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FDA ALERT [02/28/2005]
suspended marketing of Tysabri and all further dosing of
patients in on-going clinical trials. This decision was
made after confirmation of one fatal case and one
additional case of progressive multifocal
leukoencephalopathy (PML) in patients receiving Tysabri
for multiple sclerosis (MS). Both patients were enrolled
in a long-term clinical trial and had been taking
Tysabri for more than two years. There have been no
previous cases of PML reported in patients taking
Tysabri. Studies are underway by Biogen-IDEC to
determine as rapidly as possible whether there is
evidence of PML from patients that have received Tysabri
in clinical trials.
Although these two confirmed cases of PML do not
necessarily represent a causal association between use
of this agent and PML, additional information needs to
be obtained to fully understand the connection between
Tysabri use and PML.
reflects FDA?s preliminary analysis of data concerning
this drug. FDA is considering, but has not reached a
final conclusion about, this information. FDA intends to
update this sheet when additional information or
analyses become available.
Thursday, 25th November 2004
TYSABRI is the first humanized monoclonal antibody approved for the treatment
of multiple sclerosis (MS).
Cambridge, MA; San Diego, CA; Dublin, Ireland ? November 23, 2004 ?
Biogen Idec and Elan Corporation announced today that the U.S. Food and Drug Administration (FDA) has
approved TYSABRI (natalizumab), formerly referred to as ANTEGREN?, as
treatment for relapsing forms of multiple sclerosis (MS) to reduce the
frequency of clinical relapses. FDA granted Accelerated Approval for
TYSABRI following Priority Review based on one-year data from two Phase
III studies, the AFFIRM monotherapy trial and the SENTINEL add-on trial
with AVONEX? (Interferon beta-1a).
TYSABRI, the first humanized monoclonal antibody approved for the
treatment of MS, inhibits adhesion molecules on the surface of immune
cells. Research suggests TYSABRI works by preventing immune cells from
migrating from the bloodstream into the brain where they can cause
inflammation and potentially damage nerve fibers and their insulation.
"TYSABRI is a powerful and innovative therapy that offers new hope
for hundreds of thousands of people living with MS," said James C.
Mullen, chief executive officer, Biogen Idec. "We believe TYSABRI will
revolutionize the treatment of MS and become the leading choice for
patients and physicians."
"TYSABRI is a significant breakthrough for patients with MS," said
Kelly Martin, president and chief executive officer, Elan. "The approval
of TYSABRI, with its unique mechanism of action and new level of
efficacy, has the potential to make a genuine difference in the lives of
patients and families who struggle with the debilitating effects of this
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About Multiple Sclerosis
MS is a chronic disease of the central nervous system that affects
approximately 400,000 people in North America and more than one million
people worldwide. It is a disease that affects more women than men, with
onset typically occurring between 20 and 40 years of age. Symptoms of MS
may include vision problems, loss of balance, numbness, difficulty
walking and paralysis.
Results of the AFFIRM Monotherapy Trial
AFFIRM is a two-year, randomized, multi-center, placebo-controlled,
double-blind study of 942 patients conducted in 99 sites worldwide, in
which patients were randomized to receive either a fixed 300 mg IV
infusion dose of TYSABRI (n=627) or placebo (n=315) every four weeks.
TYSABRI reduced the rate of clinical relapses by 66 percent relative to
placebo (p<0.001), the primary endpoint at one-year. The annualized
relapse rate was 0.25 for TYSABRI-treated patients versus 0.74 for
AFFIRM also met all one-year secondary endpoints, including MRI
measures. In the TYSABRI-treated group, 60 percent of patients developed
no new or newly enlarging T2 hyperintense lesions compared to 22 percent
of placebo-treated patients (p<0.001). On the one-year MRI scan, 96
percent of TYSABRI-treated patients had no gadolinium enhancing lesions
compared to 68 percent of placebo-treated patients (p<0.001). The
proportion of patients who remained relapse free was 76 percent in the
TYSABRI-treated group compared to 53 percent in the placebo-treated
Results of SENTINEL Add-on Study
Approval was also based on the results of another Phase III clinical
trial, SENTINEL. SENTINEL is a two-year, randomized, multi-center,
placebo-controlled, double-blind study of 1,171 AVONEX-treated patients
in 123 clinical trial sites worldwide.
In the SENTINEL trial, AVONEX-treated patients who continued to
experience disease activity were randomized to add TYSABRI (n=589) or
placebo (n=582) to their standard regimen.
SENTINEL achieved its one-year primary endpoint. The addition of
TYSABRI to AVONEX resulted in a 54 percent reduction in the rate of
clinical relapses over the effect of AVONEX alone (p<0.001). The
annualized relapse rate was 0.36 for patients receiving TYSABRI when
added to AVONEX versus 0.78 with AVONEX plus placebo.
SENTINEL also met all secondary endpoints, including MRI measures. In
the group treated with TYSABRI plus AVONEX, 67 percent of patients
developed no new or newly enlarging T2 hyperintense lesions compared to
40 percent in the AVONEX plus placebo group (p<0.001). On the one-year
MRI scan, 96 percent of TYSABRI plus AVONEX-treated patients had no
gadolinium-enhancing lesions compared to 76 percent of AVONEX plus
placebo-treated patients (p<0.001). The proportion of patients who
remained relapse-free was 67 percent in the TYSABRI plus AVONEX-treated
group compared to 46 percent in the AVONEX plus placebo-treated group
"I believe TYSABRI will be an important therapeutic advance for
patients with relapsing MS," said Richard Rudick, MD, lead investigator
of the SENTINEL trial and director, Mellen Center for Multiple
Sclerosis, Cleveland Clinic Foundation. "Patients who have discontinued
therapy, are newly diagnosed with MS, or have persistent active disease
despite being on a current therapy will benefit from TYSABRI."
Common adverse events associated with TYSABRI include headache,
fatigue, urinary tract infection, depression, lower respiratory tract
infection, joint pain and abdominal discomfort. The rate of infection in
both studies was approximately one per patient-year in both TYSABRI-treated
patients and placebo-treated patients.
Serious infections occurred in 1.3 percent of placebo-treated
patients and 2.1 percent of TYSABRI-treated patients. Serious infections
included bacterial infections such as pneumonia and urinary tract
infection, which responded appropriately to antibiotics. TYSABRI has
been associated with hypersensitivity reactions, including serious
systemic reactions, which occurred at an incidence of less than 1
percent of patients.
Immunogenicity All biologics have the potential to induce
patient antibodies. Analysis of the one-year Phase III MS trials
indicate a low level of immunogenicity associated with TYSABRI. Patients
were tested for antibodies every 12 weeks in the AFFIRM and SENTINEL
trials. Antibodies were detected in approximately 10 percent of patients
at least once during treatment, with 6 percent of patients remaining
persistently positive. Persistently positive antibodies were associated
with a substantial decrease in efficacy and an increase in certain
infusion-related adverse events. Almost all patients who tested positive
for antibodies did so within the first 12 weeks of treatment.
AFFIRM and SENTINEL are two-year trials. Two-year results are
anticipated beginning in the first half of 2005. Patients who complete
these trials are eligible for enrollment in a long-term safety extension
"The MS community is pleased that the FDA approval of TYSABRI
provides an additional treatment option for people with relapsing forms
of MS. There are many people living with MS who may benefit from this
different treatment approach," said Stephen C. Reingold, PhD, vice
president for research, the National MS Society.
Biogen Idec and Elan are collaborating equally on the development of
TYSABRI in MS, Crohn's disease (CD), and rheumatoid arthritis (RA). In
September 2004, a Marketing Authorisation Application (MAA) for CD was
filed with the EMEA based on Phase III studies, and another Phase III
induction trial for CD is ongoing. A Phase II trial is also underway to
evaluate TYSABRI in RA. To date, more than 2,800 patients have received
TYSABRI in clinical trials.