43073 Pharmacokinetics, Safety and Pharmacodynamics of VTX2735, A Potent and Selective NLRP3 Inhibitor, In Healthy Adult Volunteers

Background: VTX2735 is a novel, selective inhibitor of the NLRP3 inflammasome, that when activated triggers release of the proinflammatory cytokines IL1< and IL-18 leading to chronic inflammation. A large-scale serum proteome analysis identified upregulation of TNFa and IL-1< in hidradenitis suppurativa (HS) relative to healthy volunteers (HV) and psoriasis (Navrazhina, 2022). Furthermore, lipocalin 2, expressed in dermal draining tunnels in HS (Navrazhina, 2021), induces NLRP3 inflammasome activation (Song, 2017), suggesting therapeutic potential of NLRP3 inhibition. The VTX2735 Phase 1 study included single and multiple ascending doses (SAD and MAD) to evaluate safety, tolerability, and pharmacokinetics of VTX2735. Fifty-nine HV received up to 200mg as a single oral dose or daily dose for 10 days. VTX2735 was well tolerated at all doses, all drug related adverse events (AEs) were mild, with no laboratory abnormalities or dose related trend in the frequency of AEs; a maximum tolerated dose was not reached. Drug exposures in SAD and MAD cohorts were proportionate to dose. Ex vivo IL1< release in response to LPS+ATP stimulation in HV whole blood samples correlated with VTX2735 exposures (>90% inhibition of IL-1< release for >8 hours at 200mg, returning to baseline at 24 hours), demonstrating dose and exposure related inhibition of IL-1< release downstream of NLRP3. VTX2735 also reduced high sensitivity CRP levels 50% from baseline. These data support further development of VTX2735.