Ingredient in New MS Drug Linked to Serious Brain Disease06/10/13
WEDNESDAY, April 24 (HealthDay News) -- The active ingredient in
a drug that's expected to become a popular treatment for multiple
sclerosis has been linked to four European cases of a rare but
sometimes fatal brain disease called progressive multifocal
The ingredient, dimethyl fumarate, is used in a drug called
Fumaderm that was approved in Germany in 1994 to treat the skin
condition psoriasis. It is also in a different but closely related
medication called Tecfidera, which was just approved by the U.S.
Food and Drug Administration in March for the treatment of multiple
sclerosis (MS). It is known as a fumaric acid ester, which is
commonly used as a food additive and has been used to treat
psoriasis in Germany for 30 years.
According to reports published in the April 25 issue of the
New England Journal of Medicine, however, three patients who
were taking Fumaderm to treat their psoriasis developed PML. One
other patient developed the brain condition after taking a separate
medication from a compounding pharmacy that also contained dimethyl
In a letter responding to the reports, Biogen, the company that
makes both drugs, said Tecfidera may be safer because it contains
only dimethyl fumarate, while Fumaderm also contains three other
fumaric acid esters.
The company also noted that none of the patients taking
Tecfidera during clinical trials (then known as BG-12) developed
PML. Since Tecfidera is a pill rather than an injection, and was
effective and well-tolerated by patients in clinical trials,
analysts have predicted it would soon become the top-selling
multiple sclerosis treatment.
But the German doctor who treated one of the psoriasis patients
who got PML thinks there is still cause for concern.
Dr. Jorg Schulz, a neurologist at Rheinisch-Westfaelische
Technische Hochschule Aachen, a research university in Aachen, said
the two drugs are virtually identical once they are broken down in
"The problem is that the studies with BG-12 covered a two-year period, but no longer periods," Schulz said, and he believes it may take prolonged treatment with the drug for PML to surface.
"With the publication of our case, we wish to create awareness that treatment with any form of fumaric acid may bear the risk of developing PML," Schulz said.
In their response, Biogen countered that while patients had been
only tracked for an average of two years at the time Tecfidera
received FDA approval for MS, many of the patients in these trials
have now been on the drug for five years with no reports of PML.
The company added that over the 20 years that German patients have
used Fumaderm, only three case reports of PML have arisen, and
those cases involved additional risk factors for the illness.
PML is caused by the JC virus, which normally lies dormant in
the body and causes no harm. About half of multiple sclerosis
patients have antibodies to the JC virus in their blood, suggesting
a current or former infection. When the immune system is depleted
by illnesses like cancer or AIDS or suppressed by certain
medications, the virus can flare and destroy nerve cells in the
Ironically, PML is a lot like multiple sclerosis, but it
progresses more rapidly as it causes weakness, paralysis,
confusion, memory loss and loss of vision or speech. Quick
treatment can stop the damage, although patients may be permanently
PML is rare, but it is so serious that Genentech pulled its
psoriasis treatment Raptiva off the market in 2009 after reports of
four cases in patients who were taking the biologic medication.
Biologic drugs are medications derived from living organisms that
are used to prevent certain diseases, including ones where the
immune system malfunctions.
Another biologic, Tysabri, a treatment for multiple sclerosis
and Crohn's disease, was shelved in 2005 for about a year after
three patients involved in clinical trials of the drug developed
PML. Tysabri returned to the market in 2006 with strict new
safeguards in place. Before starting the drug, for example,
patients must get an MRI of their brains. They also may get blood
tests to check for antibodies to the JC virus. They also are
monitored by doctors every three to six months while taking the
medication, which is also made by Biogen.
No such precautions are currently recommended for Tecfidera,
which has been hailed as a less toxic alternative to other
treatments. Other multiple sclerosis drugs are known to cause
flu-like symptoms, chest pain, and heart, liver and eye
In clinical trials, the main side effects reported with
Tecfidera were comparatively mild, and included facial flushing,
stomach upset and low white blood cell counts.
"The main reason why our [psoriasis] patient developed PML after three years of treatment with Fumaderm is prolonged lymphocytopenia [low white blood cell counts]," Schulz said. "In both BG-12 trials published in the New England Journal of Medicinein 2012, 4 percent to 5 percent of patients developed this kind of severe lymphocytopenia and are in my view at risk to also develop PML."
Dr. Robert Fox is a staff neurologist at the Mellen Center for
Multiple Sclerosis at the Cleveland Clinic in Ohio, and he was also
on the steering committee for one of the studies that tested the
He called the new PML case reports, "very important additions to
our understanding of this class of therapy." Fox, who has in the
past also been a paid consultant for Biogen, added that, "although
we haven't seen any PML cases in patients treated with Tecfidera, I
think there's good reason to apply the lessons learned here to
For more on the risks and benefits of multiple sclerosis
treatments, visit the
National Multiple Sclerosis Society.
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