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In 1985, a clinical trial designed
to evaluate the effects of gamma interferon on MS was dramatically stopped.
Far from improving the symptoms
of MS, the drug actually made things much worse, with almost 40 per cent
of patients in the trial suffering relapses when treated with gamma interferon
for 1 month. This apparent ability of gamma interferon to stimulate new
disease activity was a vital finding in the understanding of MS pathophysiology.
Prior to this, studies with natural beta
interferon yielded promising results, but the drug had to be injected
into the spinal cord (intrathecal administration) - clearly not very practical
for a long-term treatment. In addition, other compounds that affect the
immune system in different ways were tested, with unsatisfactory results.
Researchers decided to reconsider beta interferon. Let's take a look at
the reasons behind their interest.
Interferons are naturally occurring substances, first identified in 1957,
that are produced by cells when they become infected by a virus or certain
bacteria, or if factors are present that stimulate the immune system.
They have the ability to inhibit virus growth and are effective in treating
certain cancers. In humans, three types of interferon are produced from
specific cell types: alpha from white blood cells, beta from fibroblasts
and gamma from lymphocytes.
As ‘messenger molecules’ of the immune system, all three are intrinsically
involved in the autoimmune ‘attack’ that MS wages on the body’s own tissues.
Their precise modulatory effects on the immune system differ significantly,
however; alpha interferon and beta
interferon can suppress, whereas gamma interferon may enhance
a local immune response, as demonstrated so graphically in the 1985 trial.
This fundamental difference is the key to interferon therapy in the treatment
of MS.
At the time of the 1985 trial, scientists had already been working on
developing the therapeutic potential of beta
interferon for over 5 years. In 1980, experts in genetic engineering
cloned
beta interferon using bacteria, then modified,
improved and stabilised it to yield a recombinant
interferon beta-1b - BETAFERON® (BETASERON®
in the USA and Canada). This new product retains the activity of native
human beta interferon, but in a more stable form. It was predicted, therefore,
that its use would rapidly eliminate the problems of availability, potency
and purity that had been experienced in earlier clinical
trials evaluating natural interferons. To test this hypothesis, a
small pilot study was initiated to clarify the functions of interferon
beta 1b at the molecular level, define the maximum tolerated dose and
specify the therapeutic benefits - if any - afforded by its use in the
treatment of relapsing-remitting
MS.
The findings of this pilot trial were substantiated in 1991 at the end
of a landmark, phase-III, 3-year
study performed across the USA and Canada during which the safety of
high-dose treatment with interferon-beta-1b
for people with relapsing-remitting MS was investigated. In addition
to clinical parameters to measure efficacy, magnetic
resonance imaging - a highly sophisticated technique that allows
the number, age (new or old) and type (active or silent) of lesions
to be monitored - was used during the trial to study the effect of interferon-beta-1b
on MS lesions in the brain.
Many of the patients enrolled in this original trial remained on treatment
for a further 2 years. As a result of positive data from the 2-, and
3-year trials, on July 23 1993, BETASERON® became the first
new therapy to be approved for the treatment of MS by the US Food and
Drug Administration. To date, over 85,000 people with MS have used interferon-beta-1b.
In Europe, BETAFERON® has been available
since early 1996 following its approval in November 1995.
In February 1999, BETAFERON® became the first drug
available for the treatment of secondary progressive MS. Approval was
granted in Europe after a pivotal trail was stopped early by an independent
advisory board, who recommended that all patients receiving placebo should
be switched to BETAFERON®. The trial showed that BETAFERON® delays disease
progression by 9-12 months in people with secondary progressive MS. Importantly,
time to becoming wheelchair dependent was delayed by up to 1 year.
From recombinant
genes to clinical reality, the development of BETAFERON® for the
treatment of MS marks a significant step forward in our understanding
of the underlying pathology of the disease.
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