Vedolizumab and More: Anti-Integrin Therapies for Inflammatory Bowel Disease

Emmanuelle Bellaguarda, MD, assistant professor of medicine at Northwestern University, gave a deep dive into the results from clinical trials and real-world data on vedolizumab, an anti-integrin agent for the treatment of ulcerative colitis (UC) and Crohn disease (CD), at the Advances in Inflammatory Bowel Diseases regional meeting in Chicago on July 23.

Dr Bellaguarda reviewed the anti-integrin mechanism of action, explaining how integrins allow leucocytes to begin migrating through the vascular wall into the inflamed tissue.

In the GEMINI I trial evaluating vedolizumab in both the induction and maintenance setting for UC, there were higher rates of clinical response, clinical remission, and mucosal healing with vedolizumab at week 6 compared to placebo. At week 52, vedolizumab showed higher rates of clinical response, clinical remission, steroid-free remission, and mucosal healing compared to placebo. The counterpart GEMINI II trial, evaluating vedolizumab in both the induction and maintenance setting for CD, had similar results: higher rates of clinical response and clinical remission at week 6; and higher rates of clinical response, clinical remission, and steroid-free remission at week 52 with vedolizumab compared to placebo.

According to the results of a post-hoc analysis of GEMINI II and III, Dr Bellaguarda stated that “vedolizumab in combination with steroids may improve induction of clinical response/remission in moderate to severely active CD.” A phase 3 trial that evaluated a treatment regimen of 2 loading doses of intravenous vedolizumab at week 0 and week 2, followed by subcutaneous vedolizumab every 2 weeks, found that clinical remission, endoscopic remission, and durable clinical response were higher in the treatment arm compared to placebo at week 52. Patients who had not previously been treated with a tumor necrosis factor inhibitor (TNFi) had better outcomes than those who were TNFi-exposed.

When evaluating the long-term safety of vedolizumab for patients with UC and CD, data from the GEMINI trials found there were “no increased risks for systemic and GI infections,” according to Dr Bellaguarda. She also reported that there were no cases of progressive multifocal leukoencephalopathy, and no increased risk for malignancies. Clinical remission and clinical response rates were both maintained in the long-term in these assessments, she said.

Dr Bellaguarda stated that “interrupted therapy increases immunogenicity” with vedolizumab. A higher percentage of patients who had interrupted therapy with vedolizumab, in both the UC and CD spaces, were found to be positive for antidrug antibodies.

Adding an immunomodulator therapy, such as thiopurine or methotrexate, did not improve outcomes for patients treated with vedolizumab. However, in a small retrospective study, two-thirds of patients with refractory UC who were treated with calcineurin inhibitors, such as cyclosporine or tacrolimus, for induction followed by vedolizumab for maintenance were able to avoid colectomy.

For patients who have previously been treated with anti-TNF agents, therapies other than vedolizumab may be the better option. Dr Bellaguarda reported that these patients with CD were shown to have higher rates of corticosteroid-free remission and biochemical remission at weeks 12, 24, and 52 when treated with ustekinumab, compared to vedolizumab. Patients with UC who had previously not responded or lost response to an anti-TNF agent had higher rates of steroid-free clinical remission and endoscopic healing with tofacitinib, compared to vedolizumab.

When comparing vedolizumab to anti-TNF agents, however, vedolizumab seems to perform better, particularly among patients who were anti-TNF-naïve. Vedolizumab supported better endoscopic mucosal healing and histologic remission at week 52 than adalimumab for patients with moderate to severe UC. In routine clinical practice, vedolizumab induces higher rates of remission than anti-TNF agents. For patients with UC, vedolizumab is associated with higher rates of remission compared to anti-TNF agents, as well as lower rates of adverse events among those patients who are anti-TNF naïve.

The EVOLVE study, evaluating mucosal healing outcomes of first-line vedolizumab and anti-TNF agents in patients with UC and CD, found that the two therapies yielded “similar rates of clinical effectiveness up to 2 years,” with the anti-TNF agents having a more favorable safety profile.

The VICTORY study, Dr Bellaguarda stated, also found that “vedolizumab efficacy in UC correlates inversely with previous anti-TNFα exposure, especially in those patients who have failed 2 or more agents.” VICTORY also found that disease duration impacted outcomes on vedolizumab. She noted, “vedolizumab-treated patients with a CD duration of longer than 2 years had increased rates of steroid-free clinical remission and endoscopic remission.”

Looking ahead, Dr Bellaguarda reviewed some new molecules in the pipeline. PN-943 and AJM300 are both oral anti-integrin agents currently being evaluated in phase 2 trials for UC in the induction setting. Abrilumab and ontamalimab are 2 subcutaneous human monoclonal IgG2 antibodies. Abrilumab is being evaluated in a phase 2 induction trial for UC, while ontamalimab is being evaluated in an extension study for CD.

—Allison Casey

Reference:
Bellaguarda E. Anti-integrin therapies: What’s new in 2022. Presented at: Advances in Inflammatory Bowel Disease Regionals Meeting; July 23; Chicago, IL