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#Post#: 527--------------------------------------------------
1st PML case in an MS patient on Tecfidera
By: agate Date: October 23, 2014, 1:00 am
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An MS patient who had been taking Tecfidera for 4 years
developed PML and died of pneumonia. It hasn't been established
whether the PML is clearly linked to the Tecfidera but Biogen is
worried.
However, the patient had had "severe prolonged" decreased white
cell count (lymphopenia), and one wonders why that issue wasn't
addressed...
From the Boston Globe, October 22, 2014:
[quote]Biogen Idec reports death of patient on its MS pill
By Robert Weisman | GLOBE STAFF
Biogen Idec Inc. said Wednesday that a patient who had taken its
multiple sclerosis pill Tecfidera for more than four years died
after getting a rare brain infection, sending shares of the
Cambridge biotechnology company down sharply.
While the cause of death was pneumonia and there is no evidence
conclusively linking it to the best-selling MS treatment, Biogen
Idec spokeswoman Kate Niazi-Sai said in an interview that the
company “can’t rule out Tecfidera as playing a role” in the
brain infection known as progressive multifocal
leukoencephalopathy, or PML.
Executives at Biogen Idec, the leading seller of MS drugs,
reported the death during a conference call with analysts
Wednesday after releasing stronger than anticipated
third-quarter financial results. The company’s shares plunged
$17.70 to $309.07, a loss of 5.4 percent on the Nasdaq stock
exchange.
If it is confirmed that Tecfidera caused the brain infection, it
would be the first time a PML case was tied to Biogen Idec’s
multiple sclerosis pill. Tecfidera was approved by the Food and
Drug Administration for US sale in March 2013. It has been used
by more than 100,000 patients since the company began testing it
in clinical trials more than 10 years ago.
As of last month, 495 cases of PML worldwide in patients taking
an injected Biogen Idec drug, Tysabri, have been reported. Of
those, 111 patients have died, while the rest are living with
varying degrees of disability.
Tysabri was approved by the FDA in 2004, then pulled from the
market in 2005 because of safety concerns. It was reintroduced
in 2006 with a stringent monitoring program, and the company has
since developed a test to determine which patients might be
vulnerable to the brain infection.
Niazi-Sai said the company won’t disclose the identity, age, or
gender of the Tecfidera patient who died. She said the patient
had been taking the drug for four and a half years, and for
three and a half years had experienced severe prolonged
lymphopenia, a lowering of the white blood cell count. That
condition is a known risk factor for PML.
Biogen Idec has modified its label for Tysabri to note several
risk factors for PML. But there are no current plans to change
the Tecfidera label.
“At this point, we don’t feel the risk-benefit ratio has changed
in Tecfidera,” said Niazi-Sai. “We did notify the regulatory
authorities, and if they want us to revisit our label we will
work with them.”
Up to 5 percent of Tecfidera patients have to worry about low
white blood cell counts, Eric Schmidt, biotechnology analyst for
financial firm Cowen & Co., wrote in a note to investors
Wednesday. He cited data from industry consultants. A change in
the drug’s label could persuade many of those patients --
especially those with a virus known as a PML risk factor -- to
stop taking the pill, he said.
Nonetheless,” wrote Schmidt, “the first report of PML in over
100,000 patients treated [with Tecfidera] should not be
concerning for the other 95 percent of the MS population.”
Tecfidera sales have been brisk of late, making it Biogen Idec’s
fastest-growing product. Revenue from the drug more than doubled
to $787.1 million in the three months ending Sept. 30 compared
with the same quarter last year.[/quote]
The article can be seen here
HTML http://www.bostonglobe.com/business/2014/10/22/biogen-idec-reports-death-patient-that-had-taken-its-multiple-sclerosis-pill-tecfidera/xrAtOBsxA7eHZN3BB0phxJ/story.html.
More here:
HTML http://www.fiercepharma.com/story/biogen-ms-superstar-tecfidera-misses-estimates-hit-first-confirmed-pml-case/2014-10-22
HTML http://www.fiercepharma.com/story/biogen-ms-superstar-tecfidera-misses-estimates-hit-first-confirmed-pml-case/2014-10-22
#Post#: 528--------------------------------------------------
Re: 1st PML case in an MS patient on Tecfidera
By: agate Date: October 23, 2014, 10:27 am
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PML was known to occur with fumaric acid in some dermatologic
cases, as in this case described in the New England Journal of
Medicine, April 2013. Dimethyl fumarate (Tecfidera) is a fumaric
acid ester:
HTML http://www.nejm.org/doi/full/10.1056/NEJMc1211805
HTML http://www.nejm.org/doi/full/10.1056/NEJMc1211805
#Post#: 542--------------------------------------------------
Re: 1st PML case in an MS patient on Tecfidera
By: agate Date: November 4, 2014, 7:33 pm
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More on this case from the MS Foundation (October 28, 2014),
with remarks by Dr. Ben Thrower:
[quote]Biogen reports death of patient taking Tecfidera
10/28/2014
Pharmaceutical firm Biogen Idec Inc. reported last week that a
patient who took Tecfidera for four-and-a-half years died after
being infected with progressive multifocal leukoencephalopathy,
PML.
Biogen Idec spokeswoman Kate Niazi-Sai told the Boston Globe
that even though the patient officially died of pneumonia and
that its MS drug was not directly linked to the death, Biogen
“can’t rule out Tecfidera as playing a role.”
Dr. Ben Thrower, a member of the Multiple Sclerosis Foundation’s
Medical Advisory Board, said that progressive multifocal
leukoencephalopathy is a serious viral infection of the brain,
sometimes resulting in death. According to news reports, the
company reported the death during a conference call with
analysts.
"We have confirmed a case of PML in a patient being treated with
Tecfidera, who recently died from complications of pneumonia.
Despite this tragic loss, we believe that the overall positive
benefit/risk profile of Tecfidera remains unchanged," Biogen
Chief Executive Officer George Scangos said on the call.
Niazi-Sai told the Globe that the company would not release the
age, gender or identity of the individual. Scangos told analysts
the patient had severe lymphopenia, or low white blood cell
counts, for three-and-a-half of the four-and-a-half years the
patient had been taking the drug.
“This case illustrates the need for regular monitoring of blood
counts in patients on Tecfidera,” said Dr. Thrower. “The current
recommendations are for a CBC within 6 months of starting
Tecfidera and then annually or sooner if indicated. My personal
feeling is that these recommendations are not enough. At (the
Shepard Center) we do blood testing, including a CBC and more
sensitive T-cell subset analysis, before starting Tecfidera and
then every three months.”
Since entering the U.S. market in March 2013, more than 100,000
patients have taken Tecfidera. Scangos said Tecfidera's label
contains a warning for lymphopenia, a known risk factor for PML.
“I suspect that new FDA guidelines will be issued that will
suggest more rigorous safety monitoring,” said Dr. Thrower.
“While this case of PML is serious and our hearts go out to the
patient and his family, it does not mean everyone needs to stop
Tecfidera. It does mean that the risks and benefits need to be
discussed and that more frequent lab testing should be
considered.”
[/quote]
#Post#: 573--------------------------------------------------
More about the patient who developed PML on Tecfidera
By: agate Date: November 30, 2014, 7:20 pm
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From DG News, November 25, 2014:
[quote]FDA Warns About Case of PML With MS Drug Dimethyl
Fumarate
ROCKVILLE, Md -- The US Food and Drug Administration (FDA) is
warning that a patient with multiple sclerosis (MS) who was
being treated with dimethyl fumarate (Tecfidera) developed
progressive multifocal leukoencephalopathy (PML) and later died.
The patient who died was not taking any other drugs that affect
the immune system or drugs that are thought to be associated
with PML. This is the only confirmed case of this rare and
serious brain infection reported in patients taking dimethyl
fumarate.
As a result, information describing this case of PML is being
added to the drug’s label.
The drug manufacturer, Biogen Idec, notified the FDA when the
patient died after developing PML. The patient had taken
dimethyl fumarate for more than 4 years. Prior to developing
PML, the patient had a very low number of lymphocytes in her
blood. It is unknown whether the low lymphocyte count
contributed to the development of PML in this patient, or if low
lymphocyte counts are a risk factor for PML development in
dimethyl fumarate -treated patients.
We urge health care professionals and patients to report side
effects involving dimethyl fumarate to the FDA MedWatch program,
using the information in the “Contact FDA” box at the bottom of
the page.
Healthcare professionals should:
•
develop any symptoms that may be suggestive of PML. Symptoms of
PML are diverse, progress over days to weeks, and include the
following: progressive weakness on one side of the body or
clumsiness of limbs; disturbance of vision; and changes in
thinking, memory and orientation, leading to confusion and
personality changes.
•
symptom suggestive of PML and perform an appropriate diagnostic
evaluation.
•
according to approved labelling.
Data Summary
A 54-year-old patient with MS being treated with dimethyl
fumarate in a clinical trial died after developing PML. The
patient, who had an 18 year history of MS, had no known medical
conditions that would predispose her to the development of PML.
She had no history of prior use of immunosuppressive medications
and was not taking any concomitant immunosuppressive or
immunomodulatory medications.
She had taken glatiramer acetate (Copaxone) for 3 years prior to
being enrolled in a dimethyl fumarate clinical trial. In the
clinical trial, she had received placebo for 2 years followed by
dimethyl fumarate for approximately 4.5 years prior to
developing PML. During dimethyl fumarate treatment, she had
severe lymphopenia, with lymphocyte counts consistently below
500 cells/mcL for 3.5 years before developing PML.
Two months prior to her death, the patient was hospitalised with
a presumed MS relapse and treated with corticosteroids. Her
condition continued to worsen, and dimethyl fumarate was stopped
at that time. A diagnostic evaluation suggested PML, and this
diagnosis was confirmed when tests identified John Cunningham
(JC) viral DNA in the cerebrospinal fluid. The patient developed
aspiration pneumonia due to dysphagia and died approximately 7
weeks after discontinuation of dimethyl fumarate.
PML has previously been reported in Europe in patients treated
with other drugs containing dimethyl fumarate. The FDA was aware
of 4 PML cases at the time of dimethyl fumarate approval in
2013. Three cases occurred in patients with psoriasis who took a
combination product sold in Germany that includes dimethyl
fumarate and 3 different salts of monomethyl fumarate, and 1
case in a patient treated with a compounded product that
included dimethyl fumarate. In 2 of these cases, the patients
had previous exposure to immunosuppressive therapy. In the other
2 cases, patients had prolonged lymphopenia with documented
lymphocyte counts below 500 cells/mcL. The contribution of
dimethyl fumarate to the development of PML in these cases is
unknown.
Healthcare professionals and patients are encouraged to report
adverse events or side effects related to the use of these
products to the FDA's MedWatch Safety Information and Adverse
Event Reporting Program:
•
www.fda.gov/MedWatch/report.htm
•
form, then complete and return to the address on the
pre-addressed form, or submit by fax to 1-800-FDA-0178
SOURCE: US Food and Drug Administration
[/quote]
#Post#: 714--------------------------------------------------
NEJM letter about MS patient on Tecfidera who died of PML
By: agate Date: April 8, 2015, 7:01 pm
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From the New England Journal of Medicine, April 8, 2015. There
is another letter in the same issue about a psoriasis patient
who also died of PML while taking Tecfidera. It will be posted
below in another message window.
[quote]PML in a Patient with Lymphocytopenia Treated with
Dimethyl Fumarate
To the Editor:
We report the case of a 54-year-old woman with multiple
sclerosis who was treated with delayed-release dimethyl fumarate
(DMF; Tecfidera, Biogen Idec) and who died on October 13, 2014,
from complications related to aspiration pneumonia and
progressive multifocal leukoencephalopathy (PML) with severe,
prolonged lymphocytopenia.
The patient, who had received the diagnosis of multiple
sclerosis in 1996 and had been treated with glatiramer acetate,
was randomly assigned to the placebo group in the 2-year
Determination of the Efficacy and Safety of Oral Fumarate in
Relapsing–Remitting Multiple Sclerosis (DEFINE) trial. She
subsequently received delayed-release DMF (at a dose of 240 mg
three times daily) for 4.5 years in the open-label extension
study. Twelve months after the initiation of delayed-release
DMF, severe lymphocytopenia (lymphocyte count, 290 to 580 cells
per cubic millimeter) developed and persisted for 3.5 years.
Although the patient had no clinical disease activity since the
first month of active treatment, she presented with new
neurologic signs and symptoms consistent with a relapse in
multiple sclerosis (severe gait disorder, speech disorder, and
difficulties in left arm coordination) on August 11, 2014. Her
condition did not improve with the administration of intravenous
methylprednisolone (1 g once daily on August 11 to 13, 2 g once
daily on August 20 to 22, and 2 g once daily on September 20 to
22) and plasmapheresis for the suspected relapse (5 courses, 1
per day; September 26 to 30). Delayed-release DMF treatment was
discontinued on August 23. PML was diagnosed on the basis of
results on magnetic resonance imaging ... and positive results
on polymerase-chain-reaction assay for JC virus DNA in
cerebrospinal fluid obtained by means of lumbar puncture on
October 7. The patient had received no previous
immunosuppressant drugs or natalizumab.
Since delayed-release DMF was approved in the United States in
March 2013, more than 135,000 patients with multiple sclerosis
have been treated, representing approximately 112,000
person-years of exposure as of December 31, 2014. As of
September 26, 2014, a total of 3112 patients with multiple
sclerosis had received delayed-release DMF in clinical trials,
representing approximately 7429 person-years of exposure. To
date, there has been no overall increase in the risk of serious
infection, including other opportunistic infections. However,
delayed-release DMF can cause lymphocytopenia, a known risk
factor for PML. Thus, a contributory role of lymphocytopenia in
this patient cannot be ruled out.
In controlled and uncontrolled studies involving patients with
multiple sclerosis, there was a decrease in the mean lymphocyte
count of approximately 30% during the first year of treatment
with delayed-release DMF. The mean lymphocyte count then
plateaued and remained above the lower limit of the normal range
....
Approximately 2% of patients had reduced lymphocyte counts
(<500 cells per cubic millimeter) that persisted for more than 6
months.In this subgroup of patients, which was identifiable
within the first year of treatment, lymphocyte counts of less
than 500 per cubic millimeter were generally maintained with
continued therapy.... Periodic monitoring of absolute lymphocyte
counts to identify patients at increased risk for severe,
prolonged lymphocytopenia and consideration of treatment
interruption in these patients may mitigate the risk of PML.
Studies to evaluate the effect of delayed-release DMF on
lymphocyte subgroups are ongoing.
______
Thorsten Rosenkranz, M.D.
Asklepios Klinik Saint Georg, Hamburg, Germany
Mark Novas, M.D.
Biogen Idec, Cambridge, MA
mark.novas@biogenidec.com[/quote]
[References omitted]
The letter can be seen here
HTML http://www.nejm.org/doi/full/10.1056/NEJMc1415408?query=TOC.
#Post#: 715--------------------------------------------------
Re: 1st PML case in an MS patient on Tecfidera
By: agate Date: April 8, 2015, 7:07 pm
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From the New England Journal of Medicine, April 8, 2015 (see
another letter from the same issue in the post above this one).
This is a letter about a psoriasis patient who died of PML while
taking Tecfidera and contains some remarks about possible safety
concerns for this drug.
[quote]PML in a Patient without Severe Lymphocytopenia Receiving
Dimethyl Fumarate
To the Editor:
Fumaric acid esters, which are prescribed for the treatment of
psoriasis and multiple sclerosis, are considered to have a
favorable risk profile. However, treatment-related progressive
multifocal leukoencephalopathy (PML) has been described in
association with long-lasting, severe lymphocytopenia (<500
lymphocytes per cubic millimeter). This has led to the
recommendation that lymphocyte counts should be monitored in
patients receiving these drugs in order to prevent opportunistic
infections such as PML. Here, we report a case of fatal PML
after treatment with compounded dimethyl fumarate (DMF) in a
patient without severe lymphocytopenia.
On July 18, 2014, a 64-year-old woman presented with a 2-week
history of progressive apraxia. She had been receiving topical
glucocorticoids and compounded delayed-release DMF (Psorinovo;
compounding pharmacy, Mierlo-Hout) for the treatment of
psoriasis since June 2012. Magnetic resonance imaging (MRI) of
the brain showed multiple subcortical white-matter lesions ....
Leukocyte and lymphocyte counts were normal before DMF treatment
but reached a nadir of 4000 cells and 792 cells per cubic
millimeter, respectively, in June 2014.
Analysis of the cerebrospinal fluid showed normal levels of
leukocytes, protein, and glucose. The patient was seronegative
for the human immunodeficiency virus. At that time, a diagnosis
of PML was considered. However, testing of the cerebrospinal
fluid for JC virus DNA on polymerase-chain-reaction (PCR) assay
was negative. Treatment with DMF was discontinued, and the
patient received the diagnosis of atypical ischemic stroke.
Owing to progressive hemiparesis and somnolence, she was
transferred to our hospital on August 14, 2014. Follow-up MRI
showed a rapid and widespread dissemination of lesions
suggestive of PML–immune reconstitution inflammatory syndrome
(IRIS)....Treatment with mefloquine, mirtazapine, and
glucocorticoids was initiated. The patient's condition continued
to deteriorate, and she died on August 26, 2014. PML was
confirmed on histologic analysis of brain tissue ...and positive
results on PCR assay for JC virus DNA in brain tissue and
cerebrospinal fluid ....
In our opinion, this case represents DMF-associated PML, since
other immunosuppressive medications or coexisting medical
conditions were absent. To our knowledge, this is the first
reported case of compounded DMF–associated PML in a patient
without severe lymphocytopenia, a situation that was previously
thought to be unlikely.
Since the number of patients who are being treated with DMF is
rapidly increasing after approval of delayed-release DMF
(Tecfidera) as first-line treatment for relapsing–remitting
multiple sclerosis, our case raises important questions with
respect to safety monitoring. Although more than 100,000
patients with multiple sclerosis have been treated with
Tecfidera since 2013, the safety profile for long-term treatment
is unknown. On October 22, 2014, the first case of PML in a
patient receiving Tecfidera was reported; this patient had
persistent, severe lymphocytopenia. Our case shows that PML can
develop during treatment with compounded DMF in patients in whom
reduced lymphocyte counts are less severe than those in cases
that have been reported previously.
________
Dennis J. Nieuwkamp, M.D., Ph.D.
Jean-Luc Murk, M.D., Ph.D.
Charlotte H.P. Cremers, M.D.
University Medical Center Utrecht, Utrecht, the Netherlands
d.nieuwkamp@umcutrecht.nl
Joep Killestein, M.D., Ph.D.
VU University Medical Center, Amsterdam, the Netherlands
Marco C. Viveen, B.A.S.
Wim Van Hecke, M.D.
University Medical Center Utrecht, Utrecht, the Netherlands
Daphne W. Frijlink, M.D.
Medical Center Zuiderzee, Lelystad, the Netherlands
Mike P. Wattjes, M.D., Ph.D.
Bob W. van Oosten, M.D., Ph.D.
VU University Medical Center, Amsterdam, the Netherlands[/quote]
[References and supplementary material omitted]
The letter can be seen here
HTML http://www.nejm.org/doi/full/10.1056/NEJMc1413724?query=TOC.
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