Abstract Details

Title Natalizumab Related PML: An Evolving Risk Stratification Paradigm

Topic MS and Related Diseases

Presentation(s) S30 - (-)

Poster/Presentation
Number 002

Objective

Background PML remains an important issue when considering natalizumab as an MS therapy. Our group has analyzed many demographic factors and potential biomarkers to reduce PML risk. We have identified patient body mass as a novel potential predictor of PML susceptibility. Dose interval extension has been suggested as a possible PML risk mitigation tactic. We present data providing insight on the pharmacokinetic/pharmacodynamic effects of dose extension.

Design/Methods Primary demographic and clinical data was collected in a cohort of 301 natalizumab-infusing patients at a single clinic. This data set was compared to an aggregate of natalizumab-infusing patients worldwide, including a cohort of natalizumab-related PML cases.

Results Mean natalizumab plasma concentrations rose from approximately 16 to 32 ug/ml over the first two years of therapy. Patients with a body mass of <= 75 kg have higher mean natalizumab concentrations and VLA-4 lymphocyte saturations. Initial data analysis of 29 PML cases revealed a body mass of <= 75 kg in 83% and was statistically different from the single site comparative population (n=301). We will present additional PML cases, reference populations, and the relationship of natalizumab concentration to dosing interval extension.

Conclusions Patients with high natalizumab concentrations, resulting from a low body mass and/or natalizumab exposure duration, may be at a higher risk for PML. We hypothesize that high natalizumab plasma concentrations reduce immunosurveillance of the JC virus in the brain, allowing for the development of PML. Increasing the interval between natalizumab infusions may be an effective method for reducing plasma natalizumab concentrations and may decrease PML risk. Further research confirming this hypothesis is warranted.

Authors/Disclosures
John F. Foley, MD, FAAN (Rocky Mountain MS Clinic) PRESENTER	The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Octave. Dr. Foley has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics . The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Horizon Therapeutics. The institution of Dr. Foley has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sandoz. Dr. Foley has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Foley has stock in InterPRO Bioscience. The institution of Dr. Foley has received research support from Biogen. The institution of Dr. Foley has received research support from Novartis. The institution of Dr. Foley has received research support from Octave. The institution of Dr. Foley has received research support from Genentech. The institution of Dr. Foley has received research support from Imstem. The institution of Dr. Foley has received research support from Aegir.
Nicola De Stefano, MD (University of Siena)	Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Healthcare KGaA. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Immunic AG. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis Pharma AG. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck Serono S.p.A. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. De Stefano has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche S.p.A.. The institution of Dr. De Stefano has received research support from Italian MS Society. The institution of Dr. De Stefano has received research support from Merck Healthcare KGaA.

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