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Fistulizing Crohn's disease (CD) is disabling for affected patients and challenging to treat for physicians. In search of more effective therapies, international ENTERPRISE study investigators recently evaluated two intravenous (IV) dosing regimens of the monoclonal antibody vedolizumab (Entyvio) in patients with moderate-to-severe perianal fistulizing CD. They found sustained improvements in fistula healing, as well as in health-related quality of life, with both dosing regimens.

The findings were published online in . Lead author David Schwartz, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, and co-author Shashi Adsul, MD, MBA, of Takeda Pharmaceuticals International in Zurich, Switzerland, discussed the promising results with the Reading Room.

What was the clinical context that gave rise to the ENTERPRISE study?

Schwartz/Adsul: Perianal fistulae are one of the most common complications of CD. Fistulizing CD is often treatment-refractory and recurrences are frequent. Fistulae rarely heal spontaneously, and affect around 25% of patients, imposing a significant burden, with a profound negative impact on health-related quality of life.

Treating fistulizing CD requires a multidisciplinary approach combining medication and surgery for best results. Although a range of medical and surgical options are available for CD, effective options for fistulizing disease are limited. Infliximab [Remicade], a tumor necrosis factor antagonist, has been approved by both the U.S. and European regulatory agencies.

What did earlier research show?

Schwartz/Adsul: The GEMINI II study showed that treatment with vedolizumab at 300 mg IV every 8 weeks or every 4 weeks maintained remission in the broad CD population and achieved fistula closure in a small subpopulation of patients who had draining fistulae at baseline.

Also in GEMINI II, an additional dose at week 10 increased clinical response rates in CD patients who had not responded at week 6. The regimen, including the additional week 10 infusion, is approved in Europe for patients with CD, but not in the U.S.

Thus, we hypothesized that an additional dose of vedolizumab 300 mg IV at week 10 may be beneficial. Our prospective clinical trial was designed to provide guidance on an optimal dose regimen for this complex patient population.

What is vedolizumab's mechanism of action?

Schwartz/Adsul: Vedolizumab is a humanized immunoglobulin G1 monoclonal antibody directed against the human lymphocyte integrin α4β7. This lymphocyte mediates lymphocyte trafficking to the gastrointestinal mucosa and gut-associated lymphoid tissue. Vedolizumab binds α4β7 integrin and impairs the migration of gut-homing lymphocytes into the mucosa, thereby acting as a gut-selective anti-lymphocyte-trafficking immunomodulator.

Based on this mechanism of action, vedolizumab efficacy in perianal disease may correlate with rectal CD localization at baseline. However, its impact on fistulae in our study appeared to be independent of rectal involvement, warranting further exploration of mechanisms of action leading to closure of fistulae.

What was the study population? What were the various treatments compared?

Schwartz/Adsul: From 2016 to 2018, we enrolled adults 18 to 80 years of age diagnosed with moderate-to-severe CD at least 3 months before enrollment. On MRI, eligible patients had one to three perianal draining fistulae ongoing for at least 2 weeks before entry.

Patients were randomized 1:1 to receive vedolizumab 300 mg IV at weeks 0, 2, 6, 14, and 22, or the same regimen plus an additional dose at week 10. If a seton was placed as part of standard of care, it had to be removed by week 14. All patients were prescribed companion antibiotics, from day 1 until week 6, and were followed for 30 weeks for efficacy and up to 48 weeks for safety.

What were the main findings?

Schwartz/Adsul: Of 32 patients with post-baseline healing assessment, 28 (14 per dosing regimen) had at least one draining fistula at baseline.

Rapid and sustained fistula closure was observed, with 53.6% of patients achieving at least a 50% decrease in draining fistulae, and 42.9% achieving a 100% fistulae closure, at week 30. The proportion responding to treatment was encouraging, indicating vedolizumab efficacy was maintained over 30 weeks' treatment. An additional dose at week 10 did not appear to alter treatment outcomes, and the safety profile was consistent with other vedolizumab studies, with no new signals observed.

Any improvements noted in inflammatory markers and patients' quality of life?

Schwartz/Adsul: Yes. The mean changes from baseline to week 30 in fecal calprotectin and C-reactive protein were -123.0 μg/g and -4.7 mg/L, respectively. Decreases were consistent with the reduction in draining fistulae and health-related quality of life amelioration, supporting a pattern of global improvement in vedolizumab-treated patients with CD or ulcerative colitis.

Furthermore, the mean baseline value for total Inflammatory Bowel Disease Questionnaire score was 137.6, and the mean change from baseline to week 30 was 25.5. In addition, EuroQol five-dimensions (index and visual analog scale) scores increased from baseline to week 30.

Any significant study limitations?

Schwartz/Adsul: One limitation was the lack of a placebo and/or seton plus antibiotic arm, precluding determination of the rate of fistula closure without vedolizumab treatment. Also, the generalizability of the results is limited by the small study population due to early closure of enrollment.

You can read the abstract of the study here, and about the clinical implications of the study here.