OP09 Oral ritlecitinib and brepocitinib in patients with moderate to severe active Crohn’s Disease: Data from the PIZZICATO umbrella study

Abstract

Abstract Background Oral ritlecitinib (RIT; JAK3/TEC family kinase inhibitor) and brepocitinib (BRE; TYK2/JAK1 inhibitor) are being assessed in a 64-week (wk) phase 2a randomised, double-blind, induction-maintenance, umbrella study (PIZZICATO; NCT02958865) in participants (pts) with moderate-to-severe active Crohn’s disease (CD) with inadequate, loss of response or intolerance of corticosteroids, immunosuppressants or biologics. We report the efficacy and safety results from the 12-wk induction period. Methods Pts 18-75 years old with endoscopic confirmation of active CD with Simple Endoscopic Score for CD (SES-CD) ≥7/≥4 for isolated ileal disease, and average daily liquid/soft stool frequency (SF) ≥2.5 or daily abdominal pain (AP) ≥2.0 were included. Pts were randomised to RIT 200 mg once daily (QD) for 8 wks then 50 mg QD for 4 wks and matching placebo (PBO) in a 2:1 ratio or BRE 60 mg QD for 12 wks and matching PBO in a 2:1 ratio. Pts continued in their respective arms with open-label RIT 50 mg or BRE 30 mg QD for 52 wks. PBO arms were combined for analysis. Pts achieving SES-CD 50 (≥50% reduction in SES-CD from baseline [BL]; primary endpoint Wk 12), Clinical Disease Activity Index (CDAI) remission (CDAI<150) and CDAI-100 response for pts with BL CDAI≥220, clinical response (≥30% reduction from BL in AP or SF; neither worse than BL) and remission (SF≤1.5 and AP≤1; neither worse than BL) were assessed. Safety was also evaluated. Results A total of 244 pts were randomised and received treatment in the induction period with BL mean age of 34.6-36.5 years, median SES-CD 11-14, and prior biologics experience 69-76% across groups. The proportion of pts achieving SES-CD 50 was significantly higher at Wk 12 with RIT 200/50 mg QD and BRE 60 mg vs PBO (change from PBO: RIT 14.3% [90% CI, 4.0, 24.5], BRE 21.4% [10.0, 32.9]; Table). Statistical significance vs PBO was observed for RIT at Wks 8 and 12 and BRE at Wk 12 for CDAI remission, CDAI-100, clinical response and remission by SF or AP. Most treatment emergent adverse events (TEAEs) in both groups were mild or moderate. Herpes infections occurred in 1 pt in each group and serious infections in 1 pt in RIT and 2 in BRE. No deaths or malignancies occurred. No events of thromboembolism or MACE occurred for RIT. One pt on BRE had a TEAE of pulmonary embolism. There were no clinically significant observations for labs. Conclusion Both RIT and BRE met the primary endpoint in the induction period with significant clinical improvement vs PBO in pts with active CD. Other meaningful efficacy endpoints had similar results to the primary endpoint for both therapies. RIT and BRE had an acceptable safety and tolerability profile that was consistent with previous studies.