FDA Approves MAYZENT (Siponimod) for the Treatment of Relapsing Forms of Multiple Sclerosis

On March 26, 2019, the U.S. Food and Drug Administration (FDA) approved MAYZENT (siponimod) for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Before initiation of treatment with MAYZENT, determine CYP2C9 genotype, review results of a recent complete blood count, obtain ophthalmic and cardiac evaluations, test for antibodies to varicella zoster virus, and obtain recent transaminase and bilirubin levels. If patients are taking antineoplastic, immunosuppressive, or immune-modulating therapies, or if there is a history of prior use of these drugs, consider possible unintended additive immunosuppressive effects before initiating treatment with MAYZENT (see drug interactions below).

The approved recommended dosage of MAYZENT is based on CYP2C9 genotype:

  • CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2: Initiate MAYZENT with a 5-day titration (Day 1: 0.25 mg, Day 2: 0.25 mg, Day 3: 0.50 mg, Day 4: 0.75 mg, and Day 5: 1.25 mg). If one titration dose is missed for more than 24 hours, reinitiate treatment with Day 1 of the titration regimen. After treatment titration, the recommended maintenance dosage of MAYZENT is 2 mg taken orally once daily starting on Day 6.
  • CYP2C9 Genotypes *1/*3 or *2/*3: Initiate MAYZENT with a 4-day titration (Day 1: 0.25 mg, Day 2: 0.25 mg, Day 3: 0.50 mg, and Day 4: 0.75 mg). If one titration dose is missed for more than 24 hours, reinitiate treatment with Day 1 of the titration regimen. After treatment titration, the recommended maintenance dosage of MAYZENT is 1 mg taken orally once daily starting on Day 5.

Because initiation of MAYZENT treatment results in a decrease in heart rate (HR), first-dose 6 hour monitoring is recommended for patients with sinus bradycardia [HR less than 55 beats per minute (bpm)], first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure.

MAYZENT is contraindicated in patients who have: a CYP2C9*3/*3 genotype; in the last 6 months experienced myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization, or Class III or IV heart failure; or presence of Mobitz type II second-degree, third-degree AV block, or sick sinus syndrome, unless patient has a functioning pacemaker.

Additional information regarding dosage and administration and important warnings and precautions, such as risk of infection, macular edema, bradyarrhythmia and atrioventricular conduction delays, respiratory effects, liver injury, increased blood pressure, and fetal risk can be found in the full prescribing information linked below.

Mechanism of Action (MOA), Pharmacokinetics (PK), and Pharmacodynamics (PD)

MOA: Siponimod is a sphingosine-1-phosphate (S1P) receptor modulator. The mechanism by which siponimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

General PK: Siponimod mean Cmax was 30.4 ng/mL and mean AUCtau was 558 h*ng/mL on day 10 after administration of siponimod 2 mg once-daily over 10 days. Siponimod concentration increases in an apparent dose-proportional manner after multiple once-daily doses of siponimod 0.3 mg to 20 mg. Steady-state plasma concentrations are reached after approximately 6 days of once-daily dosing, and steady-state levels are approximately 2-3-fold greater than the initial dose.

Absorption: The time to reach maximum plasma concentrations of siponimod was about 4 hours (range 3 to 8 hours) after administration of immediate release oral dosage forms. Siponimod absorption is ≥ 70%. The absolute oral bioavailability of siponimod is approximately 84%.

Distribution: Siponimod mean volume of distribution is 124 L. Siponimod fraction found in human plasma is 68%. Protein binding of siponimod is > 99.9%.

Elimination: The apparent elimination half-life is approximately 30 hours. The apparent systemic clearance was estimated to be 3.11 L/h in MS patients.

Metabolism: Siponimod is metabolized primarily by CYP2C9 (79.3%) and to a lesser extent by CYP3A4 (18.5%).

Excretion: Siponimod is excreted via biliary/fecal route. Unchanged siponimod was not detected in urine.

PD:

  • Immune System: MAYZENT induces a dose-dependent reduction of the peripheral blood lymphocyte count within 6 hours of the first dose.
  • Heart Rate and Rhythm: A transient, dose-dependent decrease in heart rate was observed during the initial dosing phase of MAYZENT, which plateaued at doses greater than or equal to 5 mg, and bradyarrhythmic events (AV blocks and sinus pauses) were detected and bradyarrhythmic events (AV blocks and sinus pauses) were detected at a higher incidence under MAYZENT treatment, compared to placebo.
  • Pulmonary Function: Dose-dependent reductions in absolute forced expiratory volume over 1 second were observed in MAYZENT-treated patients and were greater than in patients taking placebo.

Cardiac Electrophysiology: In a thorough QT study, siponimod 2 mg and 10 mg (5 times the recommended dose) doses resulted in a prolongation of QTc, with the maximum mean (upper bound of the two-sided 90% CI) of 7.8 (9.93) ms at 2 mg dose and 7.2 (9.72) ms at 10 mg dose. No dose and exposure-response relationship for QTc effects were found with the 5-fold dose. No subject had absolute QTcF > 480 ms or ΔQTcF > 60 ms for siponimod treatment.

Drug Interactions

  • Anti-Neoplastic, Immune-Modulating, or Immunosuppressive Therapies: Use caution during concomitant administration because of the risk of additive immune effects during therapy and in the weeks following administration. When switching from drugs with prolonged immune effects, consider the half-life and mode of action of these drugs in order to avoid unintended additive immunosuppressive effects. Initiating treatment with MAYZENT after alemtuzumab is not recommended. MAYZENT can generally be started immediately after discontinuation of beta interferon or glatiramer acetate.
  • Anti-Arrhythmic Drugs, QT Prolonging Drugs, Drugs that may Decrease Heart Rate: If concomitant use of MAYZENT with Class Ia (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) anti-arrhythmic drugs is considered, seek advice from a cardiologist as these anti-arrhythmic drugs have been associated with cases of Torsades de Pointes in patients with bradycardia. Treatment with MAYZENT should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties, heart rate lowering calcium channel blockers (e.g., verapamil, diltiazem), or other drugs that may decrease heart rate (e.g., ivabradine, digoxin) because of the potential additive effects on heart rate. If concomitant use of MAYZENT with QT prolonging drugs is considered, seek advice from a cardiologist regarding the switch to non-heart-rate lowering drugs or appropriate monitoring for treatment initiation
  • Beta-Blockers: Use caution when MAYZENT is initiated in patients receiving treatment with a beta-blocker because of the additive effects on lowering heart rate; temporary interruption of the beta-blocker treatment may be needed prior to initiation of MAYZENT. Beta-blocker treatment can be initiated in patients receiving stable doses of MAYZENT.
  • Vaccination: Vaccinations may be less effective during and for up to one month after discontinuation of treatment with MAYZENT. Pause MAYZENT treatment 1 week prior and for 4 weeks after vaccination. Avoid live attenuated vaccines during MAYZENT treatment and for up to 4 weeks after discontinuation of treatment with MAYZENT due to the risk of infection.
  • CYP2C9 and CYP3A4 Inhibitors: Concomitant use of MAYZENT with moderate CYP2C9 and moderate or strong CYP3A4 inhibitors is not recommended. Use caution with moderate CYP2C9 inhibitors.
  • CYP2C9 and CYP3A4 Inducers: Concomitant use of MAYZENT with moderate CYP2C9 and strong CYP3A4 inducers is not recommended. Use caution with moderate CYP2C9 inducers. Concomitant use of MAYZENT and moderate or strong CYP3A4 inducers is not recommended for patients with CYP2C9*1/*3 and*2/*3 genotype.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of siponimod were observed based on gender, race/ethnicity (Japanese and Caucasians), renal impairment, or hepatic impairment.

CYP2C9 Genotype: The CYP2C9 genotype has a significant impact on siponimod metabolism. MAYZENT is contraindicated in patients homozygous for CYP2C9*3 (i.e., CYP2C9*3/*3 genotype) because of substantially elevated siponimod plasma levels. MAYZENT dosage adjustment is recommended in patients with CYP2C9 *1/*3 or *2/*3 genotype because of an increase in exposure to siponimod.

Efficacy and Safety

Efficacy of MAYZENT was demonstrated in a randomized, double-blind, parallel-group, placebo-controlled, time-to-event study in patients with secondary progressive multiple sclerosis who had evidence of disability progression in the prior 2 years, no evidence of relapse in 3 months prior to study enrollment, and an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 at study entry. The primary endpoint was the time to 3-month confirmed disability progression, defined as at least a 1-point increase from baseline in EDSS (0.5-point increase for patients with baseline EDSS of 5.5 or higher) sustained for 3 months. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (incidence > 10%) are headache, hypertension, and transaminase increases.


Full prescribing information is available at https://go.usa.gov/xESgK.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.