Monday, May 12

NEW STUDY: Low Body Weight Linked to PML Risk With Tysabri/Natalizumab in MS

An intriguing new study suggests that low body mass may be associated with an increased risk for developing progressive multifocal leukoencephalopathy (PML) in the setting of therapy with natalizumab (Tysabri, Biogen Idec) for multiple sclerosis (MS). "Higher PML incidence definitely trends toward lower body weights," said John Foley, MD, a neurologist at Rocky Mountain Multiple Sclerosis Clinic, Salt Lake City, Utah. There is about a 54% excess in PML cases in Europe Union compared with expected cases based on percentage of world-wide use, Dr. Foley pointed out.

Natalizumab concentration clearly increases with time, he said, and in this study, high natalizumab concentrations appeared to occur particularly in patients with lower body weight. "High natalizumab saturations correlate best to populations with both low body weight and very high drug level per kilogram. Extended-dose therapy can decrease concentration and saturation as you might expect, and may well be a viable therapy for PML risk reduction."

The findings were presented here at the American Academy of Neurology (AAN) 65th Annual Meeting. The study was supported by Biogen Idec/Elan Pharmaceuticals.

Lower Weight, Higher Risk?

Natalizumab is an effective treatment for MS, but the risk for PML is an important issue, considering its use, the study abstract notes. Factors that have already been identified as predictors of PML susceptibility include duration of therapy and positivity for antibodies to the JC virus upon starting therapy.

The so-called EU/US paradox in PML cases has been described previously, he said. If cases were evenly distributed between these regions on the basis of use, there should be approximately 125 cases of PML in the EU. Instead, there have been 193 cases, a 54% excess over expected numbers, much of which has been ascribed previously to an increased use of immunosuppressants in the EU, he noted.

In this study, Dr. Foley looked at pharmacokinetic and pharmacodynamic effects of prolonging the interval between doses of natalizumab as a possible risk mitigation strategy against PML.

He collected demographic and clinical data from a cohort of 301 natalizumab-infusing patients at their clinic and compared their data with an aggregate of such patients worldwide, including a cohort of 38 patients with PML.

Looking at drug concentrations, results showed a tight correlation coefficient between drug saturation of VLA-4 lymphocytes and the concentration per kilogram, ranging from 85% mean saturation to 95% in those with the lowest weight. "This weight relationship was also recognized early on in the natalizumab experience, and actually is in the PI [prescribing information], that higher drug clearance was seen in patients with higher body weight," Dr. Foley noted.

The researchers then stratified saturation by both weight and concentration and found that most patients with saturations of 90% to 95% were in the lower weight category, but they also mapped into the higher concentration category. "When you look at what we called our 'ultra-saturators,' our 95%-plus saturators, here you start seeing stratification into this really high concentration and low-weight group."

On the basis of these findings, he said, "we hypothesized that if increased concentrations and saturations occur in low body weight populations, and are germane to PML risk, then we should see more PML cases in patients with lower body weight."

By collaborating with several other centers, they were able to collect data on 38 patients with PML (almost 12% of the reported cases associated with natalizumab treatment) to look at the weight distribution between EU and US populations. In this PML cohort, the median weight was 64 kg, with a mean of 70 kg across all patients, and no significant difference was seen between the European and US populations in weight distribution among PML cases.

However, at their institution in Salt Lake City, Dr. Foley noted, "our median weight is 78 kilos, 14 kg greater than the average PML case. And in keeping with the theory, we do see in the Swedish cohort, which we are using as a surrogate for the EU population, as being much closer to the PML cohort at 69 kg."

They then divided patients into weight "bins" to try and elucidate the relationship further. In their clinic, 13% of patients fell into the 60 kg or less bin, whereas in the Swedish population of 1127 natalizumab-treated patients, 22% fell into the 60 kg or less bin. "And what we see is there is a striking elevation in PML cases in that lowest-weight category, almost 3-fold different from the US and almost 2-fold different from the combined (EU and US) data," he said.

"The other question is then what happens when you do dose extension, and here we're dose extending from a standard 28 to 30 days, to a 6-week regimen," Dr. Foley concluded. They don't yet have a lot of patients receiving this 6-week regimen, but they saw a significant reduction in mean concentration with the 6-week dosing cycle; in addition, saturation dropped roughly 6.5% in this small cohort

"It's one of those observations where only time will tell but it's certainly really fascinating," she told Medscape Medical News. The question is, though, which came first, she points out; lower body weight may mean the patients are healthier, or it may mean they are more ill, and therefore more likely to get PML.

"So there are a lot of unknowns, but I think it's just fascinating," she concluded.

The study was supported by Biogen Idec/Elan Pharmaceuticals. Dr. Foley reports having received personal compensation for activities with Biogen Idec, Teva Neuroscience, and Genzyme Corporation as a consultant and research support from Biogen Idec and Novartis. Dr. Jung Henson has received personal compensation for activities with Biogen Idec, Teva Neuroscience, Genzyme Corporation, Novartis, and Pfizer Inc. One of her family members holds stock and/or stock options in Merck & Co Inc. She has received research support from Biogen Idec, Novartis, and Genzyme Corporation.

American Academy of Neurology (AAN) 65th Annual Meeting. Abstract S30.002. Presented March 20, 2013.