Once-daily oral ritlecitinib or brepocitinib versus placebo in patients with moderate-to-severely active Crohn's disease (PIZZICATO): an international, randomised, phase 2a trial.

Background: Crohn's disease (CD) has a high unmet need for treatment. Ritlecitinib (Janus Kinase [JAK]3/tyrosine kinase expressed in hepatocellular carcinoma [TEC] family kinase inhibitor) or brepocitinib (tyrosine kinase 2 (TYK2)/JAK1 inhibitor) are promising therapeutic targets. We aimed to evaluate efficacy, safety, pharmacokinetics, and pharmacodynamics of ritlecitinib and brepocitinib versus placebo in patients with moderate-to-severely active CD. Methods: PIZZICATO was a multicentre, randomised, placebo-controlled, parallel-group, induction-maintenance, phase 2a study in patients with moderate-to-severely active CD. Eligible patients (18-75 years old) had an established diagnosis (endoscopic and histopathology) of ileal, ileocolonic, or colonic active CD at least 3 months before the study started and had documented treatment failure with at least one conventional CD therapy. This study was double-blind during the 12-week induction phase and was open label for the subsequent 52-week open-label extension (OLE) phase. Study participants were enrolled from 140 sites in 26 countries and were randomly assigned (1:1:1) to receive once-daily oral ritlecitinib (200 mg [8 weeks] followed by 50 mg [4 weeks]) or brepocitinib (60 mg [12 weeks]) or placebo in the induction phase, followed by a reduced dose of 50 mg ritlecitinib or 30 mg brepocitinib during the 52-week OLE phase. The primary efficacy endpoint was the proportion of patients who achieved Simple Endoscopic Score (SES) for CD (SES-CD 50; defined as ≥50% reduction from baseline) at Week 12 (ritlecitinib versus placebo; brepocitinib versus placebo), and was assessed in the full analysis set (FAS; all participants who received at least one dose of the study drug or placebo). The primary endpoint was changed from clinically-meaningful endoscopic improvement (CMEI) by protocol amendment during study execution. The safety profile of ritlecitinib and brepocitinib was assessed as a secondary endpoint during the induction phase and as a primary endpoint during the OLE phase. Safety was assessed in the safety analysis set (SAS; same as FAS). This trial was registered with ClinicalTrials.gov, NCT03395184, and EudraCT, 2017-003359-43. Findings: Between Feb 2, 2018, and Oct 19, 2023, 244 patients (median age: 33.0 [18, 71]) were randomly allocated into study groups (ritlecitinib n = 93; brepocitinib n = 72; placebo n = 79) and included in the FAS and SAS. Of 244 participants dosed in the induction phase, 217 (88.9%) completed the induction phase and entered the OLE phase; 216 were dosed in the OLE phase. Disease activity was generally similar across groups and the majority of participants were tumour necrotizing factor (TNF) inhibitor experienced. For the primary outcome at Week 12, a significantly higher proportion of participants achieved SES-CD 50 with ritlecitinib (difference versus placebo: 14.3% [90% CI 4.0-24.5]; p = 0.012) or brepocitinib (21.4% [10.0-32.9]; p = 0.0012) than did those receiving placebo. Regarding safety, during the induction phase, 146 (59.8%) patients reported 334 treatment-emergent adverse events (TEAEs); for the OLE phase, 169 (78.2%) patients reported 521 TEAEs. Most TEAEs were mild or moderate. Most common being severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test positive (six patients, 6.5%). In the ritlecitinib 200/50 mg group, headache (five patients, 6.9%) in the brepocitinib group, and worsening of underlying CD (eight patients, 10.1%) in the placebo during the induction phase; and worsening of underlying CD in the ritlecitinib 200/50 mg to 50 mg (12 patients, 14.3%) and brepocitinib 60 mg to 30 mg (11 patients, 17.2%) group, and SARS-CoV-2 infection (six patients, 16.7%) in the placebo to ritlecitinib 50 mg group during the OLE phase. No deaths were reported. Interpretation: Ritlecitinib and brepocitinib showed significant improvement in the primary outcome versus placebo for treatment of moderate-to-severely active CD, with acceptable safety profiles. This should be considered as preliminary evidence of efficacy. It is not known how effective these treatments are likely to be in patients with milder disease. Further studies are required for both molecules and to better understand responder and non-responder populations. Funding: Pfizer Inc.