Ozanimod effective as induction, maintenance therapy for ulcerative colitis

A once-daily oral formulation of ozanimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, outdid placebo as induction and maintenance therapy for moderate-to-severe* active ulcerative colitis (UC), findings from the phase III True North study have shown.

Traditional treatments (ie, aminosalicylates) for UC mostly target moderate disease. [Am J Gastroenterol 2019;114:384-413] Glucocorticoids are not recommended for maintenance due to adverse effects, [Aliment Pharmacol Ther 2016;44:1018-1029; Aliment Pharmacol Ther 2007;26:779-794] while newer agents (eg, biologics, Janus kinase inhibitors) lose efficacy in the long term and are tied to infusion reactions, infections, and cancers. [Eur J Gastroenterol Hepatol 2015;27:804-812] “[As such, there is a need] for new oral treatments for UC that are safe and glucocorticoid-sparing, and have durable efficacy,” said the researchers.

The 10-week induction period comprised a double-blind (DB) and an open-label (OL) phase. A total of 645 participants were randomized 2:1 to receive oral ozanimod hydrochloride 1 mg or placebo QD in the DB phase, while 367 were given ozanimod at the same dose in the OL phase. The maintenance period followed thereafter, wherein those with a clinical response** to ozanimod during the induction phase (n=457) were rerandomized 1:1 to receive ozanimod or placebo through week 52. [N Engl J Med 2021;385:1280-1291]

At week 10, more patients on ozanimod achieved clinical remission*** compared with those on placebo (18 percent vs 6 percent). Ozanimod also outdid placebo in terms of key secondary endpoints of clinical response (48 percent vs 26 percent), endoscopic improvement (27 percent vs 12 percent), and mucosal healing (13 percent vs 4 percent; p<0.001 for all).

The maintenance phase also favoured ozanimod over placebo in terms of clinical remission (37 percent vs 18 percent), clinical response (60 percent vs 41 percent), endoscopic improvement (46 percent vs 26 percent), and mucosal healing (30 percent vs 14 percent; p<0.001 for all).

“These results were observed in patients with active disease that had been inadequately controlled by conventional agents, as determined based on required concomitant therapy with aminosalicylates or glucocorticoids at trial entry,” said the researchers.

The current findings also reinforce phase II data reflecting the efficacy of ozanimod for moderate-to-severe UC and Crohn’s disease (CD). [N Engl J Med 2016;374:1754-1762; Lancet Gastroenterol Hepatol 2020;5:819-828]

Safety profile

The researchers explored adverse events of special interest (AESIs; eg, macular oedema, cancer, and serious infections) based on their reported associations with S1P receptor modulation. [Acta Neurol Belg 2017;117:821-827; Lancet 2018;391:1263-1273] While these did occur with ozanimod (n=3, 3, and 12, respectively), the incidences were low, the researchers noted.

The incidence of bradycardia – another AESI – was greater with ozanimod vs placebo during the induction phase (n=5 vs 0) but not during maintenance phase (none in both arms). There were no cases of second-degree type 2 atrioventricular (AV) block or third-degree AV block. “The absence of clinically significant bradycardia or cardiac conduction abnormalities may have been due to mitigation by the 7-day dose-escalation schedule,” the researchers explained.

Despite the higher rate of elevated liver aminotransferase levels ozanimod vs placebo (≥2× ULN^#, 25 percent vs 6 percent), none had drug-induced (as per Hy’s law criteria) or severe liver injury. Also, liver events were generally mild or moderate, with a study regimen discontinuation rate of <1 percent.

These findings align with evidence reflecting the favourable safety profile of ozanimod for UC, CD, or relapsing multiple sclerosis. [Drugs 2020;80:841-848; Lancet Neurol 2019;18:1009-1020; Lancet Neurol 2019;18:1021-1033]

The open-label extension phase is underway to validate the current results.