Pharmacology

Pharmacodynamics. Lymphocyte exit from lymph nodes and their recirculation into blood is controlled by the sphingolipid sphingosine 1-phosphate (S1P). Ponesimod, an S1P1 immunomodulator, blocks S1P signaling and stops lymphocytes from leaving lymph nodes, which reduces the number of circulating immune cells and prevents them from infiltrating target tissues. Animal experimental studies have shown that selective activation of S1P1 using ponesimod leads to blood lymphocyte count reduction and efficacy in models of lymphocyte-mediated tissue inflammation (06). In patients with relapsing multiple sclerosis, ponesimod prevents lymphocytes from crossing the blood-brain barrier and entering the central nervous system and prevents them from causing damage to myelin. Immune cell count reduction is rapid, dose-dependent, and maintained with continued dosing. Ponesimod’s effect is reversible and wears off within one or two weeks of discontinuation.

Pharmacokinetics. The pharmacokinetics of ponesimod are similar in healthy subjects and patients with multiple sclerosis, with 25% intersubject variability across studies. Important points regarding the pharmacokinetics of ponesimod in various phase 1 studies include the following (02):

Routes of administration. Oral

Clinical trials

Ponesimod was tested at different doses in a phase 2 trial (NCT01006265): 10 mg, 20 mg, and 40 mg. Results showed that ponesimod significantly reduced the number of new active lesions on MRI brain scans and reduced the frequency of relapses in patients with multiple sclerosis (05). An extension study (NCT01093326) confirmed the findings.

A phase 3 randomized clinical trial showed that ponesimod was superior to teriflunomide on annual relapse rate reduction, fatigue, MRI lesions, and brain volume loss, with no evidence of disease activity, but disability accumulation could not be confirmed (03). The safety profile was in line with the previous safety observations of ponesimod and the known profile of other S1PR modulators.

Indications

Ponesimod is indicated for the treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults.

Contraindications

Contraindications include patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or class III/IV heart failure during the 6 months prior to treatment. The presence of Mobitz type II second-degree, third-degree atrioventricular block, or sick sinus syndrome are contraindications, unless the patient has a functioning pacemaker.

Goals and duration of treatment

As a disease-modifying therapy, ponesimod aims to prevent relapses in multiple sclerosis. The beneficial effect was demonstrated in the latest phase 3 clinical trial during 2015 to 2019. The drug was introduced into practice in 2021, and the long-term benefit in multiple sclerosis remains to be demonstrated in future studies.

Dosing

Titration is required for initiation of treatment with a 2 mg dose and daily increase according to the recommended schedule until day 15, when the maintenance dosage of 20 mg is reached and taken orally once daily thereafter.

Special considerations

Pregnancy. Animal studies indicate that ponesimod may harm the fetus in the absence of maternal toxicity. There are no adequate and well-controlled studies of ponesimod in pregnant women. Women with childbearing potential should use effective contraception to avoid pregnancy during, and for 1 week after stopping, ponesimod treatment because it takes approximately 1 week to eliminate the drug from the body. There are no data on the presence of ponesimod in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

Pediatrics. It is not known whether ponesimod is safe and effective in children.

Interactions

Ponesimod can interact with the following categories of medicines: antiarrhythmics, antihypertensives, calcium channel blockers, beta-blockers, and immune modulators such as alemtuzumab. It may also interact with rifampin, phenytoin, or carbamazepine.

Live vaccines should not be used during treatment with ponesimod, for at least 1 month before starting, and for 1 to 2 weeks after stopping use of ponesimod as this may activate the infection that the vaccine aims to prevent.

Coadministration of ponesimod is not expected to decrease the efficacy of an oral hormonal contraceptive.

Adverse effects

The most commonly reported side effects of ponesimod during clinical trials were upper respiratory tract infections, elevated liver enzymes, and hypertension. Bradycardia may occur at the start of treatment with ponesimod. Therefore, first-dose monitoring with ECG is recommended in patients with certain preexisting cardiac conditions.

S1PR modulators, including ponesimod, have been associated with an increased risk of approximately 1.1% of macular edema, particularly in patients with a history of uveitis and diabetes mellitus.