What is the clinical indication for ponesimod?

Ponesimod is an oral medication approved by the Food and Drug Administration to treat relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting MS, and secondary progressive MS with activity.

At the Mellen Center, ponesimod is used as both an option for initial therapy as well as a second-line option among those who have failed other therapies due to inadequate efficacy or adverse effects.

What is the mechanism of action of ponesimod?

Ponesimod is a selective sphingosine 1-phosphate receptor (S1PR) modulator that binds with high affinity to the S1PR type 1 (S1PR1). Unlike the previously approved S1PR modulators, whose proposed mechanism of action is mediated by S1PR1 but which also bind with high affinity to subtypes 3, 4, and/or 5, ponesimod has at least a 10-fold higher affinity for S1PR1 than any other subtype, theoretically lowering its risk for adverse effects.

Binding of ponesimod results in receptor internalization and functional antagonism, thereby eliminating responsiveness to the S1P gradient required for lymphocyte egress from lymph nodes and the thymus. This leads to a reversible, dose-dependent reduction in the circulating blood lymphocytes available to infiltrate the central nervous system (CNS).

What are the kinetics of ponesimod?

Ponesimod reaches maximal plasma concentration in 2.5 to 4 hours after dosing, with maximum plasma lymphocyte reduction after 6 hours. After 1 week of maintenance dosing, the absolute mean lymphocyte count may decrease to 20-30% of baseline, and up to 40% thereafter. Ponesimod’s elimination half-life is approximately 32 hours and there are no active metabolites. Thus, following discontinuation, 90% of patients will have peripheral lymphocyte counts within normal range at 1-2 weeks.

Does ponesimod have any significant interactions?

The absence of active metabolites limits the potential for drug-drug interaction. However, special consideration should be given with respect to ponesimod’s metabolism and potential side effect profile.

Concomitant use of strong CYP3A4 and UGT1A1 inducers (for example rifampin, phenytoin, or carbamazepine) may decrease the systemic exposure of ponesimod and is not recommended. In addition, because of the potential additive effects on heart rate, consultation with a cardiologist should be considered before initiating ponesimod in patients on QT prolonging agents with known arrhythmogenic properties, as well as with any heart rate lowering medications. Beta-blocker treatment can be initiated in patients already tolerating stable doses of ponesimod.

What did the clinical trials for ponesimod show?

Ponesimod was approved for the treatment of MS based on the results of two clinical trials. The first was a randomized placebo-controlled Phase IIb trial during which patients received once-daily oral ponesimod at 10, 20 or 40 mg, or placebo for 24 weeks. The primary endpoint was the cumulative number of new T1 gadolinium-enhanced lesions (T1 Gd+) from weeks 12 to 24 after drug initiation, with secondary endpoints of annualized relapse rate (ARR) and time to first confirmed relapse. Ponesimod treatment at all doses significantly reduced the number of new T1 Gd+ lesions (10mg: rate ratio (RR) 0.57, P=0.0318; 20 mg: RR 0.17, P<0.0001, and 40 mg: RR 0.23, P<0.0001), showed a beneficial effect on clinical endpoints, and had similar proportions of patients reporting at least one treatment-emergent adverse event (TEAE).

In OPTIMUM, a Phase 3, multicenter, randomized, double-blind, active-comparator superiority trial, ponesimod 20mg was compared to teriflunomide 14mg. The primary endpoint was ARR, with secondary endpoints including: changes in symptom domain of Fatigue Symptom and Impact Questionnaire–Relapsing Multiple Sclerosis (FSIQ–RMS) at week 108, the number of combined unique active lesions per year on MRI, and time to 12-week and 24-week confirmed disability accumulation; percent change in brain volume and no evidence of disease activity (NEDA) status were exploratory endpoints. Ponesimod was superior to teriflunomide on ARR reduction (RR: 0.202 vs 0.290, P<.001), fatigue (mean difference in FSIQ-RMS: −0.01 vs 3.56, P<.001), MRI activity (RR of unique active lesions: 1.405 vs 3.164, P<.001), brain volume loss (–0.91% vs –1.25%, P<.001), and NEDA achievement (25.0% vs 16.4%; P<.001). It was not superior in confirmed disability accumulation (10.1% vs 12.4%; P=.29). Regarding safety, incidence of TEAE was similar for both groups, though treatment discontinuation due to adverse events was more common in the ponesimod group (49 of 565 [8.7%] vs 34 of 566 [6.0%]).

When might ponesimod be used instead of other S1P modulators?

Overall, ponesimod has a similar dosing frequency, monitoring and safety profile (though theoretically a lower risk for adverse events) compared to the previously approved S1P modulators. Additionally, there is no data to suggest that ponesimod is inferior in efficacy. Two possible advantages of ponesimod therapy may include the rapid plasma clearance following discontinuation (female patients can try to conceive 1-2 weeks after stopping therapy compared to 2-3 months with other S1P modulators), and the absence of worsened fatigue compared to teriflunomide in a phase 3 clinical trial (though fatigue was not studied as a key outcome in other Phase 3 S1P receptor modulator trials).

What are the major adverse events associated with ponesimod?

In clinical trials, the most common adverse reactions (incidence of at least 10%) in ponesimod-treated patients were upper respiratory tract infection, hepatic transaminase elevation, and hypertension. Adverse reactions with an incidence of at least 2% included: urinary tract infection, bradycardia, dyspnea, dizziness, cough, somnolence, pyrexia, hypercholesterolemia, and peripheral edema.

Cases of basal cell carcinoma and other skin malignancies have been reported in patients treated with S1P receptor modulators, including ponesimod, at rates of <1%. At the Mellen Center we recommend patients follow all age-appropriate cancer screening guidelines and undergo prompt evaluation of skin lesions.

Does ponesimod cause lymphopenia?

Ponesimod reduces the circulating absolute lymphocyte count (ALC), which is its intended pharmacodynamic effect. The magnitude of reduction is dose-dependent and is approximately 30-40% of baseline. In clinical trials, lymphopenia (defined as ALC <200/μL) occurred in 3.2% of patients, however no correlation between lymphopenia and an increased risk of infections, including PML, has been found.

How is lymphopenia managed?

Currently, there are no data to suggest that the lymphopenia produced by ponesimod leads to a higher risk of infection. We recommend routine clinical monitoring for infections for all ponesimod patients, especially for those who develop ALC <200/μL with concomitant leukopenia, or for patients with a history of frequent infections. If the ALC is <200/μL, we recommend rechecking in one month. For persistent ALC <200/μL we consider switching to another therapy, especially if total WBC also is reduced and/or infections are increased.

Is macular edema associated with ponesimod?

In OPTIMUM, macular edema was reported in 1.1% of ponesimod-treated patients compared to none of the patients receiving teriflunomide. OCT or an ophthalmologic evaluation is recommended before starting treatment and if there is any change in vision going forward. Diabetes mellitus and uveitis may increase the risk of macular edema while on ponesimod, so in addition to baseline screening, these patients should maintain regular follow-up exams.

Is ponesimod associated with progressive multifocal leukoencephalopathy (PML)?

There have been no cases of PML reported in patients treated with ponesimod, although PML has been reported with another S1P modulator (fingolimod) at very low rates. At the Mellen Center, a positive JC virus serology does not preclude patients from treatment with ponesimod.

Is ponesimod associated with other infections?

Cases of herpes viral infection were reported in the development program for ponesimod as well as during treatment with other S1P receptor modulators. However, in OPTIMUM, the rate of herpetic infections was 4.8% for both ponesimod-treated patients and those receiving teriflunomide 14 mg; the rate of overall infection, consisting mostly of upper respiratory infections, was also similar. Additionally, while not reported for ponesimod, rare cases of cryptococcal meningitis have been reported in patients taking fingolimod.

Who should not receive ponesimod?

Contraindications to ponesimod include patients with significant heart rhythm or conduction abnormalities (unless the patient has a functioning pacemaker), or who within the preceding six months had a myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure, or Class III or IV heart failure.

What testing is done before starting ponesimod?

Prior to starting treatment with ponesimod, we recommend the following tests:

  • Complete blood count (CBC) with differential
  • Electrocardiogram (ECG)
  • Liver function tests (LFTs)
  • Varicella Zoster IgG antibody testing (VZV) and VZV vaccination in antibody-negative patients prior to starting ponesimod
  • Ophthalmologic evaluation: OCT to screen for macular edema, can also perform ophthalmologic examination to screen for asymptomatic uveitis
  • It is also recommended to ensure that patients not start treatment during an active infection

How is ponesimod given?

Ponesimod is a once daily oral medication that follows a 14-day titration schedule starting at 2 mg. On Day 15 and thereafter, patients continue a maintenance dose of 20 mg daily. If fewer than 4 consecutive doses are missed during titration, the titration schedule can be resumed at the first missed titration dose. If 4 or more consecutive doses are missed during either the titration or maintenance period, a full 14-day titration regimen must be re-initiated.

Titration Day

 Dose
Days 1 and 2 2mg
Days 3 and 4 3mg
Days 5 and 6 4mg
Day 7 5mg
Day 8 6mg
Day 9 7mg
Day 10 8mg
Day 11 9mg
Days 12, 13, and 14 10mg
Day 15 and thereafter 20mg

Is first dose observation required for ponesimod as with fingolimod?

For most patients, first dose observation is not necessary. 4-hour monitoring after the first dose is recommended for patients who have a history of myocardial infarction, heart failure, sinus bradycardia (HR<55 beats per minute), or first- or second-degree AV block as detected on baseline ECG. This monitoring should include hourly measurements of pulse and blood pressure, as well as an ECG prior to and at the end of the observation period.

Is genetic testing required before starting ponesimod as with siponimod?

No, unlike siponimod, testing for the CYP2C9 genotype is not required prior to starting ponesimod.

What monitoring is done during ponesimod treatment?

Although routine monitoring is not stipulated in the prescribing information, at the Mellen Center we recommend measuring blood pressure during office visits, checking a complete blood count with differential and liver function tests 3-6 months after starting treatment, and then every 6-12 months thereafter. We expect to see a 30-40% reduction in ALC, but we monitor for lymphopenia (ALC < 200/μL) and elevated liver enzymes. For any significant abnormalities, more frequent monitoring is reasonable.

What should be known when stopping ponesimod?

Currently, there are no reports of rebound or severe relapses following discontinuation of ponesimod. However, severe exacerbation of disease has been reported with other S1PR modulators, thus this possibility should be considered.

Is ponesimod safe during pregnancy?

Although there are no data on the safety of ponesimod in pregnant woman, in utero exposure to ponesimod in animal studies resulted in embryo lethality and fetal malformation. In humans, S1PR1 has also been demonstrated to have an important role in vascular and neural development. Therefore, female patients of childbearing potential should use effective contraceptive methods while on ponesimod and wait at least 1 week (based on the elimination half-life) after the last dose before attempting to conceive.

Is ponesimod safe while breast feeding?

There are currently no data on the safety of ponesimod on the breastfed infant, however animal studies have shown that it is secreted into breast milk. A discussion of the risks and benefits of breastfeeding while on ponesimod should occur with each patient individually. At the Mellen Center, we typically do not start/restart ponesimod during breast feeding.

Which vaccines should a patient receive while on ponesimod?

VZV IgG levels should be checked prior to starting ponesimod, and patients who are antibody-negative should receive VZV vaccination. Additionally, any live attenuated vaccines required by the patient should be given at least 1 month prior to starting ponesimod.

After starting ponesimod, the use of live attenuated vaccines carries the risk of infection. Such vaccines should be avoided during treatment and for up to 1-2 weeks after discontinuation. Also, while on treatment and for up to 1-2 weeks after treatment discontinuation, vaccines may be less effective. At the Mellen Center, we typically proceed with non-live virus, age-appropriate vaccines but advise patients of the potential that these may be less effective, including the SARS-CoV-2 vaccines.

References

  • Kappos L, Fox RJ, Burcklen M, et al. Ponesimod Compared With Teriflunomide in Patients With Relapsing Multiple Sclerosis in the Active-Comparator Phase 3 OPTIMUM Study: A Randomized Clinical Trial. JAMA Neurol. 2021;78(5):558-567. doi:10.1001/jamaneurol.2021.0405
  • Brossard P, Derendorf H, Xu J, Maatouk H, Halabi A, Dingemanse J. Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study. Br J Clin Pharmacol. 2013;76(6):888-896. doi:10.1111/bcp.12129
  • Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208. doi:10.1136/jnnp-2013-307282
  • McGinley MP, Cohen JA. Sphingosine 1-phosphate receptor modulators in multiple sclerosis and other conditions [published correction appears in Lancet. 2021 Sep 25;398(10306):1132]. Lancet. 2021;398(10306):1184-1194. doi:10.1016/S0140-6736(21)00244-0
  • Piali L, Froidevaux S, Hess P, et al. The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther 2011;337:547–56.
  • Ponvory (Ponesimod) Full Prescribing Information; 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022527s008lbl.pdf