Filenews 14 December 2021
The European Commission has granted a Marketing Authorisation to ozanimod for the treatment of adults with moderate to severe active ulcerative colitis, who experienced an inadequate response, loss of response or intolerance to conventional treatment or a biological agent.
Ozanimod, a drug administered orally once daily, is a modifier of the 1-sphinx phosphate (S1P) receptors, which binds selectively to subtypes 1 (S1P1) and 5 (S1P5) of the 1-sphinx phosphate (S1P) receptors. Ozanimod is the first and only oral S1P receptor modifier approved for ulcerative colitis and represents a new way of treating this chronic immuno-induced disease.
The approval was based on data from the True North study, a Phase 3 pilot study to evaluate ozanimod as a supply and maintenance-versus placebo treatment in adult patients with moderate to severe active ulcerative colitis.
Key findings from the study are:
• During the raid phase at Week 10 (ozanimod N=429 vs. placebo N=216), the study achieved the primary endpoint of clinical remission (18% vs. 6%, p<0.0001) as well as the main secondary endpoints including clinical response (48% vs. 26%, p<0.0001), endoscopic improvement (27% vs. 12%; p<0.0001) and endoscopic-histological improvement of the mucosa (13% vs. 4%, p<0.001) for ozanimod compared to placebo, respectively.
• During the maintenance phase at Week 52 (ozanimod N=230 vs. placebo N=227), the study achieved the primary endpoint of clinical remission (37% vs. 19%, p<0.0001) as well as the main secondary endpoints including clinical response (60% vs. 41%, p<0.0001), endoscopic improvement (46% vs. 26%; p<0.0001), clinical remission without corticosteroids (32% vs. 17%, p<0.001) and endoscopic-histological improvement of the mucosa (30% vs. 14%, p<0.001) for ozanimod compared to placebo, respectively. There was a decrease in the individual score for rectal bleeding and the frequency of stools as early as Week 2 (i.e. 1 week after completion of the required 7-day dose titration) in patients treated with ozanimod.
• In the assault and maintenance phases of the True North study, the overall safety profile was equivalent to the known safety profile for ozanimod and patients with moderate to severe ulcerative colitis. The most commonly reported side effects (>5%) in controlled periods of clinical studies of adults with multiple sclerosis and ulcerative colitis are nasopharyngitis, increased levels of alaninic aminotransferase (ALT) and increased levels of gamma-glutayltransferase. The most common side effects that led to discontinuation of treatment were associated with increased levels of liver enzymes (1.1%) in clinical studies of multiple sclerosis. The increased levels of liver enzymes that led to discontinuation of treatment were observed in 0.4% of patients in the controlled clinical studies of ulcerative colitis. The overall safety profile was similar for patients with multiple sclerosis and ulcerative colitis.
«The findings from the True North study show that ozanimod showed significant and lasting efficacy in patients with moderate to severe ulcerative colitis at many main endpoints such as clinical improvement, endoscopic improvement and mucosal healing and clinical remission. The effects in terms of endoscopic improvement and histological remission are particularly important, since they are usually achieved very difficult. This fact shows that ozanimod has the potential to be an effective oral treatment option for clinicians who monitor adult patients with this serious chronic disease," according to Dr Silvio Danese, M.D., Director, Department of Gastroenterology and Endoscopy of the IRCCS Institute at San Raffaele Hospital and the University of Vita-Salute San Raffaele in Milan.
«In Europe, more than 3 million people suffer from inflammatory bowel disease and ulcerative colitis is a difficult and often debilitating form of the disease. I am thrilled that we now have a new treatment option for patients and their caregivers to be able to manage the symptoms of a disease that can have an extremely negative impact on their quality of life." said Luisa Avedano, CEO of the European Federation of Organizations for Ulcerative Colitis and Crohn's Disease (EFCCA).
Ozanimod is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients, listed in the Summary of Product Characteristics, as well as in patients with immunodeficiency; in patients who in the last six months have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization or class III/IV heart failure at the New York Heart Association (NYHA); in patients with a history or presence of a second degree of AV type II blockade or a third-degree AV blockade or sinus nodular septal syndrome unless the patient has a functional pacemaker; in patients with severe active infections, active chronic infections, such as hepatitis and tuberculosis, active malignancies; in patients with severe hepatic impairment (Class C according to Child-Pugh) as well as during pregnancy and in women with the possibility of childbearing who do not use effective contraception.
About the True North study
The True North study is a multicentre, randomized, double-blind, placebo-controlled Phase 3 clinical trial that evaluated the efficacy and safety of ozanimod 0.92 mg in patients with moderate to severe active ulcerative colitis who showed an inadequate response or were intolerant to any of the following drugs: oral aminosalicylates; corticosteroids, immunomodulators or a biological agent. Patients had to be treated with oral aminosalicyl and/or corticosteroids before and during the on-board treatment.
Overall, 30% of patients had failed or had developed tolerability in previous treatment with tumour necrosis factor (TNF) inhibitors. Among these patients, 63% received at least two biological agents including TNF inhibitors. At the time of inclusion in the study, the average age was 42 years, 60% were men and the average duration of the disease was 7 years. The treatment groups were well balanced in terms of patient characteristics.
As part of the 10-week raid study (UC Study 1), a total of 645 patients were randomly distributed (randomized in a 2:1 ratio) to receive ozanimod (n=429) treatment or placebo therapy (n=216), of which 94% and 89%, respectively, completed the assault study. No new security incidents were observed during the assault phase.
During the maintenance phase (UC Study 2), a total of 457 patients treated with ozanimod in either the UC Study 1 or one open label strand and who received a clinical response at Week 10 were re-randomised in a ratio of 1:1 and treated with ozanimod 0.92 mg (n=230) or placebo (n=227) for 42 weeks (UC Study 2); completing a total of 52 weeks of treatment. Simultaneous reception of aminosalicylates had to be carried out in stable doses by week 52. Patients receiving corticosteroids at the same time had to gradually reduce their dose upon inclusion in the maintenance study. Of these, 80% and 54.6% of patients taking ozanimod and placebo, respectively, completed the study. During the maintenance phase, the overall safety profile was equivalent to the known safety profile for ozanimod and patients with moderate to severe ulcerative colitis. More information about the True North study is available on the www.clinicaltrials.gov website, NCT02435992.
The clinical findings from the True North study, under the title 'Ozanimod as an assault and maintenance treatment for ulcerative colitis', were published in the September 30 issue of the medical journal The New England Journal of Medicine.
All prospective patients joined an open expansion study, which is ongoing and is designed to evaluate the long-term profile of ozanimod for the treatment of moderate to severe active ulcerative colitis. In patients who joined the study, clinical remission, clinical response, endoscopic improvement and symptomatic remission were generally maintained until week 142. No new safety incidents were identified as part of the study's extension to patients with ulcerative colitis.
About ulcerative colitis
Ulcerative colitis, a chronic inflammatory bowel disease (FL), is characterized by an abnormal, chronic immune response that creates inflammation and ulcers (wounds) on the mucosa (inner layer of the wall) of the colon (colon) or rectum. Symptoms include stools with blood, severe diarrhea and frequent pain in the abdomen. Ulcerative colitis has a significant impact on patients' quality of life, affecting physical functioning, social and emotional well-being and the ability to be present at work/at school. Many patients show an inadequate response or do not respond at all to the available treatments. It is estimated that about 12.6 million people live with FLNe worldwide.
