Siponimod receives FDA approval for SPMS


Siponimod (Mayzent), a second-generation sphingosine-1-phosphate (S1P) receptor modulator, has received approval by the U.S. Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome (CIS), relapsing-remitting MS and active secondary-progressive MS (SPMS).

The estimated prevalence of SPMS in the U.S. is 37.1 per 100,000 population (Khurana et al. AAN 2018; abstract P2.380), or approximately 122,000 patients. Only two prior therapies have received approval for SPMS: mitoxantrone, which is infrequently used due to cardiotoxicity; and interferon-beta-1b (in Canada), which is considered to be ineffective in slowing worsening disability (La Mantia et al. Cochrane Database Syst Rev 2012;1:CD005181).

The approval of siponimod was based on the phase III EXPAND trial (Kappos et al. Lancet 2018;391:1263-1273), in which 1645 patients with SPMS received either siponimod 2 mg/day or placebo. Median time on study was 21 months; median drug exposure was 18 months. The study population was not enriched as to age and baseline inflammatory activity. Mean age at entry was 48 years; the mean duration of MS was 12-13 years; and mean duration of SPMS was 3.6-3.9 years. Two-thirds of patients had no relapses in the two years prior to enrolment, and 75% had no Gd+ lesions.

The rate of three-month confirmed disability progression was 26% with siponimod versus 32% with placebo, a reduction of 21%. The rate of six-month confirmed disability progression was 20% with siponimod versus 26% with placebo, a reduction of 26%. There was no significant effect on Timed 25-Foot Walk (>20% worsening confirmed at three months).

The treatment regimen is a five-day dose titration followed by a daily maintenance dose. The starting dose is 0.25 mg on Days 1-2, 0.5 mg on Day 3, 0.75 mg on Day 4 and 1.25 mg on day 5. The maintenance dose is 2 mg/day starting on Day 6. The titration regimen must be re-started if one of the titration doses is missed for over 24 hours. During maintenance, the drug must be re-initiated if a patient misses four or more consecutive days.

Pre-initiation requirements include a CBC, an ECG, an eye examination of the fundus, a liver function test within the preceding six months, and varicella zoster virus (VZV) antibody testing. Since siponimod is dose-titrated, a six-hour first-dose observation period is not required. First-dose observation is recommended in patients with bradycardia (less than 55 beats/minute), AV block or a history of myocardial infarction or heart failure.

Genotyping for cytochrome (CYP)-2C9 variants is required since AUC is 2-4 fold higher in individuals who are poor metabolizers (CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) (Gardin et al. Clin Pharmacokinet 2019; 2019;58:349-361). The frequency of the CYP2C9*2/*3 genotype is highest in the Ashkenazi Jewish (2.6%) and Caucasian (1.9%) populations and less than 1% in other groups. The frequency of the CYP2C9*3/*3 genotype is highest in the Ashkenazi Jewish population (0.7%) and less than 0.5% in all other groups (Scott et al. Pharmacogenomics 2010;11:781-791). No FDA-approved test for CYP2C9 analysis is currently available.

During treatment, periodic blood-pressure monitoring is required. Pulmonary function testing and an ophthalmic exam are recommended if clinically indicated. Women of childbearing age should avoid pregnancy during treatment and for 10 days following drug discontinuation.

Fingolimod (Gilenya) was the first of the S1PR class of drugs and was approved in 2010. Second-generation agents were developed to improve upon the pharmacokinetics and receptor-interaction profile. The half-life of siponimod is 22-38 hours and is eliminated in about 7 days (Gergely et al. Br J Pharmacol 2012;167:1035-1047). The drug is selective for the S1PR1 subtype expressed on lymphocytes, which blocks lymphocyte egress from secondary lymphoid organs; and S1PR5, which is expressed on astrocytes, oligodendrocytes, and neurons. Unlike fingolimod, siponimod is not a functional inhibitor of S1PR3 expressed on cardiac myocytes, which was expected to reduce its effects on cardiac function. However, siponimod does produce transient bradycardia due to its effects on S1PR1, an effect that can be mitigated by dose titration (Gajofatto A. Drug Des Devel Ther 2017;11:3153-3157).

In the EXPAND trial, the most common adverse events were headache, hypertension and transaminase increases. Adverse events of interest were herpes zoster (2% vs. placebo 1%), bradyarrhythmia (3% vs. placebo 0.4%), macular edema (2% vs. placebo < 1%), and elevated ALT (1% vs. placebo < 1%). The incidence of infections was the same with siponimod and placebo (49%). The rate of discontinuation due to serious adverse events was similar (siponimod 3% vs. placebo 2%).

Mayzent is expected to become commercially available in the U.S. next week. Application has been made to Health Canada and other regulatory authorities and further approvals are expected over the next few months.

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