BHV-8000, a Selective Brain-penetrant TYK2/JAK1 Inhibitor in Development for Neuroinflammatory and Neurodegenerative Diseases, Demonstrates Efficacy in an Alpha-Synuclein Overexpressing Parkinson’s Disease Mouse Model
Chris Liang1, Wei Tang1, Bavani Shankar2, Bruce Car2, Irfan Qureshi2, Vlad Coric2, Lindsey Lair2
1Highlightll Pharmaceutical, 2Biohaven Pharmaceuticals
Objective:
To assess the effects of an investigational TYK2/JAK1 inhibitor on behavioral and histopathologic outcomes in an α-Syn overexpressing Parkinson’s disease (PD) mouse model
Background:

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 disease-modifying therapy in PD.

 

Design/Methods:
An α-Syn overexpressing mouse model was established by stereotactic unilateral injection of AAV-hm-α-Syn into the substantia nigra of 8-week-old C57BL/6J male mice. BHV-8000 was administered twice daily by oral gavage for 39 consecutive days at 10 and 30 mg/kg/day starting on Day 3 post-AAV-hm-α-Syn injection. Behavioral testing, immunostaining of tyrosine hydroxylase (TH+) neurons and allograft inflammatory factor 1 (Iba1+) microglia, and cytokines were assessed to evaluate the efficacy and neuroprotective effects of BHV-8000. 
Results:

Administration of BHV-8000 at 10 and 30 mg/kg increased the movement distance of model animals in open-field by 36.8% and 61.4%, the time on rotarod by 14.8% and 64.4%, and the maximal force in grip strength test by 48.5% and 47.5%, respectively. Additionally, BHV-8000 administration mitigated microglial activation determined by reductions of Iba1+ microglia, and promoted neuronal survival indicated by increased counts of TH+ neurons in parallel with reduced IL-6 expression.

Conclusions:

BHV-8000 administration reduced abnormal locomotor behavior deficits, inhibited inflammatory microglial activation, and protected against neurodegeneration in α-Syn overexpressing mice. These results support the potential of JAK1/TYK2 inhibition with BHV-8000 as a novel, disease modifying approach to the treatment of PD and other neuroinflammatory and neurodegenerative diseases.

10.1212/WNL.0000000000208701
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