Long-Term Safety of 3 Years of Ozanimod in Moderately to Severely Active Ulcerative Colitis: An Interim Analysis of the True North Open-Label Extension

Ozanimod is a selective modulator of the sphingosine-1-phosphate (S1P) receptor. The drug is approved for the treatment of moderately to severely active ulcerative colitis (UC) and has demonstrated a favorable safety profile in UC as well as in multiple sclerosis.¹ The phase 3 True North study evaluated ozanimod vs placebo in patients with moderately to severely active UC.² The study included a 10-week induction phase, a 42-week maintenance phase, and a 94-week open-label extension (OLE) study. For induction, 645 patients in cohort 1 were randomized 2:1 to receive placebo or ozanimod (0.92 mg, daily), while 367 patients in cohort 2 received open-label ozanimod (0.92 mg, daily). At week 10, patients in the placebo arm who exhibited a response continued with placebo (n=69). Responding patients in either cohort 1 or cohort 2 who received induction treatment with ozanimod were evenly randomized to receive placebo (n=227) or continue with ozanimod (n=230). The OLE study included patients who did not respond to induction, patients who lost a response in the maintenance phase, and patients who completed the maintenance phase.

In comparison with placebo, ozanimod demonstrated efficacy in both the induction and maintenance phases of the True North study. At week 10, ozanimod was superior to placebo in respect to clinical remission (18.4% vs 6.0%), clinical response (47.8% vs 25.9%), endoscopic improvement (27.3% vs 11.6%), and mucosal healing (12.6% vs 3.7%). Similarly, at week 52, outcomes were superior with ozanimod vs placebo, including clinical remission (37.0% vs 18.5%), clinical response (60.0% vs 41.0%), endoscopic improvement (45.7% vs 26.4%), mucosal healing (29.6% vs 14.1%), and others. Prior analyses of data from the True North OLE have shown a favorable safety profile in 131 patients with UC treated with ozanimod for up to 146 weeks.³

An interim analysis evaluated the cumulative long-term safety of ozanimod in all patients who entered the True North OLE study.⁴ This group of 823 patients represented 2219 patientyears of exposure to ozanimod, with a mean duration of exposure of 2.7 ± 1.6 years per patient. Patients in this analysis had a mean age of 41.7 ± 13.6 years, and 59.3% were male. The mean age at UC diagnosis was 34.5 ± 13.3 years, and the mean time since UC diagnosis was 7.4 ± 7.0 years. At screening, 32% of the patients were using corticosteroids. The exposure-adjusted incident rate per 100 patient-years (EAIR₁₀₀) was 87.6 for treatment-emergent adverse events (AEs) in 672 patients (81.7%), 7.4 for serious treatmentemergent AEs in 149 patients (18.1%), and 2.5 for treatment-emergent AEs leading to discontinuation of ozanimod in 55 patients (6.7%). The most frequent treatment-emergent AEs included lymphopenia (EAIR₁₀₀, 6.4) in 128 patients (15.6%), anemia (EAIR₁₀₀, 4.2) in 86 patients (10.4%), and nasopharyngitis (EAIR₁₀₀, 4.1) in 85 patients (10.3%). The most common infections included serious infection in 41 patients (5.0%; EAIR₁₀₀, 1.9), nasopharyngitis in 85 patients (10.3%; EAIR₁₀₀, 4.1), COVID-19 in 66 patients (8.0%; EAIR₁₀₀, 3.0), and upper respiratory tract infection in 56 patients (6.8%; EAIR₁₀₀, 2.7; Table 1). The most common malignancy was basal cell carcinoma (EAIR₁₀₀, 0.3), followed by prostate cancer, colon adenocarcinoma, breast cancer, rectal adenocarcinoma, and rectal cancer stage II, each of which had an EAIR₁₀₀ of 0.1. AEs of special interest included hypertension (EAIR₁₀₀, 2.3), macular edema (EAIR₁₀₀, 0.2), bradycardia (EAIR₁₀₀, 0.1), and third-degree atrioventricular block (EAIR₁₀₀, 0.1). The EAIR₁₀₀ for opportunistic infection was 1.5. An absolute lymphocyte count below 200/mm³ was observed in 7.8% of patients in the analysis and was not associated with an increased rate of opportunistic infections.

Table 1.

The Most Frequent TEAEs for All Patients Who Entered the OLE From TN

	All TN Patients Enrolled in the OLE (N=823)
Adverse Event	n (%)
TEAEs	672 (81.7)
Serious TEAEs	149 (18.1)
TEAEs leading to treatment discontinuation	55 (6.7)
Most frequent TEAEs (occurring in ≥5% of patients) Lymphopenia Anemia Nasopharyngitis Decreased lymphocyte count Increased alanine aminotransferase Arthralgia COVID-19 Headache Upper respiratory tract infection Increased γ-glutamyl transferase Hypertension UC exacerbation Cough	128 (15.6) 86 (10.4) 85 (10.3) 84 (10.2) 74 (9.0) 74 (9.0) 66 (8.0) 63 (7.7) 56 (6.8) 54 (6.6) 49 (6.0) 44 (5.3) 42 (5.1)

OLE, open-label extension; TEAE, treatment-emergent adverse event; TN, True North; UC, ulcerative colitis. Adapted from Abreu et al. Abstract 950. Presented at: DDW 2023; May 6-9, 2023; Chicago, Illinois.⁴