3
follow a mechanistic rather than a clini-
cal approach. The aims of the treat-
ment are to: 1) reduce relapse rates; 2)
prevent fixed disability directly attrib-
uted to relapse; 3) provide sympto-
matic management of fixed neurologi-
cal deficits; 4) prevent disability ac-
quired through progression; and 5)
treat established progression.
Since permanent disability can be
caused by incomplete recovery from
episodes, relapse frequency is bound
to correlate with accumulation of dis-
ability in the relapsing-remitting form
of MS. Based upon promising Phase
III clinical data, three biologicals were
initially approved by the Food and
Drug Administration (FDA) to reduce
the frequency of relapse. These are the
three beta-interferons: interferon beta-
1a [Avonex, Biogen (NASDAQ:
BGEN) and Rebif, Serono (NSYE:
SRA)], and interferon beta-1b
[Betaseron, Chiron (NASDAQ:
CHIR)]. Although the recombinant
interferons were first used in MS for
their anti-viral action, given that viral
infections frequently triggered relapse,
their mechanism of action is immuno-
logical and complex. The three beta-
interferons were studied in separate
placebo-controlled, two year trials of
between 301 and 560 patients with
RRMS. Some extension studies have
also been performed. In all, the annual
relapse rate for individuals treated with
beta interferon was significantly re-
duced by 30-37%. Interestingly, only
in the trials with the interferon beta-1a
preparations and not in the interferon
beta-1b trials, was this change in re-
lapse rate also accompanied by a re-
duction in the accumulation of disabil-
ity.
A fourth compound has also re-
ceived market approval by the FDA for
reducing the frequency of relapsing-
remitting MS. This compound is re-
ferred to as Copaxone, and is marketed
by Teva Pharmaceuticals (NASDAQ:
TEVA). Copaxone is comprised of a
mixture of synthetic polypeptides com-
posed of four amino acids. The exact
mechanism of action has not been de-
termined, but Copaxone is thought to
be capable of binding and altering the
activity of T cells associated with the
autoimmune disease, which would
suggest that Copaxone is capable of
reducing damage attributed to re-
lapses. This assumption has in fact
been substantiated by gadolinium-
enhanced MRI imaging.
Betaseron was the first recomb i-
nant interferon approved by the FDA
in 1993, followed by Avonex in 1996,
and later by Rebif in 2001. Because of
its ability to reduce disability associ-
ated with relapse, Avonex commands
the majority of the U.S. market. Mean-
while, it is clear that Rebif's entry into
the U.S. market has negatively im-
pacted Avonex's prescription growth.
Avonex has lost market share since
December 2001, with market share at
about 53% at the time, versus a De-
cember 2002 market share of 45%. Re-
bif now holds 7% market share and
during that same period, Betaseron's
share has increased to 21% from 19%,
while Copaxone's share has remained
unchanged at 28%. The total U.S. mar-
ket grew 22% in this same time period.
The competition is focused on the
estimated 10,000 to 15,000 newly diag-
nosed MS patients each year in the U.
S. In the face of potential increased
competition, Biogen has already in-
creased its U.S. sales force by 25% to
approximately 85 persons to offset Se-
rono's sales force and co-promotion
arrangement with Pfizer for Rebif in the
U.S. Biogen has indicated the number
of patients on Avonex in Europe is in
the 40,000s and this number continues
to increase by about 500-1000 patients
per quarter.
In the labeling for Rebif there are
no superiority claims over Avonex
based on the EVIDENCE study that
Serono sponsored. Importantly, the
label notes that while adverse reac-
tions were generally similar between
Rebif and Avonex, there were excep-
tions. Injection site disorders occurred
in 80% of the patients treated with Re-
bif compared to 24% of the patients
with Avonex. Further, Rebif treated
patients showed higher incidences of
hepatic function disorders (14%) and
leukopenia (39%) compared to Avonex
treated patients (7% and less than 1%,
respectively).
Seeking marketing leverage for
Avonex over Rebif, in early April 2002
Biogen announced the initiation of a
long-term international study to com-
pare Avonex to high-dose Rebif. This
study is being conducted in two
phases with the first phase represent-
ing a retrospective study to evaluate
the safety and efficacy of patients over
15-21 months. The second phase will
follow these patients for an additional
three years. The initial results from the
first phase of the study may be avail-
able in late 2003, with interim results
from the second phase available in
2004 and 2005.
Probably the most distinct advan-
tage Rebif has over the other beta-
interferons is that it is packaged as a
liquid formulation in a pre-filled sy-
ringe and therefore does not require an
additional preparation step. Avonex
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