FDA approves ozanimod in MS


The U.S. Food and Drug Administration has approved ozanimod (Zeposia) for the treatment of relapsing forms of MS, including clinically isolated syndrome (CIS), RRMS and active SPMS. The drug was developed by Receptos, then acquired by Celgene before Celgene was acquired in turn by Bristol-Myers Squibb. Ozanimod was submitted for review by Health Canada in December 2019.

Ozanimod is the third in a class of sphingosine 1-phosphate (S1P) receptor agonists (functional antagonists) that includes fingolimod and siponimod. Like siponimod, ozanimod binds to S1P receptors 1 and 5 and is dose titrated to minimize a first-dose effect. Ozanimod is administered with or without food at a dose of 0.23 mg on days 1-4, 0.46 mg on days 5-7 and 0.92 mg/day thereafter. The approved doses are slightly lower than those used in clinical trials. 

Approval was based on the results of two phase III trials in relapsing MS. In the SUNBEAM study, 1,346 patients were randomized to one of two daily doses of ozanimod (0.5 and 1.0 mg) or weekly intramuscular interferon-β-1a for one year (Comi et al. Lancet Neurol 2019;18:1009-1020). The annualized relapse rate (ARR) was 0.18 with the 1-mg/day dose, 0.24 with the 0.5-mg dose and 0.35 with IFN-β. The same study design was used in the 24-month RADIANCE-B trial (Cohen et al. Lancet Neurol 2019;18:1021-1033). ARR was 0.17 and 0.22 with the two ozanimod doses versus 0.28 with IFN-β.

The most common adverse reactions reported in clinical trials included elevated liver enzymes, urinary tract infection and hypertension. The label includes warnings for infections (e.g. UTI, herpes zoster), fetal risk and macular edema.  

Ozanimod was developed as an S1P modulator with better cardiac safety and an improved pharmacokinetic profile compared to fingolimod, although both areas have proved to be problematic. Despite S1P-1,5 selectivity, treatment may be associated with transient bradycardia (mean 1.2 beats/minute in Hour 5; maximal effect on day 8) and transient atrioventricular (AV) conduction delays. An ECG is required prior to drug initiation to rule out cardiac conduction abnormalities. The product monograph does not have provisions for first-dose observation (FDO); rather, a cardiologist should be consulted for patients with cardiac conduction abnormalities, ischemic heart disease or other pre-existing cardiac conditions.

The pharmacology of the drug has also been a challenge. Manufacturer Celgene received a Refuse to File letter when it initially submitted to the FDA in 2018; the nonclinical and clinical pharmacology sections were deemed to be insufficient for a complete review. At issue appears to be CC-112273, the major active metabolite of ozanimod, which produces most of the clinical effects of the drug, suggesting that ozanimod is largely acting as a pro-drug. While ozanimod has a shorter half-life than fingolimod (21 hours vs. 168 hours), the half-life of the CC-112273 metabolite is considerably longer (about 264 hours), which would require a washout period of 2-3 months.

Ozanimod/CC-112273 may be associated with significant drug interactions. As with monoamine oxidase (MAO) inhibitors, ozanimod may be associated with a “cheese effect” – excess tyramine consumption  may result in severe hypertension and patients receiving ozanimod should be counselled to avoid foods high in tyramine (e.g. aged cheese, cured/smoked meats and fish, fava beans). Co-administration of ozanimod with MAO-A or MAO-B inhibitors (e.g. phenelzine, selegiline) is contraindicated. Concomitant use of serotonergic drugs (e.g. SSRIs, SNRIs, tricyclic antidepressants) is not recommended. The monograph notes that there may be a risk of severe side effects in patients taking opioids. There are also significant drug-drug interactions with CYP2C8 inducers (e.g. rifampin) and inhibitors (e.g. trimethoprim); and breast cancer resistance protein (BCRP) inhibitors (e.g. omeprazole, cimetidine, rosuvastatin, leflunomide, HIV protease inhibitors). As teriflunomide is the active metabolite of leflunomide, it may be prudent for patients to undergo an active elimination protocol prior to switching to ozanimod. CC-112273 exposure is also 50% lower in smokers, suggesting that clinical efficacy may be lower in smokers. Use of ozanimod following alemtuzumab is not recommended.

Recommend to a Colleague

Related Posts

Go back to home page