Announcement • Jun 02

Biohaven Initiates First-In-Human Dosing of Oral Pkm2 Modulator Bhv-8100 Targeting Metabolic Restoration and Immunomodulation

Biohaven Ltd. announced the initiation of first-in-human dosing for BHV-8100, its oral, brain-penetrant pyruvate kinase M2 isoform (PKM2) modulator. BHV-8100 is an orally administered, brain-penetrant PKM2 modulator; a novel therapeutic class addressing the bioenergetic and immunometabolic basis of systemic and central nervous system disorders. First-in-human study initiated with dose escalation ongoing; preliminary data in healthy participants demonstrates favorable pharmacokinetics supporting convenient, once-daily dosing and well a tolerated profile at projected therapeutic exposures. BHV-8100 penetrates blood-brain barrier and reverses metabolic dysfunction with 3-fold improvement in glucose utilization in human, whole brain model (Bexorg BrainEx platform, physiologically reactivated brains from human donors); preferential metabolic rescue in Alzheimer's disease donor brains vs controls. BHV-8100 exhibits robust beneficial effects across a spectrum of preclinical models of Alzheimer's, and multiple sclerosis: restores metabolic deficits, reduces inflammation and neurodegeneration, and enhances remyelination. PKM2 modulation offers a potential new paradigm for treating large, underserved, and high-value indications in neurology, ophthalmology, and immunology. PKM2 is the final, rate-limiting enzyme in glycolysis, converting phosphoenolpyruvate to pyruvate, and it serves as a master metabolic regulator in energy-intensive cells and tissues, including the brain, retina, and immune system. The accumulation of the less enzymatically active, dimeric form of PKM2 leads to bioenergetic deficits and drives disease pathogenesis. Conversion to its more active, tetrameric form by an allosteric PKM2 modulator, such as BHV-8100, can restore energy homeostasis and promote health. The brain and retina are two of the most metabolically demanding tissues in the body with a significant reliance on glucose to produce cellular energy as adenosine triphosphate (ATP). When glucose uptake and ATP generation are deficient, as has been documented in multiple neurodegenerative and retinal diseases, including aging, Parkinson's disease, multiple sclerosis, age-related macular degeneration (AMD), and retinitis pigmentosa, neurodegeneration and immune activation result. Compelling evidence from preclinical models employing BHV-8100 and the literature suggest a breadth of disease indications for which BHV-8100 could provide significant benefit. By pharmacologically increasing ATP generation from glycolysis and through fueling the tricarboxylic acid (TCA) cycle, as well as rebalancing glycolytic biosynthetic intermediates, neurons, photoreceptor cells and glial cells become resilient and are better able to sustain cell function, plasticity, and survival. BHV-8100 is an oral, potent, selective, small-molecule PKM2 allosteric modulator designed for once-daily administration. By binding to and stabilizing the active tetrameric form of PKM2, BHV-8100 restores flux through the glycolytic pathway, producing three interconnected therapeutic effects: Rescues metabolic deficits: Increased PKM2 activity drives cytoplasmic ATP production, while further fueling mitochondrial TCA cycle ATP production thereby correcting inadequate ATP levels in neurons, glia and retinal cells. Adequate ATP enables cellular resilience based on restoring energetically expensive processes such as supporting am efficient unfolded protein response (UPR), antioxidant mechanisms, ion channel function, synaptic signaling, and axonal transport which all collectively deteriorate in neurodegeneration. Reduces neuroinflammation: PKM2 modulation to the tetramer form clears glycolytic intermediates, robustly suppressing pro-inflammatory cytokine production (including IL-1ß, TNF-a) and shifting microglia/macrophages toward anti-inflammatory, neuroprotective phenotypes. Th17 lymphocyte specific inhibition is noted in the neuroinflammatory processes associated with allergic encephalomyelitis (EAE).

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Biohaven Begins First Human Trials of Oral BHV-8100 Targeting Metabolic and Immune Disorders

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Biohaven Initiates First-In-Human Dosing of Oral Pkm2 Modulator Bhv-8100 Targeting Metabolic Restoration and Immunomodulation

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