The investigational monoclonal antibody etrolizumab effected clinical remission in significantly more patients with refractory ulcerative colitis than did placebo, an industry-sponsored trial showed.
Two tested doses of the drug achieved significant benefit over placebo, although the larger – 300 mg biweekly with a 420-mg loading dose – was slightly less effective, Dr. Séverine Vermeire and colleagues wrote in the May 9 issue of the Lancet (2014 [dx.doi.org/10.1016/S0140-6736(14)60661-9]).
The drug also significantly improved the incidence of endoscopic remission, which the authors said was a more stringent test of effect than was the clinical score.
"In our study, a relatively high proportion of patients in the placebo group achieved a clinical response – probably because ... this endpoint is less rigorous," wrote Dr. Vermeire of the University of Leuven (Belgium) and coauthors. "By contrast, endoscopic remission is an extremely rigorous endpoint, especially for the treatment-refractory patients included in this study, and thus was achieved in a small proportion of actively treated patients compared with no patients in the placebo group."
The 10-week phase II study comprised 124 patients with ulcerative colitis who had been unresponsive to conventional therapy. They were randomized to placebo injections or to etrolizumab: either 100 mg at weeks 0, 4, and 8, with placebo at week 2, or a 420-mg loading dose at week 0 followed by 300 mg at weeks 2, 4, and 8.
By 10 weeks, clinical remission had occurred in 21% of the 100-mg group, 10% of the 300-mg group, and none of the placebo group. Clinical response had occurred in 33% of the 10-mg group, 31% of the 300-mg group, and 29% of the placebo group – not significantly different.
By week 8, endoscopic and rectal bleeding subscores of 0 (endoscopic remission) had occurred in one patient in the placebo group, three in the 100-mg group, and one in the 300-mg group – also not significantly different.
By week 10, however, this endpoint did reach statistical significance, with no patients in the placebo group achieving the 0 score, compared with four in the 100-mg group and three in the 300-mg group.
Adverse events occurred in 61% of the 100-mg group, 48% of the 300-mg group, and 72% of the placebo group. These included rash (7%, 3%, and 2%, respectively), influenzalike illness (7%, 0%, and 2%), and arthralgia (15%, 5%, and 9%).
There were 12 serious adverse events: 5 (12%) in the 100-mg group, 2 (5%) in the 300-mg group, and 5 (12%) in the placebo group. These were related to the disease, the investigators said. There were no serious opportunistic infections. Four patients in the 300-mg group and two in the placebo group experienced mild injection site reactions.
Etrolizumab works by inhibiting the interaction of alpha-4 beta-7 integrin with mucosal addressin cell adhesion molecule-1. This action inhibits the movement of immune cells into the intestine while avoiding the broad immunosuppressive effects of other antibodies.
Genentech sponsored the study. Dr. Vermeire had no financial ties with the company, although she disclosed relationships with other pharmaceutical companies. The coauthors also had multiple relationships with drug manufacturers, including Genentech.
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