What disease-modifying therapies offer
Introduction
There are currently 3 types of treatments available that have been clearly shown to change the clinical course of certain forms of MS. They are beta interferon-1b (Betaferon), beta interferon-1a (Avonex®, Rebif®) and glatiramer acetate (Copaxone®). The interferons are naturally derived hormones involved in controlling the body's immune system whilst glatiramer acetate is a mixture of short chains of amino acids (the building blocks of proteins) which modulates the immune response in a way yet to be defined.
These have each been shown to be effective in preventing relapse and some have shown the ability to slow the progression of the disease, including lengthening the time to disability. The following is a short description of the results of the main clinical trials for each of these products. The term EDSS is for the measure of disability that is used in all these trials and described elsewhere on this site. (link) MRI is a brain imaging technique used to visualise the damage done to the nervous system by MS, which is also described elsewhere.
MS treatments compared
Because of a variety of factors in the way the trials were conducted, it is not possible to compare accurately the effectiveness of the treatments by looking at their results. Instead, it is necessary to use comparative trials where two disease modifying treatments are used side-by side.
An independent trial compared interferon beta-1b 8 MIU injected subcutaneously (sc., under the skin) every other day with interferon beta-1a 6 MIU injected intramuscularly (i.m., deep into muscle) once a week.2
The results after 2 years were in favour of INF beta-1b every other day (eod) In terms of relapse control, EDSS progression and lowering MRI lesions INF beta-1b eod. was superior to INF beta-1a once weekly (ow).
The researchers were of the opinion that the higher weekly dose and greater frequency of injection with interferon beta-1b, probably acting together, were responsible for its greater effectiveness.2
Further evidence for increasing effectiveness with more frequent and higher doses
In another study the two interferons beta-1a (Rebif® and Avonex®) were compared with each other. The study confirmed the greater benefits of higher and more frequent doses of interferon beta-1a thrice weekly s.c. over interferon beta-1a once weekly i.m.3
Patients with more and higher dosages of interferon beta-1a had fewer exacerbations and remained to a higher percentage relapse-free. Patients with once weekly i.m. injections of interferon beta-1a had 50% more new lesions on MRI then patients with thrice weekly injections s.c.
Studies in the laboratory have shown that beta interferon exerts the following effects in a dose related manner:
- Beta interferon inhibits the mechanism by which T-cells are able to break down the blood-brain barrier and gain access to the central nervous system
- Beta interferon reduces the proliferation of T-cells and increases production of cytokines that suppress the immune response
- Beta interferon may suppress the enzyme producing nitric oxide involved in damaging nerve cells
- Beta interferon stimulates the release of nerve growth factor
In animal models of MS, beta interferon also shows dose related ability to suppress the disease.
In healthy volunteers, markers in the blood of the effect of interferon beta increase in proportion to the dose given. It is not important whether it was given sc. or im. What is important is how often the dose is given because even at high doses the effect only lasts a maximum 5 days.4
A number of clinical trials have shown that the higher the dose of beta interferon, the greater the effect, but this may partly be due to the fact that it is given more often. Although higher doses cause more side effects such as chills, fevers and injection site reactions, it has been shown that these can be controlled with drugs like e.g. paracetamol or ibuprofen.5
References
1 Goodin DS, Frohman EM et al. Disease modifying therapies in multiople sclerosis. Report of the Therapeutics and TechnologyAssessment Subcommittee of the American Academy of Neurtology and the MS Council for Clinical Practice Guidelines. Neurology 2002;58:169-178.
2 Durelli L et al. and the Independent Comparison of Interferon (INCOMIN) Trial Study Group. Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 2002;359:1453-1460.
3 EVIDENCE Study Group. Results of comparative efficacy trial using two formulations of interferon beta-1a in RRMS. Journal of Neurological Science 2001;187 (Suppl.1):S436.
4 Stuerzebecher S, Maibauer R et al. Pharmacodynamic comparison of single doses of IFN beta-1a and IFN beta-1b in healthy volunteers. J Interferon Cytokine Res 1999;19:1257-1264.
5 Goodin DS. Interferon-β Therapy in Multiple Sclerosis. Evidence for a Clinically Relevant Dose Response. Drugs 2001;61(12):1693-1703.
