Multicenter Retrospective Study Of Extended Dosing Of Natalizumab In Multiple Sclerosis: A Strategy For Mitigating Risk Of Progressive Multifocal Leukoencephalopathy While Maintaining Efficacy? (P2.251)

OBJECTIVE: Investigate whether Natalizumab extended dosing schedule mitigates Progressive Multifocal Leukoencephalopathy risk while maintaining clinical and radiological efficacy in Multiple Sclerosis. BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is the most serious complication associated with use of Natalizumab (NTZ) in patients with Multiple Sclerosis (MS). PML risk after previous JCV exposure may be as high as 8.5/1,000 in long term NTZ recipients with high JCV antibody index. PML susceptibility may reflect, at least in part, excessive reduction in discrete tissue compartment trafficking of immune cells required for JCV surveillance. While current MS treatment guidelines utilize a standard 300 mg NTZ dose administered every 4 weeks, percentage saturation of α4β1 integrin receptor on circulating lymphocytes is contingent upon NTZ serum concentrations, which in turn may be influenced by individual metabolism, body mass, dosage, and dose frequency. Pivotal trial and postmarketing data suggest MRI and clinical activity generally recur 12-16 weeks following cessation of NTZ therapy. We hypothesized that transition to an 8-week dosing regimen would, in a sense, establish the phenomenon of oscillating and therapeutic anti-microbial immune reconstitution against a ubiquitous viral pathogen, JCV. DESIGN/METHODS: Retrospective analysis of data provided by six MS Centers for patients who received NTZ extended dosing (ED) schedules (every 6,7 or 8 weeks) will be presented. RESULTS: 586 patients have received ED NTZ for at least 3 consecutive doses. Average age: 44 years; Male:female 32:68%; mean duration NTZ treatment (total): 37 doses; mean duration NTZ (ED): 12 doses; JCV immunopositivity: 63%.Relapse rate and MRI progression remained extremely low despite trend toincrease with increasing ED interval. Not a single case of PML was reported. Subgroup analysis, tolerability data, annualized relapse rates and MRI analysis will be presented. CONCLUSIONS: Our collective observations support the hypothesis that extended dosing NTZ regiment may represent an effective strategy to mitigate PML risk, while maintaining clinical and radiological efficacy in MS. Prospective study is planned.