According to information released yesterday by Biogen Idec, there have been 24 confirmed cases of progressive multifocal leukoencephalopathy (PML, a viral infection of the brain that usually leads to death or severe disability) among people who have used Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) after it became available for prescription in July 2006.
As of the end
of September 2009, 60,700 people have used Tysabri worldwide. Although
the absolute risk for PML in patients treated with Tysabri cannot be
precisely determined, the sponsor has now released data suggesting that
the risk increases with increasing time on therapy, starting out lower
than the one-in-one thousand level that was estimated at the time of
Tysabri’s re-approval in 2006, and rising after two years of infusions
to about one in one thousand. There is insufficient information to
determine the risk of PML in those who have been on therapy for three
years or more. Right now only 2,000 people have been on the therapy for
over three years.
This release followed an October 23
announcement from the EMEA, the European equivalent of the U.S. FDA,
indicating that one of its advisory committees was launching a review of
the risks and benefits of Tysabri in light of the increasing number of
new cases of PML.
Signs of PML: Typical symptoms associated with PML progress quickly over days to weeks, and can include:
• personality or behavioral changes
• changes in thinking, memory, and orientation leading to confusion
• onset of seizures, clumsiness or progressive weakness on one side of the body
• disturbances of vision
individuals taking Tysabri experience new, unusual symptoms, they
should contact their prescribing physician immediately. Physicians who
need guidelines on the protocol to follow when they have a patient on
Tysabri who experiences unusual symptoms should contact Biogen Idec.
Details of Cases:
According to the company, the 24 cases of PML have occurred in both men
and women who had been given infusions of Tysabri every four weeks for a
duration ranging from one year to three and a half years, with an
average of two years.
16 of the cases occurred in Europe, and 8 in the United States
4 of the 24 died
of disability in the 20 survivors is a wide spectrum: at the milder
end, some have recovered enough to return to work, and at the other
extreme, some are confined to bed, requiring extensive assistance with
activities of daily living, and others were in between this range.
Further details of their condition were not provided.
appears that when PML is detected and treated early, it generally
improves outcomes. It is important that individuals taking this drug and
their doctors be vigilant in monitoring for any occurrence of new,
unusual symptoms that might indicate PML.
these cases, the sponsor stressed that, contrary to prior information,
the presence of gadolinium-enhancing lesions on MRI does not exclude the
possibility of PML. Likewise, the absence of JC virus DNA in the spinal
fluid does not exclude PML.
There has been no
characteristic among those who have developed PML that would give
substantial clues to who might be more likely to develop it, except that
half of the cases had prior histories of having been on
immunosuppresive therapies, such as mitoxantrone, and less commonly,
azathioprine and methotrexate.
Right now there is no
test that can predict who is more likely at risk for developing PML
while using Tysabri; in a large company-sponsored study, testing of
blood cells, plasma, serum and urine for the causative JC virus in
people before and after 48 weeks of Tysabri therapy (Rudick et al.
ECTRIMS 2009) did not show any differences in the presence of the virus
in those fluids.
The results of these studies,
performed at the U.S. National Instituties of Health, differ somewhat
from an earlier study (N. Engl. J. Med., 361:1067, 2009) suggesting
higher virus levels after treatment.
When PML was
suspected, Tysabri infusions were halted. There is no specific therapy
to treat PML, but the best hope is to reconstitute a person’s immune
responses. In most of the 24 cases, once PML was confirmed, Tysabri was
removed from their systems with the blood-cleansing treatments of either
plasma exchange or immunoadsorption.
aftermath of PML, as the immune system begins to recover, a condition
called IRIS (immune reconstitution inflammatory syndrome) usually occurs
about 4 weeks after the removal of Tysabri from the system. The
sponsors suggested that some of the treating physicians found that
prompt use of intravenous steroids to treat this brain inflammation led
The FDA provides post-marketing safety
warnings on Tysabri at this link, although the updated information above
is not currently provided.
Read the report at National MS Society