TORONTO, ON -- November 27, 2003 -- Three recent independent publications in The Lancet, Neurology, and Brain journals provide compelling evidence that immunogenicity is an emerging and important consideration for neurologists in selecting immunomodulator therapy for the treatment of multiple sclerosis (MS).
The Lancet Study1
According to study results published October 11, 2003 in The Lancet, annual relapse rates increased by more than 50% in Multiple Sclerosis (MS) patients who tested positive for neutralizing antibodies (NAbs) caused by beta interferon (IFN beta), a first-line treatment for MS. The study, entitled "Clinical Importance of NAbs against IFN beta in patients with Relapsing-Remitting MS", represents the longest comparative study to date on this topic. The findings confirm that the presence of neutralizing antibodies against beta interferon reduces its effect, as measured by relapse rate, time-to-first relapse, and EDSS [Expanded Disability Status Scale] disease progression.
The independently-funded study utilizing the Danish National MS Treatment Database, measured NAbs every 12 months for up to 60 months in 541 patients with MS, randomly selected from all patients on a beta interferon. Antibodies were measured blindly, employing an antiviral neutralization bioassay, using high, medium and low sensitivity. Neutralizing antibody positivity was defined as neutralization capacity „ 20% in the medium sensitivity assay.
The study's key results include:
-- An increase in the yearly relapse rate by more than 50% in patients who were NAb positive compared to those
who were NAb negative.
-- A significant increase in the time-to-first relapse of over 8 months (244 days) in patients who were NAb negative at 12 months.
-- An increase in the mean EDSS in NAb positive patients after 42 months.
-- Interferon beta-1a (Avonex®) was the least immunogenic of the three interferons studied at all time points.
The Consortium of MS Centres NAbs Consensus Statement2
A series of articles published November 11, 2003 in Neurology and based on an independent consensus conference of 33 international MS opinion leaders (including five from Canada) further support the link between the presence of NAbs and the lack of response to immunomodulating treatment in MS patients.
The following consensus statements (as defined by more than 70% agreement from participants) were agreed upon:
-- High levels of anti-IFN beta in the sera of MS patients interfere with the bioactivity of injected INF beta.
-- INF beta-1b (Betaseron®) is more immunogenic than IFN beta-1a (Avonex®, Rebif®).
-- Antibody-mediated decreased bioactivity (ADB) is a graduated phenomenon rather than an all-or-nothing effect. The magnitude of decrease in bioactivity depends on the amplitude, avidity, and epitope-binding characteristics of the anti-IFN beta antibody population.
-- ADB of injected IFN beta in patients with MS can be reliably detected by decreased levels of MxA, an IFN beta-induced gene product.
-- The clinical sequelae of ADB depend on the duration and severity of decreased bioactivity and the underlying activity of the patient's MS. Thus, the persistence of high levels of anti-IFN beta antibodies in patients with active MS will eventually lead to clinical evidence of loss of efficacy of IFN beta.
-- Because of the therapeutic effects if IFN beta may be delayed, analysis of the clinical effects of ADB would best be performed in a period delayed several months after demonstration of persistent ADB.
-- Immunogenicity of an IFN beta preparation should be one of the factors considered in selecting an IFN preparation for an MS patient.
-- The assay for binding and neutralizing antibodies should be standardized.
-- Clinicians need to change their approach to the patient if the patient is NAb positive, and they need to consider discontinuing IFN beta or changing therapy.
The Brain Study3
In a study by Salama et al, published in Brain this August, it was reported that patients treated with glatiramer acetate (GA; Copaxone®) developed GA-specific serum antibodies that blocked the in-vitro effect of GA on T-cells. The findings raise an important clinical issue as to whether the occurrence and high titres of GA antibodies may impair the treatment effect of GA in multiple sclerosis.
What Do These Results Mean for Neurologists?
It is important that neurologists are aware of the fact that high levels of NAbs interfere with the therapeutic effect of beta interferon therapy in MS. The negative effects of neutralizing antibodies should also be considered with glatiramer acetate.
"When we choose a beta interferon in MS, we have many factors to consider," says Dr. Stan Hashimoto, neurologist and past Clinical Director of the MS Clinic at University Hospital in Vancouver, B.C. "One important property is the rate and persistence of neutralizing antibodies since they can significantly decrease the clinical efficacy of these expensive therapies in the long-term," add Dr. Hashimoto. "Neurologists should consider the relative immunogenicity of beta interferons when selecting treatment options for their patients. Avonex® is less immunogenic when compared to Rebif® and Betaseron®. Persistence of the antibodies appears to differ from one product to another and this needs further study. It would also be interesting to further investigate the results of glatiramer acetate specific serum antibodies."
Multiple sclerosis is the most common neurological condition affecting young adults in Canada. MS most often strikes young adults – women and men between 20 and 40 who are in their productive family and career years.
AVONEX® is a registered trademark of Biogen Idec MA Inc. Copaxone® is a registered trademark of Teva Inc. Rebif® is a registered trademark of Serono Inc. Betaseron® is a registered trademark of Schering Inc.
References:
1. Sorensen, Per Soelberg et al, "Clinical Importance of Neutralising Antibodies Against Interferon Beta in
Patients with Relapsing-Remitting Multiple Sclerosis," The Lancet. Vol. 362, pp 1184-1191, October 11, 2003.
2. Pachner, Andrew R., "Anti-IFN€ Antibodies in IFN€-Treated MS Patients," Supplement to Neurology. Vol. 61,
No. 9, Supplement 5, November 11, 2003.
3. Salama et al. Brain Vol. 126, pp1-10, 2003.
SOURCE: Biogen Idec
