Siponimod – new data in SPMS

 

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Siponimod, the selective sphingosine-1-phosphate (S1P) receptor modulator (S1P1,5), produces a sustained reduction in worsening disability for up to five years in patients with secondary-progressive MS (SPMS), according to data submitted to the American Academy of Neurology annual meeting (Kappos et al. AAN 2020; abstract S40.003).

Siponimod (Mayzent) was recently approved in Canada as the first treatment specifically developed for SPMS. The Health Canada indication is to delay disability in SPMS patients with active disease evidenced by relapses or imaging features characteristic of MS inflammatory activity. Mayzent received FDA approval a year ago for relapsing forms of MS, including CIS, RRMS and active SPMS (see Siponimod receives FDA approval for SPMS, NeuroSens, March 29, 2019).

Approval was based on the results of the phase III EXPAND trial, which randomized 1651 SPMS patients to siponimod 2 mg/day or placebo (Kappos et al. Lancet 2018;391:1263-1273). The study population was not enriched with respect to age and baseline inflammatory activity, in contrast to other progressive MS trials. Mean age at entry was 48 years (range 22-61); 78% had no relapses in the year prior to screening; and 75% had no Gd+ lesions at baseline. Mean duration of MS was 12-13 years; mean duration of SPMS was 3.8 years; and mean EDSS score was 5.4. The median duration of siponimod exposure was 18 months. The proportion with 3-month confirmed disability progression (CDP) was 26% with siponimod versus 32% with placebo, a 21% risk reduction. The proportion with 6-month CDP was 20% and 26%, respectively, a 26% risk reduction. Differences in time to 3-month confirmed worsening on the Timed 25-Foot Walk were not significant.

Two subgroup analyses have been performed on patients with and without ongoing inflammatory activity. There was a 37% reduction in 6-month CDP in patients with active SPMS (n=779) (Gold et al. ECTRIMS 2019; abstract P750). Also noteworthy was a separate analysis that reported an 18% reduction in 6-month CDP in non-relapsing patients (n=1051) (Cree et al. AAN 2018; abstract S8.005), suggesting some effect of treatment on the neurodegenerative component (ICER Final Evidence Report, June 20, 2019).

EXPAND was a short, event-driven trial but longer-term data are now available for up to five years (Kappos L. AAN 2020; abstract S40.003). The time to six-month CDP was longer with continuous siponimod versus placebo/siponimod (21.0 vs. 13.6 months), a 54% reduction. The median time to six-month CDP was not reached with continuous siponimod (vs. 51.7 months with placebo/siponimod). ARR was 0.054 versus 0.097 for the continuous and delayed groups, respectively. The risk of worsening SDMT score was reduced 23% with immediate versus delayed siponimod. There were no new safety findings.

Two other analyses from EXPAND were also scheduled for AAN. A prospective magnetization transfer ratio (MTR) substudy reported that changes from baseline in MTR values at 24 months were superior with siponimod versus placebo with respect to normal-appearing brain tissue (61% reduction), normal-appearing white matter (98% reduction), and cortical grey-matter (55% reduction) (Arnold DL. AAN 2020; abstract S40.006). A separate post-hoc analysis reported that siponimod significantly reduced grey-matter atrophy by 48-116% depending on the subgroup analysed (Fox RJ. AAN 2020; abstract S40.005).

The siponimod treatment regimen is a five-day dose titration (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) followed by a daily maintenance dose. The usual maintenance dose is 2 mg/day starting on Day 6. 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 < 1% in other groups. The recommended maintenance dose for these patients is 1 mg/day. Siponimod is contraindicated in patients with the CYP2C9*3/*3 genotype, which occurs with a frequency of about 0.7% in the Ashkenazi Jewish population and < 0.5% in all other groups (Scott et al. Pharmacogenomics 2010;11:781-791).

The estimated time to absolute lymphocyte count (ALC) nadir is 3-7 hours post-dose (Shakeri-Nejad et al. Clin Ther 2020;42:175-195). The estimated half-life is 30 hours, with ALC recovery to normal values in >90% of patients within 10 days, which may be clinically useful if treatment is interrupted or switched.

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