Development at Biohaven. "As a brain-penetrant, selective inhibitor of TYK2 and JAK1, BHV-8000 has the potential to modulate critical inflammatory pathways, in the periphery and in the CNS, that results in neuronal loss and functional decline in people living with PD."
Preclinical and Phase I Results
In the Phase I clinical program, BHV-8000 demonstrated a favorable safety profile with no reported serious adverse events and no clinically meaningful adverse trends in laboratory values. The drug showed target engagement with significant reductions in TYK2- and JAK1-related inflammatory biomarkers, including IP-10, hsCRP, and IFN-gamma, relative to placebo.
Pharmacokinetic studies revealed robust brain penetration, with approximately 50% plasma exposure available as unbound drug in the central nervous system, providing sustained coverage above TYK2 and JAK1 EC50s at clinical doses.
Clinical Significance and Unmet Need
The trial addresses a substantial unmet medical need in Parkinson's disease treatment. "There are currently no available disease-modifying therapies to treat Parkinson's disease – a devastating and relentlessly progressive neurological disorder whose global prevalence is expected to double by 2050," Ackerman noted.
Stuart Isaacson, MD, Director and Founder of the Parkinson's Disease and Movement Disorders Center of Boca Raton and Principal Investigator in the trial, emphasized the potential of the approach: "Targeted, small-molecule therapies that inhibit TYK2 and other JAKs have demonstrated robust efficacy in autoimmune, dermatologic, and gastrointestinal disorders. A brain penetrant inhibitor of TYK2/JAK1, such as BHV-8000, has the potential to leverage these validated immune targets to treat brain disorders."
Broader Development Program
Beyond Parkinson's disease, BHV-8000 is being investigated for other neuroinflammatory conditions including Alzheimer's disease, multiple sclerosis, and the prevention of amyloid-related imaging abnormalities (ARIA) in individuals starting anti-amyloid treatments.
The selectivity of BHV-8000 for TYK2 and JAK1 is designed to avoid the safety liabilities associated with JAK2 and JAK3 inhibition, potentially optimizing the therapeutic window while reducing the risk of severe toxicities.
