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Entyvio, Corticosteroid Combination may Improve Crohn’s Induction Response
Using a combination of Entyvio and stable doses of corticosteroids as a baseline therapy may help induce remission or clinical response in patients with moderately to severely active Crohn’s disease, according to research published in Inflammatory Bowel Diseases.
“Guidelines provide only weak recommendations regarding combination induction therapy for CD,” Bruce E. Sands, MD, of the Icahn School of Medicine at Mount Sinai, and colleagues wrote. “Given the limited evidence available to date, further data are needed about therapies that provide benefits when combined with conventional corticosteroid treatment.”
Researchers conducted a post hoc exploratory analysis using data from the GEMINI 2 and GEMINI 3 trials, which evaluated outcomes following induction therapy over 6- and 10-week periods, respectively. They stratified patients based on corticosteroid use at baseline and assessed for clinical remission — CD Activity Index (CDAI) of at least 150 points — and enhanced clinical response — decrease of greater than 100 points in CDAI score from baseline.
Researchers found that Entyvio (vedolizumab, Takeda) plus corticosteroids resulted in higher clinical remission rates at week 6 of the GEMINI 2 trial (19% vs. 4.6%), as well as week 6 and week 10 of the GEMINI 3 trial (19.8% vs. 10.2%; 34.2% vs. 11.1%) compared with corticosteroids plus placebo. Patients who received the combination therapy also experienced more clinical remission than patients who received vedolizumab alone.
Combination therapy also resulted in higher enhanced clinical response at each time point compared with corticosteroid and placebo (GEMINI 2 week 6, 36% vs. 18.5%; GEMINI 3 week 6, 38.7% vs. 22.2%; GEMINI 3 week 10, 53.2% vs. 22.2%), and compared with vedolizumab and placebo.
Incidence of adverse events was similar across all groups.
Sands and colleagues wrote that their findings suggest that this combination therapy may improve induction of clinical response or remission without any additional safety or tolerability concerns.
“In patients who have responded to treatment with vedolizumab, corticosteroids may then be reduced and/or discontinued in accordance with the standard of care,” they wrote. “Additional data could confirm whether the favorable outcomes observed during induction continue after patients have tapered corticosteroids and are receiving maintenance therapy.” – by Alex Young
Disclosures: Sands reports receiving consulting fees and research grants from 4D Pharma, AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Boehringer-Ingelheim, Capella Biosciences, Celgene, EnGene, Ferring, Gilead, Janssen, Lilly, Lyndra, MedImmune, Oppilan Pharma, Otsuka, Palatin Technologies, Pfizer, Progenity, Rheos Pharmaceuticals, Seres Therapeutics, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, and Vivelix Pharmaceuticals; consulting fees and research grants from Celgene, Janssen, Takeda; and honoraria for speaking in a CME program from Vindico Medical and WebMD. Please see the full study for all other authors’ relevant financial disclosures.
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The large data sets in phase 3 studies in ulcerative colitis and Crohn’s disease have afforded an opportunity for an expanding series of post-hoc analyses investigating sub-groups that were not assessed as primary outcomes. Several of these retrospective studies have led to erroneous conclusions when the outcomes were re-tested in prospective trials.
Most informative, perhaps, is the re-assessment of monotherapy with Remicade (infliximab, Janssen) compared with combination therapy with azathioprine. The pivotal phase 3 ACCENT study did not identify different clinical outcomes for patients who had not responded to azathioprine when treated with infliximab compared with infliximab monotherapy for patients not receiving azathioprine. However, when a prospective trial that was adequately powered to detect differences between biologic-naive and thiopurine-naive patients randomly assigned to monotherapy vs. combination therapy, statistical and clinically relevant differences were identified.
The recent post-hoc assessment of the GEMINI trials by Sands and colleagues suggest that combination therapy with Entyvio (vedolizumab, Takeda) and corticosteroids lead to improved clinical outcomes again relies on non-randomized participants but did find statistical differences in clinical outcomes that favored combination therapy in Crohn’s disease. As the authors admit, prospective studies are needed to confirm such results. Further, there are several other considerations. Steroids can affect symptoms more than mucosal healing and no endoscopic data were evaluated. The same trial design was also used in the GEMINI I trial in ulcerative colitis. We have yet to see a similar post-hoc analysis to determine if similar “differences” are noted in the UC population in which case endoscopic data are available.
While valuable at hypothesis generation, we must remain cognizant that these post-hoc analyses do not necessarily represent the “truth” in the absence of adequately controlled and powered prospective studies.
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Vedolizumab (Entyvio) is an anti-integrin that has been formulated and marketed to target the bowels and has a favorable side effect profile compared to other biologic agents. It can provide benefit to people who have not found relief with more experienced and less expensive agents such as anti-TNF.
Compared to other biologics it has a slower onset of action; in GEMINI 2 only 14.5% clinically responded in 6 weeks, and in GEMINI 3 26.6% in 10 weeks. It can often take 3 to 6 months to achieve the full effect of the medication.
The study by Sands and colleagues uses post hoc analysis to begin the discussion of how best to put an active Crohn’s patient with moderate to severe disease into remission. Given the options of using corticosteroids (CS), vedolizumab or the combination of corticosteroids and vedolizumab, this study suggests that the last option is the most effective.
The effect was noted in GEMINI 3 patients at week 10. In GEMINI 2 and 3 the addition of CS was more effective than vedolizumab alone. Other results were not found significant but suggest further testing could be insightful.
It should be noted that steroid dosing here is somewhat atypical for clinical practice. The starting dose was either ≤ 30 mg of prednisone or 9 mg of budesonide that was continued without taper for 10 to 14 weeks in GEMINI 2 and 3 respectively.
In addition, the end point was clinical symptom improvement without an objective marker such as endoscopy which is now a target that practitioners should be aiming for.
The two benefits of this study are that practitioners can feel more confident in using CS with vedolizumab, though perhaps for a longer duration than we typically do, and that it provides a focus for future research efforts to better clarify the data.