Tysabri: Virus Reactivation and PML Treatment

While Elan has another 16 days to rework a buyout deal with JNJ—the new crux of which is the potential rights to the MS drug Tysabri (natalizumab)*—this week's NEJM offers 3 reports on the mAb-associated risk of PML.

Chen et al detected the subclinical reactivation of JC virus (the cause of PML) in 19 patients receiving natalizumab monotherapy. After 12 months of treatment, the prevalence of the virus increased significantly, from 19% to 63%, in urine. After 18 months of treatment, JC virus was detected in 20% (3/15) of plasma samples and in 9 of 15 samples of peripheral mononuclear cells. The shedding of JC virus was associated with a significant drop in the virus-specific cellular response.

Wenning et al describe the rocky, but successful, treatment of natalizumab-associated PML in a 52-year-old woman with MS. After 12 mAb infusions, the patient underwent plasma exchange and immunoadsorption therapy to remove natalizumab. She briefly improved but then developed immune reconstitution syndrome (IRS)—a condition otherwise familiar to HIV docs. Pulsed corticosteroid therapy resulted in clinical stability, followed by improvement.

A similar clinical course is provided by Linda et al, who describe the emergence of PML-consistent symptoms after 14 months of natalizumab treatment. Initially JC virus DNA was not detected in the spinal fluid by means of PCR; however, the virus was detected by quantitative PCR after 16 months of therapy (in association with clinical deterioration). Plasma exchange was performed. Three weeks later, the patient developed IRS; JC virus was no longer detected. Ultimately the patient improved.

The risk of PML with natalizumab therapy appears to depend on the length of therapy—an issue addressed in yesterday's WSJ by Shirley Wang. According to Biogen, the comarketer of Tysabri (along with Elan), there have been 11 cases of PML among 56,500 treated patients since the drug's 2006 reentry into the US market, for a crude, absolute risk of 0.02%.**

But the risk of natalizumab-associated PML appears to increase with prolonged therapy (eg, >12 months)—a fact that necessitates the use of an actuarial calculation (although Biogen disagrees). Wang calculates the actuarial risk of natalizumab-associated PML at about 0.08%. Citing neurologist Robert Fox, she also reports a risk of greater than 0.1% when therapy extends beyond 30 months. 

A quantitative risk-benefit analysis of natalizumab treatment, published last year, indicated that the "actual" risk of PML with the mAb would have to increase more than 7 times to reduce the relative benefit of therapy below that of interferon beta. The authors used an annual PML risk that was based on the published risk estimate of 1 per 1000 patients treated for an average of 17.9 months.

* For the necessary biz background, check out the In Vivo blog and the WSJ blog.

** Biogen actually calculates the absolute risk at about 0.01%, according to the WSJ.

HIV = human immune deficiency virus; mAb = monoclonal antibody; MS = multiple sclerosis; PCR = polymerase chain reaction; PML = progressive multifocal leukoencephalopathy.