Ozanimod

Q: What is the clinical indication for ozanimod?

A: Ozanimod 0.92 mg PO daily is FDA approved to treat relapsing forms of multiple sclerosis (MS) - clinically isolated syndrome, relapsing- remitting multiple sclerosis, and active secondary progressive multiple sclerosis (patients who are in a progressive phase of the disease but continue to have clinical relapses). The benefit of ozanimod in patients with primary progressive MS and secondary progressive MS without relapses has not been studied.

At the Mellen Center, ozanimod is used as both an option for initial therapy as well as a for a second-line option among those who have failed other therapies due to inadequate efficacy or adverse effects.

Q: What is the mechanism of action of ozanimod?

A: Ozanimod is a selective sphingosine 1-phosphate receptor (S1P) modulator that binds with high affinity to S1P receptor types 1 and 5. Functional antagonism of S1P receptor 1 blocks the ability of lymphocytes to exit lymph nodes, thereby reducing the number of lymphocytes circulating in the peripheral blood and presumably infiltrating the central nervous system.

Fingolimod has a similar mechanism of action but is a broader S1P receptor modulator binding to S1P receptor types 1, 3, 4, and 5. As a more selective S1P modulator, ozanimod was designed to attempt to limit some of the side effects seen with fingolimod including bradycardia.

Q: What are the kinetics of ozanimod?

A: The plasma half-life of ozanimod is approximately 21 hours and the half-life of its active metabolites is approximately 11 days. Complete elimination from the body occurs at approximately 55 days. The circulating absolute lymphocyte count begins decreasing following the first dose and decreases to approximately 45% of baseline at 3 months. The lymphocyte count recovers to the normal range at a median of 30 days with 90% of patients reaching the normal range by 3 months.

Q: Does ozanimod have any significant interactions?

• Class Ia and Class III anti-arrhythmics and known QT prolonging drugs should not be used in combination with ozanimod without advice from a cardiologist.
• Monoamine oxidase inhibitors (e.g., selegiline, phenelzine, linezolid) should not be used in combination with ozanimod due to potential for severe hypertension. Ozanimod should be discontinued at least 14 days before initiating monoamine oxidase inhibitor treatments.
• Tyramine containing foods and beverages with more than 150mg of tyramine could cause severe hypertension and should be avoided. See appendix I for a list of examples of high tyramine foods/ beverages.
• Medications which increase serotonin and/or norepinephrine (e.g., opioids, selective serotonin reuptake inhibitors, selective norepinephrine reuptake inhibitors, tricyclics) may cause hypertension when used in combination with ozanimod. At the Mellen Center we occasionally use these agents in combination but do so in conjunction with close blood pressure monitoring at regular office visits.
• CYP2C8 inhibitors (e.g., gemfibrozil) and CYP2C8 inducers (e.g., rifampin) affect the metabolism of ozanimod and should be avoided. See appendix II for a list of common CY2C8 inhibitors and inducers.
• Breast cancer resistance protein inhibitors (e.g., cyclosporine, eltrombopag) affect metabolism of ozanimod and should be avoided.

Q: What did the clinical trials of ozanimod for MS show?

A: Ozanimod was approved for treatment of MS based on the results of 2 phase III trials in relapsing-remitting MS: the 1-year SUNBEAM trial and the 2-year RADIANCE trial comparing 2 daily doses of ozanimod, 0.5mg ozanimod HCL (equivalent to ozanimod 0.46mg) and 1mg ozanimod HCL (equivalent to ozanimod 0.92mg) to weekly intramuscular interferon beta-1a. Both trials showed superior benefit of ozanimod on annualized relapse rate (ARR). The RADIANCE trial found ARR of 0.17 (95% CI 0.14-0.21) for ozanimod 1mg compared to ARR of 0.28 (95% CI 0.23-0.32) for interferon beta-1a. The SUNBEAM trial showed ARR of 0.18 (95% CI 0.14-0.24) for ozanimod 1mg compared to ARR of 0.35 (95% CI 0.28-0.44) for interferon beta-1a. Additionally both trials showed superior benefit of ozanimod on MRI lesion activity and brain volume loss including whole brain, cortical grey matter, and thalamic volumes. In a pooled analysis, the percentage of participants with of 3-month and 6-month confirmed disability progression was low in both the ozanimod 1mg group at 5.8% and interferon beta-1a group at 4.0% with no significant difference between the groups (HR 1.41, 95% confidence interval 0.92-2.17).

Q: What are the major adverse events associated with ozanimod?

• Cardiac effects: Ozanimod, like other S1P receptor modulators, may lead to bradycardia and atrioventricular conduction slowing with initiation of therapy. In clinical trials up titration with initiation of treatment largely mitigated these effects, with the greatest mean decrease in heart rate from baseline was 1.8 bpm on Day 1 of treatment. Symptomatic bradycardia was reported in 2 of 1775 of the ozanimod treated phase III clinical trial participants. There were no second- or third-degree atrioventricular blocks observed in the ozanimod groups.
• Blood pressure effects: Like other S1P receptor modulators, ozanimod may increase blood pressure. The average increase in blood pressure was 1-2mmg Hg in systolic pressure with no effect on diastolic pressure. This effected noted at 3 months and persisted with continued treatment.
• Respiratory effects: Reductions in forced expiratory volume (FEV1) and forced vital capacity (FVC) were observed in ozanimod treated patients in clinical trials at 3 months. The decline in FEV1 from baseline was 60 mL. The mean difference in predicted FEV1 at 12 months between ozanimod and interferon beta-1a groups was 1.9%.
• Liver Injury: Elevation of hepatic transaminases was seen in 10% of the ozanimod treated group in clinical trials. Elevations 3-fold the upper limit of normal occurred in 5.5% of the ozanimod group and 3.1% of the interferon beta-1a group at median time of 6 months. The majority of trial patients continued ozanimod with values returning to less than 3-fold the upper limit of normal in 2-4 weeks.
• Malignancies: Malignancies including melanoma, basal cell carcinoma, breast cancer, and seminoma were reported in the ozanimod group in clinical trials. An increased risk of cutaneous malignancies has been reported with fingolimod, another S1P receptor modulators. At the Mellen Center we recommend patients follow all age-appropriate cancer screening guidelines and undergo prompt evaluation of skin lesions.
• Posterior Reversible Encephalopathy Syndrome (PRES): PRES has been reported in patients receiving S1P receptor modulators. In the ozanimod clinical trials, 1 case of PRES was reported.

Q: Is macular edema associated with ozanimod?

A: In the clinical trials, the rate of macular edema in the ozanimod group was equal to that of the interferon beta-1a group at 0.3%. However, other S1P receptor modulators have been associated with macular edema. At Mellen Center we typically complete a baseline ophthalmological evaluation using optical coherence tomography (OCT) on all patients prior to starting ozanimod. Subsequent OCT monitoring for macular edema is done if visual symptoms develop.

However, patients with a prior history of uveitis and diabetes mellitus are at increased risk to develop macular edema while taking ozanimod. While this is not an absolute contraindication, these patients undergo a baseline ophthalmologic evaluation as well as regular follow-up examinations.

Q: Is ozanimod associated with progressive multifocal leukoencephalopathy (PML)?

A: A single case of PML was reported in a patient treated with ozanimod in the long-term extension study. PML has also been reported to occur with fingolimod, another S1P receptor modulator in very low rates. Currently, at the Mellen Center we do not preclude patients with a positive JC virus serology from treatment with ozanimod.

Q: Is ozanimod associated with other infections?

A: In clinical trials, the infection rates among participants receiving ozanimod and interferon beta-1a were similar including for serious infection. The ozanimod group had higher rates of upper respiratory infection, herpetic infection, and urinary tract infections. While not reported for ozanimod, 8 cases of cryptococcal meningitis and 3 cases disseminated cryptococcal infections have been reported with fingolimod. Some of these cases have been associated with significant long-term cognitive and neurological impairment or death.

Q: Does ozanimod cause lymphopenia?

A: Ozanimod reduces the circulating absolute lymphocyte count (ALC), its intended pharmacodynamic effect. The magnitude of the effect in trials was an ALC decrease to approximately 45% of baseline at 3 months (approximate mean ALC was 0.8 x10^9) and these lower counts were maintained during treatment. Notably, ALC<200/uL occurred in 3.3% of ozanimod treated patients in clinical trials. However, ALC generally improved to > 200/uL while patients remained on ozanimod treatment.

Who should not receive ozanimod?

Q: Ozanimod is contraindicated in patients with the following:

• In the last 6 months suffered myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III or IV heart failure
• Significant heart rhythm abnormalities (unless the patient has a functioning pacemaker)
• Severe untreated sleep apnea
• Taking a MAO inhibitor

Q: What testing is done before starting ozanimod?

A: Prior to starting treatment with ozanimod, we recommend the following tests:

• Complete blood count (CBC) with differential
• Electrocardiogram (ECG)
• Liver function tests (LFTs)
• Varicella Zoster IgG antibody testing (VZV), and we recommend vaccinating VZV antibody-negative patients prior to starting treatment
• Ophthalmologic evaluation: OCT to screen for macular edema, can also perform ophthalmologic examination to screen for asymptomatic uveitis
• It is also recommended that patients not have active infections when starting ozanimod

Q: How is ozanimod given?

A: Ozanimod is a once-daily oral medication that follows an initial titration shown in the table below. If a dose is missed during the first 2 weeks of treatment the titration should be restarted. If more than 7 consecutive days are missed between Day 15 and Day 28 of treatment, or more than 14 consecutive days after Day 28 of treatment reinitiate treatment using the dose escalation regimen. For shorter treatment interruptions patients may resume daily 0.92mg directly.

Table 1: Dose Titration Regimen

Days 1-4	0.23mg once daily
Days 5-7	0.46mg once daily
Day 8 and thereafter	0.92mg once daily

 

Q: Is first dose observation required for ozanimod as with fingolimod?

The up titration of ozanimod largely mitigates the first dose cardiac effects that are seen with fingolimod. At the Mellen Center, we do not routinely perform first-dose monitoring in patients starting ozanimod. However, data on initiating ozanimod in patients dissimilar to the trial population (i.e., outside of the trial age range of 18-55 years old or those with cardiovascular abnormalities such as long QT interval or resting heart rate less than 55 bpm) are limited. In these scenarios we recommend referral to Cardiology for evaluation.

Q: Is genetic testing required before starting ozanimod as with siponimod?

A: No, unlike siponimod, testing for the CYP2C9 genotype is not required prior to starting ozanimod.

Q: What monitoring is done during ozanimod treatment?

A: Although routine monitoring is not stipulated in the prescribing information, at the Mellen Center, we recommend measuring blood pressure during office visits and checking CBC with differential and LFTs 3-6 months after starting treatment, then every 6-12 months while on the medication. On these labs we expect to see around a 45% reduction in ALC from baseline, but we monitor for severe lymphopenia (ALC<200) and elevated ALT/AST.

Q: How is lymphopenia managed?

A: Currently, there are no data on the level of lymphopenia produced by ozanimod that leads to higher risk of infection. We recommend routine clinical monitoring for infection in all ozanimod patients, especially those who develop ALC<200/uL with concomitant leukopenia, or for patients with a history of frequent infections. If ALC <200/uL we recommend rechecking in one month. For persistent ALC<200/uL we consider switching to another therapy, especially if total WBC also is reduced and/or infections are increased.

Q: What should be known when stopping ozanimod?

A: Severe exacerbation of disease including disease rebound has been reported with discontinuation of S1P receptor modulators. The possibility of severe exacerbation should be considered when stopping ozanimod.

Q: Is ozanimod safe during pregnancy?

A: Although ozanimod has not been studied for use in pregnant women, animal studies suggest it may cause fetal harm including embryo loss. Therefore, female patients with childbearing potential should use effective contraceptive methods while on ozanimod and wait at least 3 months (based on the half-life of the active metabolites) after the last ozanimod dose before attempting to conceive.

Q: Is ozanimod safe while breast feeding?

There currently are no data on the safety of ozanimod on the breastfed infant, however animal studies have shown the medication is secreted into breast milk. At the Mellen Center we typically do not start/restart ozanimod during breast feeding.

Q: Which vaccines should a patient receive while on ozanimod?

A: VZV antibodies should be checked prior to starting ozanimod, and patients who are antibody-negative should receive VZV vaccination. Additionally, should the patient require any live attenuated vaccines, these should be given at least 1 month prior to starting ozanimod.

After starting ozanimod, the use of live attenuated vaccines carries the risk of infection and should be avoided during treatment and for up to 3 months after discontinuation. Also, while on ozanimod treatment and for up to 3 months after treatment discontinuation, vaccines may be less effective. At the Mellen Center we typically proceed with non-live virus, age-appropriate vaccines but advise patients of the potential that these may be less effective, including the SARS-CoV-2 vaccines.

Approach last updated: May, 13 2021

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References

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Appendix I

High Tyramine foods

Tyramine is an amino acid which occurs naturally in the body and in certain foods. As foods age tyramine levels typically increase. Foods and beverages with 150mg of tyramine or greater should be avoided in combination with ozanimod. Examples of high tyramine foods may need to be avoided with ozanimod include:

• Strong or aged cheeses, such as aged cheddar, Swiss and Parmesan; blue cheeses such as Stilton and Gorgonzola; and Camembert.
• Cured meats, such as dry-type summer sausages, pepperoni and salami.
• Smoked or processed meats, such as hot dogs, bologna, bacon, corned beef or smoked fish.
• Pickled or fermented foods, such as sauerkraut, kimchi, caviar, tofu or pickles.
• Sauces, such as soy sauce, shrimp sauce, fish sauce, miso and teriyaki sauce.
• Soybeans and soybean products.
• Snow peas, broad beans (fava beans) and their pods.
• Dried or overripe fruits, such as raisins or prunes, or overripe bananas or avocados.
• Meat tenderizers or meat prepared with tenderizers.
• Yeast-extract spreads, such as Marmite, brewer's yeast or sourdough bread.
• Alcoholic beverages, such as beer — especially tap or homebrewed beer — red wine, sherry and liqueurs.
• Improperly stored foods or spoiled foods. While you're taking an MAOI, your doctor may recommend eating only fresh foods — not leftovers or foods past their freshness dates.

Appendix II

CY2C8 Inhibitors and Inducers Examples

Inhibitors	Inducers
Abiraterone	Rifampin
Clopidogrel
Deferasirox
Gemfibrozil
Teriflunomide
Trimethoprim
Tucatinib