Mayzent (siponimod)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations.

Company:

Approval Status:

Approved March 2019

Specific Treatments:

relapsing multiple sclerosis

Therapeutic Areas

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General Information

Mayzent (siponimod) is a sphingosine1-phosphate receptor modulator.

Mayzent is specifically indicated 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. 

Mayzent is supplied as a tablet for oral administration. Prior to administration the following should be assessed:

• CYP2C9 Genotype Determination: Test patients for CYP2C9 variants to determine CYP2C9 genotype. An FDA-cleared or -approved test for the detection of CYP2C9 variants to direct the use of siponimod is not currently available.

• Complete Blood Count: Review results of a recent complete blood count (CBC).

• Ophthalmic Evaluation: Obtain an evaluation of the fundus, including the macula.

• Cardiac Evaluation: Obtain an electrocardiogram (ECG) to determine whether preexisting conduction abnormalities are present. In patients with certain preexisting conditions, advice from a cardiologist and first-dose monitoring is recommended. Determine whether patients are taking drugs that could slow heart rate or atrioventricular (AV) conduction.

• Current or Prior Medications: If patients are taking anti-neoplastic, 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.

• Vaccinations: Test patients for antibodies to varicella zoster virus (VZV) before initiating Mayzent; VZV vaccination of antibody negative patients is recommended prior to commencing treatment with Mayzent.

• Liver Function Tests: Obtain recent (i.e., within last 6 months) transaminase and bilirubin levels.

The recommended dosing is as follows:

Patients With CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2

Maintenance Dosage After treatment titration: (see Treatment Initiation), the recommended maintenance dosage of Mayzent is 2 mg taken orally once daily starting on Day 6. Dosage adjustment is required in patients with a CYP2C9*1/*3 or *2/*3 genotype. Treatment Initiation: Initiate Mayzent with a 5-day titration. Please refer to drug label for titration schedule. A starter pack should be used for patients who will be titrated to the 2-mg maintenance dosage.

Patients With CYP2C9 Genotypes *1/*3 or *2/*3

Maintenance Dosage: In patients with a CYP2C9*1/*3 or *2/*3 genotype, after treatment titration (see Treatment Initiation), the recommended maintenance dosage of Mayzent is 1 mg taken orally once daily starting on Day 5. Treatment Initiation: Initiate Mayzent with a 4-day titration. Please refer to the drug label for titration schedule. Do not use the starter pack for patients who will be titrated to the 1-mg maintenance dosage.

First Dose Monitoring in Patients With Certain Preexisting Cardiac Conditions

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.

First Dose 6-Hour Monitoring: Administer the first dose of Mayzent in a setting where resources to appropriately manage symptomatic bradycardia are available. Monitor patients for 6 hours after the first dose for signs and symptoms of bradycardia with hourly pulse and blood pressure measurement. Obtain an ECG in these patients at the end of the Day 1 observation period.

Additional Monitoring After 6-Hour Monitoring: If any of the following abnormalities are present after 6 hours (even in the absence of symptoms), continue monitoring until the abnormality resolves: • The heart rate 6 hours post-dose is less than 45 bpm; • The heart rate 6 hours post-dose is at the lowest value post-dose, suggesting that the maximum pharmacodynamic effect on the heart may not have occurred; • The ECG 6 hours post-dose shows new onset second-degree or higher AV block. If post-dose symptomatic bradycardia, bradyarrhythmia, or conduction related symptoms occur, or if ECG 6 hours post-dose shows new onset second degree or higher AV block or QTc greater than or equal to 500 msec, initiate appropriate management, begin continuous ECG monitoring, and continue monitoring until the symptoms have resolved if no pharmacological treatment is required. If pharmacological treatment is required, continue monitoring overnight and repeat 6-hour monitoring after the second dose.

Reinitiation of Mayzent After Treatment Interruption

After the initial titration is complete, if Mayzent treatment is interrupted for 4 or more consecutive daily doses, reinitiate treatment with Day 1 of the titration regimen; also complete first dose monitoring in patients for whom it is recommended.

 

Clinical Results

FDA Approval

The FDA approval of Mayzent was based on the phase III EXPAND trial. This was a randomized, double-blind, placebo-controlled study comparing the efficacy and safety of Mayzent versus placebo in 1,651 subjects with secondary progressive multiple sclerosis (SPMS) 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 3.0-6.5 at study entry. Patients were randomized to receive either once daily Mayzent 2 mg or placebo, beginning with a dose titration. Evaluations were performed at screening, every 3 months during the study, and at the time of a suspected relapse. MRI evaluations were performed at screening and every 12 months. The primary endpoint of the study was the time to 3-month confirmed disability progression (CDP), 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. Mayzent significantly reduced the risk of three-month confirmed disability progression (CDP) (primary endpoint; 21% reduction versus placebo, p=0.013; 33% reduction versus placebo in patients with relapse activity in the two years prior to screening, p=0.01). Mayzent also reduced the annualized relapse rate (ARR) by 55%.

Side Effects

Adverse effects associated with the use of Mayzent may include, but are not limited to, the following:

headache

hypertension

transaminase increases

Mechanism of Action

Mayzent (siponimod) is a sphingosine-1-phosphate (S1P) receptor modulator. Siponimod binds with high affinity to S1P receptors 1 and 5. Siponimod blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. 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. 

Additional Information

For additional information regarding Mayzent or relapsing multiple sclerosis, please visit https://www.mayzent.com/