Treatment with a Janus kinase inhibitor or sphingosine-1 phosphate modulator is associated with increased likelihood of clinical and endoscopic remission in patients with ulcerative colitis, and JAK inhibitors are effective for inducing clinical remission in Crohn’s disease, according to data presented at UEG Week 2022.
In a systematic review and meta-analysis, a multinational team of researchers, led by Virginia Solitano, MD, from Humanitas University, in Milan, searched MEDLINE, Embase, the Cochrane Central Registry of Controlled Trials, conference proceedings and trial registries for randomized controlled trials (RCTs) examining the effects of JAK inhibitors and S1P receptor modulators in adults with inflammatory bowel disease (abstract P0483).
They included 33 studies (24 in UC and nine in CD), evaluating nine JAK inhibitors and four S1P receptor modulators (Table 1). The researchers used a random-effects model to pool outcomes, including clinical, endoscopic, histologic and safety data.
| Table 1. Agents Evaluated Across 33 Trials |
| JAK inhibitors |
|---|
| Brepocitinib (Roivant/Pfizer) |
| Deucravacitinib (Sotyktu, BMS) |
| Filgotinib (Eisai/Gilead) |
| Peficitinib (Astellas) |
| Ritlecitinib (Pfizer) |
| SHR0302 (Reistone) |
| Izencitinib (Theravance) |
| Tofacitinib (Xeljanz, Pfizer) |
| Upadacitinib (Rinvoq, AbbVie) |
| S1P receptor modulators |
| Amiselimod (Mitsubishi Tanabe) |
| Etrasimod (Pfizer) |
| KRP203 (Novartis) |
| Ozanimod (Zeposia, Celgene) |
| BMS, Bristol Myers Squibb; JAK, Janus kinase; S1P, sphingosine-1 phosphate. |
Calling the study design interesting, Dana Lukin, MD, PhD, the clinical director of translational research and an associate professor of clinical medicine at Weill Cornell Medicine’s Jill Roberts Center for IBD, in New York City, who was not involved in the research, noted that the study “combines all data for numerous medications within the JAK and S1P classes and attempts to assess class-attributable effects for each disease state.”
Improved Outcomes
Dr. Solitano and her co-investigators found that patients with UC taking a JAK inhibitor were significantly more likely to experience clinical remission and endoscopic remission at eight to 12 weeks relative to those taking placebo (Table 2). Similar trends were seen when comparing the likelihood of induction of clinical and endoscopic response in patients receiving a JAK inhibitor versus placebo. Patients with UC taking S1P modulator therapy also were significantly more likely to achieve clinical and endoscopic remission at eight to 12 weeks.
| Table 2. Induction Phase Outcomes For IBD Advanced Orals Versus Placeboa | ||
| Drug class | Outcomeb | Risk ratio (95% CI) |
|---|---|---|
| Ulcerative colitis | ||
| JAK inhibitor | Clinical remission | 2.95 (1.86-4.66) |
| Endoscopic remission | 4.05 (2.15-7.60) | |
| Clinical response | 1.91 (1.49-2.44) | |
| Endoscopic response | 2.33 (1.41-3.84) | |
| S1P modulator therapy | Clinical remission | 2.52 (1.88-3.39) |
| Endoscopic remission | 2.39 (1.07-5.33) | |
| Clinical response | 1.66 (1.46-1.88) | |
| Endoscopic response | 2.11 (1.70-2.63) | |
| Crohn’s disease | ||
| JAK inhibitor | Clinical remission | 1.53 (1.19-1.98) |
| Endoscopic remission | 4.78 (1.63-14.06) | |
| Clinical response | 1.47 (1.20-1.80) | |
| Endoscopic response | 5.01 (1.30-19.31) | |
| S1P modulator therapy | Clinical remission | 0.70 (0.37-1.31) |
| Endoscopic response | NR | |
| Clinical response | 0.90 (0.58-1.40) | |
| Endoscopic remission | NR | |
| JAK, Janus kinase; S1P, sphingosine-1 phosphate; NR, not reported. a Measured at 8-12 weeks for UC and 4-12 weeks for Crohn’s disease. b Not all agents were evaluated for each outcome measure. | ||
Several compounds, namely etrasimod, filgotinib, ozanimod (Zeposia, Celgene) and upadacitinib (Rinvoq, AbbVie), also were associated with improved histologic outcomes (histologic remission or response) in patients with UC at eight to 12 weeks. Etrasimod and ozanimod were more effective in inducing histologic remission in UC compared with placebo (relative risk [RR], 2.21; 95% CI, 1.48-3.32).
Among JAK inhibitors, filgotinib and upadacitinib were associated with histologic improvement (histologic remission RR, 1.86; 95% CI, 1.34-2.60; histologic response RR, 3.59; 95% CI, 1.36-9.49).
Maintenance of some clinical and endoscopic outcomes at 52 to 58 weeks also were superior in UC patients taking the JAK inhibitors filgotinib, tofacitinib (Zeljanz, Pfizer) and upadacitinib, compared with placebo (clinical remission RR, 3.19; 95% CI, 2.47-4.12; endoscopic remission RR, 3.25; 95% CI, 1.95-5.40). A similar trend was seen among UC patients taking the S1P modulators etrasimod and ozanimod, with maintenance of some clinical and endoscopic outcomes relative to placebo at 32 to 52 weeks (clinical remission RR, 2.92; 95% CI, 1.63-5.21; endoscopic response RR, 2.44; 95% CI, 1.45-4.10).
Among patients with Crohn’s disease, the investigators found that JAK inhibitor therapy was statistically superior to placebo for induction of clinical (RR, 1.38; 95% CI, 1.04-1.84) and endoscopic remission at four to 12 weeks (RR, 1.38; 95% CI, 1.04-1.84).
There was no significantly elevated risk for adverse events in patients with UC or CD taking either class of drug relative to placebo.
Maintenance of Outcomes in Crohn’s
Although there have been trials assessing the effects of individual JAK inhibitors on maintenance of outcomes in CD, the results could not be pooled in this analysis. Based on the individual trial results, however, the authors noted that “JAK inhibitors may provide a benefit for maintenance of remission.”
Dr. Lukin expressed some skepticism of this class-level conclusion, noting that “the included agents target several different JAK targets, with earlier non-selective JAK studies failing to demonstrate efficacy in Crohn’s disease contrasting with recent forward-looking results seen with RCT data with JAK1-selective antagonists.”
The researchers concluded that their meta-analysis showed that “JAK inhibitors and S1P receptor modulators are effective for inducing clinical and endoscopic remission in UC, and that JAK inhibitors are also effective for inducing clinical remission in CD,” which, Dr. Lukin pointed out, is “in line with the regulatory approvals for both classes for UC.” However, given that the “data for S1P modulators are limited to amiselimod trials in the CD analysis,” Dr. Lukin told Gastroenterology & Endoscopy News that “the induction data should be interpreted with caution, as additional agents are currently under investigation in this disease state.”
—Natasha Albaneze
Dr. Lukin reported financial relationships with AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Janssen, Palatin, Pfizer and Takeda. Dr. Solitano reported no relevant financial relationships. Dr. Lukin is a member of the Gastroenterology & Endoscopy News editorial board.
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This article is from the February 2023 print issue.