UCSF Multiple Sclerosis CenterOn June 5, 2006 The U.S. Food and Drug Administration (FDA)
approved the reintroduction of Tysabri (natalizumab).
Tysabri is indicated as monotherapy for the treatment of patients with
relapsing forms of multiple sclerosis to reduce the frequency of clinical
exacerbations and delay the accumulation of physical disability. The
safety and efficacy of Tysabri beyond two years are unknown.
Tysabri increases the risk of progressive multifocal leukoencephalopathy
(PML), an opportunistic viral infection of the brain that usually
leads to death or severe disability. As a result, Tysabri will
generally be recommended for patients who have had inadequate
response to, or are unable to tolerate, alternate MS therapies.
Please contact your physician at the MS Center for more information
about PML and the risks associated with the use of Tysabri.
Tysabri will only be available under a special restricted
distribution program called the TOUCH Prescribing Program. Only
authorized, trained, and registered prescribers, infusion centers,
and pharmacies associated with TOUCH will be able to prescribe,
distribute, and infuse Tysabri to patients.
The MS Center is working actively with Biogen-Idec and UCSF
Medical Center representatives to provide Tysabri infusions to
patients within the next few weeks. Updated information will be
posted on our website shortly.
Additional information about Tysabri, PML and the TOUCH Program
can found at www.TYSABRI.com.
(click for Letter from Biogen-Idec & Elan)
Today, Biogen-Idec and Elan Corporation voluntarily suspended the drug
TYSABRI (natalizumab) from the market. This action has been
taken in consultation with the U.S. Food and Drug Administration (FDA).
Specifically, it was stated that "this decision is based on very recent reports
of two serious adverse events that have occurred in patients treated with
TYSABRI (natalizumab) in combination with Avonex (Interferon beta-1a) in
clinical trials.
These events involve one fatal, confirmed case and one suspected case of progressive
multifocal leukoencephalopathy (PML), a rare and frequently fatal, demyelinating
disease of the central nervous system. Both patients received more than two years
of TYSABRI therapy in combination with Avonex."
The linkage between PML and TYSABRI has not yet been fully clarified – particularly
with respect to whether or not the apparent risk is due to the combination of drugs
or due to the TYSABRI by itself. Nevertheless, because PML is a very serious illness
with no known effective treatment, Biogen-Idec and Elan Corporation have also announced
the suspension of TYSABRI usage in all clinical trials currently underway.
If you have questions or concerns, please contact either the UCSF MS Center
(415) 514-1684 or your physician.
On November 23, 2004, the U.S. Food and Drug Administration (FDA) approved
Tysabri® (natalizumab), formerly known as Antegren, to treat relapsing forms of
multiple sclerosis (MS) to
reduce the frequency of clinical relapses. The FDA
accelerated their approval of
Tysabri following a Priority Review of one-year data from
two Phase III studies,
the Affirm monotherapy trial and the Sentinel add-on
trial with Avonex®
(weekly i.m. interferon beta-1a).
Biogen Idec and Elan collaboratively developed and tested Tysabri for MS, Crohn’s
disease,
and rheumatoid arthritis, providing it to more than 2,800 patients in clinical
trials. Information about Tysabri, including prescribing information, is
available by calling 1-800-456-2255 and at www.tysabri.com.
Although FDA-approved, Tysabri is still not clinically available to our patients.
Labeling, pricing, and re-imbursement from health insurers are issues being currently
worked out. It is now appropriate for you to discuss this treatment option with your
physician during your next regularly scheduled visit.
Please revisit our Web site for more up-to-date information as it becomes
available.
What Tysabri Does
Tysabri (natalizumab) is a monoclonal antibody directed against a protein (alpha
4-integrin) on the surface of white blood cells. By inhibiting adhesion
molecules on the surface of these immune cells, Tysabri interferes with
movement of these cells from the bloodstream into the brain and spinal cord
where they can cause inflammation and damage nerve fibers and their insulation.
Tysabri is given by monthly intravenous infusion.
The Affirm Study
The Affirm study is a two-year, randomized, multi-center, placebo-controlled,
double-blind study of 942 patients conducted in 99 sites worldwide. Patients
were randomly assigned to receive either a fixed 300 mg IV infusion dose of
Tysabri (n=627) or a placebo (n=315) every four weeks. The preliminary one-year
results indicate a significant benefit for Tysabri treatment, compared with placebo
treatment in reducing MS attacks by up to 68 percent (p<0.001, adjusted annualized
mean number of attacks) and in lowering the number of new brain lesions visible in
magnetic resonance imaging (MRI). 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). In the Tysabri-treated group, 76 percent of
the patients remained relapse free, compared to 53 percent of the placebo-treated
group (p<0.001).
The Sentinel Add-On Study
The Sentinel study is a two-year, randomized, multi-center, placebo-controlled,
double-blind study of 1,171 patients (all of whom continued to receive Avonex
throughout the study) at 123 clinical trial sites worldwide. In this study,
patients who continued to experience disease activity were randomly assigned to
also receive Tysabri (n=589) or a placebo (n=582). For these patients, adding
Tysabri to Avonex produced a 53 percent reduction in clinical relapses
(p<0.001, adjusted annualized mean number of attacks) over the effect of
Avonex alone. On their one-year scan, 96 percent of the patients receiving both
Tysabri and Avonex displayed had no gadolinium-enhancing lesions, compared to 76
percent of patients receiving Avonex and a placebo (p<0.001). In the group receiving
both Tysabri and Avonex, 67 percent of the patients remained relapse-free, compared to
46 percent in the group receiving Avonex and a
placebo (p<0.001).
Safety Issues
Common side effects associated with Tysabri include headache, fatigue, urinary
tract infection, depression, lower respiratory tract infection, joint pain and
abdominal discomfort. 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.
A Low Level of Immunogenicity
All biologics have the potential to induce patient antibodies. In both the
Affirm and Sentinel trials, patients were tested for antibodies every 12 weeks.
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.
Two-year Results
Both Affirm and Sentinel are two-year trials. Two-year results are anticipated, beginning
in the first half of 2005. Results on various disability measures will then be released.
Patients who complete these trials are eligible for enrollment in a long-term safety
extension study.
Natalizumab is a monoclonal antibody directed against a protein (alpha 4-integrin) on
the surface of white blood cells. It interferes with movement of these cells from the
bloodstream into the brain and spinal cord. It is given by monthly intravenous infusion.
A previous, six-month placebo-controlled trial of natalizumab in MS suggested that the
drug was well tolerated, reduced new brain lesions, and reduced the number of clinical relapses.
The 1-year results of the soon-to-be completed AFFIRM study (a 2-year trial of natalizumab
compared to a placebo in 942 patients) were recently released in preliminary form.
The 1-year data apparently demonstrated a significant benefit for natalizumab treatment
compared with placebo in reducing MS flares (attacks) and in lowering the number of new
brain lesions on MRI. In general the drug was well tolerated, with the most common side
effects associated with therapy being headache, fatigue and joint pain.
These data are part of a file previously submitted to the U.S. Food and Drug Administration
(FDA) for possible expedited approval. The FDA will make a statement by the end of this month
regarding their expedited review. The full 2-year data set should be available by early next year.
The medication will not be available prior to FDA approval and, even after such an approval, the
time frame for the drug’s availability will depend upon a number of factors. If your MS is stable,
it is appropriate for you to discuss this treatment option with your physician during your next
regularly scheduled visit.
Please revisit our website for more up-to-date information as it becomes available.