Updated Incidence of Natalizumab-associated Progressive Multifocal Leukoencephalopathy (PML) and Its Relationship with Natalizumab Exposure Over Time (2815)

Objective: To update the natalizumab-associated PML incidence over time in the global postmarketing setting and evaluate the relationship of PML incidence with natalizumab exposure over time. Background: Whether a change in PML incidence has occurred since the 2012 identification of 3 risk factors for natalizumab-associated PML—the presence of anti–JC virus antibodies, prior immunosuppressant use, and longer treatment duration—is of clinical interest. Design/Methods: The incidence of confirmed PML cases in Biogen’s global safety database from November 2009 to December 2018 was evaluated retrospectively. Overall incidence in all exposed patients was calculated using the estimated total number of patients ever exposed to natalizumab and the number of confirmed PML cases. Changes in natalizumab exposure patterns over time were evaluated over 12-infusion epochs. Results: As of December 31, 2018, 195,071 patients worldwide had received ≥1 natalizumab dose (total exposure: 711,946 patient-years); overall natalizumab-associated PML incidence was 4.14/1000 patients. The increase in overall monthly incidence reported from 2012 onward appeared to level off in mid-2016; overall incidence remained between 4.14/1000 and 4.18/1000 in 2018. PML incidence was greatest in later, higher-risk infusion epochs (37–48, 49–60, and 61–72); however, the number of patients in these higher-risk epochs increased over time, with the most dramatic percentage increase before 2015. Increases in the proportion of patients in later exposure epochs (>24 infusions) slowed from 2014 to 2016 and further from 2016 to 2018, coinciding with a slower increase in overall PML incidence from 2013 onward and the flattening observed since mid-2016. Conclusions: These data confirm and extend previous findings that overall global PML incidence in natalizumab-treated patients has remained stable since mid-2016. This stabilization coincides with the publication of new PML risk estimates, suggesting that risk stratification factors are being incorporated into clinical practice and may continue to impact PML incidence in the future.