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The investigational anti-α4β7 integrin antibody abrilumab in different doses significantly improved 8-week remission rates versus placebo in refractory patients with moderate to severe ulcerative colitis (UC), a phase IIb trial found. Significant improvements were also observed in clinical response and mucosal healing at week 8, according to the international team of researchers.

"Our data further support the mechanism of targeting the anti-α4β7 pathway as a therapeutic option for the management of moderate to severe UC and the use of anti-α4β7 levels as a potential prognostic indicator in UC," wrote William J. Sandborn, MD, of the University of California San Diego, and colleagues.

As they explained in their study online in , the influx of immune cells into gut mucosa, mediated through integrin-dependent leukocytes, plays an important role in IBD pathogenesis. The cellular adhesion molecule α4β7 integrin mediates stable adhesion to high endothelial venules and promotes lymphocyte migration across the endothelial wall.

The team noted that restricting homing of lymphocytes to the gastrointestinal tract by blocking essential integrin-mediated interactions has been an area of intensive clinical research over the past 2 decades, and targeting gut-selective is a promising therapeutic strategy in IBD.

Study Details

During 2012-2015, Sandborn and co-authors recruited 359 patients with a mean age of 40 from 92 centers in North America, Europe, and Australia. Patients had a total Mayo Score of 6-12 and a rectosigmoidoscopy score of ≥2 with inadequate response or intolerance to immunosuppressives, tumor necrosis factor (TNF) antagonists, and/or corticosteroids. Participants were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo.

Demographic and disease characteristics were similar across the three groups. The primary endpoint was remission (total Mayo Score ≤2 points, no individual subscore >1 point) for the two highest dosages at week 8. Key secondary endpoints were response and mucosal healing at week 8. After the initial double-blind phase, treatment continued through 24 weeks.

Following randomization, a total of 354 patients were included in the 8-week double-blind phase. Of these, 238 patients received ≥1 dose of the investigational drug and 116 received placebo. By week 8, 332 patients had completed the initial phase.

The non-adjusted remission rates were 4.3% for the placebo group and 13.3% and 12.7%, for the abrilumab 70-mg and 210-mg groups, respectively (P<0.05 for both doses versus placebo). That translated into an odds ratio (OR) of achieving remission with abrilumab 70 mg of 3.35 (90% CI 1.41-7.95, P=0.021) and with 210 mg of 3.33 (90% CI1.34- 8.26, P=0.030).

The authors noted, however, that these rates were lower than the 21% anticipated in the sample size calculation.

The 8-week clinical response and mucosal healing rates at the two higher doses were also significantly greater versus placebo, with ORs of 2.78 at 70 mg and 2.57 at 210 mg. The odds of mucosal healing were also higher: ORs of 2.34 and 2.10, respectively.

Adverse event rates were comparable across groups through treatment week 24, with 68% of placebo recipients and 63% of abrilumab recipients reporting at least one treatment-emergent adverse event of any grade. The safety profile is comparable to that of vedolizumab (Entyvio), the authors noted.

Higher baseline concentrations of the antibody were a favorable prognostic indicator in UC disease activity and Mayo Score response, but not a predictive biomarker of abrilumab response. No cases of progressive multifocal leukoencephalopathy or deaths occurred.

The researchers cited several limitations to the study, including a systematic misalignment of treatments that led some patients randomized to the abrilumab 7-mg group to erroneously receive 70 mg, and some randomized to the 21-mg group to erroneously receive placebo. These patients were analyzed based on the actual treatment received with no impairment of blinding and minimal change to the study's power of detection, Sandborn and co-authors noted.

Additionally, they said, because the study was short term, it did not fully evaluate continued treatment following induction of remission at 8 weeks. "Although we observed a trend toward treatment effect at week 24 for the 70-mg multi-dose group, longer-term phase III studies evaluating clinical remission and response rates beyond 24 weeks are required to draw conclusions on the durability of treatment response," the researchers wrote. "Finally, conclusions regarding treatment responses based on previous TNF antagonist treatment are limited, but initial findings suggested potential benefit in both naive and exposed patients."

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