RESEARCH & DEVELOPMENT

-Gill Higgins-

A new formulation of interferon-/3-1a has shown great promise as a treatment for remitting-relapsing multiple sclerosis (MS) in a phase m trial involving 560 patients. This is the largest trial ever conducted to investigate a treatment for this condition. The new formulation, which is manufactured by Ares-Serono, is now awaiting approval from European regulatory authorities. Speaking to Inpluuma, Professor Lance Blumhardt from Queen's Medical Centre, Nottingham, UK, who was one of the lead investigators in the trial, said that he believes that the drug offers certain advantages over currently available treatments.

Ares-Serono's formulation of interferon-/3-la ['Rebif'] is genetically identical to naturally occurring human interferon. It offers advantages over the commercially available synthetic formulation because it is less likely to be immunogenic.

However, 'Rebif' is not the ftrst recombinant interferon-/3-la product. Biogen also has one, which is known as 'Avonex'. The two products have identical biological activity, but they are available in different formulations. 'Avonex' has been licensed for 1M delivery only, whereas Ares-Serono's agent is suitable for SC or 1M delivery. Professor Blumhardt says that SC formulations are much more acceptable to patients.

Largest bial to date Ares-Serono's SC formulation of interferon-~-la

was used in the recent phase III clinical trial. The study was the biggest to date, involving 560 patients with MS in 9 countries. * The trial was also unique in that the doses of interferon used were higher than any that have been investigated in previous phase III studies.

In the double-blind trial, patients with relapsing­remitting MS were randomised to receive SC interferon-/3-1 a 22 or 44llg 3-times weekly, or placebo, for 2 years. Patients' disability status was reviewed every 3 months, and within 7 days of any acute attack of MS. Further data on patients' conditions were provided by magnetic resonance imaging scans. These provide information on the effects of treatment on brain tissue inflammation.

Improvement all round A preliminary analysis of the trial data has

indicated that treatment with this formulation of interferon-/3-la has a positive effect on all major outcomes, compared with placebo [see table]. This is the ftrst time that a drug has shown such broad activity, said Professor Blumhardt. He added that it provides 'by far the most convincing evidence yet that interferon works in this condition'.

Recombinant interferon-~-l a had a signiftcant effect on reducing all 3 major outcomes measured in the trial. The size of it's effect on relapse rate was comparable to that seen in trials of other formulations of interferon, and copolymer-I, but it had a greater effect on slowing the progression of disability, and reducing brain tissue inflammation than previously seen, said Professor Blumhardt. In terms of brain tissue inflammation, this formulation almost closed down the blood-brain barrier completely, he added.

* See also Jnphanna 1108: 11, 11 Oct 1997; lRJ618393

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The study data also showed that the agent was well tolerated.

Direct comparisons impossible Professor Blumhardt said that no direct

comparisons of the results of this trial could be made with the results of trials of other interferons tested in MS. This is because the trials involved different methodologies, and different patient cohorts. For example, the trial of 'Avonex' involved only patients with mild relapsing-remitting MS, while the phase III 'Rebif' trial involved patients with either mild or moderate disease.

Professor Blumhardt says that he is very impressed by the results obtained with 'Rebif', considering that data from 98% of patients were included in the intent­to-treat analysis. Less than 5% of patients withdrew from the study, compared with a withdrawal rate of more than 20% in the phase III trial of interferon-~-1 b ['Betaferon', 'Betaseron'; Chiron, Berlexl, and more than 50% with 'Avonex'.

Implications for managing MS Interferon has been available in synthetic and

recombinant formulations for the treatment of relapsing-remitting MS for some time. In the UK, the ftrst interferon agent was licensed for treating this condition in 1995. Yet, it's use varies considerably from one region to the next.

This is because it is up to individual health authorities to decide whether or not it is a cost­effective option. Professor Blumhardt believes that the new data from this recent trial will provide a much stronger case for the use of interferon. 'If this data doesn ~ convince people, I'd be very surprised. It's not a cure, but we can see it's very effective. If I had MS, I'd want to be treated' , Professor Blumhardt commented. The price of Ares-Serono's product has not yet been revealed, but it is likely to be reasonably expensive due to the recombinant technology used in the production process. Despite this, Professor Blumhardt says that he thinks it will still be the best option for treatment, as the trial data show that it

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improves every outcome associated with MS regression, and therefore is likely to have a valuable effect on improving quality of life. Quality of life data to support this notion are currently being analysed from the recent trial.

Still much to learn The trial investigators are also collecting more

follow-up data to establish the treatment's long-term effects, and they are looking for factors which could help them to identify which patients are most likely to respond to treatment.

In more general terms, researchers would like to identify which antigen is involved in the development of MS, and to unravel the complex immunological interactions that occur in patients with this condition. Such work could reveal new targets for drug therapy.

Until this time, Professor Blumhardt considers interferon to be the most effective treatment option available for relapsing-remitting MS. He expects many researchers will now look at combining the agent with other treatments, as several therapies with different mechanisms of action have shown partial efficacy .

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