Tecfidera and Vumerity, the fumarates, kick off the series on the approved disease-modifying therapies for MS. I am trying to give a good overview, but it does not claim to be complete information. The order is simple. It starts with a rather broad mechanism of action, which works for a good proportion of those affected, through to the increasingly specific mechanisms of action, which work for the majority of all MS patients. Detailed advice can only be given by MS specialists and cannot be provided by me.
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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, 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 dimethyl fumarate (Tecfidera) and diroximel fumarate (Vumerity) classified in immunotherapies?
There are currently three different therapeutic approaches to preventive, i.e. disease-modifying therapy (DMT) for multiple sclerosis. The most unspecific is immunomodulation, which includes the fumarates Tecfidera and Vumerity. In migration inhibition, certain immune cells are prevented from traveling further in the body. And in depletion, developing immune cells die off. 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) & diroximel fumarate (Vumerity),
- Glatiramer acetate (Copaxone, Clift / Brabio),
- Interferons: 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 dimethyl fumarate and diroximel fumarate approved for?
Dimethyl fumarate and diroximel fumarate are approved for the treatment of relapsing forms of multiple sclerosis. The German Multiple Sclerosis Competence Network (KKNMS) and the German guideline recommend their use in mild or moderate forms of the disease. This might differ from country to country.
What is the situation for special patient groups?
Children and Teenagers
Dimethyl fumarate is currently not approved for children under the age of 18, but international approval studies are underway that are comparing the efficacy of several drugs in a blinded manner. This special type of study design was chosen due to the fortunately small number of children and adolescents with MS, in order to achieve scientifically correct, i.e. evidence-based, results as quickly as possible. This means that off-label use will no longer be necessary in the future and this young target group will also have access to a broad selection of effective medications.
Pregnancy and Breastfeeding
There is also no approval for pregnant women. In the German MS and Fertility Register, DMSKW for short, more than 450 pregnancies have been documented to date (as of May 2024) under dimethyl fumarate. No increased risk of miscarriage or malformations was found. There is no interaction with the pill (oral contraception). However, diarrhea can reduce or completely eliminate the effectiveness of the pill as a side effect of the therapy.
No statement can be made on the use of Tecfidera and generics beyond the first trimester of pregnancy. If an unplanned pregnancy occurs, the medication should be discontinued.
If you are planning a pregnancy, please talk to your neurologist or seek advice from MS experts in the field of pregnancy.
With regard to breastfeeding, there are only two patients in the DMSKW who have been examined and in whom a very low transition into breast milk was detected. Please also talk to your neurologist or seek advice on which strategy you would like to choose for breastfeeding.
Recommendation of the European (EMA) and American regulatory authorities (FDA)
Dimethyl fumarate (Tecfidera and generics) and diroximel fumarate (Vumerity) should not be used during pregnancy and in women of childbearing age without reliable contraception. Exceptions are only permitted if the potential benefit to the mother outweighs the potential risk to the fetus.
In addition, both drugs should not be used for breastfeeding, as a risk to the baby cannot be ruled out. The mother or parents and the neurologist should decide together whether breastfeeding should be discontinued or treatment with dimethyl fumarate or diroximel fumarate should be avoided.
Who should avoid dimethyl fumarate and diroximel fumarate?
Persons with hypersensitivity or allergies to dimethyl fumarate or diroximel fumarate or other components of the preparation. In the case of severe diseases of the digestive tract such as ulcers in the stomach or duodenum, but also in the case of chronic inflammatory diseases of the intestine such as Crohn’s disease or ulcerative colitis. Severe liver and kidney diseases are also an exclusion criterion.
Anyone already suffering from a chronic infectious disease such as HIV, hepatitis B and C should choose a different immunotherapy, as a negative effect on immunocompetence cannot be ruled out.
If you already have severe lymphopenia, the medication is not suitable for you. And if you have overcome or already have PML (progressive multifocal leukoencephalopathy), dimethyl fumarate (Tecfidera and generics) or diroximel fumarate (Vumerity) should not be taken either.
How do dimethyl fumarate (Tecfidera and generics) and diroximel fumarate (Vumerity) work?
Dimethyl fumarate has an anti-inflammatory effect and possibly neuroprotective and myelin-protective properties (Wilms et al. 2010; Linker et al. 2011). However, the overall mechanism of action is not yet fully understood.
Both dimethyl fumarate and diroximel fumarate are converted into monomethyl fumarate in the body. Immunomodulatory and regulatory T cells increase. Inflammation-increasing and cell-damaging cells are reduced. It is assumed that this active form boosts a protein that increases the production of antioxidants and thus helps to control the activity of the immune system and reduce damage to the brain and spinal cord in MS patients.
The effect sets in after ten to twelve weeks. A dose of 3x/day was also tested in the approval studies, but this showed no benefit, which is why the dose was set at twice daily.
How is it taken?
Both dimethyl fumarate and diroximel fumarate are taken by themselves twice daily as tablets.
Tolerance is better with meals and especially after the intake of dairy products.
The duration of therapy is currently not limited. Tolerance and risk-benefit assessment should always be taken into account. With increasing age, the immune system changes, so that a situation can arise where the effect of the medication only brings little or no benefit, while side effects persist. MS patients have completely different courses of the disease, so there is no general recommendation, but an individual decision must be made.
How effective are dimethyl fumarate (Tecfidera and generics) and diroximel fumarate (Vumerity)?
Gavin Giovannoni, an MS expert from the UK, and his team have developed the MS Selfie Cards. They are a very simplified method of comparing the various DMTs with each other and providing an overview of the most important key data. Of course, such a simplification always involves the risk of oversimplifying things that may be more complex, especially as there have been almost no direct comparisons of immunotherapies with each other to date. Therefore, take the information contained on the MS-Selfie Cards for what it is, a rough idea, and discuss individual therapy recommendations with your MS specialist. Every MS progresses differently and therefore there is no one therapy that everyone should take, but it should be a choice based on your disease activity, general health, plans and preferences.
On the MS-Selfie cards you’ll find a ranking from one to ten, with one being slightly effective and ten being maximally effective. In his estimation, dimethyl fumarate and diroximel fumarate both scored a 4 in preventing relapses and long-term disability.
In the registration study, dimethyl fumarate led to 53% fewer relapses and slowed disability progression by 38% compared to placebo.
Risks and side effects of dimethyl fumarate and diroximel fumarate
In general, dimethyl fumarate (Tecfidera and generics) and diroximel fumarate (Vumerity) are safe medications. About four out of ten patients experience mild side effects.
These include discomfort with the digestive system, urinary tract infections, feeling hot and flushing. The digestive complaints and flushing occur very frequently in the first month after starting therapy, but then decrease significantly.
Safety precautions – lab parameters
A complete blood count is taken before starting and after three months. The liver values are checked before the start, after the third month, after the sixth month and every six to twelve months from then on. The same procedure applies to the kidney function test. It is carried out before the start, after three and six months and then only every six to twelve months. If the lymphocytes, the white blood cells, remain below a certain level for longer than six months, treatment with Tecfidera will be discontinued.
You do not need to worry about this. This will be checked for you. But please take the examinations seriously and if you are unable to attend an appointment, make up for the check-ups and don’t skip them altogether.
There is a very low risk of PML (progressive multifocal leukoencephalopathy). The data has been collected since 2017 and so far the risk has been 0.002 percent (eleven cases out of more than 500,000 patients treated, with one person dying).
On the aforementioned MS selfie card, the side effects are rated on a scale from one for few or rare to ten for many or frequent, as follows
- Normal side effects at five
- Long-term side effects with three
- Cancer risk with three
Dimethyl fumarate and diroximel fumarate also receive the following rating on the MS Selfie Card’s brief classification of effects:
- Clinic visits: many
- Family planning: incompatible in the short term
- Vaccinations: good response
What is different about diroximel fumarate (Vumerity)?
Dimethyl fumarate was further developed in order to achieve better tolerability. The intensity of the gastrointestinal side effects was significantly reduced, so that patients had much less discomfort.
Furthermore, in the EVOLVE-MS-2 study, only 46 percent of patients taking diroximel fumarate had flushs, compared to 55 percent for dimethyl fumarate. However, one in ten people developed cold symptoms.
Vaccinations
All vaccinations are permitted during therapy with dimethyl fumarate (Tecfidera and generics) or diroximel fumarate (Vumerity). However, live vaccines should be avoided if the lymphocyte (white blood cell) count is low. There are no warnings for newborns whose mothers have taken dimethyl fumarate or diroximel fumarate during pregnancy.
Vaccination against herpes zoster, which leads to shingles, may be necessary before starting therapy. In this case, vaccination with the inactivated vaccine Shingrix is recommended.
Sources
I used the following sources to create the content:
- Lecture on dimethyl fumarate (Tecfidera and generics) and diroximel fumarate (Vumerity) by Prof. Mathias Mäurer as part of the Multiple Sclerosis Management master program
- Quality manual of the KKNMS on dimethyl fumarate
- 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
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:
See you soon and try to make the best out of your life,
Nele
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