|
Head-to-head Clinical Trial Results:
Rebif versus Avonex Use in Multiple Sclerosis
Betaseron versus Avonex
Use in Multiple Sclerosis
Medical Update Memo
JULY 12, 2001
Summary
The results of two separate head-to-head studies of the three
different beta interferon products were presented at two major
medical meetings in late June and May. In the EVIDENCE study,
the results indicate that after six months Rebif showed a statistically
significant benefit over Avonex for all primary and secondary
endpoints including the proportion of people remaining relapse-free
and the accumulation of MRI-detected lesions in the brain. In
the INCOMIN study, at the end of the second six-month period,
Betaseron showed a statistically significant-benefit over Avonex
for both primary and secondary endpoints including a lower rate
of MS exacerbations. Reacting to the study, Biogen Inc., which
manufacturers and markets Avonex, criticized the interpretation
and design of the studies. The Multiple Sclerosis Society of
Canada noted the studies provide additional information about
the therapies over a short period of time. It is not known as
yet if one therapy is superior over a longer period.
Details
The results of two separate head-to-head studies of the
three different beta interferon products were presented at two
major medical meetings in late June and May.
EVIDENCE Study
Dr. Patricia Coyle, State University of New York at Stony Brook,
presented data from the six month head-to-head clinical trial
of the Serono product Rebif (interferon beta-1a) against the
Biogen product Avonex (interferon beta-1a) at the World Congress
of Neurology June 22, 2001. While both products are interferon
beta-1a, they are administered differently and in different
dosages. Serono Inc. sponsored the study.
The results of the EVIDENCE study indicate
that after six months Rebif showed a statistically significant
benefit over Avonex for all primary and secondary endpoints
including the proportion of people remaining relapse-free and
the accumulation of MRI-detected lesions in the brain. The study
took place at 56 research sites and involved 677 people with
relapsing-remitting MS. EVIDENCE stands for Evidence for Interferon
Dose Effect: European-North American Comparative Efficacy).
Each product was given at its standard dose strength and method
of delivery. Avonex is injected into the muscle once a week
at a total dose of 30 mcg. Rebif is injected under the skin
three times a week at a total weekly dose of 132 mcg (high dose
version).
The primary endpoint was the proportion of
participants relapse free at the end of six months which was
announced as 74.9% for those on Rebif and 63.3% for those on
Avonex. Looked at another way, of those treated with Rebif,
25.1% had MS relapses during the six months, compared with 36.7%
of those treated with Avonex. The relative risk of having a
relapse during the trial was 37% lower for those treated with
Rebif than those treated with Avonex. Steroid use to treat MS
relapses was lower in the Rebif group, as reported by Dr. Coyle.
Participants also had monthly magnetic resonance
imaging (MRI) scans during the six month period. Those on Avonex
showed 50% more "combined unique lesions" than those
on Rebif, based on the average of new lesions detected per scan
in both groups. There was also a statistically significant reduction
in the proportion of MRI scans showing lesion activity for those
on Rebif and a statistically significant reduction in individuals
showing no lesion activity with Rebif during the study.
The two interferon beta-1a therapies (Rebif
and Avonex) are available in Canada and many other countries
but not in the United States where Avonex is protected from
competition by a similar therapy under U.S. Orphan Drug status
until 2003. Serono has stated that it intends to submit data
from the study to the U.S. Food and Drug Administration to gain
marketing approval for Rebif.
Reaction by Biogen
EVIDENCE study conclusions have been challenged by Biogen. The
company received an injunction from a Swiss court which ordered
Serono to stop saying that those in the Rebif arm of the study
had a 90% greater chance of remaining relapse-free during the
24-week treatment period (this number was calculated on the
basis of an adjusted odds ratio of relapse-free participants),
and that those treated with Avonex had more MRI-detected brain
lesions than those on Rebif. A spokesperson for Biogen said
the company also has concerns about the design of the study
and the conclusions that have been drawn from it. Despite the
court injunction, the presentation at the World Congress of
Neurology in London went ahead.
INCOMIN study
Dr. Luca Durelli, director, University MS Centre, Torino, Italy,
presented the results of a 12-month comparison study of Betaseron
(interferon beta-1b) and Avonex (interferon beta-1a) at the
American Academy of Neurology meeting in May. The study was
sponsored by the MS Foundation of Italy and the Italian Ministry
of Health. INCOMIN stands for Independent Comparison of Interferon.
The study took place at 15 MS centres in
Europe and involved 188 people with relapsing-remitting MS.
Each product was given at its standard dose and method of delivery.
Betaseron is injected under the skin every other day at a total
weekly dose of 24-32 MIU. Avonex is injected into the muscle
once a week at a total dose of 30 mcg.
At the six-month mark, participants on Avonex
had a lower rate of MS attacks and fewer people had relapses
compared to Betaseron. However, at the end of the second six-month
period this had reversed in favour of Betaseron: those on Betaseron
had an exacerbation rate of 0.13 and 11% of people had relapses
while those on Avonex had an exacerbation rate of 0.24 and 20%
had relapses. Using the one-year treatment period as a whole,
7% of people on Betaseron had a sustained progression of disease
as measured by the Expanded Disability Status Scale compared
to 25% on Avonex.
Using MRI scans of the brain at the one-year
mark, participants on Betaseron had fewer new lesions (15% vs
30% for Avonex); had fewer enhancing lesions (9% vs 22% for
Avonex) and had less MRI activity (18% vs 35% for Avonex), as
reported by Dr. Durelli.
Reaction by Biogen
In a letter to physicians following the study results release,
Biogen Canada said the study was not properly blinded and was
of short term duration. In addition, among other criticisms,
the company said it appeared the clinical and MRI data were
not adjusted to take into account that the Avonex-treated group
had higher numbers of MRI lesions at the beginning of the study.
Multiple Sclerosis Society of Canada Comments
Dr. William J. McIlroy, MS Society of Canada National Medical
Advisor, commented: "While these studies provide additional
information, there are still a number of unknowns. The studies
provide short-term data only while MS is a lifetime disease.
We still don't know if one therapy is superior over the long
run. These two head-to-head studies are another step forward,
however, it may be too early to draw definitive conclusions."
"Another unanswered question is whether the interferon
betas lose effectiveness over time because of the development
of so-called neutralizing antibodies in reaction to the injected
medications. There is some evidence that neutralizing antibodies
develop more rapidly in the higher dosage therapies, however,
there is still controversy as to whether these antibodies actually
have an impact on effectiveness. In addition, neither the EVIDENCE
nor the INCOMIN study results have been published as yet in
a peer-reviewed medical journal which would permit physicians
greater access to the study data," Dr. McIlroy advised.
Disclaimer
The Multiple Sclerosis Society of Canada is an independent,
voluntary health agency and does not approve, endorse or recommend
any specific product or therapy but provides information to
assist individuals in making their own decisions.
|
