Benefit seen for both induction and maintenance

Patients with ulcerative colitis achieved a significantly greater remission rate with daily ozanimod induction therapy compared to placebo, and that benefit was maintained with ozanimod maintenance therapy, researchers report in The New England Journal of Medicine.

William J. Sandborn, MD, of the University of California San Diego in La Jolla, and True North co-investigators studied ozanimod as both induction and maintenance therapy and found that induction therapy with 1 mg daily of oral ozanimod was associated with a 18.4% clinical remission rate compared to 6.0% in placebo controls (P<0.001). Moreover, the remission rate in the maintenance phase was “(37.0% versus 18.5% [among patients with a response at week 10], P<0.001). The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% versus 25.9%, P<0.001) and maintenance (60.0% versus 41.0%, P<0.001),” they wrote.

Sandborn and colleagues said the findings confirm that a once-daily oral formulation of ozanimod, an S1P receptor modulator, demonstrated clinical, endoscopic, and histological improvement 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.”

In a review article looking at biologic and small molecule therapies for inflammatory bowel disease published in the same issue, Daniel C. Baumgart, MD, PhD, of the University of Alberta in Edmonton, and Catherine Le Berre, MD, of the Institut des Maladies de l’Appareil Digestif, Nantes University Hospital, Nantes, and the Department of Gastroenterology, Nancy University Hospital, Université de Lorraine, Vandœuvre-lès-Nancy, both in France, noted that in a phase II trial of ozanimod, also by Sandborn et al (TOUCHSTONE), the reported remission rate was 16% for the 1 mg dose and 14% for a 0.5 mg dose versus 6% for placebo patients.

“In the phase 3 True North trial… the clinical remission rate was significantly higher among patients receiving ozanimod than among those receiving placebo during both induction (18.4% [at a dose of 1 mg] versus 6.0%, P<0.001) and maintenance (37.0% versus 18.5% [among patients with a response at week 10], P<0.001), which led to FDA approval of ozanimod in May 2021 for the induction and maintenance of remission in adult patients with moderately or severely active ulcerative colitis,” Baumgart and Berre wrote.

But the review authors pointed to the fact that the benefit is not without risk: “Ozanimod treatment has been associated with serious adverse events, including opportunistic infections, bradycardia, atrioventricular conduction delays, liver injury, and macula edema.”

Sandborn and colleagues acknowledged the safety issues, noting that “[C]ancer, opportunistic infection, and macular edema were observed in patients who received ozanimod, but the incidences were low. Patients were excluded from the trial if they had macular edema at baseline or if they did not have immunity to varicella–zoster virus or had not received vaccination against varicella–zoster virus. Nonserious infections were more common with ozanimod than with placebo during the maintenance phase of the trial. The incidences of elevated alanine aminotransferase levels were higher among patients who received ozanimod than among those who received placebo… Overall, our results were consistent with safety findings that have previously been reported regarding ozanimod therapy in phase 3 trials involving patients with multiple sclerosis.”

The 52-week True North trial included a two-cohort, 10-week induction phase in which patients were assigned to ozanimod (n=429) or placebo (n=216) or a cohort that received the same ozanimod dose in open-label design (n= 367). Two-thirds of all participants were men, and the average age was 42.

At 10 weeks, patients with a clinical response—233 from cohort 1 (54.3%) and 224 from cohort 2 (61.0%)—were again randomized in blinded fashion to ozanimod or placebo as maintenance. In the maintenance phase, 230 patients received ozanimod and 227 received placebo.

“The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Safety was also assessed,” Sandborn et al wrote.

During the induction phase there was no significant difference in the rate of serious infection between the treatment groups, but during the maintenance phase the infection rate was higher in the ozanimod group, and elevated liver aminotransferase was more common with ozanimod. “The most common reason for discontinuation in the maintenance period was disease relapse (in 31 patients [13.5%] in the ozanimod group and in 77 [33.9%] in the placebo group),” they wrote. The frequency of serious infections was less than 2% in each group.

Among the limitations noted by Sandborn and colleagues was the likelihood that “the trial population may not be representative of the broader patient population in a routine clinical setting.” The trial was also limited by the lack of long-term data, but the investigators said that an open-label extension trial is ongoing.

In their article, Baumgart and Le Berre closed by mixing caution with optimism: “Currently available therapies cannot cure IBD, but many of them target various inflammatory pathways, resulting in more or less durable remission. However, these therapies come at a high price economically and physically, with potentially life-threatening side effects. The rapidly growing number of targeted medications that are available calls for multidisciplinary teams of expert gastroenterologists, specialized colorectal surgeons, nurses, researchers, and dieticians, as well as collaboration with pediatricians for a successful transition from adolescent to adult care.”

  1. In the True North trial daily treatment with 1 mg oral ozanimod increased remission as both an induction and maintenance therapy for patients with ulcerative colitis.

  2. Be aware that treatment with ozanimod is associated with an increased risk of serious adverse events.

Peggy Peck, Editor-in-Chief, BreakingMED™

The study was funded by Bristol Myers Squibb, True North.

Sandborn disclosed consultant agreements with Abbvie, Abivax, Admirx, Alfasigma, Alimentiv, Alivios Therapeutics, Allakos, Allergen, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avexegen Threpeutics, BauschHealths (Salix), BelGene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Celgene, Celitrion, Cellularity, Conatus, Cosmo, Eli Lilly and Company, Equilliuym, Escalier Biosciences (stock options), Ferring, Forbion, Genentech, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Gossamer Bio, Immunic, Incyte Corboration, Index Pharmaceuticals, Intact Therapeutics, Iveric Bio, Janssen Biotec, Janssen Research & Development LLC, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma, Otsuka Pharmaceutical, Pendion, Paul Hastings, Pfizer, Progenity (stock option), Prometheus Biosciences (Fiduciary Officer, Member Baord of Directors), Prometheus Laboratories, Inc., Protagonists Therapeutics, Provention Bio, Reistone, Reistone Biopharma, Ritter Pharmaceuticals, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Inc., Thetis Pharmaceuticals, Tigenix, Tillots Pharma, UCB Pharma, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Virrean Biosciences, and Zealand Pharmaceuticals.

Baumgart reported personal fees and non-financial support from AbbVie, Merck (MSD), Takeda,Dr. Falk /Falk Foundation, Ferring, Pfizer, Gilead. Also personal fees from Recordati, Nestlé, Genentech (Roche Group), CSL Behring, Norgine, Medronic, Storz, Tillotts, and Exeliom. He reported grants, personal fees and non-financial support from Janssen-Cilag, all outside the submitted work.

Le Berre reports personal fees from Janssen, Gilead, MSD, and Takeda and personal fees and non-financial support from Abbvie, Ferring, and Pfizer outside the submitted work.

Cat ID: 188

Topic ID: 77,188,730,188,20,192,925