Products
Siponimod was approved in film-coated tablet form in the United States in 2019 and in many countries in 2020 (Mayzent).
Structure and properties
Siponimod (C29H35F3N2O3, Mr = 516.6 g/mol) is present in the drug as a 2:1 co-crystal with the fumaric acid and as a white powder. The drug was developed starting from fingolimod, the first representative of this group of drugs. The goal of drug discovery was to increase selectivity for S1P receptors and decrease half-life. Unlike fingolimod, siponimod is not a prodrug.
Effects
Siponimod (ATC L04AA42) has immunomodulatory and neuroprotective properties. The effects are based on high-affinity, selective, and dual binding to S1P receptors 1 and 5. Siponimod inhibits the egress of lymphocytes from lymph nodes and reduces their numbers in the peripheral circulation. Furthermore, siponimod crosses the blood–brain barrier and exerts additional neuroprotective and anti-inflammatory effects in the central nervous system mediated by S1P receptor binding. Siponimod is more selective than fingolimod, which interacts with four of the five receptor subtypes (1,3,4,5). Interaction with subtype 3 should be avoided because it has been associated with the development of bradycardia and vasoconstriction. The half-life is in the range of 30 hours, which is significantly shorter than that of fingolimod. Thus, the effects are more rapidly reversible after discontinuation.
Indications
For the treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with inflammatory disease activity as demonstrated by clinical relapses or imaging.
Dosage
According to the SmPC. Treatment is initiated with dose titration to reduce the risk of cardiovascular adverse events. Subsequently, tablets are taken once daily, independent of meals. CYP2C9 genotyping must be performed before initiating therapy.
Contraindications
For complete precautions, see the drug label.
Interactions
Siponimod is metabolized primarily by CYP2C9 as well as by CYP3A4, and corresponding interactions with inhibitors and inducers may occur. Other interactions have been described with the following drugs:
- Immunosuppressive, immunomodulatory, and antineoplastic agents.
- Antiarrhythmic agents, agents that prolong the QT interval.
- Agents that lower the heart rate
- Beta blockers
- Vaccines
Adverse effects
The most common possible adverse effects include headache and hypertension. Siponimod may increase the risk of infectious diseases. Bradycardia and delay in atrioventricular conduction may occur, particularly at the beginning of therapy. The risks are addressed with various precautions (see the SmPC).
