Update Shows Higher Incidence of Natalizumab-Associated PML

Kate Johnson

June 07, 2011

June 7, 2011 (Montreal, Quebec) — Numbers are higher than previously reported for the postmarketing incidence of progressive multifocal leukoencephalopathy (PML) associated with the use of natalizumab (Tysabri, Biogen Idec), according to an update presented here at the Consortium of Multiple Sclerosis Centers 25th Annual Meeting.

As of May 2011, there have been 124 reported cases of natalizumab-associated PML worldwide among 83,300 patients treated for multiple sclerosis (MS), said John Foley, MD, from Rocky Mountain Multiple Sclerosis Clinic, in Salt Lake City, Utah, and a consultant for the company.

That is an overall incidence of 1.4 cases per 1000 patients — an increase from the 1.2 per 1000 rate announced by the US Food and Drug Administration (FDA) and reported by Medscape Medical News in April.

Rare Opportunistic Infection

Natalizumab was first approved by the FDA in 2004 to treat relapsing forms of MS but was temporarily withdrawn from the market the following year because of its association with PML — a rare opportunistic infection of the central nervous system infection caused by the John Cunningham virus (JCV).

The drug was reintroduced in 2006 with stricter safety warnings and monitoring recommendations, and this spring, labeling was updated to quantify postmarketing PML incidence rates according to duration of exposure.

Now, a further update presented at this meeting shows the highest PML incidence continues to be in patients who have received 2 to 3 years of monthly natalizumab infusions — in whom there is a current PML rate of 1.89 cases per 1000 patients, up from the previously reported 1.5 cases, reported Dr. Foley.

In contrast, patients who have received between 3 and 4 years of infusions continue to have a lower incidence, at 1.10 cases per 1000 — up from 0.9 cases.

"We're, of course, very interested in what's happening here," commented Dr. Foley. "Is this real or a statistical artefact? We still have small numbers of patients out in this range."

Finally, the lowest PML rates continue to be in patients who have received 2 years or less of monthly infusions, in whom the most recent incidence is 0.49 cases per 1000 patients — up from 0.3 cases, he said.

"Clearly, the statistics are suggesting that the longer you're on the drug, the higher the risk. It also looks like there's a more definitive association being established with prior immunosuppressant therapy. And, we now have, probably what you might call a secondary risk stratification factor — that being the JCV antibody — [for which a screening test] is currently completing its experimental phase and will likely move into a commercial phase most likely this year."

JCV Antibody

According to company data, all cases of PML in which anti-JCV antibody status had been determined at least 6 months before symptom onset have been antibody positive, said Dr Foley.

In a subset of 79 such cases (median follow-up, 9.3 months from symptom onset), prior exposure to immunosuppressant therapy and longer duration of natalizumab exposure also appeared to confer a greater risk.

Among patients with anti-JCV antibody positivity and up to 2 years of monthly infusions, the incidence of PML was 0.35 cases per 1000 in those without prior immunosuppressant exposure, compared with 1.2 cases per 1000 in those with prior immunosuppressant exposure.

Similarly, among antibody-positive patients with up to 4 years of monthly infusions, the incidence of PML was 2.5 cases per 1000 among those without prior immunosuppressant exposure and 7.8 cases per 1000 in those with prior immunosuppressant exposure.

"Obviously, this is of significant concern, and I think the majority of practitioners are moving to rearrange this [latter] category as far as therapeutics," he said.

Among the 79 cases there has been a 20% mortality rate, "which is significantly lower than in the HIV population and might suggest that patients with normally functioning immune systems do better with PML," noted Dr. Foley. The median time from diagnosis to death was approximately 2 months.

However, among those patients who have survived with at least 6 months of follow-up, most (87%) rate moderate to severe on the Karnofsky Performance Status Scale.

"Usually, patients look fairly encephalopathic, there are changes in behavior and personality, there's often times motor paresis, usually hemiparesis, language disturbance is very common, and visual field defects are very common. [Magnetic resonance imaging] usually shows nonenhancing T2 lesions...and usually the JCV DNA cell counts are fairly low — reemphasizing the fact that a high-sensitivity assay really needs to be done if there's a suspicion of the disease," he said.

Despite treatment with either plasma exchange or immunoadsorption, "the vast majority" of patients developed immune reconstitution inflammatory syndrome usually by 4 weeks after diagnosis, he added.

PML survival appears to be associated with rapid diagnosis and treatment, as well as younger age — with the average age of patients with fatal cases being 52 years compared with 43 years in the patients with nonfatal cases, he reported.

In addition, localized unilobar disease had the lowest mortality rate (12.5%) compared with multilobar disease (25%), with widespread disease carrying a 63% mortality rate.

"Clearly, clinical vigilance is very important — we have hope that the JC antibody will help us as a stratification measure, and we continue to look at and hopefully define some further secondary and tertiary risk stratification measures to better manage natalizumab in this patient population," said Dr. Foley.

No Cause for Complacency

Although JCV antibody status appears to be associated with PML risk, it is premature to rely too heavily on it, based on retrospective data, warned Mark S. Freedman, MD, professor and director of multiple sclerosis research at the University of Ottawa, in Ontario, Canada.

"They have yet to find someone who had PML that did not have antibody positivity — but not everyone who had PML had an antibody test done," he explained to Medscape Medical News.

What I'm against is people saying it's a 'fait accompli' that if this test is negative you have no risk. Based on retrospective data you probably have a lower risk, but is it zero?

"The big question is, if you're antibody negative does that assure you 100% safety? The retrospective data suggest this might be true — but now they need to look prospectively. What I'm against is people saying it's a 'fait accompli' that if this test is negative you have no risk. Based on retrospective data, you probably have a lower risk, but is it zero? How high is that risk? We don't know."

In addition, although the data show an 80% survival rate, this comes at a price, he said. "This is a miserable disease. If you got it, you'd probably rather be dead because there's no treatment for it — it destroys brain tissue. Eighty percent to 90% of people are highly disabled if they survive PML."

And although the latest figures suggest a slight downturn in incidence after 3 years of treatment duration, Dr. Freedman says this is no cause for complacency.

"I think the fall-off was really that people started getting cold feet about leaving people on it for 3 or 4 years, so the incidence went down because they took patients off it," he said. "Now it's going back up because they were all reassured. We've now got the data from 48 to 72 months and it's back up again."

Dr. Foley declared consulting fees from Biogen Idec, Genzyme, and Teva and honoraria from Biogen Idec and Teva. Several of the study's coauthors are Biogen Idec employees. Dr. Freedman declared consulting fees from Biogen Idec, Bayer HealthCare, Celgene, Sanofi-Aventis, Novartis, Merck Serono, and Genzyme. Dr. Freedman is also an uncompensated member of the editorial advisory board for Medscape.

Consortium of Multiple Sclerosis Centers (CMSC) 25th Annual Meeting: Abstract P15. Presented June 2, 2011.

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