Sunday, August 3, 2008
Tysabri “News” Highlights Value of RNAi Therapeutic Against JC Virus
Tysabri made the headlines again late Thursday when Biogen Idec and Elan Corporation revealed the first two cases of progressive multifocal leukoencephalopathy (PML) following the re-launch of the multiple sclerosis (MS) drug almost two years ago. Although this had been widely expected, a sensational media and stock market reaction that wiped out $10B off the market cap of the two biotech companies, gives me an opportunity to discuss ongoing efforts to develop an RNAi Therapeutic against JC virus, the etiologic agent of the disease. Such an RNAi Therapeutic has the potential to play a crucial role in the risk management strategy of Tysabri and beyond.
Most of us are carriers of JC virus, a double-stranded DNA polyoma virus. PML is the result of re-activation of the virus following immunosuppression. PML really only became a medical problem with the AIDS epidemic, but cases of organ transplant-related and other immunosuppressive drug-related PML infections are increasing. In fact, it perplexes me why a drug like Tysabri that I believe, based on impressive clinical trial results and countless patient and physician testimonials, is the one in a dozen drugs that really makes a big difference for patients, has been singled out for this type of special treatment.
This is, however, not to downplay the potentially deadly nature of the disease. Tysabri, a monoclonal antibody aimed at neutralizing VLA-4 integrins, prevents the migration of leukocytes from the blood vessels into tissues, thereby preventing effective immunosurveillance of infections. In what the drug label estimates to be 1 in a 1000 cases, this allows the latent JC virus to become reactivated which may lead to de-myelination linked to viral replication.
An unparalleled surveillance program instituted by the companies with guidance by the regulatory agencies ensures that everybody involved in the treatment of Tysabri is fully aware of the risks. The heightened awareness should lead to early detection by PCR and MRI and the discontinuation of the immunosuppressive drug. In many cases this is enough to allow the immune system to catch up with the virus. An RNAi Therapeutic should increase the likelihood for that to occur both by decreasing viral load as well as potentially inflammatory viral protein expression which may cause the demyelination.
Clearly, in the absence of a proven antiviral, the potential of an RNAi Therapeutic targeting JC virus in the brain has not been lost on Biogen Idec. Three months after the re-launch of Tysabri in June 2006, Biogen Idec said that it would collaborate with Cambridge, Mass, neighbor Alnylam on the development of such a treatment. The last update was provided at the Keystone RNAi meeting earlier this year in Vancouver, and the data were quite encouraging and clinical trials may not be too far off.
The data supported those reported by others (here and here) that siRNA treatment is able to inhibit viral replication in vitro, both when administered before the initiation of viral replication, and more therapeutically relevant, after the initiation of viral replication. Since a reliable in vivo model for JC viral infection is lacking, further proof for true therapeutic potential came from demonstrating 55-75% target-specific knockdown of an oligodendrocyte marker gene (CNP) in rodents and non-human primates. Oligodendrocytes were chosen as the primary site of JC virus infection.
Given that localized delivery of RNAi to the brain appears to be closer to the clinic than systemic alternatives, with the exception of perhaps the intriguing publication last year on the use of rabies peptides for the delivery of siRNAs across the blood-brain barrier following systemic administration, the main question should be whether such delivery can not only get into the right cell types, but also achieve sufficient coverage to stall the virus.
Early detection will help by decreasing the size and number of viral replication sites that need to be treated. Unlike the name would suggest, PML infection is as often unifocal as it is multifocal, and localized siRNA/DNA-directed viral vector administration to limited numbers of infection sites based on the PML-diagnostic MRI seems reasonable.
Finally, a word on the stock market reaction to the Tysabri “news”. It is quite remarkable that the report of the expected PML cases was able to trigger 30% and 50% declines in the stock prices of Biogen Idec and Elan, respectively. Sensational media and scare-mongering analyst reports, some of them fabricated, accompanied short-selling tactics aimed at suggesting rock-bottom valuations. At one point for example, Elan traded down over 75% in relatively light German trading. Also noteworthy was that 5 minutes before the market close and announcement of the PML cases, 30,000 August '08 Elan put options were traded for what must have been an amazing $30M-dollar-in-5-minute gain.
As the financial world is starting to realize, abusive short-selling aimed at destroying the ability of companies to grow, which in the case of biotechs is designed to undermine their ability to fund drug development, is very real. This should be of great concern to the biotech industry, and it is hoped that trade organizations such as BIO seize the opportunity to put pressure on the SEC to address this problem not just for the benefit of a select number of financial companies.
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