What is the clinical indication for siponimod?
Siponimod is a medication that has been approved by the FDA to treat relapsing forms of multiple sclerosis, which has been defined to include relapsing remitting multiple sclerosis (RRMS), clinically isolated syndrome (CIS), and secondary progressive multiple sclerosis (SPMS) with active disease. SPMS with active disease refers to those patients who are in a progressive phase of the disease and continue to have clinical relapses.
In the clinical trials, siponimod appeared to have the most benefit for patients who were younger, had gadolinium-enhancing lesions, lower disability, and shorter disease duration. The benefit of siponimod in patients with SPMS without relapses is less clear.
What is the mechanism of action of siponimod?
Siponimod is a sphingosine 1-phosphate receptor (S1P) modulator that selectively binds the S1P subtypes 1 and 5. It acts as a functional antagonist, as binding to S1P1 induces receptor internalization and degradation in T and B cells. The ultimate result is prevention of lymphocyte egress from the lymphoid tissue into the central nervous system (CNS). Additionally, preclinical studies have shown that siponimod inhibits demyelination, and attenuates the production of TNFα, IL-6, and IL-17 by astrocytes and microglia. This suggests that siponimod may act directly on the CNS in addition to its role in decreasing circulating lymphocytes.
What are the kinetics of siponimod?
Siponimod has a rapid onset of action, and reduces circulating T and B cells within 4-6 hours. Its half-life is approximately 30 hours. Circulating lymphocytes counts recover within a week after treatment discontinuation. Complete elimination of siponimod from the body takes approximately 10 days.
Siponimod is metabolized in the liver through the Cytochrome P450 system (primarily through CYP2C9, subsequently by CYP3A4). Genetic variants to the CYP2C9 enzyme can slow siponimod metabolism. This is important in determining the correct dose and titration schedule for a given patient, as patients with the *3 variant of CYP2C9 demonstrated slower rates of drug metabolism. Specifically, heterozygotes with CYP2C9 *3 have moderately slowed metabolism, and homozygotes with CYP2C9 *3/*3 have severely impaired metabolism. As a result, CYP2C9 *3 heterozygotes should follow a lower dose titration and lower final dose; CYP2C9 *3/*3 genotype is a contraindication to siponimod.
Does siponimod have any significant drug interactions?
While siponimod does not induce nor inhibit the CYP450 system, its metabolism can be affected by medications that are CYP2C9 inhibitors or inducers. For example, a patient who takes warfarin, a CYP2C9 inhibitor, may have increased levels of siponimod. We recommend a careful review of a patient’s medication list, and would use siponimod cautiously in patients who take CYP450 modulators.
What did the clinical trials of siponimod for MS show?
Siponimod was approved for treatment of MS based on the results of two clinical trials. The first was BOLD, which was a phase II randomized, double-blind, dose-finding, placebo comparison trial for patients with RRMS. This showed that siponimod at a dose of 2mg approached peak efficacy as measured by a reduction in the number of new or enlarging T2 lesions or new enhancing lesions. It also showed that the medication had favorable tolerability and safety. While there were two significant cardiovascular adverse events, both of these patients had preexisting cardiac risk factors, and both of these events occurred after drug discontinuation and washout. The BOLD safety 24-month extension study did not identify any new serious safety signals compared to the original study.
The second study was EXPAND, which was a randomized, double-blind, placebo-controlled phase III trial of patients with SPMS. EXPAND demonstrated that siponimod reduced the risk of confirmed disability worsening in patients with SPMS by 21%, reduced the risk of relapses compared to placebo by 55%, and slowed the rate of radiographic disease activity and brain atrophy.
What are the major side effects of siponimod?
The side effects of siponimod that occurred in greater than 10% of patients in clinical trials are as follows:
- Headache (16%)
- Nasopharyngitis (19%)
- UTI (16%)
- Falls (13%)
What are the major adverse events of siponimod?
- Bradycardia: Siponimod, similar to other S1P modulators, can lead to temporarily bradycardia immediately following the first dose, although a five-day titration appears to mitigate first-dose bradycardia. There were no symptomatic bradycardic events or adverse reactions, nor clinically significant changes in baseline blood pressure observed in the trials.
- Conduction abnormalities: Siponimod also induced cardiac conduction abnormalities in 3% of patients in clinical trials, including first- and second-degree AV block.
- Elevated LFTs: Approximately 1% of patients in clinical trials experienced increases in alanine aminotransferase (ALT).
- Macular edema: 2% of siponimod patients developed macular edema, compared to less than 1% of placebo patients.
Is macular edema associated with siponimod?
In the clinical trial EXPAND, macular edema was seen in 2% of siponimod patients compared to <1% of placebo patients. Patients with a prior history of uveitis and patients with diabetes mellitus are at increased risk of macular edema when taking siponimod. While this is not an absolute contraindication, we recommend obtaining a baseline ophthalmologic evaluation. We typically complete this using optical coherence tomography (OCT). OCT monitoring for macular edema is only done if symptoms suggestive possible macular edema. OCT monitoring for macular edema is only done if symptoms suggestive possible macular edema.
Is siponimod associated with progressive multifocal leukoencephalopathy (PML)?
There have been no cases of PML reported in patients treated with siponimod, although PML has been associated with another S1P modulator fingolimod. Infingolimod the rate of PML is very low. . Accordingly, a risk of PML during siponimod treatment cannot be excluded. We believe that if PML is to develop in patients taking siponimod, it will occur at the same low rate as was seen in fingolimod. Currently, we do not feel that positive JC virus serology should preclude treatment with siponimod.
Is siponimod associated with other infections?
Clinical trials showed that the overall rate of infections was comparable between siponimod and placebo group (49.0% vs 49.1%, respectively), and the rate of serious infection was slightly increased for the siponimod group compared to placebo (2.9% vs 2.5%). The siponimod group had a higher rate of herpetic infections (including VZV), bronchitis, upper respiratory infection, and fungal skin infection. While not reported for siponimod, rare cases of cryptococcal meningitis have been reported in patients taking fingolimod, another S1P modulator.
Does siponimod cause lymphopenia?
Siponimod reduces the circulating absolute lymphocyte count (ALC), which is its intended pharmacodynamics effect. The magnitude of reduction is dose-dependent, and is approximately 20-30%. Lymphopenia (defined as ALC < 200/µL) occurred in 1% of patients, however there is no correlation between lymphopenia and an increased risk of infections, including PML.
Who should not receive siponimod?
Contraindications to siponimod include patients homozygous for the CYP2C9*3/*3 genotype; significant heart rhythm or conduction abnormalities (unless the patient has a functioning pacemaker); or in the past six months has had myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure, or Class III or IV heart failure.
How is siponimod given?
Siponimod is a once-daily oral medication that follows an initial titration. Prior to starting the medication, CYP2C9 genotype must be tested in order to determine how the drug will be metabolized for a specific patient. This determines the titration strategy and target dosage. If a titration dose is missed for more than 24 hours, treatment should be restarted with Day 1 of the titration schedule. If treatment is interrupted for more than 4 days, patients should repeat the titration.
- For patients with CYP2C9 Genotypes *1/*1, *1/*2, or *2/*2: initiate siponimod therapy with the standard 5-day titration, followed by the maintenance dose of 2 mg taken once daily beginning on day 6. This standard titration should be prescribed using the starter pack (which includes 12 pills of 0.25mg), followed by a separate prescription for the 2mg maintenance pills.
Titration for wild-type CYP2C9 Genotypes (*1/*1, *1/*2, or *2/*2)
| Titration Day | Titration Dose |
|---|---|
| Day 1 | 0.25 mg (1 pill) |
| Day 2 | 0.25 mg (1 pill) |
| Day 3 | 0.50 mg (2 pills) |
| Day 4 | 0.75 mg (3 pills) |
| Day 5 | 1.25 mg (5 pills) |
| Day 6 | 2 mg (maintenance dose) |
- For patients with CYP2C9 Genotypes *1/*3, or *2/*3: initiate siponimod therapy with an altered 4-day titration, followed by the maintenance dose of 1 mg taken once daily beginning on day 5. The titration should be given as a prescription for siponimod 0.25 mg x 7 pills, followed by a separate prescription for the 1mg maintenance dose.
Titration for heterozygote CYP2C9 Genotypes (*1/*3, or *2/*3)
| Titration Day | Titration Dose |
|---|---|
| Day 1 | 0.25 mg (1 pill) |
| Day 2 | 0.25 mg (1 pill) |
| Day 3 | 0.50 mg (2 pills) |
| Day 4 | 0.75 mg (3 pills) |
| Day 5 | 1 mg (maintenance dose) |
- Siponimod is contraindicated for patients with the *3/*3 CYP2C9 genotype due to dangerously prolonged siponimod metabolism.
What testing is done before starting siponimod?
Prior to starting treatment with siponimod, we recommend the following tests:
- CYP2C9 genotype: this can be done in a patient’s home at no cost to the patient through the pharmaceutical company
- Complete blood count with differential (CBC)
- Liver function tests (LFT)
- Varicella Zoster: Virus IgG antibodies (VZV), and we recommend vaccinating VZV antibody-negative patients prior to starting treatment
- Ophthalmic evaluation: OCT to screen for macular edema, can also consider ophthalmologic examination to screen for asymptomatic uveitis
- EKG
- It is also recommended that patients not have active infections when starting siponimod
Is monitoring required during the first dose like with fingolimod?
For the majority of patients, first dose observation is not necessary. First-dose 6 hour monitoring is recommended for patients who have a history of myocardial infarction, heart failure, sinus bradycardia (HR < 55 bpm), or first- or second-degree AV block as detected on baseline EKG. This monitoring should include hourly measurements of pulse and blood pressure, as well as an EKG at the end of the observation period.
What monitoring is done during siponimod treatment?
Although routine monitoring is not stipulated in the prescribing information, we at the Mellen Center recommend measuring blood pressure during office visits, and checking CBC with differential and LFTs 3-6 months after starting treatment, then every 6-12 months while on the medication. On these labs, we expect to see a 20-30% reduction in ALC, but we monitor for lymphopenia (ALC < 200/µL) and elevated ALT. For any significant abnormalities, more frequent monitoring is reasonable.
How is lymphopenia managed?
Currently, there are no data to suggest that the lymphopenia produced by siponimod leads to a higher risk of infection. We recommend routine clinical monitoring for infections for all siponimod patients, especially for those who develop ALC < 200/µL with concomitant leukopenia, or for patients with a history of frequent infections.
What about other potential risks?
For other S1P modulators such as fingolimod, rebound disease activity may occur after drug discontinuation. While this phenomenon was not seen in the siponimod clinical trials, we consider it a potential risk, and therefore patients should be monitored closely for relapses, MRI lesion activity, or disability worsening after stopping the drug.
Additionally, rare cases of posterior reversible encephalopathy syndrome (PRES) have occurred in patients receiving other S1P modulators, though this has not yet been reported in siponimod patients. It is therefore considered a potential risk, and should be considered in the differential diagnosis for any patient who develops a new neurologic symptom or deficit.
Is siponimod safe during pregnancy?
Although there are no data on the safety of siponimod in pregnant woman, siponimod has been shown to cause teratogenicity in various animal models. Therefore, female patients of childbearing potential should use effective contraceptive methods while on siponimod, and wait at least 2 months (based on the half-life of the drug) after the last siponimod dose before attempting to conceive.
Is siponimod safe while breastfeeding?
There are currently no data on the safety of siponimod on the breastfed infant, however animal studies have shown that the medication is secreted into breast milk. A discussion of the risks and benefits of breastfeeding while on siponimod should occur with each patient individually.
Which vaccines should a patient receive while on siponimod?
Prior to starting siponimod therapy, VZV antibodies should be checked, and patients who are antibody-negative should receive VZV vaccination. After starting siponimod, patients should receive all age-appropriate vaccines, including the annual flu vaccine, though we recommend avoiding any live vaccines. Killed or inactivated vaccines are considered to be relatively safe.
References:
- Chaudhry B, Cohen JA, Conway DS, Sphingosine 1-Phosphate Receptor Modulators for the Treatment of Multiple Sclerosis. Neurotherapeutics 2017, 14: 859-73.
- Farez MF et al., Practice guideline update summary: Vaccine-preventable infections and immunization in multiple sclerosis. Neurology Sep 2019, 93 (13) 584-594.
- Gardin A et al., Comparison of Siponimod (BAF312) Pharmacokinetics in Healthy Subjects with Different Genetic Variants of the Cytochrome(P450)2C9 Enzyme. Neurology 2016, 86 (16 Supplement): P3.088.
- Hammond ER, Perspectives on Safety and Efficacy – the BOLD Phase 2 Extension Study of Siponimod in Relapsing-Remitting Multiple Sclerosis. JAMA Neurology 2016, 73 (9): 1052-4.
- Kappos L et al., Longer-term Safety With Siponimod Treatment in Multiple Sclerosis: Pooled Analysis of Data From the BOLD and EXPAND Trials and Their Extensions. ECTRIMS 2018 conference proceedings, P911.
- Kappos L et al., Safety and Efficacy of Siponimod (BAF312) in Patients with Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study. JAMA Neurology 2016, 73 (9): 1089-98.
- Kappos L et al., Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomized, phase 3 study. Lancet 2018, 391: 1263-73.
- Mayzent prescribing information. Accessed online 10/8/2019: https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/mayzent.pdf.
- Selmaj K et al., Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurology 2013, 12: 756-67.
