Extract from Nature Biotechnology academic articles.
It quotes one of the world experts on PML, Igor Koralnik, who is working together with Biogen and Elan. They seem to buy the COMBO argument.
Nature Biotechnology 23, 397 - 398 (2005)
Tysabri raises alarm bells on drug class.
What could have triggered Tysabri's adverse events?
Tysabri's mechanism of action, now the focus of intense scrutiny, is thought to involve preventing the migration of circulating inflammatory immune cells into inflamed tissues, such as the central nervous system in the case of MS, by binding the 4 subunit of 41 and 47 integrins. But in blocking damaging immune cells from crossing the blood-brain barrier, could Tysabri, an IgG4 monoclonal antibody (most other marketed antibodies are of the IgG1 isotype), also interfere with the passage into the CNS of immune cells that protect against PML?
The condition, which can occur in highly immunosuppressed individuals, is caused by reactivation of the human polyoma virus JC (JCV), a pathogen normally present in a dormant state in around 85% of healthy individuals.
Last year Igor Koralnik, associate professor of neurology at Harvard Medical School in Boston, Massachusetts, and colleagues detected JCV-specific CD8+ T-cells in 8 out of 11 (73%) healthy volunteers, indicating that circulating cytotoxic T-lymphocytes (CTLs) may be involved in preventing the development of PML in healthy subjects (J. Virol. 78, 10206−10210; 2004). That finding opens up one potential line of inquiry for the expert panel, of which Koralnik is a member. "It's as if the cops are patrolling the streets but they cannot get to the buildings where the drug dealers are," he says.
"It's just not clear if there are additional parts to that we don't understand," says UC neurologist Zamvil. The selection criteria for recruitment to the SENTINEL(COMBO) trial required subjects to be on Avonex therapy for at least one year before being administered Tysabri. The interferon, which has several immunomodulatory effects, influences the expression of over 1,000 genes, he says, including those for matrix metalloproteases that also have a role in lymphocyte trafficking across the blood-brain barrier. "Maybe if you attack the immune system from two different angles, it may be enough to allow the virus to become active," says Koralnik.
The specificity of the adverse events seen in the SENTINEL trial is "very peculiar", says Lawrence Steinman, professor of neurology at Stanford University in Stanford, California. Although Tysabri, in combination with Avonex, may be interfering with immune surveillance functions, he says, why this has not caused other opportunistic infections is not clear.