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Interferons are a family of naturally occurring Proteins and GlycoProteins that are produced by Eukaryotic Cells in response to Viral Infection and other biological inducers.
Three major Interferons have been distinguished:
Interferon (alpha) & ß (beta), form the Type 1 class of Interferons; and Interferon (gamma) is a Type 2 Interferon.
These Interferons have overlapping, but clearly distinct biological activities.
GlycoSylation of Proteins is known to affect their stability, activity, biodistribution and half-life in blood. However, the effects of GlycoSylation of Interferon-ß on these properties have not been fully defined.
Interferons are Cytokines that mediate AntiViral, AntiProliferative and ImmunoModulatory activities in response to Viral Infection and other biological inducers.
Interferon-ß exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of IntraCellular events that leads to the expression of numerous Interferon induced Gene products and markers.
These include 2', 5'-Oligoadenylate synthetase, ß2-MicroGlobulin and Neopterin. These products have been measured in the Serum and Cellular fractions of Blood.
On May 17 1996, the US Food and Drug Administration (FDA) approved the use of Avonex®, a recombinant human Interferon-ß-1a product manufactured by Biogen, Inc. (Cambridge, Massachusetts), for use in treating Relapsing Forms of Multiple Sclerosis (MS).
Avonex® is the first drug to demonstrate in clinical trials the ability to slow the Progression of MS, in addition to reducing the frequency of Neurologic attacks.
Avonex® ß-1a is given in a dose of 30 mcg once a week IM, which gives Avonex® a longer half-life than Betaseron and may explain why Avonex® has a better side-effect profile.
This approval was based on the results of a multi-center, placebo controlled, double-blinded clinical trial that compared MS patients who received weekly intramuscular injections of Interferon-ß-1a, to those who received similar injections of a placebo.
And on the recommendations of an FDA advisory panel in December 1995.
The clinical trial, reported in the medical journal Archives Of Neurology, in March 1996, showed that over two years the risk of significant progression of physical disability was reduced by 37%, in people taking Interferon-ß-1a compared to those receiving placebo.
For this study, significant progression of disability was defined as an increase of one or more points on the Kurtzke Expanded Disability Status Scale (EDSS), a standard measure of disability used in clinical studies of MS, sustained for at least six months.
In addition, those who completed the full two years of the study and received Interferon-ß-1a had 32% fewer attacks, or flare-ups of symptoms, than those who received placebo.
For all patients in the study, some of whom did not complete the full two years, the people who received Interferon-ß-1a had about 20% fewer attacks than those who received placebo.
The main Side-Effects of Interferon-ß-1a, reported significantly more often by those taking the drug, were Flu-Like symptoms: Fever, Chills, Muscle Aches and Fatigue.
Biogen is making Avonex® available by prescription through retail pharmacies throughout the country on Monday, May 20, 1996.
Biogen will sell a four-week supply of Avonex® to wholesalers for $710 or $9,230 for one year's supply. The price to patients will depend on retail markup and health plan coverage.
The price of Interferon-ß-1a treatments increased to around $1,500 a month in 2006, and currently in 2009 it is now $2,400 for a month's supply.
Interferon-ß-1a is administered by intramuscular injection once a week, under the guidance and supervision of a physician.
If patients and their physicians determine that it is appropriate, patients may inject Interferon-ß-1a themselves after proper training and with appropriate medical follow-up.
Information about Avonex®, injection training, home delivery, and reimbursement counseling are available from Biogen at the toll-free number listed below.
Interferon-ß-1a is the first FDA-approved treatment shown to slow the progression of disability in people with Multiple Sclerosis, and provides an alternative treatment for Relapsing Forms of Multiple Sclerosis.
Individuals who want more information about Avonex®, including availability and reimbursement, should contact their personal physicians, or Biogen at: 1 - 800 - 456-2255.
Johns Hopkins Medicine - November 15, 1999
Source: Neurology 1999;53:1698-1704
July 14, 1995
Initial clinical trials of Betaseron for ambulatory Relapsing/Remitting MS showed that two to three years of treatment with every-other-day, 8 MIU, injections resulted in reduced relapse rate and relapse severity and reduced accumulated lesion burden detected by Brain MRI, compared with placebo-treated patients.
These data were reported in 1993 and data from two years of the trial were the basis of the U.S. Food and Drug Administration's approval for marketing of this agent for ambulatory Relapsing/Remitting MS.
Now, in the July 1995 issue of the Archives Of Neurology, additional data are reported which indicate the continued benefit and safety of Betaseron for at least four to five years.
In the Betaseron studies, in 11 U.S. and Canadian centers, 372 individuals with ambulatory Relapsing/Remitting MS participated in a randomized, placebo-controlled study that was three years in duration.
However, because of the time needed to identify and enroll all patients at all centers, those who were enrolled first were on experimental treatment - high-dose medication, low-dose medication or placebo - for as long as five years (median for patients in all groups in the study was almost four years).
The new data show that individuals on high-dose Betaseron had about a 30% reduction in annual relapse rate compared with placebo-treated patients in each of the five years of examination.
While equivalent reduction in relapse rate was seen in each of five years of study, progressively fewer patients completed three, four and five years of treatment with drug or placebo.
For this and other reasons, the data in each of these additional years do not show statistical significance. There was also a lower rate of moderate and severe exacerbations in the treated group.
Additionally, and importantly, there was no increase in annually measured MRI-detected lesion burden over five years in the high-dose treatment group compared with their lesion burden prior to treatment.
Those treated with placebo for the same length of time showed significant increase in lesion burden.
However, by about 18 months on treatment, 38% of patients on high-dose Betaseron had developed Neutralizing AntiBodies against the agent.
Those who did develop such AntiBodies showed a significant decline in treatment benefit: relapse rates were not different than for placebo-treated patients.
But the 62% of patients who did not develop such AntiBodies continued to show excellent benefit from treatment, with a highly significant 50% reduction in relapse rate.
As with results from the first two and three years of treatment, there was no statistically significant difference in numbers of treated versus placebo patients with confirmed disease progression at four and five years, although there was a trend favoring slower progression in the treated patients.
However, this study was not optimally designed to determine an effect of treatment on accumulated disability or speed of progression. A new clinical study, currently in the planning stages, is needed to address this question.
Flu-Like Side-Effects, which were present in 52% of high-dose treated patients in the first several months of the study, dropped to 8% of high-dose treated patients after a year, and remained present in about 3-8% of all high-dose treated patients through five years.
Thus, there was no increase in Flu-Like side effects over this longer treatment period. Interestingly, larger patients and those who were older experienced fewer such side effects, indicating a dose relationship that may be important in future studies.
Injection-site reactions dropped from about 80% in the early phases of the study to about 44-50% of high-dose treated patients at years four and five.
Through five years of observation, symptoms of Depression remained slightly higher in the high-dose treated patients than in placebo patients.
Some laboratory abnormalities, in particular a Drop in White Blood Cell Count, were slightly more common in the later years than earlier in the study.
Significant Side-Effects in Betaseron treatment
These events occurred at an incidence of 5% or more in the 124 MS patients treated with 0.25 mg of Betaseron every other day for periods of up to 3 years in the controlled trial, and at an incidence that was at least twice that observed in the 123 placebo patients.
Common adverse clinical and laboratory events associated with Betaseron were:
Also See: Betaseron's Adverse-Effects
The clinical data from this report support the previously documented benefit of Betaseron on reduced relapse rate in ambulatory Relapsing/Remitting MS and indicate that the benefit can last at least four to five years while on treatment.
The continued benefit seen on MRI- determined lesion burden in the high-dose group is an important finding and implies continued benefit of Betaseron on underlying disease pathology.
In addition, while these studies did NOT show statistically significant slowing of progression with treatment, there was a clear but small correlation between MRI-determined lesion burden and disability in patients.
This suggests that the MRI-determined effects of treatment MAY well signal slowing of progression of disability, but clinical demonstration of this requires larger numbers of patients studied over a longer time period in a separate study.
The development of Neutralizing AntiBodies against Betaseron in a proportion of treated patients, and the correlation of those AntiBodies with reduced efficacy in terms of relapse rate, are concerns.
While the full implications of these findings are not clear, additional AntiBody analysis is underway to confirm and expand these findings, and the role of Neutralizing AntiBodies in Betaseron treatment will be followed closely in ongoing studies.