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Friday, November 13, 2009

Tysabri News - Update

Source: Rocky Mountain MS Center

With the recent announcement confirming the increased number of PML cases, other information has become available as well. Of the 24 cases, two-thirds have been in Europe and one-third in the U.S. This is surprising considering that about 60% of exposed patients have been in the U.S. and only 40% in Europe. Why there appears to be a higher risk of PML in European MS patients on Tysabri is unclear. Additionally, the bulk of the cases have occurred in year three of Tysabri treatment. Specifically, in year one the risk is less than 1/30,000; in year two, it is approximately 1/3,000; and in year three the risk increases to approximately 1/800. The risk is real: in addition to the four reported deaths due to PML, mild to severe disability has been reported in those who have survived their bouts with the brain infection.

The above data suggest that the longer patients are treated with Tysabri, the higher the risk of PML. Does that mean that in year four and year five the risk increases? Few patients have reached four and five years of treatment, so we do not yet know the answer. As to the skewing between the number of cases in the U.S. and Europe, European patients may be more likely to have been treated with chemotherapy before beginning Tysabri. Does that mean that chemotherapy treatment increases the risk of PML, as some MS-specialists speculate? That remains unclear, but we do know that most Tysabri patients who develop PML have no history of other immunosuppressant therapies, which makes that hypothesis unlikely.

Despite the risks, Tysabri has proven itself to be a very effective and tolerable MS treatment, with an average efficacy rate of 70% compared to 30% for the first-line agents (Avonex, Betaseron, Copaxone and Rebif). Aside from the concern regarding PML, the therapy’s safety profile is well-developed and positive. According to Dr. Vollmer, were it not for PML, Tysabri would most certainly be a first-line agent for most MS patients. Therefore, one must wonder: what is the future of this effective, yet worrisome, therapy?

Three main possibilities exist, among them that the FDA and the manufacturers may opt to change the label so that Tysabri would be recommended for only 2 years of treatment or less; that research may advance to the point of identifying patients who innately have a higher risk of PML, although to date very few advances have been made in this area; or that Tysabri doses may be changed and/or the therapy used in combination with other treatment agents.

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2 comments:

Erin said...

I found the introduction of Copaxone and Tysabri to be interesting. I'm glad they're testing that. I've said that if I were to have to stop taking Tysabri, I'd go on Copaxone before an interferon.
I do know someone who has had over 5 years of infusions. Granted, she had to take a break when it was pulled, but she's been on it continuously since it was reintroduced. Only time will tell.

Lauren said...

In my opinion, Dr. Vollmer's assessments are full of contradictions. For example:

1. "Why there appears to be a higher risk of PML in European MS patients on Tysabri is unclear."

The majority of PML patients which appear in Germany were previously treated with Novantrone/Mito which can last in the body for many months even after discontinuation. Because there is no Touch program in the EU, it is unknown how long these patients were off Novantrone prior to starting Tysabri, as neurologists in Germany are very lax.

2. "we do know that most Tysabri patients who develop PML have no history of other immunosuppressant therapies".

That statement is ridiculous as the data suggests that almost all patients on Tysabri and then developed PML have a clear history of prior immunosuppression therapies such as Azathioprine, Methotrexate, Novantrone, Remicade, IVIG treatments, and Solu-Medrol (even regular pulse Steroids).

3. ".., the FDA and the manufacturers may opt to change the label so that Tysabri would be recommended for only 2 years of treatment or less".

I highly doubt that... for example: while there have been just three “officially” acknowledged fatalities from PML associated with Rituxan, at least 57 PML cases [51 fatal] in the approximately 100,000 patients who have ever taken Rituxan, there may be many more fatalities than are acknowledged by Biogen Idec, Genentech and Roche. See the October 2009 notification from Biogen Idec and Genentech:

http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM187792.pdf as well as a similar November 9, 2009 notification from Roche sent to medical professionals in Europe.

A total of 57 PML cases, 51 of which were fatal, were reported in an article by Charles Bennett, MD of Northwestern University and colleagues, published in the May 14, 2009 issue of the medical journal "Blood", covering the period 1997 through 2008. According to Dr. Bennett and his colleagues, of the 51 fatalities among the 57 PML patients identified, the median time between their diagnosis and death was about two months.

I find it very curious that neither the FDA, the EMEA, Biogen Idec, Genentech nor Roche mention the other approximately 54 PML cases in patients taking Rituxan, nor the fact that there were an additional 48 fatalities identified by Bennett et al., just the three fatal cases acknowledged by the drug companies. Of course, there is no TOUCH-like risk management plan in place for Rituxan, so some Rituxan-related PML cases and even some fatal PML cases may have been missed.

So, how does the current total of 24 cases of PML in Tysabri (including four fatal cases) among 60,700 total Tysabri patients compare to the 2008 total of 57 cases of PML in Rituxan (including at least three and possibly 51 fatal cases) among 100,000 total Rituxan patients?

My understanding is that Rituxan is generally used short term, while Tysabri is generally used indefinitely. It would appear that the incidence of PML in Tysabri patients taking the drug for less than two years is fairly low compared to the incidence of PML in Rituxan patients (most of whom, as I understand it, take the drug for two years or less).

What I find interesting is that some of the Tysabri trial patients have been on Tysabri for approximately 5 years (taking into account the 18 months it had been voluntarily removed from the market), and there are zero cases of PML in any of these patients.

In my opinion (I am not a doctor), all three of Dr. Vollmer's "possibilities" either place the MS patient at risk for developing antibodies to Tysabri & eventual lesser efficacy should the FDA or the manufacturers place further restrictions on the medication; should patients be forced to take a drug holiday; and/or place patients at increased risk of experiencing further relapses and disease progression while not on Tysabri.

Lauren