Biohaven Ltd. has announced the initiation of first-in-human dosing for its oral, blood-brain-barrier-penetrant pyruvate kinase M2 (PKM2) modulator, BHV-8100. This novel therapy is designed to treat systemic and central nervous system disorders involving metabolic and immune dysfunction.

BHV-8100 functions by modulating PKM2, a key rate-limiting enzyme in the glycolytic pathway. In cells and tissues with high energy demands, the accumulation of PKM2 in a less active dimeric form can lead to bioenergetic insufficiency and drive disease pathogenesis. As an allosteric modulator, BHV-8100 converts PKM2 into a more active tetrameric form, thereby restoring energy homeostasis and promoting health.

Preclinical data indicate that BHV-8100 can cross the blood-brain barrier. It tripled glucose utilization in a human whole-brain model and demonstrated preferential metabolic rescue in brains from Alzheimer's disease donors. Furthermore, the drug showed robust beneficial effects in various preclinical models of Alzheimer's disease and multiple sclerosis: restoring metabolic deficits, reducing inflammation and neurodegeneration, and enhancing remyelination.

Dr. Bruce Car, Chief Scientific Officer at Biohaven, stated, "BHV-8100 represents a potentially groundbreaking class of drugs with therapeutic potential for systemic and brain disorders involving metabolic and immune dysfunction. PKM2 sits at the interface of metabolism and immune function. By modulating PKM2, we aim to correct the core energy deficits known to contribute to a range of inflammatory and neurological conditions, including atopic dermatitis, Alzheimer's disease, and retinitis pigmentosa."

Preliminary data from the ongoing first-in-human study show that BHV-8100's pharmacokinetic profile supports once-daily oral dosing and is well-tolerated at projected therapeutic exposure levels. Most adverse events were mild and self-limiting.

PKM2 modulation offers a potential new paradigm for treating a large number of underserved, high-value indications in neurology, ophthalmology, and immunology. Alzheimer's disease alone affects over 6.5 million people in the United States, with a global prevalence exceeding 55 million. The market for retinal diseases is projected to surpass $15 billion annually by 2030, where oral, disease-modifying therapies represent the most urgent unmet need. Biohaven believes BHV-8100 can address this gap.

Dr. Bharat Awsare, Executive Medical Director of Clinical Development at Biohaven, noted, "The first-in-human dosing of BHV-8100 initiates a potential new paradigm for a broad range of systemic, neurodegenerative, neuroinflammatory, retinal, and age-related diseases."