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The oral sphingosine-1-phosphate (S1P) receptor modulator ozanimod (Zeposia) was effective for induction in moderately to severely active ulcerative colitis (UC), meeting the primary endpoint in a phase III trial.
At week 10, clinical remission was achieved by 18.4% of patients randomized to ozanimod 0.92 mg daily compared with 6% of those given placebo, which represented a difference of 12.4% (95% CI 7.5%-17.2%, P<0.0001), reported Brian Feagan, MD, of Western University in London, Ontario.
Clinical remission was defined as having the following on the 3-component Mayo score: rectal bleeding score of zero, stool frequency score of 1 or less and decrease from baseline of at least 1, and endoscopy subscore of 1 or less without friability, he explained during a poster presentation at the Advances in Inflammatory Bowel Diseases virtual meeting.
In physiologic conditions, approximately 2% of the total lymphocyte pool is located in the circulation. S1P regulates lymphocyte migration from lymphoid tissue to sites of inflammation. Ozanimod binds to and internalizes the S1P subtype 1 receptor, preventing certain proinflammatory lymphocytes from exiting the lymph nodes and circulating to the intestinal tissue. This mechanism has also been seen to be effective in multiple sclerosis, the original indication for which ozanimod was approved earlier this year.
Ozanimod previously demonstrated efficacy and tolerable safety in patients with moderate to severe UC for up to 32 weeks in the phase II .
The current study consisted of a 10-week induction period and a 52-week maintenance phase.
Participants were allowed to be on stable doses of oral aminosalicylates, prednisone in doses of 20 mg/day or less, or budesonide.
A key secondary endpoint was clinical response, which was defined as a reduction in the Mayo score of at least 2 points and a reduction in rectal bleeding score of 1 or more points or absolute rectal bleeding score below 1 point. That endpoint was met by 47.8% of the ozanimod group compared with 25.9% of the placebo group (P<0.0001).
Another endpoint was endoscopic improvement, with a mucosal endoscopy subscore of 1 or less, which was met by 27.3% of the ozanimod group versus 11.6% of the placebo group (P<0.0001), while mucosal healing was achieved by 12.6% versus 3.7%, respectively (P<0.001).
When the results were stratified according to prior tumor necrosis factor (TNF) inhibitor use, a significantly greater proportion of those without previous exposure achieved clinical remission (22.1% vs 6.6%, P<0.0001) and a trend was seen for those with previous exposure (10% vs 4.6%, P=0.195).
The most frequent adverse events observed in the ozanimod and placebo groups, respectively, were anemia (4.2% and 5.6%), nasopharyngitis (3.5% and 1.4%), and headache (3.3% and 1.9%). In the ozanimod group, other events included bradycardia, observed in 0.5%, and hypertension, in 1.4%.
"Statistically significant and clinically meaningful improvements were seen in clinical remission, clinical response, endoscopic outcomes, mucosal healing, and histologic remission," Feagan concluded.
Results from the maintenance phase of the trial also were presented at the virtual meeting, in a separate poster presentation by Stephen Hanauer, MD, of Northwestern University Feinberg School of Medicine in Chicago.
At week 52, after patients who had a clinical response at week 10 were re-randomized to ozanimod 0.92 mg/day or placebo, clinical remission was observed in 37% compared with 18.5%, respectively (difference of 18.6%, 95% CI 10.8%-26.4%, P<0.0001).
Ozanimod was also significantly superior to placebo on various secondary endpoints at week 52:
- Clinical response, 60% vs 41% (P<0.0001)
- Endoscopic improvement, 45.7% vs 26.4% (P<0.001)
- Maintenance of remission, 51.9% vs 29.3% (P=0.0025)
- Steroid-free remission, 31.7% vs 16.7% (P<0.001)
- Mucosal healing, 29.6% vs 14.1% (P=0.003)
Adverse events at week 52 included increases in alanine aminotransferase in 4.8% of patients receiving ozanimod and in 0.4% of those on placebo, and UC exacerbations in 0.4% and 4%, respectively.
"These findings support ozanimod as a potential treatment approach for patients with moderately to severely active UC," Hanauer concluded.
Disclosures
The studies were sponsored by Celgene.
The investigators reported numerous financial relationships, including with Celgene.
Primary Source
Advances in Inflammatory Bowel Diseases
Sandborn W, et al "Ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during induction in the phase 3 True North study" AIBD 2020; Poster 025.
Secondary Source
Advances in Inflammatory Bowel Diseases
Danese S, et al "Ozanimod efficacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during maintenance in the phase 3 True North study" AIBD 2020; Poster 030.