Safety, tolerability, pharmacokinetics and pharmacodynamics of VTP-43742, a RORγt inhibitor, in normal healthy volunteers

VTP-43742 is an orally active RORγt inhibitor being developed for the treatment of autoimmune disorders, including psoriasis, through inhibition of IL-17A production and down regulation of the IL-23 receptor. Safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of VTP-43742 were assessed in two, randomized, double-blind, placebo-controlled studies in which VTP-43742 was administered to normal healthy volunteers. The first study was a single ascending dose (SAD) study (N = 53) in which participants were randomized to a one-time administration of VTP-43742 (7 dose levels, 30–2000 mg) or placebo. The second study (NCT02555709) was a multiple ascending dose (MAD) study in which participants (N = 40) received VTP-43742 (5 dose levels, 100–1400 mg/d) or placebo once daily for 10 days. VTP-43742 was shown to be safe and generally well tolerated at all dose levels in both studies. No serious adverse events were reported, and all study subjects completed dosing. No clinically significant clinical chemistry, hematologic or ECG abnormalities were observed, and dose proportionality was demonstrated across all dose levels. In the SAD study, VTP-43742 had a terminal plasma half-life of ~30 hours. In an ex vivo whole blood assay (WBA) of IL-17A secretion, VTP-43742 suppressed RORγt dependent secretion of IL-17A in a dose-responsive manner; u003e90% inhibition was observed at the higher doses which was mostly maintained over 24 hours. In the MAD study, those receiving VTP-43742 showed u003e90% inhibition of RORγt dependent IL-17A secretion in the WBA for a full 24hrs in all but the lowest dose cohort. These data support the further development of VTP-43742 for the treatment of autoimmune disorders.