Efficacy and safety of a potent and highly selective oral tyrosine kinase 2 inhibitor, BMS-986165, in patients with moderate-to-severe plaque psoriasis: a phase II, randomized, placebo-controlled trial

BACKGROUND/PURPOSE: BMS-986165, a potent and highly selective oral tyrosine kinase 2 inhibitor, inhibits signal transducer and activator of transcription (STAT)-dependent signalling pathways of interleukin-23 and type I interferons involved in the pathology of immune-mediated diseases. A 12-week (wk), placebo (pbo)-controlled, Phase II, dose-ranging study (ClinicalTrials.gov, NCT02931838) investigated the efficacy and safety of BMS-986165 in patients (pts) with moderate-to-severe plaque psoriasis (PsO). METHODS: Adults with PsO for ≥6 months and moderate-to-severe disease (body surface area [BSA] ≥10%, Psoriasis Area and Severity Index [PASI] ≥12, static Physician Global Assessment [sPGA] ≥3) were randomized to pbo or BMS-986165 (3 mg every other day [QOD], 3 mg every day [QD], 3 mg twice daily [BID], 6 mg BID, 12 mg QD). Primary endpoint was PASI 75 at Wk 12. Pain was assessed by ACR pain visual analog scale (VAS). RESULTS: For the 267 pts randomized and treated, baseline characteristics (mean age 45 years, male 73%, median disease duration 15 years, prior biologic experience 43%, mean BSA 23%, mean PASI score 18.0) were generally balanced among treatment arms. At Wk 12, a significantly greater proportion of pts achieved PASI 75, PASI 90 and sPGA 0/1 at doses ≥3 mg QD vs pbo (p<0.05), with dose response observed across all efficacy measures (Table 1). Efficacy was observed in both biologic-naïve and biologic-experienced pts, with rapid onset of response by Day 15. Pain VAS score showed a dose-dependent decrease, with the three top dose groups reaching ~70% decrease at Wk 12 (Figure). None of the five serious AEs were considered drug-related: two events in one pbo pt (hemorrhagic anemia, hemorrhoidal hemorrhage) and three events with BMS-986165 (3 mg QOD: gastroenteritis rotavirus; 3 mg QD: eye injury; 3 mg BID: dizziness). AEs were reported in 51% (pbo), 59% (3 mg QOD), 55% (3 mg QD), 64% (3 mg BID), 80% (6 mg BID) and 77% (12 mg QD) of pts. The most common AEs reported by pts across treatment arms (ranges) included nasopharyngitis (2–16%), headache (4–9%), and diarrhea (2–9%). AEs were generally mild to moderate and resulted in drug discontinuation in 4% of pbo pts and 2–7% of pts across the active doses. There were no significant changes in liver enzymes, blood counts or lipid levels. CONCLUSION: In pts with moderate-to-severe PsO, BMS-986165 demonstrated statistically greater efficacy on skin measures vs pbo at doses ≥3 mg QD and a dose-dependent decrease in pain. BMS-986165 was generally well tolerated. Further evaluation in PsO and psoriatic arthritis is warranted.