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TOUCHSTONE: Ozanimod Shows Promise as Induction, Maintenance Therapy for UC
Phase 2 trial results showed that 1 mg ozanimod induced clinical remission of moderate to severe ulcerative colitis in a slightly higher proportion of patients vs. controls, and had a good safety profile.
Interim data from the double blind, placebo controlled TOUCHSTONE trial of ozanimod (RPC1063, Receptos) was previously presented at the 2016 European Crohn’s and Colitis Organization Congress. The new report published in New England Journal of Medicine includes week 8 histology data and week 32 clinical response, clinical remission, mucosal healing and histology data.
“Ozanimod is an oral S1P modulator with improved specificity for the S1P1 receptor subtype,” William J. Sandborn, MD, professor of medicine at University of California San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health, told Healio Gastroenterology.
William J. Sandborn
According to a press release, the drug belongs to a new class of immunotherapies that traps white blood cells in the lymph nodes to prevent them from escaping into the gut and causing inflammation.
“The goal of the study was to evaluate the efficacy of ozanimod for induction and maintenance of clinical response, clinical remission, mucosal healing, and histologic healing, and to evaluate its safety and tolerability, in patients with moderate to severe ulcerative colitis,” Sandborn said. “The results showed highly consistent effects across these range of endpoints, and good safety and tolerability.”
From December 2012 through April 2015, Sandborn and colleagues randomly assigned 197 patients with moderate to severe ulcerative colitis from 57 centers in 13 countries to receive oral ozanimod at 0.5 mg or 1 mg or placebo once daily during the induction phase of the trial. Patients first underwent dose escalation during week 1, then received their randomly assigned dose for 8 weeks. Clinical responders (n = 103) then continued their regimen during the maintenance period through week 32, while nonresponders were invited to cross over to open-label treatment.
The researchers evaluated patients by flexible sigmoidoscopy with colonic biopsy at screening and at weeks 8 and 32, collected blood samples at each visit, and collected stool samples at baseline and at weeks 8 and 32.
Week 8 clinical remission defined as a Mayo Clinic score no greater than two and with no subscore greater than one served as the primary endpoint. Week 32 clinical response and remission, mucosal healing and change in Mayo Clinic score, and histologic remission at weeks 8 and 32 served as exploratory endpoints.
Week 8 clinical remission was achieved by 16% of patients who received 1 mg ozanimod and 14% of those who received 0.5 mg ozanimod vs. 6% of those who received placebo (P = .048 and P = .14 for each respective dose vs. placebo).
“Given the nonsignificant findings for the comparison of the remission rate at week 8 in the group that received 0.5 mg of ozanimod with that in the placebo group, all subsequent analyses were considered to be exploratory and the results not significant,” the researchers wrote.
At 8 weeks, clinical response was achieved by 57% of the 1 mg group and 54% of the 0.5 mg group vs. 37% of the placebo group (P = .02 and P = .06, respectively), mucosal healing was achieved by 34% and 28% vs. 12% (P = .002 and P = .03, respectively), and histologic remission was achieved by 22% and 14% vs. 11% (P = .07 and P = .63, respectively).
From baseline to week 8, absolute lymphocyte counts decreased by 49% in the 1 mg group and by 32% in the 0.5 mg group.
At 32 weeks, the clinical remission rate was 21% in the 1 mg group and 26% in the 0.5 mg group vs. 6% of the placebo group (P = .01 and P = .002, respectively), the clinical response rate was 51% and 35% vs. 20% (P < .001 and P = .06, respectively), the mucosal healing rate was 33% and 32% vs. 12% (P = .005 and P = .006, respectively) and the histologic remission rate was 31% and 23% vs. 8% (P < .001 and P = .02, respectively).
Adverse events were comparable between groups.
The researchers concluded that once-daily oral ozanimod at the 1 mg dose resulted in slightly higher rates of clinical remission at week 8 compared with placebo, and that patients in this dose group continued to have higher rates of clinical remission and response, mucosal healing, histologic remission and lower Mayo scores compared with placebo at week 32.
“The increases in the proportions of patients with clinical remission and with histologic remission at week 32, as compared with week 8, raise the possibility that extended treatment may be associated with enhanced efficacy,” the researchers wrote. They also acknowledged that the trial was not large or long enough to adequately evaluate safety, and further trials are required to establish clinical efficacy.
“Ozanimod is a promising new oral drug for the treatment of ulcerative colitis,” Sandborn said.
In the press release, he added that “unlike other currently available drugs for inflammatory bowel disease, ozanimod can be orally administered and does not suppress the immune system to the point of increasing likelihood of infection or cancer.” – by Adam Leitenberger
Disclosure: Sandborn reports he has a past consulting relationship with the study sponsor, Receptos. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Multiple treatments exist to alleviate symptoms and to prevent relapses in patients with ulcerative colitis (UC); however maintenance therapy is needed for most patients and a subset are refractory to treatment. Immune suppressants or biologics are indicated for patients with UC that do not respond to aminosalicylates or corticosteroids and for those at high risk for colectomy. Although effective, biologics are given parenterally and both immune suppressants and biologics are associated with an increase in the risk of infection and paradoxical autoimmune reactions and certain cancers such as lymphoma and skin cancer. Therefore, there is an unmet need to develop new therapies for UC.
Ozanimod is an oral “small molecule” that activates the sphingosine-1-phosphate (S1P) subtype 1 and 5 receptors which play a crucial role trafficking of lymphocytes. Activation of S1P causes internalization of S1P, trapping leukocytes in the lymph node and reducing circulating lymphocytes. These actions may result in decreased inflammation in diseases like multiple sclerosis and UC.
A phase 2, randomized, controlled trial in patients with moderate to severe UC compared either placebo or ozanimod (0.5 or 1 mg) daily. 57% and 16% of patients given 1 mg of ozanimod achieved clinical response and remission, respectively, after 8 weeks; response and remission rates were similar at week 32 and 1/3 of patients achieved mucosal healing. Ozanimod does not inhibit other S1P subtypes (2-4); thus it is thought to have less cardiac, hepatic and ocular adverse events (AEs). Although the trial was too small to determine the safety of ozanimod, adverse events were not different between placebo and ozanimod-treated patient and few patients experienced cardiac or hepatic AEs.
Ozanimod is a promising new oral medication for patients with UC. Large phase 3 trials are underway to determine the efficacy and safety of ozanimod.