To assess the safety, tolerability, pharmacokinetics and pharmacodynamics of an investigational TYK2/JAK1 inhibitor in healthy adults.

BHV-8000 is a novel, brain-penetrant, oral small molecule highly selective against the TYK2 and JAK1 enzymes within the JAK-STAT pathway, avoiding the safety liabilities of JAK2/3 inhibition. TYK2 and JAK1 signaling is essential to the mixed inflammatory response driving progression of many neuroinflammatory conditions. BHV-8000 is being explored as a disease-modifying therapy in PD, MS, and AD, and as a preventative strategy against ARIA.

BHV8000-101 is a Phase 1 single- and multiple-ascending dose (SAD/MAD) study that explored BHV-8000 between 6 and 30mg for ≤14 days. BHV8000-102 is a Phase 1 study in which BHV-8000 (20mg) was administered daily for 7 days. Across all cohorts, 8 participants were randomized 3:1 to receive blinded BHV-8000 (extended-release formulation) or placebo. Inflammatory biomarkers were measured in the -101 MAD phase and cerebrospinal fluid (CSF)-to-plasma ratio was estimated in the -102 study.

BHV-8000 geometric mean t1/2 ranged from 11-14 hours. Accumulation at steady state for AUC and Cmax was ~1.7-fold. Mean (CV%) CSF-to-plasma ratio at 6- and 24-hours post-dose was 0.43 (10.1) and 0.50 (13.3), respectively.  

Overall, comparable rates of adverse events (AEs) occurred between participants receiving BHV-8000 and placebo (~20%). All AEs were mild in intensity except one (moderate headache). There were no serious AEs. In the MAD phase, dose-associated lowering of platelets (limited to CTCAE Grade 1) was observed, consistent with JAK1 class effects. There were no adverse trends across other laboratory parameters. Reductions in inflammatory biomarkers (IP-10, hsCRP, and IFN-ß) were numerically greater for BHV-8000 versus placebo.

In healthy adults, BHV-8000 was generally safe and well-tolerated, while demonstrating anti-inflammatory effects and a favorable PK profile in the periphery and CNS. These results support continued development of BHV-8000 for neurodegenerative conditions, including PD, MS, AD, and ARIA.