Inhibition of leukocyte trafficking to the gut can also reduce the inflammation associated with IBD.1 Vedolizumab binds to the α4β7 integrin, reducing the recruitment of leukocytes to the intestine. The efficacy of vedolizumab in patients with UC has been demonstrated as both induction therapy and maintenance therapy in the GEMINI 1 trial.2 The VARSITY study then demonstrated the superiority of vedolizumab vs adalimumab as maintenance therapy in patients with moderately to severely active UC, for both clinical remission (31.3% vs 22.5%; P=.0061) and mucosal healing (39.7% vs 27.7%; P=.0005) at week 52.
Using data from the GEMINI 2 trial, which evaluated vedolizumab in patients with CD, the Clinical Decision Support Tool (CDST) was developed to predict which patients with CD are more likely to respond to therapy with vedolizumab.3,4 The findings were validated using data from the VICTORY cohort of patients who were treated with vedolizumab for 26 weeks. Factors associated with a greater likelihood of response to vedolizumab treatment included prior treatment with a TNF inhibitor, prior bowel surgery, prior fistulizing disease, baseline albumin level, and baseline level of CRP. The CDST showed a high sensitivity in predicting clinical remission (92%), corticosteroid-free remission (94%), mucosal healing (98%), clinical remission and mucosal healing (100%), and corticosteroidfree remission with mucosal healing (100%). However, the CDST did not successfully predict outcomes to ustekinumab therapy in patients with refractory CD.5 A prospective study examining T-cell populations and transcriptional profiles in patients with IBD found that the best predictors of response were use of thiopurines at baseline, the metabolic state of regulatory T cells in the ileum, and the gene signature of regulatory T cells in the peripheral blood.6
Inhibition of leukocyte trafficking provides therapeutic targets by inhibiting either egress out of lymph nodes (S1P modulators) or ingress into the gut mucosa from the bloodstream (vedolizumab). S1P modulators are safe, effective, once-daily oral therapies for UC and are being evaluated in CD. Vedolizumab can now be administered intravenously or subcutaneously.
– Stephen B. Hanauer, MD
Gene expression in macrophages, neutrophils, and dendritic cells was examined in biopsy specimens of the ileum and colon prospectively collected from 54 patients with UC or CD.7 Principal component analysis based on the transcriptional profiles yielded distinct groups that reflected the location of the tissue. The expression of genes associated with inflammation was higher in the colon, and ileum samples showed higher levels of expression of metabolic genes. The study identified specific pathways that were upregulated in the colon vs the ileum. For example, pathways related to innate immune system function were upregulated in the colon, whereas upregulation of metabolic pathways was observed more often in the ileum. The study identified genes and pathways that could be targeted as therapy for IBD.
Ozanimod and etrasimod are sphingosine 1-phosphate (S1P) receptor modulators that have been evaluated in phase 3 trials of patients with UC. The True North study evaluated ozanimod vs placebo in 1012 patients with moderately to severely active UC.8 At week 10 of induction therapy, the rate of clinical remission was 18.4% with ozanimod vs 6.0% with placebo (P<.001), thus meeting its primary endpoint (Figure 4). Ozanimod therapy also yielded a superior rate of clinical response (47.8% vs 25.9%; P<.001), endoscopic improvement (27.3% vs 11.6%; P<.001), and mucosal healing (12.6% vs 3.7%; P<.001). Patients who exhibited a response in the induction phase of the trial were randomized to ozanimod or placebo for the maintenance phase of the trial. At week 52, the rate of clinical remission was 37.0% with ozanimod vs 18.5% with placebo (P<.001), meeting the primary endpoint for maintenance. All secondary endpoints also showed a superior benefit with ozanimod vs placebo, including clinical response (60.0% vs 41.0%; P<.001), endoscopic improvement (45.7% vs 26.4%; P<.001), and mucosal healing (29.6% vs 14.1%; P<.001). The True North trial included an open-label extension (OLE) study.9 In an interim analysis of the OLE, a large proportion of patients who demonstrated a response to ozanimod after 1 year of therapy continued to maintain endoscopic improvement, histologic remission, and mucosal healing after an additional 2 years of ozanimod therapy. Safety data from the True North OLE reflected a favorable longterm safety profile with ozanimod in patients with UC.10
Figure 4.
Induction period at week 10 and maintenance period at week 52 of ozanimod vs placebo for patients with moderately to severely active ulcerative colitis from the True North study.
Adapted from Abreu et al. Leukocyte trafficking. Presented at the Advances in Inflammatory Bowel Disease Conference; Orlando, Florida; December 14-16, 2023.1
Etrasimod maintenance therapy was evaluated in patients with moderately to severely active UC in the ELEVATE UC 12 and ELEVATE UC 52 trials.11 Approximately 38% of patients had previously been exposed to JAK inhibitors or other advanced therapies. The studies met their primary endpoints, demonstrating a superior rate of clinical remission with etrasimod vs placebo after 12 weeks of induction (27.0% vs 7.4%; P<.001) and at week 52 of maintenance (32.1% vs 6.7%; P<.001). In both the induction and maintenance portions of the trials, the superiority of etrasimod vs placebo was underscored by secondary endpoints, including endoscopic improvement, symptomatic remission, endoscopic improvement combined with histologic remission, and clinical response (P<.001).
ABSTRACT SUMMARY Outcomes of Early vs Delayed Advanced Therapy Among Patients With Moderate Ulcerative Colitis in the United States: TARGET-IBD.
The rates of endoscopic remission were compared in 179 patients from the TARGET-IBD study based on early vs delayed initiation of advanced therapy for their moderately active UC (Abstract S10). Early treatment was defined as occurring within 2 years of the UC diagnosis. The median time from initiating advanced therapy to endoscopic remission was 10.8 months (IQR, 8.4-19.0) among early initiators vs 15.4 months (IQR, 10.6-21.7) among delayed initiators. In multivariable analysis, the likelihood of endoscopic remission was nearly twice as likely among early initiators as with late initiators (hazard ratio, 2.44; 95% CI, 1.19-4.97). The likelihood of endoscopic remission was further increased among patients who initiated treatment with an advanced therapy within 1 year of diagnosis compared with patients who initiated treatment with an advanced therapy more than 2 years after diagnosis (hazard ratio, 3.44; 95% CI, 1.45-8.15).
References
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