Fw: [MS_Community] Fwd: [Spotlight_ldn] technical paper on beta interferon therapy

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[MS_Community] Fwd: [spotlight_ldn] technical paper on beta interferon

therapy

In a message dated 01/02/2004 10:54:17 AM Eastern Standard Time,

jeff@... writes:

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, R., " Anti-IFN & #61538; Antibodies in IFN & #61538;-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