BERLIN 28 January
On January 26 the Commission of the European Communities approved Betaferon (interferon beta-1b, Schering AG) for the treatment of secondary progressive MS. This means that in Europe patients will now have access to the first medicine licensed to treat both relapsing-remitting and the more advanced secondary progressive phase of multiple sclerosis. The ECs approval was based on a positive review by EMEA the European Agency for the Evaluation of Medical Products. The US Food & Drug Administration and the Canadian Health Protection Branch are reviewing the submissions. Regulatory approval is expected within the next few months. This confirms the world-wide leading position of Betaferon in the treatment of multiple sclerosis.
The European licensing agency acted after a pivotal European trial was stopped early by an independent advisory board. In patients treated with Betaferon disability was progressing more slowly than in those treated with placebo and so the advisory board recommended not to continue the trial and to offer active treatment to all patients. In secondary progressive multiple sclerosis Betaferon is now indicated for slowing progression of disease and for the reduction of frequency of clinical relapses
The results of the study published in The Lancet, November 19981, showed that Betaferon delayed the progression of the disease by 912 months and significantly reduced, by approximately 22%, the proportion of patients with confirmed progression. In addition, when the study was stopped, 25 per cent of the placebo group had become so disabled that they had to use a wheelchair. Only 17 per cent of the Betaferon group had progressed to this point a relative reduction of around one third.
The results are particularly striking because the difference to placebo was significant after twelve months of treatment.
About forty percent of people living with MS have the secondary progressive phase of the disease. All have had relapsing-remitting MS for a number of years but have gone on to the later phase in which they become more and more disabled. People in the earlier stages of MS can usually continue to work and participate in family life with only occasional interruptions caused by illness. Secondary progressive MS, however, increasingly deprives patients of the ability to walk or to care for themselves unaided.
The approval of Betaferon offers a new perspective for people with MS and their treating specialists. "Patients would often start treatment in the later phases of relapsing-remitting disease. We were not sure about the benefits of treatment when the disease became secondary progressive," explained Prof. Ludwig Kappos, Professor of Neurology, Department of Neurology, University Hospitals, Basel, Switzerland, and one of the investigators in the recent trial. "Now we know that when we begin treatment early, we can reduce relapses throughout and delay disability even if the patient progresses to the secondary progressive form of the disease, thereby preserving mobility for a longer time," he added.
"Most of us go through a process of coming to terms with MS," said Reid Nicholson of the People with MS committee of the International Federation of Multiple Sclerosis Societies. "The message from this and other trials is that each of us should make informed decisions about treatment as soon as we feel able to and should review those decisions regularly. The data now show convincingly that intervention can reduce relapses, limit neurological damage and even slow disability in the later stages of MS. Of course treatment requires a commitment and sometimes involves side effects. We each have to decide for ourselves what we want to do. The important thing is that health care systems respect our decisions and provide treatment to those who choose it," he added. Reid Nicholson is a person living with MS.
Multiple sclerosis is a disease in which the bodys immune system attacks myelin a protective tissue around the nerves, which is important for nerve impulse conduction.
Most people with MS are first diagnosed with relapsing-remitting multiple sclerosis. Typically they will experience attacks of MS or relapses characterised by symptoms such as tiredness, partial paralysis or partial loss of vision. During this early stage of the disease, the person with MS will in most cases fully recover from each episode. Betaferon was the first MS therapy to be licensed for treatment of relapsing-remitting disease in 1993 after it was shown to reduce relapses by one third.2 Most experts now believe that, even during the earlier phases, the disease is usually causing underlying damage which gradually makes recovery more difficult.
More than 80% of people with relapsing-remitting MS will develop secondary progressive MS, a condition in which they continue to progress even between relapses3. The level of permanent disability becomes progressively worse until most patients are eventually confined to a wheelchair. This progression may occur without obvious relapses. Prior to entry in the Betaferon study, the average time from diagnosis with relapsing-remitting MS to diagnosis with secondary progressive MS has been about 6 years1.
Furthermore, natural history data show that the relapse frequency has an impact on disease progression. A patient experiencing two relapses in the first year after diagnosis reaches the disease stage when he is confined to bed most of the day after 35 years, a patient with three relapses in just 24 years.4 This underlines the possible benefit of therapy by reducing the frequency of relapses in early stages of MS.4
Some people with MS have a relatively benign form of the disease with occasional relapses but no apparent long-term disability. A minority are diagnosed with primary progressive MS in which the disease progresses from onset without relapses.
The study, which was planned to run for three years, was stopped early in 1998 after all patients had been treated for at least two years and an independent advisory board had reviewed the interim results. The results at that stage included data up to three years comprising 85% of all EDSS data of a full three-year study and already strongly and highly significantly favoured Betaferon. Therefore, all patients were subsequently offered active treatment.
The EC granted a licence to treat secondary progressive MS with Betaferon after evaluating results of a pan-European 32 centre study.1 The double-blind, placebo-controlled study showed that Betaferon slowed time to further sustained deterioration by up to one year in patients who had reached the secondary progressive stage of MS and prolonged the time before they become confined to a wheelchair by up to nine months. This is remarkable since this benefit was observed within a treated period of up to three years.
In the study, a total of 718 patients with secondary progressive MS rated 3.06.5 on the Kurtzke Expanded Disability Status Scale (EDSS) were randomised to Betaferon 8 MIU (360 patients) or placebo (358 patients) administered by subcutaneous injection on alternate days. The primary outcome of the study was confirmed progression (as measured by the EDSS) persisting over at least three months. At higher scores the Kurtzke EDSS mainly measures a persons mobility: a score of 6.5 means that a person cannot walk unaided; a score of 8 means that a person is confined to bed for most of the day.
The results showed a highly significant difference between the two patient groups in time to confirmed neurological deterioration favouring Betaferon treatment (p<0.0008). As assessed by the study criteria, half the placebo patients had deteriorated compared with only 39% of patients receiving Betaferon (p<0.0048). Whether or not patients were more or less disabled when they entered the study and whether or not they experienced relapses during the study made no difference to the positive treatment effect. This means that patients with EDSS 3 at study entry responded equally well to Betaferon as those with an EDSS of 6 a much more severe stage of the disease.
For example, by 16 to 18 months, disability had progressed in about 40 per cent of placebo-treated patients whilst, among actively treated patients, it was 30 months before the same proportion had deteriorated. Similarly, 10 per cent of the placebo group had become wheelchair bound by one year while it was 21 months before the same proportion of the Betaferon group reached the same stage.
Betaferon also significantly reduced the number of relapses by almost one third. However, in addition, treatment also benefited patients without relapses. Therefore, Betaferon is the first MS therapy demonstrated to modify the disease in those patients who experience disease progression independent of relapses.
Betaferon significantly reduced the requirement for steroids used to suppress inflammation during relapses and the number of MS-related hospital admissions by 20 per cent.
The observation of treatment benefits was supported by magnetic resonance imaging (MRI), which represents an objective way to quantify the impact of disease5. The central analysis of serial MRI scans was performed by the MS MRI Research Group, based at the National Hospital, London, UK. After two years, placebo-treated patients had about four times more new lesions than Betaferon-treated patients did. A statistically significant difference in this parameter was apparent within one month. The existing lesion burden visible on MRI was reduced by 5 per cent in Betaferon-treated patients whereas it increased by 8 per cent in placebo-treated patients. "The effect of Betaferon in reducing inflammatory etkinligini, as depicted by serial or monthly MRI scans, was at least the same if not more pronounced at the end of the second year of the study as it had been in the first six months. This is a strong indication of a sustained treatment effect," said Prof. Kappos.
Side effects, mainly injection site reactions and flu-like symptoms, were more frequent in the active treatment group. The study investigators, however, concluded that Betaferon treatment is safe in secondary progressive MS and that side effects were within the expected range.
A recently reported study of biological response parameters conducted in 16 healthy volunteers demonstrated that there were significant differences between those people administered 8MIU Betaferon subcutaneously on alternate days and those who received 6MIU interferon beta-1a intramuscularly once a week.6 The levels of neopterin, MxA protein, beta2-microglobulin and interleukin-10 (IL-10) were significantly greater in the Betaferon group IL-10 did not rise significantly above baseline in the interferon beta-1a group. The responses in the Betaferon group also lasted longer there was a substantial decline in neopterin and beta2-microglobulin levels after five days in the interferon beta-1a group, but no similar decline in the Betaferon group.
Neopterin, MxA protein and beta2-microglobulin are widely recognised markers of interferon beta etkinligini. IL-10 is an anti-inflammatory cytokine which has been shown in preclinical studies to correlate with the resolution of clinical disease symptoms in experimental allergic encephalitis (an animal model for MS), and in-vitro studies have demonstrated that IL-10 is induced following the administration of interferon beta.
Whilst the study was of a limited size and duration, these data strongly support the treatment scheme for Betaferon with subcutaneous injections every other day which has been established for both relapsing-remitting and secondary progressive forms of MS. This demonstrates the important advantages of frequent dosing for the treatment benefits of MS therapies.
Betaferon is the most widely used treatment for MS in Europe. It is also the first drug with a proven treatment effect in secondary progressive MS.1
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