Longitudinal Analysis And Sample Collection To Evaluate PML Risk Host Markers for PML Risk Host Markers for PML Risk

The underlying etiology for the association of natalizumab therapy to an increase risk of
progressive multifocal leukoencephalopathy (PML) remains unknown. It is possible that
persistently high natalizumab levels lead to sustained immune-modulation or suppression
resulting in an increased PML risk. Since 2010 we have conducted three investigator
initiated trials (IITs) at our center to measure serum natalizumab concentration, lymphocyte
alpha 4 integrin saturation, and other biomarkers to understand the association of these
markers to PML risk. A number of the patients who participated in these clinical trials are
still infusing. These studies have demonstrated that plasma natalizumab concentrations
continue to rise over time with a plateau effect not yet clearly delineated. Improved drug
clearance in patients with higher body weight is described in the prescribing information.
We have accumulated preliminary data suggesting that patients with lower body weight may be
at higher risk for PML and that this may relate to higher drug concentrations and
saturations seen in this group. Dose extension may be a viable option to lower drug
concentration (pharmacokinetic, PK) and saturation (pharmacodynamic, PD) in patients with
lower body weight to potentially impact PML incidence. In addition to the PK/PD of
natalizumab, host related biomarkers may allow for more specific PML risk stratification.
Further validation of these biomarkers is critical for our understanding of their utility.

Inclusion Criteria:

1. Ability to understand the purpose and risks of the study and provide signed and dated
consent and authorization to use protected health information (PHI) in accordance
with national and local subject privacy regulations.

2. Must be enrolled in the TOUCH Prescribing Program for Tysabri® (natalizumab) prior to
informed consent.

3. In the opinion of the Principal Investigator, must be able and willing to comply with
all study directions

4. ≥ 18 years of age at the time of informed consent

Exclusion Criteria:

1. In the opinion of the Principal Investigator, subject is unwilling or unable to
comply with study directions.

2. Subject who is pregnant, breastfeeding, or likely to becoming pregnant during the
course of the study. Women of child-bearing potential must be practicing an
acceptable form of birth control.