Table 2.

Main characteristics of the S1PR modulators approved for MS.

Fingolimod* (FTY720) Novartis Pharmaceuticals, Basel, Switzerland; generic also available	Functional antagonist at S1PR1, S1PR3, S1PR4, S1PR5 (significantly lower affinity for S1PR3).	Trials: FREEDOMS and FREEDOMS-II (placebo-controlled); TRANSFORMS (interferon beta-1a-controlled). Approvals and indications: 2010 (FDA) and 2011 (EMA) for adults with relapsing MS/highly active relapsing MS or active despite another DMT; 2018 (FDA) and 2019 (EMA) for pediatric patients 10 years and older. Decreases disease activity (clinical and brain imaging outcomes).	Adults: one 0.5 mg capsule, orally, once daily. Pediatric with body weight ≤40 kg: one 0.25 mg capsule, orally, once daily. Pediatric >40 kg: one 0.5 mg capsule, orally, once daily.	Contraindications: myocardial infarction in the previous 6 months, unstable angina pectoris, decompensated heart failure, severe heart arrhythmias requiring antiarrhythmic treatment, atrioventricular block (second-degree Mobitz II or third-degree), sick sinus syndrome without pacemaker, prolonged baseline QTc interval, stroke, or transient ischemic attack, severe lymphopenia, concurrent immunosuppression (including concomitant immunosuppressive therapies or concomitant diseases resulting in immunosuppression), ongoing cancers, severe active infections, and active chronic infections, moderate or severe liver impairment, macular edema, pregnancy or breast feeding, females with fertile potential not using effective contraceptive methods, history of PML or cryptococcal meningitis, concomitant phototherapy or photochemotherapy, untreated severe sleep apnea, hypersensitivity to the active substance or excipients. *siponimod is contraindicated in people with CYP2C9*3*3 genotypes, and reduced dose should be used in CYP2C9*2*3 or 1*3 genotypes. Caution: elderly patients; people with arterial hypertension, diabetes mellitus, baseline bradycardia or bradycardia-inducing concomitant medication, history of uveitis, syncope or cardiac arrest, uncontrolled hypertension, renal impairment; use of drugs that interfere with the metabolization of the S1PR modulators; concomitant use of other immunomodulators or immunosuppressant drugs; concomitant use of CYP430 inducers or other substances that may interfere with the metabolization of the S1PR modulator (e.g. St John’s Wort). Side effects: transient first-dose bradycardia, rarely other cardiac first-dose transient side effects (including atrioventricular block), lymphopenia (related to the mechanism of action in MS), increased liver enzymes, infections (upper respiratory and urinary tract infections, rarely VZV and HSV reactivation, and very rarely opportunistic infections, including cryptococcal meningitis and PML), hypertension, macular edema, skin cancer and very rarely other cancers, neurological side effects (convulsions, PRES), decreased efficacy of vaccines; possibly changes in ventilatory function, rebound of MS after discontinuation, paradoxical exacerbation after initiation when switching from other DMTs; birth defects and spontaneous abortions. First dose observation (for 6 hours, or longer, if needed; heart rate, blood pressure, electrocardiogram): for all patients starting fingolimod; for selected patients at risk of cardiac side effects starting siponimod, ozanimod, or ponesimod. Monitoring: complete blood counts, liver enzymes, ophthalmology, dermatology.
Siponimod (BAF312) Novartis Pharmaceuticals, Basel, Switzerland	Functional antagonist at S1PR1, S1PR5	Trials: BOLD, BOLD extension, EXPAND (placebo-controlled). Approvals and indication: 2019 (FDA), for adults with relapsing MS, and 2019 (EMA) for adults with active SPMS. Decreases disease activity and disease progression (clinical and brain imaging outcomes).	Adults*: one 2 mg tables, orally, once daily; genotypes CYP2C9*2*3 or 1*3: 1 mg daily. Titration: over 5 days, from 0.25 mg qd to 1.25 mg qd Pediatric: not tested in this population
Ozanimod (RPC1063) Bristol-Myers Squibb, Dublin, Ireland	Functional antagonist at S1PR1, S1PR5	Trials: RADIANCE and SUBEAM (30 mcg im qw interferon beta-1a-controlled). Approvals and indication: 2020 (FDA, EMA), for relapsing forms of MS. Decreases the annualized relapse rate and improves brain imaging outcomes compared with interferon beta-1a. Also approved for ulcerative colitis.	Adults: one 0.92 mg capsule, orally, once daily. Titration: over the course of 7 days, from 0.23 mg qd to 0.46 mg qd. Pediatric: not tested in this population
Ponesimod (ACT-128800) Jannsen Pharmaceuticals, Beerse, Belgium	Functional antagonist at S1PR1, S1PR5	Trials: OPTIMUM (teriflunomide-controlled). Approvals and indication: 2021 (FDA, EMA), for relapsing forms of MS. Decreases the annualized relapse rate and improves brain imaging outcomes compared with teriflunomide.	Adults: one 20 mg tablet, orally, once daily. Titration: over the course of 2 weeks, from 2 to 10 mg qd. Pediatric: not tested in this population

Abbreviations: DMTs = disease modifying treatments; EMA = European Medicine Agency; FDA = Food and Drug Administration; im = intramuscular; HSV = herpes simplex virus; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; PRES = posterior reversible encephalopathy syndrome; qw = once weekly; S1PR = sphingosine 1-phosphate receptor; SPMS = secondary progressive MS; VZV = varicella zoster virus.

References: 13–17, 40–46, 55–69.