Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Abstract

Sandborn WJ, Feagan BG, D’Haens G. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2021;385:1280–1291. Ulcerative colitis (UC) is a chronic inflammatory bowel disease (Lancet 2017;389:1756–1770). Because UC is a chronic and disabling disease, the main goals of medical therapies are to maintain symptom-free clinical remission, to achieve and maintain mucosal healing, and to block the progression of the disease (Lancet 2017;389:1756–1770). In the recent years, UC management has significantly changed owing to the development of biological drugs such as anti-tumor necrosis factor (TNF), anti-integrins, inhibitors of IL-12/23, and small molecules such as anti-JAK (J Crohn’s Colitis 2021:jjab178). However, a significant percentage of patients do not respond to therapy and require surgery. For this reason, there is a continuous effort to identify new therapeutic targets and to develop new molecules to offer further options to patients and guarantee them a better quality of life. Ozanimod is a new oral drug included in the small molecule class (N Engl J Med 2021;385:1280–1291). It is a sphingosine-1-phosphate (S1P) receptor modulator (N Engl J Med 2021; 385:1280–1291). S1P is a pleiotropic lipid mediator that binds to 5 G protein-coupled receptors termed as SP1R 1-5 (Nat Immunol 2007;8:1295–1301). It is involved in the trafficking of immune cells by regulating the outflow of lymphocytes from the lymph nodes and their entry into the circulation (J Crohns Colitis 2018;12:S678–S686). Ozanimod selectively binds to S1P1 and S1P5 receptors, limiting the capacity of lymphocytes to egress from peripheral lymphoid organs and leading to a reduction of peripheral lymphocytes (N Engl J Med 2021;385:1280–12919). This mechanism of action is effective in treating multiple sclerosis and has been shown to be successful in UC as well. Sandborn et al recently conducted a phase III randomized, double-blind, placebo-controlled clinical trial investigating the efficacy and safety of ozanimod in patients with moderate-to-severe UC (N Engl J Med 2021;385:1280–1291). The study consisted of a 10-week induction phase and a subsequent 42-week maintenance phase. In the first part of the study, a cohort of patients was randomized 2:1 to receive ozanimod 1 mg/d or placebo, and a second cohort of patients received open-label ozanimod 1 mg/d. Patients treated with ozanimod who achieved clinical response at 10 weeks (defined as a reduction of ≥3 points in total Mayo score, a decrease of ≥30% in Mayo score from baseline, or a decrease in bleeding subscore of ≥1 point), were rerandomized 1:1 to receive ozanimod 1 mg/d or placebo through week 52. The primary endpoint was the rate of clinical remission at week 10 and at week 52 (defined as rectal-bleeding subscore of 0, stool frequency subscore of ≤1, and endoscopy subscore of ≤1). Overall, 1012 patients were enrolled in the induction phase (645 in cohort 1 and 367 in cohort 2). After 10 weeks, ozanimod-treated patients had a significantly higher clinical remission rate compared with those treated with placebo (18.6% vs 6.0%; P < .001). Similarly, among the 457 patients who participated in the maintenance study, a higher rate of clinical remission at 52 weeks was detected in patients treated with ozanimod compared with placebo (37.0% vs 18.5%; P < .001). Several secondary end points were evaluated including clinical response, endoscopic improvement (endoscopic Mayo score of ≤1), mucosal healing (endoscopic Mayo score of ≤1 and Geboes histologic score of ≤2.0), and histologic remission (Geboes histologic score of ≤2.0); ozanimod was more effective than placebo in achieving all secondary outcomes (P < .001 for all comparisons). Regarding the safety profile, there was no difference between patients receiving placebo and the 2 ozanimod cohorts in the number of adverse events in the induction phase (38.0% vs 40.1% and 39.8%). Conversely, a higher percentage of patients in the ozanimod arm experienced adverse events compared with placebo during maintenance (49.1% vs 36.6%), but the absolute number of events was low, and the percentage of serious adverse events and adverse events leading to discontinuation was higher in the placebo group than in the group of patients treated with ozanimod. Likewise, the rate of infections was comparable between the 3 groups in the first 10 weeks (11.6% vs 10.7% and 12.5%), whereas it was higher in percentage, but numerically low among patients in the experimental group after 52 weeks (23.0% vs 11.9%), mainly related to nasopharyngitis and herpes zoster infection. Adverse events of special interest were recorded among patients treated with ozanimod: bradycardia in 5 patients (in the induction phase), 3 episodes of macular edema (2 in the induction phase and 1 in the maintenance phase, which resolved after treatment discontinuation), malignancy (2 basal cell carcinoma and 1 rectal adenocarcinoma), an increase in transaminases (2.6% and 1.6% in the 2 induction cohorts and 4.8% in the maintenance cohort), and a decrease in absolute lymphocyte count (26.8% and 31.7% in the induction cohorts and 43.5% in the maintenance cohort). This study finally demonstrated that ozanimod was more effective than placebo both as induction and maintenance therapy in patients with moderate-to-severe UC. Ozanimod is the first sphingosine 1-phosphate modulator to be approved for UC by the US Food and Drug Administration (www.medscape.com/viewarticle/952062; accessed November 23, 2021). The introduction of ozanimod for patients with UC allows the use of a different mechanism of action to treat colonic inflammation beside the already available medications. Data regarding other molecules such as anti-TNF, anti-integrins, anti-IL12/23, and anti-JAK show that >60% of patients do not achieve remission in the short term with any of these drugs (Aliment Pharmacal Ther 2018;47:454–465). Therefore, a new molecule that targets a different mechanism increases the chance to successfully treat patients with UC. Moreover, all molecules, except anti-JAKs, are administered parenterally. The development of oral small molecules is dramatically changing the management of UC in a more patient-friendly way. The oral administration route allows patients to treat the disease at home. This factor has a double positive effect; it decreases the costs related to the infusion room and its overcrowding, especially in the current period of the severe acute respiratory syndrome coronavirus 2 pandemic (J Crohn’s Colitis 2020;14:1330–1333) and may also decrease the out-of-pocket costs for the patients related to indirect and direct costs related to the need for hospital treatments. Furthermore, oral therapy has a potential positive effect on patient productivity; it decreases the number of working hours lost and improves patient quality of life (Eur J Gastroenterol Hepatol 2018;30:174–180). Other advantages of ozanimod are the absence of immunogenicity and its short half-life (approximately 20 hours), resulting in a rapid mechanism of action (Expert Rev Gastroenterol Hepatol 2020;14:797–806), and short clearance time, even in case of adverse events related to the drug. The safety profile of ozanimod was generally good; the majority of adverse events were not directly related to the drug. Among the drug-related side effects, the absolute number of events was very low compared with the number of patients treated. Owing to the risk of bradycardia, ozanimod is contraindicated in patients with cardiovascular and/or cerebrovascular disorders and in those with Mobitz type II second-degree or third-degree atrioventricular block, sick sinus syndrome, or sinoatrial block, except those with a functioning pacemaker (https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-Receives-Positive-CHMP-Opinion-for-Zeposia-ozanimod-as-a-Treatment-for-Adult-Patients-with-Moderately-to-Severely-Active-Ulcerative-Colitis/default.aspx; accessed November 23, 2021). For this reason, all patients should undergo an electrocardiogram (ECG) and a cardiological evaluation (in case of ECG abnormalities) before starting treatment and should be monitored with periodic ECGs during therapy. An ophthalmological evaluation is recommended before starting treatment, because of the small risk of macular edema. Elevation of transaminases and lymphocytopenia are other important aspects to consider and monitor, but they have not currently been associated with liver damage or increased risk of infections. In general, adequate pretreatment assessment of risk factors would be sufficient to select the appropriate patient to decrease the risk of adverse events. A recent indirect analysis compared the efficacy and safety of ozanimod with adalimumab and vedolizumab in patients with UC (J Am Coll Gastroenterol 2021;116:S314). Patients treated with ozanimod achieved significantly higher rates of clinical response (odds ratio [OR]: 1.53; P < .05) and endoscopic improvement (OR, 1.66; P < .05) compared with adalimumab. Clinical remission, clinical response, and endoscopic improvement were comparable between ozanimod and vedolizumab. Furthermore, antisphingosine therapy was associated with significantly lower rates of infectious adverse events compared with anti-TNF during the induction period (risk difference, –8.9%; P < .01) and compared with anti-integrin during the maintenance phase (risk difference, –46.3%; P < .01). Based on these data, ozanimod seems to be in line with the efficacy and safety profile of other medications indicated in moderate-to-severe UC. Further data are needed to understand the best position of ozanimod in the treatment algorithms for UC and long-term efficacy and safety in a real-world setting.