Ozanimod Shows Efficacy in Ulcerative Colitis in Small Trial

An experimental oral lymphocyte trafficking agent, ozanimod (Receptos), showed modest activity against ulcerative colitis (UC) in a small, early-stage clinical trial.

In the double-blind, placebo-controlled phase 2 trial in adults with moderate-to-severe UC, 16% of patients randomly assigned to receive a 1-mg daily dose of ozanimod had a clinical remission, the primary endpoint, after 8 weeks of follow-up compared with 6% of patients randomly assigned to receive placebo. This difference was statistically significant (P = .048).

However, only 14% of patients who were randomly assigned to receive a 0.5-mg daily dose of ozanimod had a clinical remission, a difference from placebo that did not reach statistical significance (P = .14), report William J. Sandborn, MD, from the University of California, San Diego, and colleagues.

"Efficacy requires further assessment in larger trials. This trial was not large enough or of sufficiently long duration to assess safety," they write in their article, published in the May 5 issue of the New England Journal of Medicine.

UC is usually treated with combinations of anti-inflammatory agents, corticosteroids, thiopurines, and biologic agents such as tumor necrosis factor blockers.

The investigators point out, however, that a "lack of universal response, the risks of infection and neoplasia, a requirement for parenteral administration, and the development of antidrug antibodies have created a need for safe and effective oral therapies."

Ozanimod is an oral agonist of the sphingosine-1-phosphate subtype 1 (S1P1) receptor, one of a group of receptors involved in the regulation of immunologic and cardiovascular processes. A related agent, fingolimod (Gilenya, Novartis), has been shown to be effective against multiple sclerosis (MS), but because it nonselectively binds to S1P1 and three other S1P receptor subtypes, it has been associated with cardiovascular, hepatic, and ocular adverse events, the investigators explain.

Ozanimod was shown in a phase 2 trial in patients with MS to be associated with a dose-dependent reduction in circulating lymphocytes that was, in turn, associated with significant reductions in both inflammatory and neurodegenerative lesions, with good safety.

To see whether ozanimod might be effective and safe in UC, another immune-mediated inflammatory condition, the investigators conducted the newly reported trial in 197 adults with UC.

Patients were randomly assigned to receive oral ozanimod 1 or 0.5 mg or placebo daily for up to 32 weeks. The patients were evaluated at 8 weeks for clinical remission, defined as a Mayo Clinic UC disease activity score of 2 or less, with no subscore greater than 1.

As noted, the 1-mg dose, but not the 0.5-mg dose, was slightly but significantly more efficacious than placebo at helping patients achieve remission in an intention-to-treat analysis.

Because of the lack of a significant difference from placebo in the lower-dose ozanimod group, analyses of secondary outcomes were considered to be exploratory only. These analyses suggested a better clinical response with the drug at each dose level compared with placebo. Clinical response was defined as a decrease in Mayo Clinic Score of at least 3 points, and 30% or greater, and a decrease in rectal bleeding subscore of at least 1 point, or a subscore of 1 point or less.

Clinical remission rates and clinical response rates at 32 weeks were also higher in the ozanimod groups. Absolute lymphocyte counts at 8 weeks declined 49% from baseline with the 1-mg dose, and 32% from baseline with the 0.5-mg dose (declines in controls were not reported).

Anemia and headache were the most common overall adverse events, although, as the authors mention, the trial was neither long enough nor sufficiently powered for a safety analysis.

Vijay Vajnik, MD, PhD, an attending physician at Massachusetts General Hospital Digestive Healthcare Center in Boston, who was not involved in the study, told Medscape Medical News that the therapeutic rationale for lymphocyte trafficking agents is sound and has been demonstrated with other agents used to treat UC, including prednisone.

He noted, however, that additional trials will be needed to determine whether ozanimod can be safe and effective in UC.

"The study design was copied from other studies, but with new mechanisms [of action,] you need new ideas, and new trials, because the drug may not be as quick-acting as you're expecting it to be," he said.

The study was sponsored by Receptos. Dr Sandborn disclosed receiving institutional grant support, consulting fees, and honoraria, six of his coauthors are employed by the company, and others reported fees or other financial relationships. Dr Yajnik has disclosed no relevant financial relationships.

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Ulcerative colitis affects the colon. The colon is also referred to as the... See Answer
References
SOURCE:

Ozanimod Shows Efficacy in Ulcerative Colitis in Small Trial. Medscape. May 05, 2016.

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