Promising data for JAK inhibitors in Crohn’s disease from phase 2 trial

Both ritlecitinib and brepocitinib were associated with improved efficacy outcomes compared with placebo in patients with moderate-to-severe Crohn’s disease (CD). The JAK inhibitors were generally safe and well tolerated in the phase 2 PIZZICATO trial.

“JAK and TEC family pathways are implicated in the pathogenesis of CD through the regulation of pro-inflammatory cytokine signalling and CD8-positive T-cell cytotoxicity,” explained Dr Séverine Vermeire (University Hospitals Leuven, Belgium) [1].

The double-blind, phase 2 PIZZICATO trial (NCT03395184) tested the JAK3/TEC family inhibitor ritlecitinib and the TYK2/JAK1 inhibitor brepocitinib in patients with moderate-to-severe CD (n=244). PIZZICATO used an umbrella trial design, which allows more than one treatment to be tested in the same trial protocol. Approximately half of the participants were randomised 2:1 to ritlecitinib or a placebo and the other half was randomised 2:1 to brepocitinib or a placebo. After 12 weeks, all participants received a maintenance dose of either ritlecitinib or brepocitinib up to week 52. The primary outcome measure was the Simple Endoscopic Score for Crohn's Disease (SES-CD) 50 at week 12.

At week 12, treatment with brepocitinib (33.8%) and treatment with ritlecitinib (27.2%) resulted in higher SES-CD 50 rates than treatment with placebo (12.8%; P=0.0012 and P=0.012, respectively). Similar results were observed for Clinical Disease Activity Index (CDAI) 100 response rates, CDAI remission (i.e. CDAI<150) rates, and outcomes related to abdominal pain or stool frequency (see Figure).

Figure: Clinical response and remission in PIZZICATO [1]



Clinical response: ≥30% reduction from baseline in abdominal pain or stool frequency, neither worse than baseline; Clinical remission: stool frequency ≤1.5 and abdominal pain ≤1, neither worse than baseline.

“Both ritlecitinib and brepocitinib were generally well tolerated and their safety profiles were consistent with previous publications on these agents,” said Dr Vermeire. Treatment-emergent adverse events that occurred in ≥5% of the participants in the brepocitinib group were headache, abdominal pain, acne, and lymphopenia. In the ritlecitinib arm, only COVID-19 was reported in ≥5% of the participants.

“Ritlecitinib and brepocitinib resulted in a statistically significant improvement in SES-CD 50 and met the primary endpoint in the 12-week induction period, compared with placebo, in participants with CD,” concluded Dr Vermeire.

1. Vermeire S, et al. Oral ritlecitinib and brepocitinib in patients with moderate to severe active Crohn’s disease: data from the PIZZICATO umbrella study. OP09, 19^th Congress of ECCO, 21–24 February 2024, Stockholm, Sweden.

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Posted on 18 April, 202418 April, 2024