Evaluating the efficacy and safety of 6-week extended interval dosing of natalizumab via a prospective, controlled, randomized, open-label, rater-blinded phase 3b study (P3.2-095)

Objective: To describe the design of a phase 3b study to evaluate the efficacy of extended interval dosing (EID) natalizumab. Background: Natalizumab, a highly efficacious therapy for relapsing-remitting multiple sclerosis (RRMS), is associated with risk of progressive multifocal leukoencephalopathy (PML). A recent analysis of the TOUCH dataset demonstrated that EID is associated with significantly lower PML risk in anti–JC virus seropositive patients. There have been no randomized studies to assess EID efficacy. Design/Methods: A prospective, interventional, randomized, controlled, rater-blinded, multinational study will be conducted. Eligibility requirements include age 18–60, diagnosis of RRMS, Expanded Disability Status Scale ≤5.5, stable on standard interval dosing (SID) natalizumab for ≥1 year with no relapses in the prior year, no prior immunosuppressant use, and no gadolinium-enhancing (Gd+) lesions at screening. Patients will be randomized 1:1 to natalizumab SID (every 4 weeks) or EID (every 6 weeks). Study duration will be 88 weeks (4 weeks screening, 72 weeks randomized treatment, 12 weeks follow-up). The primary endpoint is number of new/newly enlarging T2 lesions at 48 weeks. Key secondary endpoints include time to relapse, relapse rate, number of new MRI lesions, and incidence of serious adverse events. Exploratory endpoints include Timed 25-Foot Walk, Nine-Hole Peg Test, Symbol Digit Modality Test, and confirmed disability worsening or improvement. Natalizumab serum concentration, alpha-4 integrin saturation, lymphocyte counts, and body weight will be collected to explore relationships between pharmacokinetics/pharmacodynamics and efficacy. Results: Approximately 480 patients will be enrolled. Detailed rationales for study patient population and sample size, dosing intervals, and primary endpoint choice will be presented. Conclusions: This study will provide the first randomized, controlled efficacy data for patients treated with EID natalizumab which, in conjunction with safety data, will inform on the potential of EID as a future PML risk mitigation strategy. Disclosure: Dr. Campbell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Campbell holds stock and/or stock options in Biogen. Dr. Cohen has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consulting for Alkermes, Biogen, Convelo, EMD Serono, ERT, Gossamer Bio, Mapi, Novartis, Pendopharm, and ProValuate. Dr. Cohen has received personal compensation in an editorial capacity for Multiple Sclerosis Journal – Experimental, Translational and Clinical. Dr. Cohen has received research support from Genentech, Genzyme, Mallinckrodt, Novartis. Dr. Wiendl has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Abbvie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche Ltd, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, and TEVA. Dr. Wiendl has received research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme. Dr. Foley has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, EMDSerono. Dr. Foley holds stock and/or stock options in Abreos Biosciences. Dr. Foley has received research support from Biogen, Mallinckrodt, Adamas, Genentech and Novartis. Dr. Butzkueven has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck, Roche, Novartis, Teva, Oxford Pharamgenesis. Dr. Butzkueven has received research support from Novartis, Biogen, Merck, NHMRC Australia, MS Research Australia, UK MS Trust. Dr Zhovtis Ryerson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities from Biogen, Teva, Genezyme, Biogen and Celgene. Dr Zhovtis Ryerson received research support from Biogen. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AbbVie, Biogen, Novartis, Teva Neuroscience and Roche Diagnostics Corporation. He has also received consultancy fees for advisory board meetings for Merck-Serono, Genzyme-Sanofi, Synthon BV, and Physicians’ Summit and several medical education meetings. Dr. Giovannoni has received personal compensation in an editorial capacity for Multiple Sclerosis and Related Disorders (Elsevier). Dr. Giovannoni has received research support from Takeda Pharmaceutical Company. Dr. Arnold has nothing to disclose. Dr. Defer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Merck-Serono, Novartis, Sanofi-Genzyme, Roche and Teva. Dr. Defer has received research support from Biogen, Merck-Serono, Novartis, Sanofi Genzyme. Dr. Killestein has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dr Killestein accepted speaker and consulting fees from Biogen, Genzyme, Merck Serono, Novartis, Roche and TEVA.. Dr. Killestein has received personal compensation in an editorial capacity for the scientific journal of the Netherlands Society of Neurology, the Dutch Society of Neurosurgeons and the Society of Flemish Neurologists (Tijdschrift voor Neurologie en Neurochirurgie, TNN). Dr. Cutter has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO Pharmaceuticals, Biolinerx, Horizon Pharmaceuticals, Hisun Pharmaceuticals, Merck, Merck/Pfizer, Opko Biologics, Neurim, Novartis, Ophazyme, Sanofi-Aventis, Reata Pharmaceuticals, Receptos/Celgene, Teva pharmaceuticals, NHLBI, NICHD, Atara Biotherapeutics, Axon, Biogen, Argenix, Brainstorm Cell Therapeutics, Charleston Labs Inc, Click Therapeutics, Genzyme, Genentech, GW Pharma, Klein-Buendel Incorporated, Medimmune, Medday, Novartis, Roche, Scifluor, Somahlution, Teva pharmaceuticals, TG Therapeutics, UT Houston. Dr. Cutter has received personal compensation in an editorial capacity for Statistical editor for the Journal of the American Society of Nephrology. Dr. Cutter has received research support from Via MGFA. Dr. Ren has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Ren holds stock and/or stock options in Biogen. Dr. Ren has received research support from Biogen. Dr. Kasliwal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Stifano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Chang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Chang holds stock and/or stock options in Biogen. Dr. Ho has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen. Dr. Ho holds stock and/or stock options in Biogen.