Drug Injury Watch

April 2009 Update: Another Tysabri Patient Develops Serious Brain Infection PML

What Is Progressive Multifocal Leukoencephalopathy (PML), What Causes It, Why Is Tysabri Still On The Market?

(Posted by Tom Lamb at DrugInjuryWatch.com)

On April 17, 2009 we learned that another multiple-sclerosis patient using the multiple-sclerosis (MS) drug Tysabri developed progressive multifocal leukoencephalopathy, or PML, a rare brain infection.  This is the sixth MS patient who has been diagnosed with PML since Tysabri was reintroduced on the market in July 2006.

We get some insightful additional information from a Dow Jones article, "Biogen Says Sixth MS Patient On Tysabri Gets Brain Infection":

Tysabri - sold by the Cambridge, Mass., biotech [Biogen Idec Inc. (BIIB)] with Ireland-based partner Elan Corp. PLC (ELN) - was pulled from the market for 18 months beginning in 2005 because of a suspected link to the rare brain infection. Before Friday, the company had reported five confirmed cases, with one death, since the relaunch.

The latest case was outside the U.S., as were four of the previous five. Biogen didn't disclose additional details on the patient's condition.

Biogen plans to post a case update every Friday until July 24, the third anniversary of relaunch, by which time it expects the risk/benefit profile to be clearer.

The PML rate implied on Tysabri's label is one-per-1,000 patients. As of the end of March, about 40,000 patients were using Tysabri and about 24,900 patients have received at least one year of therapy. Chief Executive Jim Mullen, before Friday, had stressed the current rate for patients taking the drug more than 12 months is about one-per-4,000.

Some believe that duration of therapy plays a role in Tysabri's PML risk. The company said Thursday that about 6,800 patients have used the drug for more than two years, which is a rise of 2,500 from three months ago.

Earlier this month, on April 9, the biotech company Genentech announced that it was withdrawing its psoriasis medicine Raptiva from the market because it can cause PML. This Raptiva recall came after just four cases of PML had been reported in patients taking Raptiva, all of whom had reportedly been on Raptiva for at least three years.

The recent recall of Raptiva has some people asking this question: Why is Tysabri still on the market?

A good discussion of that question -- as well as an explanation of the PML disease process -- can be found in an April 20, 2009 Los Angeles Times article, "Psoriasis, Raptiva and PML: Why Genentech pulled the drug".  In relevant part:

Tysabri was pulled from the market in 2005 after three patients taking it for their multiple sclerosis developed PML. This was a big blow, because clinical trials had demonstrated the drug cut MS relapse rates -- bouts of worsening neurologic function -- by more than half. In June 2006, the Food and Drug Administration approved Tysabri's return to the market with a carefully crafted set of safety checks. Patients see their physicians monthly to be checked for features suggestive of PML -- basically, "anything new that can't be explained by the multiple sclerosis," Berger says. These include neurological symptoms, loss of white matter (which can be detected with MRI) and the presence of JC virus in spinal fluid.

Dr. Melvin Chiu, a dermatologist at the UCLA David Geffen School of Medicine who directs UCLA's Psoriasis and Phototherapy Center, says the situation with Tysabri differs from Raptiva when you consider the severity of the disease each drug is meant to treat. "That's not to say psoriasis is not disabling, but it doesn't have the life-threatening connotations that multiple sclerosis has," he says. "So from a risk-benefit analysis, it might not be worth the risk to be on Raptiva, especially given that there are several other therapies available for psoriasis patients that don't carry that risk."

We will watch for any additional reports of the brain infection PML in patients using Tysabri from Biogen -- which, as stated above, will be providing weekly reports at least  until July 24, 2009 -- or from other sources.

FDA Warns About Rare Brain Infection PML Linked To Psoriasis Drug Raptiva

European Union Regulators, On Same Day, Recommend That Raptiva Be Withdrawn Because Its Risks Outweigh The Benefits

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Update: April 2009: Raptiva Recall In U.S.

On April 8, 2009 we learned that Raptiva has been recalled due to the association between Raptiva and progressive multifocal leukoencephalopathy (PML), a rare and usually fatal disease of the central nervous system.

More information about this Raptiva recall can be found in the Genentch press release and the FDA statement:

Genentech Announces Voluntary Withdrawal of Raptiva from the U.S. Market

FDA Statement on the Voluntary Withdrawal of Raptiva From the U.S. Market

We provide the history of Raptiva in a basic timeline that is part of our April 9, 2009 article about the Raptiva recall.  (4/9/09)

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(Posted by Tom Lamb at DrugInjuryWatch.com)

On February 19, 2009 the FDA confirmed that Raptiva (efalizumab) had been linked to three cases of progressive multifocal leukoencephalopathy (PML), a rare brain infection which causes swelling of the brain and is usually fatal. The FDA said that all the cases were reported in the last six months.

That same day, across the Atlantic, the European Medicines Agency announced it had completed its safety review of Raptiva and said the Agency’s Committee for Medicinal Products for Human Use (CHMP) had concluded that the benefits of Raptiva do not outweigh its risks.  Accordingly, they recommended that the use of Raptiva should be suspended across the European Union.

Raptiva was approved by the FDA in 2003 to treat adults with moderate to severe chronic plaque psoriasis.

From the February 19 MedWatch Alert email concerning this association between Raptiva and PML:

FDA issued a Public Health Advisory to notify healthcare professionals of three confirmed, and one possible report of progressive multifocal leukoencephalopathy (PML), a rare brain infection, in patients using the psoriasis drug Raptiva. In October 2008, the labeling for Raptiva was changed to highlight, in a Boxed Warning, the risks of life-threatening infections, including PML. In addition, FDA directed Genentech, the manufacturer of Raptiva, to develop a Risk Evaluation and Mitigation Strategy, or REMS, to ensure that patients receive risk information about Raptiva. The FDA is reviewing this latest information. The agency will take appropriate steps to ensure that the risks of Raptiva do not outweigh its benefits, that patients prescribed Raptiva are clearly informed of the signs and symptoms of PML, and that health care professionals carefully monitor patients for the possible development of PML. The Public Health Advisory provides recommendations for healthcare.  [hyperlink added]

For comparison purposes, one might want to read the European Medicine Agency’s document, "Efalizumab (Raptiva): Recommendation to suspend marketing authorisation as risks outweigh benefits".  The essence of their position can be taken from this excerpt:

Although psoriasis is a disabling condition that can cause social and psychological problems for patients, it is very rarely life-threatening. The Committee concluded that the risk of PML is unacceptable for patients taking efalizumab. They recommended that the marketing authorisation should be suspended until there is adequate new evidence to identify a group of patients in which the benefits of efalizumab outweigh its risks.

From a February 19 AP article, "FDA says 3 deaths associated with Genentech drug", we get the drug company reaction to what is happening to Raptiva in the U.S.:

"We take the risk of PML very seriously and are working diligently with the FDA to put the right plans in place that will help protect patient safety," said company spokeswoman Tara Cooper.

We will wait to see if the FDA decides to follow the lead taken by its European Union counterparts and eventually issue a Raptiva recall order, here.

P.S.  At the recommendation of Health Canada, EMD Serono Canada Inc. has suspended the marketing of Raptiva in Canada due to safety concerns, including the increased risk of developing PML.  (2/21/09) 

FDA Staff Wants Amgen To Add Stronger Warning About Enbrel Side Effects In Children

June 2008 Staff Report Cites Cancers, Infections, And Neurological Problems Similar To Serious Side Effects In Adults

(Posted by Tom Lamb at DrugInjuryWatch.com)

On June 16, 2008 the FDA released a staff report, "Enbrel (etanercept) for the Treatment of Pediatric Plaque Psoriasis", which was prepared for the Dermatologic and Ophthalmic Drugs Advisory Committee's June 18, 2008 meeting.

In part, that FDA advisory committee will consider whether or not Amgen Inc. -- which markets Enbrel with Wyeth -- should be permitted to promote Enbrel for use by children with moderate to severe forms of the skin condition psoriasis.  At present, Enbrel is prescribed to treat psoriasis in children on an "off-label" basis, which means that the FDA has not approved Enbrel for that type of use but doctors are allowed to prescribe it to children with psoriasis when using their medical judgment.

According to a June 16, 2008 Reuters article, "UPDATE 2-Amgen's Enbrel in kids 'concerning'-FDA staff", by reporter Susan Heavey:

Regardless of whether the regulators approve the new use, FDA staff reviewers recommended the agency strengthen the drug's label to include reports of serious side effects in children that could lead to deaths or hospitalizations....

FDA safety reviewers looked at 949 reports of serious complications in children ages 4 to 17 taking Enbrel, or etanercept, for psoriasis as well as arthritis.

Among them, 61 reports were for psoriasis patients, according to the documents. No deaths were reported, but five patients were hospitalized.

Overall, the FDA found 14 deaths and 76 other life-threatening cases. Complications included serious infections as well as seizures and anemia.

"Given that the drug usage in pediatric population is estimated to be fairly small at this time, the numbers and types of post-marketing adverse events reported are concerning," the reviewers wrote.

The FDA staff who prepared this June 2008 report will present their findings to the Dermatologic and Ophthalmic Drugs Advisory Committee which, in turn, will make a recommendation to the FDA about whether or not Enbrel should be approved for the treatment of psoriasis in children.

As we reported recently, the FDA also is investigating whether Enbrel, along with rival products Johnson & Johnson's Remicade and Abbott Laboratories Inc's Humira, are linked to cancer in children.

According to the June 16 Reuters news article:

FDA reviewers found seven cases of cancer in children taking Enbrel, and two cases were reported in an Amgen study, according to the documents released on Monday.

We will watch for the advisory panel's recommendation about whether Enbrel should be used for pediatric psoriasis and for developments in the FDA's investigation about whether Enbrel, Humira, and/or Remicade are linked to cancer in children.

New Study Suggests Tysabri Not Likely Come Back On Market

FDA Will Determine Whether Risks Outweigh Any Potential Benefit

Serious side effects associated with Tysabri may outweigh any potential benefit, according to a study published in early November 2005, such that the once-promising drug for multiple sclerosis (MS) and Crohn's disease will not likely return to the U.S. market.

In the November 3, 2005 issue of the New England Journal of Medicine ("NEJM") appears an article about a new concerning Tysabri (natalizumab). This Tysabri study was comprised of two trials, and was supported by the drug companies responsible for Tysabri -- Elan Corp. and Biogen Idec Inc. -- as well as the National Institutes of Health.  The November 2005 NEJM article found that there was some positive response for MS patients and Crohn's patients using Tysabri.  The NEJM Tysabri study article, however, pointed out once again that one Crohn's patient died from progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal brain infection.

This is not the first time PML has been related to Tysabri, which has a short but controversial track record. Tysabri was approved by the FDA in November 2004 for the treatment of multiple sclerosis (MS) and Crohn's disease.  Soon thereafter, in February 200 Tysabri was voluntarily removed from the market by Elan Corp. and Biogen Idec Inc. after reports surfaced that three patients taking Tysabri had developed PML.  Two of three (or four, according to some reports) Tysabri patients who developed PML, an opportunistic infection, died as a result.

Dr. John F. Thompson, a professor of pediatrics and director of the Division of Pediatric Gastroenterology and Nutrition at the University of Miami's Miller School of Medicine, gave his opinion about this latest Tysabri study to HealthDay reporter Amanda Gardner:

Response rates weren't overwhelming but they were certainly exciting, particularly for people who had failed other therapies.  It probably would have become another important medication to consider for people with problematic Crohn's disease but the opportunistic infection is going to be problematic. I certainly would be uncomfortable using it in my patients.

Dr. Thompson concluded it did not seem likely that Tysabri would go back on the U.S. market, given the results of the latest Tysabri study.  Ms. Gardner points out that Dr. Thompson was not involved with the latest Tysabri study.

According to Ms. Gardner's HealthDay article, published on November 2, 2005, Tysabri maker Elan was more optimistic.  Davia Temin, an Elan spokeswoman, said:

Both [Elan and Biogen Idec] are extremely positive about its prospects for coming back onto the market.  Obviously, we want to come up with an appropriate risk analysis and patient safety comes first, but there is a huge unmet patient need....  There has been a very stringent and comprehensive risk analysis safety evaluation that's been done and that has been extremely favorable.  For PML, there were no new cases found in any population. It's the exact same three people.

According to Elan's Temin, the FDA is currently reviewing safety data on Tysabri and the agency should be done with its Tysabri review in about six months.

(Posted by: Tom Lamb)

Analyst Report Forecasts Some Choppy Waters for Return of Tysabri

FDA Adverse Event Reports Show Tysabri May Be Tied To Other Serious Side Effects

On August 29, 2005 The Wall Street Journal ("WSJ") reported that a list of adverse event reports made to the FDA related to the Tysabri included several rare infections, some of which were fatal, apart from the rare brain infection called progressive multifocal leukoencephalopathy.

Tysabri, a multiple-sclerosis drug, was withdrawn from the U.S. market on February 28, 2005 due to increasing concerns that Tysabri use could cause progressive multifocal leukoencephalopathy ("PML").  At that time, the companies responsible for Tysabri, Elan Corp. of Ireland and Biogen Idec Inc. of the U.S., said two patients with multiple sclerosis ("MS") taking Tysabri had contracted PML, with one patient dying from PML. The two companies later confirmed a second fatal case of PML in a patient using Tysabri to treat Crohn's disease, a gastrointestinal disorder.

The new WSJ article is based on information obtained through a Freedom of Information request made to the FDA by an pharmaceutical industry analyst at Morgan Stanley, Steven Harr.  Following an analysis of the Tysabri data which he received from the FDA, Mr. Harr issued a report on August 25, 2005 describing some adverse event reports for Tysabri which showed a number of Tysabri patients had died of rare infections. "We're not trying to put a death knell on Tysabri, but there are signals in there that something's going on. It's important for patients and investors to know," Mr. Harr said in an interview.

A spokesman for Biogen immediately dismissed Mr. Harr's report, stating that Biogen and Elan had performed a detailed safety analysis of Tysabri.  The companies' analysis, according to this spokesman, found no statistically significant differences between serious adverse events with patients given Tysabri and patients given a placebo in several clinical trials.  "We have an enormous amount of information in our hands," the spokesman said. "The [FDA's adverse event reports] database is a limited tool." 

According to the WSJ article, by staff reporter Sylvia Pagan Westphal:

The analyst's report describes seven non-PML deaths in patients taking Tysabri that "appear to be related to immunosuppression." One death was owing to pneumocystis pneumonia, an infection that only patients with severely debilitated immune systems get; another was because of herpes encephalitis, a rare infection of the central nervous system. Four other deaths were possibly caused by sepsis, an uncontrolled infection that spreads through the body.  The report mentioned that the FDA database contained "numerous" accounts of serious, nonfatal infections that "suggest again that the toll from Tysabri extends beyond PML."

Despite the problems that may be posed by these possible new side effects, Mr. Harr predicted that Tysabri has a good chance of returning to the market. In fact, Biogen and Elan said earlier in August 2005 that they hope to get the drug back on the market.  The companies announced, then, that they had screened more than 2,000 MS sufferers who took Tysabri in clinical trials for signs of PML. According to the companies, the screening produced "no new confirmed cases" of PML.

Lars Ekman, executive vice president and president of research and development at Elan, had this comment:

Patient safety remains our top priority....  We are committed to finalizing the safety evaluation for Crohn's disease and rheumatoid arthritis, which is progressing well and on track to be completed by the end of the summer. We look forward to working with regulatory authorities to determine the path forward for Tysabri.

Given these new adverse event reports of other serious infections in Tysabri users other than the rare brain infection PML, there seems to some choppy waters ahead for Biogen and Elan as they try to get Tysabri back on the market.

(Posted by: Tom Lamb)

Psoriasis Drug Raptiva Increases the Risk of Serious Infections

July 2005 "Dear Doctor" Letter Warns About Some Blood Disorders, Also

Genentech Inc. and the FDA announced recently that the drug company had added a new warning for the psoriasis drug Raptiva about an increased risk of serious infections.  This package insert label change for Raptiva was introduced and explained by means of a July 15, 2005 Dear Healthcare Professional letter which was sent to prescribing doctors and others.  This so-called "Dear Doctor" letter from Genentech letter also informed prescribers that Raptiva users have a higher chance of developing decreased blood platelets as well as immune-mediated hemolytic anemia.

On July 20, 2005 MedWatch - the FDA's safety information and adverse event reporting program - provided this email notification to doctors and others about the Raptiva label change:

Genentech and FDA revised the WARNINGS, ADVERSE REACTIONS sections and Patient Information Sheet for RAPTIVA (efalizumab), indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Healthcare professionals and patients were informed about reports of immune-mediated hemolytic anemia and warnings regarding postmarketing reports of thrombocytopenia and serious infections including necrotizing fasciitis, tuberculous pneumonia, bacterial sepsis with seeding of distant sites, severe pneumonia with neutropenia, and worsening of infection (e.g. cellulitis, pneumonia) despite antimicrobial treatment.

One can read the complete MedWatch Raptiva drug-safety alert, which includes links to the July 2005 Dear Doctor letter and the revised Raptiva warning label, to find out more.

(Posted by: Tom Lamb)