Author Topic: 1st PML case in an MS patient on Tecfidera  (Read 483 times)

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Offline agate

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1st PML case in an MS patient on Tecfidera
« on: October 22, 2014, 09:00:05 pm »
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.

The article can be seen here.

More here:

http://www.fiercepharma.com/story/biogen-ms-superstar-tecfidera-misses-estimates-hit-first-confirmed-pml-case/2014-10-22
« Last Edit: October 22, 2014, 09:08:28 pm by agate »
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Offline agate

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Re: 1st PML case in an MS patient on Tecfidera
« Reply #1 on: October 23, 2014, 06:27:10 am »
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:

http://www.nejm.org/doi/full/10.1056/NEJMc1211805
« Last Edit: October 23, 2014, 04:40:42 pm by agate »
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Offline agate

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Re: 1st PML case in an MS patient on Tecfidera
« Reply #2 on: November 04, 2014, 03:33:12 pm »
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.”

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Offline agate

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More about the patient who developed PML on Tecfidera
« Reply #3 on: November 30, 2014, 03:20:24 pm »
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:
•   Tell patients taking dimethyl fumarate to contact you if they 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.
•   Stop dimethyl fumarate immediately at the first sign or symptom suggestive of PML and perform an appropriate diagnostic evaluation.
•   Monitor lymphocyte counts in patients taking dimethyl fumarate 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:
•   Complete and submit the report Online: www.fda.gov/MedWatch/report.htm
•   Download form or call 1-800-332-1088 to request a reporting 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


« Last Edit: November 30, 2014, 05:48:54 pm by agate »
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Offline agate

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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

[References omitted]

The letter can be seen here.

« Last Edit: April 08, 2015, 03:13:22 pm by agate »
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Offline agate

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Re: 1st PML case in an MS patient on Tecfidera
« Reply #5 on: April 08, 2015, 03:07:11 pm »
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

[References and supplementary material omitted]

The letter can be seen here.
« Last Edit: April 08, 2015, 03:14:48 pm by agate »
MS Speaks--online for 13 years

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