DOP076 A phase 2B, multicenter, randomized, placebo-controlled dose-ranging trial of peficitinab, an oral JAK inhibitor, in patients with moderately to severely active ulcerative colitis

Background: Janus kinases (JAK) are intracellular signaling molecules central to immune responses in IBD. We studied efficacy and safety of peficitinib, an oral JAK inhibitor, in moderate-severe UC. Methods: Eligible patients had a Mayo score of 6–12, including a centrally read endoscopy subscore ≥2, and inadequate response to, or failure to tolerate corticosteroids, 6-MP/AZA, or TNF antagonists. Patients were randomized at wk0 to PBO (n=43), peficitinib 25mg qd, 75mg qd, 150mg qd, or 75mg bid (n=44 per group). Primary endpoint was change from baseline Mayo score at wk8; Multiple Comparison Procedures method was used to analyze dose response for qd regimens. Secondary endpoints (using central endoscopic subscore) were clinical response and remission and mucosal healing at wk8. Safety was evaluated through wk8. Results: 219 patients were randomized. Baseline characteristics and concomitant medications were generally similar among treatment groups. Primary endpoint of dose response for qd regimens was not met (adjusted p-values for candidate dose response curves were >0.05). Change from baseline in Mayo score at wk 8 was numerically higher for peficitinib doses ≥75mg qd vs PBO (−2.3 [25mg qd], −3.1 [75mg qd], −2.8 [150mg qd], vs −2.4 [PBO]); none reached statistical significance. Trends for efficacy were observed for doses ≥75mg qd based on proportion of patients with clinical response (34.1% [25mgqd], 54.5% [75mg qd], 54.5% [150mg qd], 54.5% [75mg bid] vs 39.5% [PBO]), clinical remission (15.9% [25mg qd], 15.9% [75mg qd], 27.3% [150mg qd],15.9% [75mg bid] vs 7.0% [PBO]) and mucosal healing (20.5% [25mg qd], 29.5% [75mg qd], 45.5% [150mg qd], 36.4% [75mg bid], vs 18.6% [PBO]). AE rates were higher across peficitinib groups vs PBO through wk8 (45.5% [combined] vs 34.9% [PBO]) mainly occurring in ≥75mg qd dose groups. Most common AEs were UC (5.7% [combined] vs 9.3% [PBO]), CPK increase (4.0% [combined] vs 0.0% [PBO]). Rates of discontinuation due to AE were similar between combined peficitinib groups and PBO (8.0% and 7.0%, respectively). SAEs were uncommon (3.4% [combined] vs 4.7% [PBO]). Incidences of infection were similar (12.5% [combined] vs 14.0% [PBO]). Serious infections were rare. There were modest increases in fasting lipids and CPK for doses of ≥75mg qd. Conclusions: Peficitinib did not demonstrate dose response based on mean change from baseline Mayo score at wk8 in patients with moderate-severe UC. Trends for greater proportions of patients achieving clinical response, clinical remission, and mucosal healing were observed at doses ≥75mg qd. The safety profile of peficitinib through wk8 was generally consistent with the known profile of JAK inhibitors.

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