Today it’s all about the group of S1P modulators, which includes fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory) and siponimod (Mayzent). The first three, i.e. Gilenya, Zeposia and Ponvory, are used as a disease-modifying therapy for active multiple sclerosis. Fingolimod (Gilenya) is even approved for pediatric MS. Mayzent is approved for active SPMS if the patient is already experiencing a worsening of MS independent of relapses, but also has localized inflammatory activity.
S1P modulators are pronounced sphingosine 1-phosphate receptor modulators and prevent the leakage of lymphocytes from the lymph nodes. This also prevents them from entering the central nervous system (CNS). The S1P receptor subgroups determine the side effect profile.
Please remember that I can only provide an overview here. Your neurologist and your MS nurse should advise you in detail on the right therapy for you. This is because they know your general state of health and you should also talk about your goals, wishes, fears and preferences so that these can be taken into account.
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Table of Contents
General Information
To get a good overview of the major topic of therapy decisions, I recommend that you first listen to episode 58: Immunotherapy in MS. A guide to efficacy and choice with Prof. Tjalf Ziemssen. There you will find out why:
- You can only compare the various disease-modifying drugs to a limited extent.
- It is important to start an effective therapy quickly.
- MRI and other examinations are important for assessing progression and provide information about effectiveness.
- Therapies should be changed as little as possible, but of course if they are not effective enough.
- In most cases, it is better to start with a highly effective therapy and only switch to a lower category at an advanced age.
- In the case of highly active MS, it may be more important to start immunotherapy quickly and tackle rehabilitation as a second step.
- Generics and biosimilars are being used more and more and which approval requirements they have to fulfill.
- The risks and side effects of a therapy must be differentiated into unpleasant side effects at the start of therapy and rare possible risks. And these must be set in relation to the usually irreversible effects of untreated MS in the long term.
- It is important to honestly discuss your opinion, wishes, goals and fears with your neurologist in order to make treatment decisions together that both sides can agree on.
- It is advantageous to be cared for by MS specialists and to stay informed yourself in order to benefit from new findings and treatment options.
- Contribute to a favorable prognosis with your own healthy lifestyle.
Another general note
The approval studies for the individual drugs were carried out at very different times. Thirty years ago, you had to be more severely affected or more advanced in the course of the disease to receive a reliable diagnosis of multiple sclerosis. Less severely affected people were probably not diagnosed or not diagnosed at first. With ever-improving examination methods, such as MRI, even small lesions in the central nervous system can now be seen better. Furthermore, 30 years ago it was not yet known that neuromyelitis optica spectrum diseases, NMOSD for short and MOGAD, are separate diseases that require their own therapies and sometimes even react negatively to MS medication. They were previously thought to be multiple sclerosis and MS therapies did not alleviate the disease activity.
How are S1P Modulators – Fingolimod (Gilenya), Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent) classified in immunotherapies?
There are currently three different therapeutic approaches for the preventive, i.e. disease-modifying therapy (DMT) of multiple sclerosis. The most unspecific is immunomodulation. Migration inhibition already narrows down the path , which also includes fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent). And the most specific is the depletion of immune cells. The DMTs are listed in alphabetical order:
- Immunomodulation – the therapies weaken the immune system. They have a very broad effect via various factors (e.g. on Th1/T17 – Th2/Treg, antigen presentation) as well as on different signaling pathways and possibly via other mechanisms: they attempt to shift the milieu from inflammatory to non-inflammatory:
- Dimethyl fumarate (Tecfidera and generics) & diroximel fumarate (Vumerity),
- Glatiramer acetate (Copaxone and generics),
- Interferon-beta: interferon beta-1a (Avonex, Rebif), interferon beta-1b (Betaferon, Extavia), peginterferon beta-1a (Plegridy)
- Teriflunomide (Aubagio)
- Migration inhibition – the migration of certain immune cells is inhibited:
- Natalizumab (Tysabri, Tyruko)
- S1P modulators: Fingolimod (Gilenya), Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent)
- Cell depletion – developing immune cells die off
- Depletion of T-cells, B-cells, NK-cells and monocytes: Alemtuzumab (Lemtrada, Campath)
- T- and B-cell depletion: Cladribine (Mavenclad, Leustat, Litakin)
- B-cell depletion: ocrelizumab (Ocrevus), ofatumumab (Kesimpta, Bonspri), rituximab (Mabthera, Rituxan), ublituximab (Briumvi)
What are fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent) approved for?
Fingolimod (Gilenya)
Fingolimod is approved for the treatment of highly active forms of RRMS that progress rapidly. It can be used in pediatric patients aged ten years and older. The German Multiple Sclerosis Competence Network (KKNMS) recommends its use in patients who have already received another disease-modifying treatment (DMT) and still have a high disease burden after a sufficient start-up period. Or for patients who have not yet received DMT but have a severe form of relapsing-remitting MS, defined by:
- two or more relapses with worsening disability have occurred within one year and
- MRI of the head shows at least one new gadolinium-enhancing lesion or a relevant increase in T2 lesions compared to a recent MRI.
In other words, an existing inflammatory activity is detectable. Different information or recommendations are possible from country to country.
Ozanimod (Zeposia)
Ozanimod is approved for the treatment of active forms of relapsing MS in adults. Participants in the approval studies had to:
- have at least one relapse in the last twelve months
- or a clinical relapse in the last 24 months plus at least one active lesion that absorbs contrast media on MRI in the last 12 months.
Over two thirds of patients were treatment naïve. New T2-hyperintense or increasing T2-hyperintense lesions are also considered MRI activity.
Ponesimod (Ponvory)
Ponesimod is approved for the treatment of active forms of relapsing MS in adults. Participants in the approval studies where included if they had an EDSS Score between 0 and 5.5 with at least:
- one relapse in the last twelve months
- or two relapses in the last two years
- or one active lesion that absorbs contrast media on MRI in the last six months.
Based on the criteria of the pivotal study, ponesimod can therefore also be used for SPMS with superimposed relapses in addition to RRMS. However, there were no explicit SPMS studies.
Siponimod (Mayzent)
Siponimod is approved for the treatment of active secondary progressive MS that show inflammatory activity. Clinical or MRI-activity is defined by:
- relapses within the last two years
- MRI activity with new or enlarging T2 lesions and / or contrast-enhancing lesions in a recent MRI (maximum three months old). In the EXPAND pivotal study, only the presence of contrast-enhancing lesions at baseline could be considered due to the study design. The KKNMS recommends that new or enlarging T2 lesions compared to previous images within the last two years should also be evaluated as MRI activity.
The FDA approved Siponimod to treat adults with relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease.
Different information or recommendations are possible from country to country.
What is the situation for special patient groups?
Children and Teenagers
Fingolimod (Gilenya) ist the only S1P Modulator that is officially approved for usage in children ten years and older. The PARADIGMS study compared Fingolimod to Interferon Beta-1a and Fingolimod lowered the annual relapse rate by 82 percent and the number of new or enlarged lesions on T2-weighted MRI by 53 percent, both numbers are relative difference.
For an individual consultation, please contact an MS specialist, preferably a neuropaediatrician.
Pregnancy and Breastfeeding: Recommendation of the European (EMA) and American regulatory authorities (FDA)
S1P receptor modulators should not be used during pregnancy or if there is a desire to have children. Women of childbearing age should use safe contraceptives during S1P receptor modulator therapy. Women should not breastfeed while taking S1P receptor modulators. The FDA also warns of a severe increase in disability after discontinuation without alternative therapy.
Recommendation of the DMSKW (German MS Fertility Register)
Recommendation based on the current data situation and experience of the DMSKW:
All four active substances are taboo for women of childbearing age who are not using safe contraception. And contraceptive protection must be maintained for the entire duration of treatment. A negative pregnancy test is required before starting treatment.
Fingolimod (Gilenya) harbors a teratogenic risk that continues to have an effect for two months after the end of therapy. Therefore, an interval of at least two months must be observed before a pregnancy can be planned.
For the newer drugs ozanimod (Zeposia), siponimod (Mayzent) and ponesimod (Ponvory), there is not yet sufficient data available, but here too a teratogenic potential is possible.
The active substances are broken down at different rates in the human body. This results in different safety margins for the onset of pregnancy. For ozanimod (Zeposia®) this interval should be at least 3 months, for fingolimod (Gilenya and generics) at least 2 months. Siponimod (Mayzent), on the other hand, only needs to be discontinued 10 days before a planned pregnancy and Ponesimod (Ponvory) only one week before.
If a pregnancy nevertheless occurs with one of the active substances, the therapy must be terminated. More intensive ultrasound diagnostics should be carried out as a precaution.
After discontinuation of therapy with fingolimod (Gilenya and generics), there may be increased disease activity. Sometimes severe relapses can occur after discontinuation, leading to disability. The same effects may occur after discontinuation of the other three drugs – ozanimod (Zeposia), siponimod (Mayzent) and ponesimod (Ponvory). There is not yet sufficient data on this. Pregnancy should therefore be planned carefully and, if necessary, therapy should be changed. Alternatives may include anti-CD-20 antibodies (MabThera, Truxima, Rixathon, Ocrevus, Kesimpta), cladribine (Mavenclad) or natalizumab (Tysabri).
After birth, if breastfeeding is not taking place, treatment can be continued with S1P receptor modulators. S1P receptor modulators should not be used for breastfeeding, as the drug is very likely to be absorbed by the infant via breast milk and a risk to breastfed children has not yet been ruled out.
Who should avoid fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent)?
- Patients with myocardial infarction, unstable angina, stroke, circulatory disorders of the brain, severe heart failure currently or in the previous six months, cardiac arrhythmia or other diseases of the heart or cerebral vessels
- Patients with moderate or severe hepatic insufficiency.
- Patients with severe active infections and patients with chronic infections (especially hepatitis B and C and tuberculosis).
- immunocompromised patients
- Patients with malignant diseases, including skin cancer.
- Patients with macular oedema, the accumulation of fluid in the area of the yellow spot of the eye. Due to the increased incidence of macular oedema, particular caution is required in this context in diabetics and patients with uveitis.
- Patients with hemophagocytic syndrome, a highly inflammatory disease of the immune system or a mutation associated with it.
- Patients with severe respiratory disease, pulmonary fibrosis or chronic obstructive pulmonary disease (COPD)
The severity of the problem might vary between the four different S1P-modulators.
How do fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent) work?
S1P1 prevents lymphocytes from leaving the lymph nodes and thus from migrating into the central nervous system (CNS).
Immune cells are not destroyed, but only imprisoned. Th17, naive T and B cells and central memory T cells (TCM) in particular are retained.
Effector memory cells (TEM) can continue to function normally.
There are fewer proinflammatory cells in the blood system.
Effect occurs very quickly. Within hours of ingestion, the number of lymphocytes decreases and, depending on the specific S1P modulator, reaches its lowest point after a few hours to a month. This is 20 to 30 percent of the initial value.
The process is reversible. When the therapy is stopped, the lymphocytes can migrate again. However, it can take a long time for everything to return to normal after prolonged treatment. This causes problems when changing therapy and there is a risk of rebound, i.e. a strong return of disease activity. How quickly everything normalizes after you stop taking the drug depends on the specific active ingredient and ranges from a few days to a month and a half. However, it can also take longer.
S1P receptor subgroups determine the side effect profile, see diagram.
Fingolimod binds to 4 of the 5 sphingosine-1-phosphate receptors, S1P1, S1P3, S1P4 and S1P5.
Ozanimod binds primarily to the sphingosine-1-phosphate receptors S1P1 and S1P5, with a 10-fold preference for S1P1.
Ponesimod binds to the S1P receptor.
Siponimod binds to two of five sphingosine-1-phosphate receptors, S1P1 and S1P5.
Fingolimod, ozanimod and siponimod cross the blood-brain barrier. The significance of the effect on the cells of the central nervous system is not yet fully understood.
How is it taken?
The capsules can be taken with or without food. Dose adjustments according to weight, gender or ethnicity are not usually made in adults. No dose adjustments are necessary for mild to moderate hepatic insufficiency.
Fingolimod (Gilenya and generics)
Fingolimod is taken orally as a 0.5 mg capsule once a day.
In children from the age of 10, a fingolimod dose of 0.5 mg once daily is recommended if the body weight is over 40 kg. Up to a body weight of 40 kg, 0.25 mg should be administered once daily.
Ozanimod (Zeposia)
Ozanimod is taken orally as a capsule once a day. The dosage must be increased slowly: Day 1 – 4: 0.23 mg once daily, day 5 – 7: 0.46 mg once daily, from day 8: 0.92 mg once daily (maintenance dose).
Ozanimod is contraindicated in severe hepatic impairment (Child-Pugh C). Renal impairment does not require a dose adjustment.
No pharmacokinetic data are available for children and adolescents under 18 years of age and for patients over 55 years of age.
Ponesimod (Ponvory)
Treatment must be started with the 14-day pack to initiate treatment. Treatment starts on day 1 with the intake of a 2 mg tablet. The dosage regimen is as follows:
- Day 1 + 2: 2 mg
- Day 3 + 4: 3 mg
- Day 5 + 6: 4 mg
- Day 7: 5 mg
- Day 8: 6 mg
- Day 9: 7 mg
- Day 10: 8 mg
- Day 11: 9 mg
- Day 12 – 14: 10 mg
- since Day 15: 20 mg
After completion of dose titration, the recommended maintenance dose for ponesimod is one 20 mg tablet once daily.
Siponimod (Mayzent)
In order to adjust the dosage individually, it is necessary to determine the metabolization status by testing the CYP2C9 genotype before starting therapy with siponimod.
In the Caucasian population, approx. 10% of patients have a polymorphism that leads to moderately rapid metabolization. Slow metabolization is present in approx. 0.5% of patients.
- In patients with normal metabolization, siponimod is administered at 2 mg once daily.
- In patients with intermediate metabolization, siponimod is administered at 1 mg once daily.
- In patients with slow metabolization, a different drug should be chosen.
The dosage is administered according to the scheme:
- Day 1 + 2: 0.25 mg
- Day 3: 0.5 mg
- Day 4: 0.75 mg
- Day 5: 1.25 mg
- Day 6: 2 mg for normal metabolization and 1 mg for intermediate metabolization.
Single-dose phase
If a titration dose has been missed for more than 24 hours, a restart at day 1 is necessary.
Intake phase after reaching the target dose
If Siponimod has not been taken for four or more consecutive days, a new dosing is necessary.
How effective are fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent)?
Gavin Giovannoni, an MS expert from the UK, has graded his MS selfie cards on a scale of one to ten, with one being low efficacy and ten being maximum efficacy. In his estimation all four S1P-Modulators score five for preventing relapses and five for avoiding long-term disability.
In the pivotal study, fingolimod led to 54% fewer relapses and slowed disability worsening by 30 percent compared to placebo. In other words, you can also look at 100 patients. 46 of these patients remain relapse-free, even on placebo. In the fingolimod group, a further 24 patients remained relapse-free. Looking at the same 100 patients, 76 remained at the same level of disability, as measured by the EDSS (Expanded Disability Status Scale), during the pivotal trial period, including the placebo group. Six people in the placebo group deteriorated who remained stable on fingolimod.
Ozanimod was compared to beta interferons and reduced relapses by 38 %. The influence on the disability progression is not yet clear.
Ponesimod was compared to teriflunomide and reduced relapses by 30 %. It is as effective at slowing disability progression.
Compared to placebo, siponimod reduced relapses by 46 % and slowed disability worsening by 37 %.
Risks and side effects of fingolimod (Gilenya), ozanimod (Zeposia), ponesimod (Ponvory), and siponimod (Mayzent)
Typical side effects for fingolimod are:
- More than one in ten get diarrhoea and headaches
- Varicella zoster virus (shingles) and herpes simplex increased.
- Cryptococcus
- Progressive multifocal leukoencephalopathy (PML) risk much lower, but present
- Basal cell carcinoma
- Macular edema
Typical side effects for ozanimod are:
- Headaches
- increased infections
- increased levels of liver enzymes
- Varicella zoster virus (shingles) rarely
Typical side effects for ponesimod are:
- increased levels of liver enzymes
- swelling in part of the retina
- basal cell carcinoma
Typical side effects for ponesimod are:
- headaches
- reduced white blood cells
- basal cell carcinoma
Safety precautions – lab parameters
Clinical neurological check-up
Clinical neurological check-ups must be carried out quarterly.
Basic laboratory program
- Routine laboratory parameters: Blood count plus differential blood count must be checked two and four weeks after the start of treatment. Thereafter, laboratory checks are necessary every three to six months.
- In the event of lymphopenia below a defined value, which is confirmed in a second measurement after two weeks, fingolimod, ozanimod, ponesimod and siponimod must be discontinued. A differential blood count must then be performed at two-week intervals and the medication can only be restarted when the absolute lymphocyte value is above the defined limit. If lymphopenia occurs repeatedly, a dose reduction may be considered in individual cases. The dose of Siponimod can be regularly reduced from two to one milligram. When treatment is restarted, the dose must be increased again.
Lymphopenia occurs with all S1P receptor modulators, which shows that the substance is effective. The tests are therefore only concerned with ensuring that the levels do not fall too low. Some patients react very strongly to the therapy, which is why the regular checks are very important, especially in the early stages, in order to be able to react if necessary until the body has become accustomed to the medication.
With all S1P receptor modulators, the liver values must be checked shortly after the start of treatment and then at three to six-month intervals.
- If certain liver values increase , weekly checks must be carried out . If defined limit values are repeatedly exceeded, the medication must be permanently discontinued.
Radiological monitoring
An MRI of the brain should be carried out once a year to assess the success of the treatment and to assess possible complications of the therapy that are relevant for differential diagnosis. Contrast agents are only necessary if there are indications of a worsening of the disease or if there is no standardized initial MRI.
Ophthalmologic control
Patients with diabetes mellitus, uveitis or known retinal disease should be examined by an ophthalmologist before starting therapy and undergo regular check-ups during treatment. With Ponesimod, all patients should also have an examination of the back of the eye, including the macula, before starting treatment.
The eye examination after three to four months of fingolimod therapy checks for macular edema. The fundus of the eye must be examined (alternatively an OCT as a supplementary examination) if visual disturbances occur during treatment with one of the four S1P receptor modulators that cannot be attributed to optic neuritis.
Dermatological control
Due to the increased incidence of basal cell carcinoma with S1P receptor modulators, a dermatological check-up is recommended one year after the start of treatment and then every six months for patients at risk.
Pulmonological check-up
If there are indications of pulmonary dysfunction, a specialist pulmonological examination should be carried out.
Cardiological check-up
During treatment with Siponimod, blood pressure should be checked after three months and then annually, and high blood pressure should be treated accordingly if necessary.
On the MS selfie card mentioned earlier, the side effects are rated on a scale from one for few or rare to ten for many or frequent as follows:
- Regular side effects at three for Fingolimod and Siponimid and four for Ozanimod and Ponesimod
- Long-term side effects at five for all four substances
- Cancer risk at seven for Fingolimod and Siponimid and at six for Ozanimod and Ponesimod
All four S1P modulators receive the following rating in the MS Selfie Card overview of the effects of therapy:
- Clinic visits: moderate
- Family planning: short-term incompatible
- Vaccinations: poor response
Vaccinations
Before starting treatment with siponimod (Mayzent), patients must be tested for varicella zoster (VZV). VZV-seronegative patients must be vaccinated against VZV before starting treatment. Treatment with Siponimod can be started at the earliest after vaccination.
The effectiveness of vaccinations may be limited during therapy and up to two months after discontinuation of fingolimod, ozanimod, ponesimod and siponimod. If necessary, the vaccination success should be checked by means of titer control.
Live vaccines should be avoided and only administered after a thorough risk-benefit assessment. All other vaccinations are permitted during treatment with S1P receptor modulators.
Vaccination against herpes zoster, which leads to shingles, is recommended for patients with immunotherapy from the age of 50. In this case, vaccination with the inactivated Shingrix vaccine is recommended.
Sources
I used the following sources to create the content:
- Lecture on S1P receptor modulator by Prof. Dr. Tobias Derfuss as part of the Multiple Sclerosis Management Master’s program
- Quality manual of the German KKNMS on fingolimod (Gilenya),ozanimod (Zeposia),ponesimod (Ponvory),and siponimod (Mayzent)
- MS-Selfie Infocards by Prof. Dr. Gavin Giovannoni
- German Multiple Sclerosis and Fertility Registry (DMSKW)
- Information from the German interview with Prof. Dr. Barbara Kornek on pediatric MS
- German DECIMS information on fingolimod
Final note
Please remember, there is no one great medication that helps everyone, but it must always be weighed up what suits a particular person best. Other illnesses, personal goals and preferences must also be taken into account. Your neurologist and MS nurse are the right persons to talk to and can make individual recommendations. This article is for information purposes only and does not constitute a recommendation. What helps one person may not help another.
I hope that, together with your neurologist and MS nurse, you will quickly find the right immunotherapy for you. And that you can lead a fulfilled, happy and self-determined life with MS, supported by a healthy lifestyle and a dose of fortune.
You may also want to look at the posts on the other DMTs:
- #061: Dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity)
- #065: Glatiramer acetate (Copaxone, Brabio)
- #068: Interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif)
- #070: Teriflunomide (Aubagio)
- #072: Natalizumab (Tysabri, Tyruko) for active relapsing remitting MS
See you soon and try to make the best out of your life,
Nele
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