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#068: Interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif, …) for CIS, RRMS & SPMS

In today’s article, I present interferon-beta, which include several active substances and are known as Avonex, Betaferon, Extavia, Plegridy, Rebif, or under other trade names. They are all approved disease-modifying drugs for relapsing forms of MS. They are used for mild and moderate courses of the disease.
Like glatiramer acetate and fumarates, which have already been presented, interferons have a broader mechanism of action. In the following, I will try to provide a good overview without delving into all the details. And as always: seek advice from MS specialists who know your individual situation, your wishes, your fears and your general state of health.

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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 is interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif, and generics) 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 interferon-beta. 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:

  1.  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)
  2. Migration inhibition – the migration of certain immune cells is inhibited:
    • Natalizumab (Tysabri, Tyruko)
    • S1P modulators: Fingolimod (Gilenya), Ozanimod (Zeposia), Ponesimod (Ponvory), Siponimod (Mayzent)
  3. 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 interferon-beta approved for?

Interferon-beta is approved for the treatment of relapsing forms of multiple sclerosis. The German Multiple Sclerosis Competence Network (KKNMS) and the German guideline recommend its use in mild or moderate forms of the disease.

In addition, some interferon-beta preparations are approved for patients with clinically isolated syndrome (CIS) who have a high risk of developing MS. This applies to Avonex, Rebif, Betaferon / Extavia and their generics.
In addition, Rebif, Betaferon / Extavia are also approved for the treatment of secondary progressive MS, provided there are still relapses.

Different specifications or recommendations from country to country are possible.

What is the situation for special patient groups?

Children and Teenagers

Interferon-beta 1a (Rebif) is approved for children aged 2 years and older. Interferon-beta 1b (Betaferon/Extavia), on the other hand, is approved for minors aged 12 years and older. The other interferons can be used off-label, but MS is often very active in children and adolescents, so stronger drugs should be used. Please contact an MS specialist, preferably a neuropaediatrician, for individual advice.

Pregnancy and Breastfeeding

There is no approval for pregnant women. However, more than 2,500 women worldwide have already been registered who were taking interferon-beta until the onset of pregnancy. In these women there was neither an increased miscarriage rate nor more malformations.

The German MS and Fertility Register, DMSKW for short, has so far examined 41 women who took beta-interferons while breastfeeding. In addition to an extremely low transfer of the drugs into breast milk (0.006% of the maternal dose), even lower in the case of pegylated beta interferons (Plegridy), the development of the babies appears to be completely normal.

Since September 2019, all beta-interferon preparations have also been approved for use during breastfeeding.

If you are pregnant or planning to become pregnant, please discuss your treatment strategy with your MS specialist.

Recommendation of the European (EMA) and American regulatory authorities (FDA)

No clear association with congenital malformations or spontaneous abortions has been observed following the administration of beta interferons during pregnancy. However, it cannot be completely ruled out. The data are based on use until the pregnancy is established. There are hardly any data from the second and third trimester. Continuation of therapy with beta interferons during pregnancy can be considered, but should only be carried out after a precise risk-benefit assessment with an MS specialist. No harmful effects on the breastfed newborn are to be expected during breastfeeding with beta interferons.

Who should avoid interferon-beta?

Persons with hypersensitivity or allergies to interferon-beta or other components of the preparation.
Severe acute depression or suicidal thoughts. Also in cases of decompensated hepatic insufficiency. In other words, when the liver is no longer able to fulfill its function.

Children under twelve or under two years of age. However, the safety profile in adolescents aged twelve to 18 years appears to be comparable to that of adults, with the exception of plegridized interferon-beta (Plegridy), which should not be administered to children under 18 years of age. The registration studies have not yet been completed.

Furthermore, people suffering from epilepsy that cannot be controlled by medication should avoid beta interferons. Anyone suffering from one or more of the following conditions should consider an alternative to beta interferons.

Patients with liver dysfunction, kidney and urinary tract disorders, abnormal laboratory values, thrombotic micorangiopathy (TMA), heart disease and depression should rather use other therapies.

How does interferon-beta works?

The mode of action of beta interferons in MS is not exactly clear. They modulate the dysregulated and overactive immune system, help to close the blood-brain barrier and inhibit inflammatory processes.
This inhibits pro-inflammatory messenger substances and at the same time promotes messenger substances that have an anti-inflammatory effect. As a result, regulatory T cells multiply and autoreactive, i.e. aggressive T cells are inhibited.

The effect occurs directly and works as long as it is used.

How is it taken?

  • Interferon-beta 1a (Avonex®) 30 μg; once a week, intramuscularly
  • Interferon-beta 1a (Rebif®) 22 μg or 44 μg; 3x weekly, subcutaneous
  • Peginterferon-beta 1a (Plegridy®) 125 μg; 2x monthly, subcutaneously and intramuscularly
  • Interferon-beta 1b (Betaferon® / Extavia® 250 μg each); every other day, subcutaneously

 

Injection aids and ready-to-use pens are available.

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 is interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif, and generics)?

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, interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif and generics) scores 1 for relapse prevention and 1 for long-term disability.

It should be noted that interferon-beta is only effective in some patients. The evaluation would therefore be shifted if only responders were rated.

In the pivotal study, interferon-beta led to 30% fewer relapses compared to placebo. In other words, you can also look at 100 patients. 30 of these patients remain relapse-free, even on placebo. In the interferon-beta group, a further 15 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 in the placebo group. Nine people in the placebo group deteriorated who remained stable on interferon-beta.

MS-Selfie Card for Interferon-beta 1a, Tradename: Avonex from Prof. Dr. Gavin Giovannoni, London, UK
MS-Selfie Card for Interferon-beta 1a, Tradename: Rebif from Prof. Dr. Gavin Giovannoni, London, UK
MS-Selfie Card for Interferon-beta 1b, Tradename: Betaferon / Extavia from Prof. Dr. Gavin Giovannoni, London, UK
MS-Selfie Card for Peginterferon-beta 1a, Tradename: Plegridy from Prof. Dr. Gavin Giovannoni, London, UK

Risks and side effects of interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif and generics)

The most common side effects with interferon-beta are injection reactions in just under half of all patients. These range from inflammatory redness, pain and itching to local inflammation and necrosis. In addition, almost a fifth of all patients have flu symptoms such as fever, headaches, muscle aches or chills. These side effects occur more frequently at the beginning and usually decrease as the therapy progresses. Anyone who has problems with depression or is predisposed to it should look for another immunotherapy, as interferon beta can increase depression.
Interferon-beta can lead to a reduction in the number of leukocytes and platelets, less frequently lymphocytes. Liver problems may also occur. During therapy with interferon-beta, persistent neutralizing antibodies (NAbs) against the drug can develop, which can negate its effectiveness.

Safety precautions – lab parameters

A differential blood count as well as liver and kidney values should be taken one month after the start of treatment. And then every three months, at least in the first year of therapy. If everything remains normal, the check-up interval can be extended to once or twice a year. The same procedure applies to the kidney function test. It is carried out before the start of treatment, after three and six months and then only every six to twelve months.

You do not need to worry about this. This 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 do not 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 seven
  • Long-term side effects at zero
  • Cancer risk at zero, only peginterferon beta-1a at one

Interferon-beta receives the following rating in the MS Selfie Card overview of the impacts of therapy

  • Clinic visits: many
  • Family planning: compatible
  • Vaccinations: good response

Vaccinations

All vaccinations are permitted during therapy with interferon-beta (Avonex, Betaferon, Extavia, Plegridy, Rebif and generics). However, live vaccines should only be administered after a thorough risk-benefit assessment. The annual flu vaccination is strongly recommended.
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

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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Nele Handwerker

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I show you how to make the best of your life with MS from family to career to hobbies. Thanks to science and research, a lot is possible nowadays.

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