Today we are talking about natalizumab, which is known under the trade names Tysabri and Tyruko. The immunotherapy is used for active, severe courses of relapsing forms of MS.
Natalizumab is a migration-inhibiting drug that prevents the migration of T and B cells into the central nervous system.
Please remember that I can only provide an overview here. Your neurologist and your MS nurse should give you detailed advice on choosing the right therapy for you. This is because they know your overall state of health and you should also talk about your goals, wishes, fears and preferences so that these can be taken into account.
Klicken Sie auf den unteren Button, um den Podcast zu laden.
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 is natalizumab (Tysabri, Tyruko) 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 natalizumab. 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 is natalizumab (Tysabri, Tyruko) approved for?
Natalizumab is approved for the treatment of active severe forms of RRMS that are rapidly progressing. The German Multiple Sclerosis Competence Network (KKNMS) and the German guideline recommend its use in patients aged 18 and over who still show disease activity after a sufficient start-up period of another disease-modifying therapy.
In addition, patients aged 18 and over with rapidly progressing severe RRMS can also be treated with natalizumab from the outset if:
- two or more relapses with disability worsening have occurred in 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 scan. In other words, an existing inflammatory activity is detectable.
Different information or recommendations are possible from country to country.
What is the situation for special patient groups?
Children and Teenagers
Natalizumab (Tysabri, Tyruko) can currently only be used off-label in children and adolescents. In a retrospective study by Huppke et al. from 2019, which included 144 children and adolescents, 42 percent or 55 patients had highly active MS and received natalizumab. This led to a 95 percent reduction in relapse rate and a 97 percent reduction in MRI activity.
For an individual consultation, please contact an MS specialist, preferably a neuropaediatrician.
Pregnancy and Breastfeeding
In the approval studies, their follow-up and the German MS Fertility Register and an Italian study in which natalizumab was taken until the onset of pregnancy, the miscarriage rate was within the usual range and so was the rate of malformations. There was also no particular pattern of malformations. A total of 650 pregnancies have been documented to date. On average, the children had a slightly reduced birth weight.
If natalizumab was continued beyond the first trimester of pregnancy, 36 percent of the children developed anemia or thrombocytopenia, which according to the current status remained harmless and without consequences and were no longer detectable after a few weeks. The data is based on 122 newborns recorded as part of the German MS and Fertility Registry.
Natalizumab passes into breast milk in very small quantities. In a small sample of 20 women from the German MS and Fertility Register, no health effects on the infants were found. The probability of natalizumab being absorbed via the infant’s gastrointestinal tract is low.
Recommendation of the European (EMA) and American regulatory authorities (FDA)
Natalizumab (Tysabri, Tyruko) should only be used in pregnancy after a strict risk-benefit assessment. The active substance can be detected in breast milk. The data on possible effects on children who have been breastfed with natalizumab are still insufficient, which is why breastfeeding with natalizumab (Tysabri, Tyruko) should be avoided.
Recommendation of the DMSKW (German MS Fertility Register)
Recommendation based on the current data situation and experience of the DMSKW:
Natalizumab (Tysabri, Tyruko) should not be discontinued before a planned pregnancy without alternative therapy. If no alternative therapy is available, the DMSKW advises, after intensive risk-benefit assessment, to continue natalizumab through pregnancy. This should take place in experienced multiple sclerosis centers. The infusion intervals should then be extended to 6-8 weeks. When the last infusion is given must be discussed with the treating neurologist. If the last infusion is given before the 30th week of pregnancy, preliminary data from our register shows that around 40% of women still suffer a relapse after giving birth. If the last infusion is given after the 30th week of pregnancy and natalizumab therapy (Tysabri, Tyruko) is started again within the first 4 weeks after delivery, the risk of relapse is low (12%), but more blood count abnormalities occur in the children (approx. 60%).
Who should avoid natalizumab?
Persons who are hypersensitive to the substance or other ingredients.
Patients who currently or in the past have suffered from progressive multifocal leukoencephalopathy (PML).
Persons at increased risk of opportunistic infections due to immunodeficiency, whether due to current or previous treatment or HIV infection.
Furthermore, patients should avoid natalizumab if they have active malignancies, unless it is a basal cell carcinoma.
Under the age of 18, natalizumab (Tysabri, Tyruko) should only be used after a careful risk-benefit assessment and only under the guidance and supervision of an experienced MS center.
How does natalizumab works?
Natalizumab does not trigger cell death, but prevents the adhesion of immune cells to the vascular wall and thus ultimately the crossing of the blood-brain barrier. The effect on the immune system is neither organ-specific (i.e. the migration of immune cells into other organs such as the intestine is also inhibited) nor selective for autoreactive immune cells. Therefore, immune cells that fight specific pathogens are also prevented from migrating.
Due to the mechanism of action, patients treated with natalizumab tend to show higher leukocyte counts in the peripheral blood. After discontinuation of the drug, these cells can rapidly migrate into the central nervous system (CNS) and possibly lead to recurring disease activity.
How is it taken?
Natalizumab is available as an intravenous infusion, known under the brand name Tysabri and since 2023 also as a biosimilar known as Tyruko.
Tysabri has also been available as a subcutaneous injection since 2021.
Natalizumab is administered intravenously as a 300 milligram infusion every four weeks.
Dose adjustments according to weight, gender or ethnicity are not necessary.
The subcutaneous injection is given at a dose of 300 milligram (divided into two injection sites) every four weeks, whereby the injection sites should be at least three centimeters (1.2 inch) apart.
The interval can be extended from four to six weeks to reduce the risk of PML. However, this should only be done by experienced MS centers.
In the first few months, permanent neutralizing antibodies may also develop, which can lead to the drug being excreted threefold. This occurs in around six percent of all patients in the first three months, rarely later than nine months.
How effective is natalizumab (Tysabri, Tyruko)?
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, natalizumab (Tysabri, Tyruko) scores eight for preventing relapses and eight for avoiding long-term disability.
It should be noted that natalizumab is effective in many people, but not for the ones that create antibodies.
In the pivotal study, natalizumab led to 68% fewer relapses and slowed disability worsening by 42 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 natalizumab group, a further 26 patients remained relapse-free. Looking at the same 100 patients, 71 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. Twelve people in the placebo group deteriorated who remained stable on natalizumab.
Risks and side effects of natalizumab (Tysabri, Tyruko)
The most common side effects of natalizumab are infusion reactions (such as dizziness, nausea and vomiting, a sore throat and itchy skin), fatigue, infections and allergic reactions.
In patients who are carriers of the JC virus, there is a risk of severe brain infection, known as progressive leukoencephalopathy (PML), which increases with long-term use of the drug. The risk is around 0.4 percent.
Safety precautions – lab parameters
A clinical neurological examination must be carried out every three months.
The blood count must be determined every three to six months. Before each natalizumab infusion or injection, a clinical check must be carried out to determine whether an infection is present. If this is the case, the medication cannot be administered. If too few white blood cells (leukopenia) or too many (leukocytosis) are measured, a differential blood count must be performed.
The liver values must be determined within the first three months after starting therapy and then every three months for the first six months. If clinical signs of liver dysfunction are detected, they must be checked accordingly. If certain liver values become too high, treatment with natalizumab must be paused until the values have returned to the normal range. Subsequently, close monitoring is required. If certain liver values rise again and are above five times the normal value, natalizumab must be permanently discontinued.
The JC virus (JCV) AC index should be determined every six months in order to better assess the individual risk situation for the development of PML.
After the basic MRI with contrast medium at the start of treatment, an MRI of the brain should be performed annually, i.e. every twelve months, without contrast medium, unless there are reasons for contrast medium administration. More frequent MRI examinations every three to six months may be useful if there is a corresponding risk constellation. If possible, the MRI examinations should be performed on the same machine and with the same sequences.
The infusion takes one hour and the follow-up takes a further hour. One hour of follow-up observation also applies to the injection.
Therapy must be discontinued immediately if there are signs of PML beginning.
You do not need to worry about this. It will be checked for you. However, please take the tests seriously and make up for them if you are unable to keep an appointment, and don’t skip them altogether.
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
- Long-term side effects at five
- Cancer risk at seven
Natalizumab receives the following rating in the MS Selfie Card overview of the effects of therapy:
- Clinic visits: moderate
- Family planning: compatible
- Vaccinations: moderate response
Vaccinations
Live vaccines should be avoided and only administered after a thorough risk-benefit assessment. All other vaccinations are permitted during treatment with natalizumab (Tysabri, Tyruko). In general, the effectiveness of vaccinations may be limited during and up to three months after discontinuation of natalizumab.
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 Natalizumab by Prof. Dr. Thomas Berger as part of the Multiple Sclerosis Management Master’s program
- Quality manual of the German KKNMS on natalizumab (Tysabri, Tyruko)
- 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 natalizumab
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)
See you soon and try to make the best out of your life,
Nele
For more information and positive thoughts, subscribe to my newsletter for free.
Click here for an overview of all podcast episodes published so far.
And at many more places.
* This text contains affiliate links. This means that I get a small compensation if you buy the product recommended by me through the link. For you nothing changes in the price of the product. And it helps me to pay for the blog and to write new posts.
