Posted by Carla Rothaus
How effective was ozanimod as compared with placebo for moderately to severely active ulcerative colitis in the trial by Sandborn et al.?
Ulcerative colitis is a chronic disease that is characterized by a dysregulated immune response and chronic inflammation in the colonic mucosa. Sandborn et al. conducted a 52-week, phase 3 trial to evaluate ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Read the NEJM Original Article here.
Q: What are the limitations of current therapies for ulcerative colitis?
A: Conventional therapies such as aminosalicylates are modestly effective in patients with moderate, but not severe, disease. Glucocorticoids have been associated with adverse events and long-term adverse health consequences and are not recommended as maintenance therapy. Newer agents, including biologic drugs and Janus kinase inhibitors, are not effective in all patients or can lose efficacy with long-term use, and they have been associated with infections, infusion reactions, and cancers. Thus, the need remains for new oral treatments for ulcerative colitis that are safe and glucocorticoid-sparing and that have durable efficacy.
Q: What is ozanimod?
A: Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P subtypes 1 and 5 (S1P1 and S1P5), leading to internalization of S1P1 receptors in lymphocytes and the prevention of lymphocyte mobilization to inflammatory sites. In a phase 2 trial, treatment with ozanimod showed significant improvements over placebo with regard to endoscopic, histologic, and clinical end points in patients with moderate-to-severe ulcerative colitis.
Morning Report Questions
Q: How effective was ozanimod as compared with placebo for moderately to severely active ulcerative colitis in the trial by Sandborn et al.?
A: In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. The results of the trial showed that a once-daily oral formulation of ozanimod provided clinical efficacy in patients with moderately to severely active ulcerative colitis. Treatment with ozanimod led to significant improvements, as compared with placebo, in the incidence of clinical remission (primary end point) and in all key secondary clinical, endoscopic, and histologic end points at weeks 10 and 52. These results were observed in patients with active disease that had been inadequately controlled by conventional agents, as determined on the basis of required concomitant therapy with aminosalicylates or glucocorticoids at trial entry.
Q: What adverse events are associated with S1P receptor modulation?
A: Bradycardia, cardiac conduction abnormalities (second-degree and higher atrioventricular block), macular edema, cancer, serious or opportunistic infection, pulmonary effects, and hepatic effects were examined as adverse events of special interest in the trial by Sandborn et al. on the basis of previous associations with S1P receptor modulation. In the trial, bradycardia occurred more frequently with ozanimod therapy than with placebo during the induction period but not during the maintenance period. No cases of second-degree type 2 atrioventricular block or third-degree atrioventricular block occurred. Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. Macular edema occurred in 3 patients receiving ozanimod; all cases resolved after treatment discontinuation. The overall incidence of nonserious infection with ozanimod therapy was similar to that with placebo during the induction period but was higher than that with placebo during the maintenance period. The frequency of serious infections was less than 2% in each group.
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