PracticeUpdate Conference Series - ANZAN 2018

Continued from page 7 Natalizumab Reduces Disease Activity More Than and Faster Than Fingolimod in Patients With Active RRMS

Annualized relapse rates decreased by 20.2% after 2 years in patients who stayed on natalizumab but increased from on-natalizumab rates by 17.8% in oral switchers (P < .001) and 108.1% in injectable switchers (P < .001). In oral switchers, shorter washout time was predic- tive of lower relapse risk (>12 vs ≤4 weeks; HR 2.03; P < .001), fewer prenatalizumab relapses (HR 1.24/ relapse in the prior year; P < .001), lower baseline EDSS score (>3.5 vs ≤3.5; HR 1.44; P = .007), and longer natalizumab duration (>3 vs ≤3 years; HR 0.76; P = .040). Dr. Butzkueven concluded that staying on natali- zumab longer than 2 years yielded better clinical outcomes than switching to oral or injectable ther- apies. Among those who discontinued natalizumab, switching to oral vs injectable therapy yielded better outcomes. Washout time, prenatalizumab relapses, EDSS score, and time on natalizumab were predictive of risk of disease activity in oral switchers. Lana Zhovtis Ryerson, MD, of New York University, and colleagues set out to evaluate extended interval dosing of natalizumab to reduce risk of progressive multifocal leukoencephalopathy (PML) vs standard interval dosing in the TOUCH® Prescribing Program. Dr. Zhovtis Ryerson explained that natalizumab, approved for 300 mg dosed intravenously every 4 weeks, is associated with risk of PML. Prior studies have been inconclusive regarding the impact of extended interval dosing on the risk of PML. The US Risk Evaluation and Mitigation Strategy program (TOUCH) offers the largest data source that can inform on risk of PML in patients receiving extended interval dosing. Dr. Zhovtis Ryerson and colleagues looked to determine whether natalizumab extended interval dosing is associated with reduced risk of PML vs standard interval dosing. The investigators finalized the statistical analysis plan while blinded to events related to PML. “My colleagues and I,” Dr. Zhovtis Ryerson told Elsevier’s PracticeUpdate , “have been working on evaluating extended interval dosing of natalizumab for many years, hoping that this approach can opti- mize this excellent drug in terms of reducing risk of progressive multifocal leukoencephalopathy while maintaining efficacy.” She continued, “Our team carried out a retrospec- tive review in 2016. Results suggested that the

efficacy of extended interval dosing of natalizumab may be maintained. Risk of progressive multifocal leukoencephalopathy, however, could not be esti- mated since it is such a rare event.” She noted, “Collaborating with Biogen to assess data in the TOUCH database gave us the best opportunity to determine whether risk of progres- sive multifocal leukoencephalopathy is reduced using this approach. The optimal extended interval dosing schedule is not known, and we wanted to avoid considering patients with poor compliance as receiving the extended interval dosing.” “We developed three vigorous definitions to capture patients who were utilizing the extended interval dosing schedule. We hoped to see a difference in even one of the definitions.” Average dosing intervals were ≥3 to <5 weeks for standard interval dosing and >5 to ≤12 weeks for extended interval dosing. The primary analysis assessed average dosing intervals during the last 18 months of infusion. The secondary analysis iden- tified any prolonged period of extended interval dosing at any during infusion. The tertiary analysis assessed average dosing intervals over the full infusion history. Only anti-John Cunningham virus antibody-positive patients with dosing intervals ≥3 to ≤12 weeks were included. Hazard ratios for PML were compared using adjusted Cox regression models and Kaplan-Meier estimates. The analyses included 13,132 patients who received standard interval dosing and 1988 who received extended interval dosing (primary), 15,424 patients who received standard interval dosing and 3331 who received extended interval dosing (second- ary), and 23,168 patients who received standard interval dosing and 815 who received extended interval dosing (tertiary). In primary analyses, average dosing interval was 30 days for standard and 37 days for extended interval dosing. Median exposure was 44 months for standard and 59 for extended interval dosing. Most patients who received extended interval dos- ing received >2 years of standard interval dosing prior to extended interval dosing. The hazard ratio for PML (95% CI) was 0.06 (0.01– 0.22; P < .001) for the primary and 0.12 (0.05–0.29; P < .001) for the secondary analysis (both favored extended interval dosing). No cases of PML were observed with extended interval dosing in tertiary analyses (Kaplan-Meier log-rank test P = .02).

Dr. Lana Zhovtis Ryerson

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PRACTICEUPDATE CONFERENCE SERIES • ANZAN 2018