Start low with brepocitinib and ritlecitinib in UC

Therapy with the oral, investigative agents brepocitinib and ritlecitinib improved clinical remission and modified clinical remission and endoscopic results in patients with moderate-to-severe ulcerative colitis (UC) over 32 weeks in the VIBRATO study. Interestingly, changes were more pronounced in patients that were treated with low doses in the induction phase of the trial.

Both the JAK3/TEC and the JAK1/TYK2 pathways are implicated in the pathogenesis of UC through regulation of pro-inflammatory cytokine signalling and CD8+ T-cell cytotoxicity. This was the rationale to assess the efficacy and safety of the JAK3/TEC inhibitor ritlecitinib and the JAK1/TYK2 inhibitor brepocitinib in patients with UC in the phase 2b VIBRATO study (NCT02958865). In this trial, both small molecules were more effective during the 8-week induction period compared with placebo, with an acceptable safety profile. Dr Kenneth Hung (Pfizer, MA, USA) pointed out that, in the induction phase, modified remission at week 8 was high, as 38% and 25.5% of patients achieved endoscopic improvement with ritlecitinib and brepocitinib respectively [1]. “Next we wanted to evaluate efficacy and safety in a 24-week period,” he explained.

In the 8-week induction phase, both agents were given in 3 doses (20, 70, or 200 mg ritlecitinib once daily or 10, 30, or 60 mg brepocitinib once daily) and compared with placebo once daily. In the chronic dosing therapy phase, all participants continued in their respective treatment cohorts to receive oral ritlecitinib 50 mg or brepocitinib 30 mg once daily for 24 weeks. At week 32, efficacy was assessed with the total Mayo score (primary endpoint), clinical remission, modified remission, and endoscopic improvement. A total of 279 participants received treatment in the chronic period. Baseline characteristics were generally similar across treatment groups. About 40% to 65% of patients had already received biologics.

“We saw great improvement from week 8 to 32 for those with lower induction dosing. However, for those cohorts with higher induction doses, we saw that the improvement was less dramatic from week 8 to week 32,” Dr Hung explained the changes in the total Mayo score (see Figure).

Figure: Improvements in total Mayo Score after 32 weeks are more pronounced in patients treated with low induction doses [1]



Similar patterns were seen for clinical remission (defined as total Mayo Score ≤2; no individual subscore >1; rectal bleeding subscore=0) and modified remission (modified Mayo Score [total Mayo Score without Physician Global Assessment]: stool frequency subscore ≤1; rectal bleeding subscore=0; endoscopic subscore ≤1). Rates of clinical remission and modified clinical remission generally continued to improve in groups receiving a lower induction dose. “These improvements were somewhat blunted in the higher induction dose groups,” Dr Hung explained.

Therapy with both agents also led to endoscopic improvements (Mayo endoscopic subscore ≤1). Changes generally continued to improve from week 8 to 32 in groups receiving a lower induction dose. Again, this improvement was generally more modest from week 8 through 32 in higher induction dose groups.

Dr Hung pointed out that both drugs were relatively safe and well tolerated across the groups. The most commonly reported adverse events included chronic urticaria, nasopharyngitis, arthralgia, and pyrexia. Moreover, there were no clinically significant observations for laboratory parameters. No thromboembolic events or malignancies were reported during the chronic period. However, there was a herpes signal: 2 participants in the chronic period suffered from herpes simplex (1 in each arm), another 4 participants had herpes zoster in the chronic dosing period (3 in the ritlecitinib and 1 in the brepocitinib arm). Only 1 of these events was moderate, all others were mild and did not lead to treatment discontinuation.

These positive study results support the further development of ritlecitinib and brepocitinib in patients with moderate-to-severe UC.

1. Sandborn WJ, et al. Ritlecitinib and brepocitinib in patients with moderately to severely active Ulcerative Colitis: chronic therapy data from the VIBRATO umbrella study. OP090, UEG Week 2022, 8–11 October, Vienna, Austria.

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Posted on 1 December 20228 April 2024