From Interferon to Interferon beta-1b: A History Bayer Pharma AG
Interferons identified
Interferons are naturally occurring substances that were first identified in 1957. They 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, many different types of interferon are produced but the main ones to concern us are: alpha from white blood cells, beta from fibroblasts and gamma from a special white blood cell called a lymphocyte. 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 shown below. This fundamental difference is the key to interferon therapy in the treatment of MS.
Gamma interferon trial stopped
In 1985, a clinical trial designed to evaluate the effects of gamma interferon on MS was dramatically stopped.1 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, a study 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 treatment2. 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.
Beta interferon gene cloned
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 had cloned the beta interferon gene using bacteria, then modified, improved and stabilised it to yield a recombinant interferon beta-1b - Interferon beta-1b (Betaseron® in the USA and Canada). This new product retained 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 interferons3. 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.4
Landmark results
The findings of this pilot trial were confirmed 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.5 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.6
BETASERON® and Interferon beta-1b become available
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 100,000 people with MS have used Interferon beta-1b (or Betaseron, in the US) since launch of the drug. In Europe, Interferon beta-1b has been available since early 1996 following its approval in November 1995.
Further development of Interferon beta-1b
In February 1999, Interferon beta-1b became the first drug available for the treatment of secondary progressive MS. Approval was granted in Europe after a pivotal trial was stopped early by an independent advisory board, who recommended that all patients receiving placebo should be switched to Interferon beta-1b.7 The trial showed that Interferon beta-1b 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. Approval was also granted in Europe in 2006 for patients who for the first time have experienced symptoms which indicate a high risk for development of multiple sclerosis. Results from the BENEFIT study showed that Interferon beta-1b 250 mcg treatment in the early phase of the disease reduced the risk of developing CDMS by 50 percent compared with placebo.8
8. Kappos L. et al. Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 2006; 67:1242–1249
References
1 Panitch HS, Haley AS et al. Exacerbations of multiple sclerosis in patients treated with gamma interferon. The Lancet 1987;893-894
2 Jacobs LD, O’Malley J et al. Intrathecal interferon reduces exacerbations of multiple sclerosis. Science 1981;214:1026-1028.
3 Knobler RL, Panitch HS et al. Systemic alpha-interferon therapy of multiple sclerosis. Neurology (Cleveland) 1984;34:1273-1279.
4 Johnson KP, Knobler RL et al. Recombinant human beta interferon treatment of relapsing-remitting multiple sclerosis: pilot study results [abstract]. Neurology 1990;40 (suppl.1):261.
5 IFNB Multiple Sclerosis study group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I: Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:655-61.
6 Paty DW, Li DKB et al. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. II: MRI analysis results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993;43:662-66.
7 European Study Group on Interferon beta-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. The Lancet. 1998;352:1491-1497.
