Siponimod

Tablet once a day, sphingosine-1-phosphate receptor modulator of lymphocytes, inhibiting migration of lymphocytes to inflammation, but specific for certain subtypes (unlike nonspecific fingolimod).

Trials
BOLD 2013 phase 2 dose finding placebo control trial in RRMS – reduced number of brain lesions by up to 80%; reduced relapse rates from 0.58 on placebo to 0.2 on siponimod

EXPAND 2018 phase 3 placebo control trial in SPMS -  reduced risk of confirmed disability by 21% and risk of relapses by 55%. In “active MS” subgroup - reduced risk of confirmed disability by 31%.

NICE approval November 2020
NICE- “Siponimod is recommended, within its marketing authorisation, as an option for treating secondary progressive multiple sclerosis with evidence of active disease (that is, relapses or imaging features of inflammatory activity) in adults.”

Active disease – relapses in last two years or MRI evidence of disease activity

NB Interferon-1b (Extavia) also NICE approved for SPMS with relapses

Side effects
Headaches, transaminitis, nasopharyngitis, falls

Adverse effects

 * Bradycardia - 1st dose observation only required in past MI, Class I or II heart failure, sinus bradycardia, or 1st degree or Mobitz type 1 heart block.  Consider not using for these patients. All other patients have specified uptitration at home over five days


 * Cardiac conduction abnormalities - Needs ECG


 * Elevated LFTs - Needs baseline testing.  Trial discontinued when >3xULN


 * Macular edema - 1.8% vs 0.2% in placebo.  May need eye exam and OCT pre treatment if diabetic, uveitis or retinal disorders. All patients after 3-4 months


 * Shingles – Needs +ve VZV abs or vaccination


 * Hypertension – Avoid uncontrolled hypertension


 * Seizures

Contraindications
CYP2C9*3 homozygotes - 0.4% prevalence


 * CYP2C9 is a subtype of Cytochrome P450


 * *1 normal; *2 = 30% reduction activity; *3 = 80% reduction


 * CYP2C9*2*3 and *1*3 have a half dose of siponimod


 * Needs genotype testing (to be provided by company)


 * Care with all CYP2C9 and CYP3A4 inhibitors and inducers (long long list!)


 * BNF interaction table


 * Medscape list of drugs that interact


 * Cytochrome P450 interaction table

Cardiac
 * Recent MI, unstable angina, decompensated or severe heart failure; untreated 3rd degree heart block, Mobitz type 2 heart block or sick sinus syndrome

Immunodeficiency

Past PML, cryptococcal infections

Peanut and soy allergy

Pregnancy
Teratogenic – women need contraception. Washout is short, 10 days. (Single case report of rebound exacerbation)

Breast feeding - unknown

Infections
Delay treatment initiation in patients with severe active infection until resolution

Risk of opportunistic infections such as PML (no cases yet but patients likely to be older)

Clinical trials
Whether on siponimod or not, patients with SPMS may be suitable for the MS-STAT2 trial, being run at BSUH.

Protocols
Southampton protocol