A new analysis suggests that ozanimod (Zeposia) may have a better safety profile than fingolimod despite being similar agents (Swallow et al. J Comp Eff Res 2020;9:275-285). Both drugs are sphingosine-1-phosphate (S1P) receptor agonists that act as functional antagonists, sequestering T cells in secondary lymphoid organs. Fingolimod acts on S1PR-1,3,4,5, whereas ozanimod (like siponimod) is selective to S1PR1,5. Ozanimod was approved in Canada for the treatment of relapsing MS in October 2020.
There are no head-to-head studies of the two S1P agents, so a matching-adjusted indirect comparison (MAIC) was performed of phase III data for ozanimod (RADIANCE-B and SUNBEAM) and fingolimod (FREEDOMS, FREEDOMS II and TRANSFORMS). SUNBEAM and TRANSFORMS were 1-year studies; the others were 2-year studies. The ozanimod trials and TRANSFORMS used intramuscular interferon-beta-1a as the active comparator.
The MAIC analysis pooled data for the two ozanimod doses tested (0.5 and 1.0 mg), although only one dose (0.92 mg/day) is recommended for use in Canada. The main difference between the two drugs was a lower risk of first-dose effects with ozanimod, such as conduction abnormalities, first-degree atrioventricular block, bradycardia and blood pressure changes.
However, these findings require some clarification. Ozanimod was developed as a more selective agent in the expectation that sparing S1P3 would result in fewer cardiac effects. Subsequent studies indicated that S1P1 caused GIRK (G-protein-coupled inwardly rectifying potassium) channel activation in atrial myocytes and bradycardia in humans (Gergely et al. Br J Pharmacol 2012;167:1035-1047). Accordingly, next-generation agents (siponimod, ozanimod, ponesimod) have used dose titration to mitigate the first-dose effects. In addition, much of the drug effect of ozanimod appears to be due to its active metabolite, CC112273, which has a long half-life (10 days). As a result, the maximum bradycardic effect with ozanimod does not occur with the first dose but rather at the end of dose titration (day 8) (FDA Summary Review, March 25, 2020). It should be noted that while first-dose observation is not required, ozanimod is contraindicated in patients with a recent cardiovascular event (myocardial infarction, transient ischemic attack, stroke) or cardiac conditions (e.g. heart failure, second- or third-degree AV block, sick sinus syndrome). Heart rate and blood pressure comparisons were confounded by how they were measured in the trials: in the supine or standing positions in the ozanimod trials and in the sitting position for the fingolimod trials.
The MAIC analysis also found that the 2-year risk of some adverse effects, such as herpes infections and lymphopenia, was lower with the ozanimod doses compared to fingolimod. The rate of macular edema with the two therapies was not statistically different.
The FDA review concluded that the benefit-risk profile of ozanimod is similar to that of other S1P receptor modulators (FDA 2020). However, one difference is that an active metabolite of ozanimod acts as a monoamine oxidase (MAO) inhibitor. As a result, the Canadian product monograph states that ozanimod should not be co-administered with MAO inhibitor drugs (e.g. phenelzine, selegiline) or foods high in tyramine (e.g. aged cheese, processed meats, red wine, beer, chocolate) due to the risk of hypertensive crisis (serotonin syndrome) (FDA 2020).