Clin Gastroenterol Hepatol. 2023 Sep;21(10):2616-2628.e7.doi: 10.1016/j.cgh.2022.12.029. Epub 2023 Jan 6.

William J Sandborn ¹, Silvio Danese ², Jaroslaw Leszczyszyn ³, Jacek Romatowski ⁴, Engin Altintas ⁵, Elena Peeva ⁶, Mina Hassan-Zahraee ⁷, Michael S Vincent ⁷, Padmalatha S Reddy ⁷, Christopher Banfield ⁷, Mikhail Salganik ⁷, Anindita Banerjee ⁷, Jeremy D Gale ⁷, Kenneth E Hung ⁷

Author information

¹University of California San Diego, La Jolla, California. Electronic address: wsandborn@health.ucsd.edu.

²Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy.

³Melita Medical, Gastroenterology, Wroclaw, Poland.

⁴Provincial Complex Hospital, Gastroenterology, Bialystok, Poland.

⁵Mersin University, Gastroenterology, Mersin, Turkey.

⁶Pfizer Global Research and Development, Cambridge, Massachusetts.

⁷Pfizer Inc, Early Clinical Development, Cambridge, Massachusetts.

Abstract

Background & aims: The efficacy and safety of ritlecitinib (oral JAK3/TEC family kinase inhibitor) and brepocitinib (oral TYK2/JAK1 inhibitor) as induction therapy were assessed in patients with active, moderate-to-severe ulcerative colitis.

Methods: This phase 2b, parallel-arm, double-blind umbrella study randomized patients with moderate-to-severe ulcerative colitis to receive 8-week induction therapy with ritlecitinib (20, 70, 200 mg), brepocitinib (10, 30, 60 mg), or placebo once daily. The primary endpoint was total Mayo Score (TMS) at week 8.

Results: Of 319 randomized patients, 317 received ritlecitinib (n = 150), brepocitinib (n = 142), or placebo (n = 25). The placebo-adjusted mean TMSs (90% confidence interval) at week 8 were -2.0 (-3.2 to -0.9), -3.9 (-5.0 to -2.7), and -4.6 (-5.8 to -3.5) for ritlecitinib 20, 70, and 200 mg, respectively (P = .003, P < .001, P < .001), and -1.8 (-2.9 to -0.7), -2.3 (-3.4 to -1.1), and -3.2 (-4.3 to -2.1) for brepocitinib 10, 30, and 60 mg, respectively (P = .009, P = .001, P < .001). Estimates (90% confidence interval) for placebo-adjusted proportions of patients with modified clinical remission at week 8 were 13.7% (0.5%-24.2%), 32.7% (20.2%-45.3%), and 36.0% (23.6%-48.6%) for ritlecitinib 20, 70, and 200 mg, respectively, and 14.6% (1.9%-25.7%), 25.5% (11.0%-38.1%), and 25.5% (11.0%-38.1%) for brepocitinib 10, 30, and 60 mg, respectively. Adverse events were mostly mild, and there were no serious cases of herpes zoster infection. Infections were observed with brepocitinib (16.9% [12.5%-23.7%]), ritlecitinib (8.7% [5.2%-13.4%]), and placebo (4.0% [0.2%-17.6%]). One death due to myocardial infarction (ritlecitinib) and 1 thromboembolic event (brepocitinib) occurred; both were considered unrelated to study drug.

Conclusions: Ritlecitinib and brepocitinib induction therapies were more effective than placebo for the treatment of moderate-to-severe active ulcerative colitis, with an acceptable short-term safety profile.

Clinicaltrials: gov number: NCT02958865.