ASCEND Phase 3 Trial Open-Label Extension Study Results: Natalizumab May Delay Disability Progression in Secondary Progressive Multiple Sclerosis (SPMS) (P5.330)

Objective: To investigate long-term (>2 years) effects of natalizumabtreatment in the ASCEND open-label extension. Background: During ASCEND’s 2-year randomized treatment period, natalizumabdid not delay disability progression in SPMS patients with advanced disease assessed by the primary composite endpoint ( Expanded Disability Status Scale[EDSS], Timed 25-Foot Walk [T25FW], and 9-Hole Peg Test [9HPT]), but did slow progression on the 9HPT (upper-limb) component. Design/Methods: Patients who completed the 2-year, randomized, placebo-controlled treatment phase and entered the extension phase received open-label natalizumab. Original treatment assignments remained blinded to investigators and patients throughout the extension. Disability progression was assessed for up to 3 years using the primary composite endpoint. Results: Of 888 randomized, dosed ASCEND patients, 566 (63.7%) participated in the open-label extension (switched-from-placebo: n=274, median follow-up=156.9 weeks; natalizumab-continuers: n=292, median follow-up=160.4 weeks). Baseline characteristics and disease history were similar between groups and consistent with the overall ASCEND population. Fewer natalizumab-continuers than switched-from-placebo patients were composite endpoint progressors (52% vs 61%; adjusted odds ratio [OR]: 0.67; 95% confidence interval [CI]: 0.47–0.94; P =0.02). Natalizumabreduced 9HPT progression (19% natalizumab-continuers vs 28% switched-from-placebo; adjusted OR: 0.59; 95% CI: 0.39–0.88; P =0.01). T25FW and EDSS progression comparisons favored natalizumab(T25FW, adjusted OR: 0.80; 95% CI: 0.57–1.12; P =0.20; EDSS, adjusted OR: 0.73; 95% CI: 0.48–1.10; P =0.13). Conclusions: The ASCEND open-label extension showed clinically meaningful benefits of natalizumabon disability progression in advanced SPMS patients. Consistent with 2-year results, the largest treatment benefit was seen on preserving upper-limb function (9HPT), but preservation of ambulatory function (T25FW and EDSS) was also observed, leading to overall benefit on the primary composite endpoint. These results suggest that, while some benefits are evident after natalizumabinitiation, full benefits on disability progression, particularly lower-limb function, in advanced SPMS patients may not be evident until after longer treatment duration. Study Supported by: Biogen Disclosure: Dr. Hartung has received personal compensation from Bayer, Biogen, CSL Behring, Grifols, Merck Serono, Novartis, Roche, and Sanofi Genzyme as a speaker and consultant. Dr. Arnold has received personal compensation for activities with Coronado Biosciences, Consortium of Multiple Sclerosis Centers, Eli Lilly, EMD Serono, Genentech, Genzyme, GlaxoSmithKline, MS Forum, NeuroRx Research, Novartis, Opexa Therapeutics, Roche, Merck Serono, S.A. Serono Symposia International Foundation, Teva, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada. Dr. Arnold holds stock and/or stock options in NeuroRx Research. Dr. Freedmanhas received personal compensation for activities with Bayer HealthCare, Biogen Idec, EMD Canada, Novartis, Sanofi, Teva Canada Innovation, Chugai, Merck Serono, Novartis, Opexa for honoraria, consulting or participating on a advisory board. Dr. Havrdova has received personal compensation for activities with Actelion, Biogen, Celgene, Merck Serono, Novartis, Roche, Sanofi Genzyme, and Teva as a speaker. Dr. Havrdova has received research support from Czech Ministry of Education of Czech Republic, project PRVOUK-P26/LF1/1. Dr. Jeffery has received personal compensation for activities with Acorda, Bayer, Biogen, Genentech, GlaxoSmithKline, Novartis, Questcor, Serono, and Teva as a speaker and consultant. Dr. Jeffery has received research support from Biogen and Genentech. Dr. Kapoor has received personal compensation for activities with Biogen, Genzyme, Karo Bio, Novartis, Roche, and Teva as consultancies, lectures, participation in advisory boards and/or support for travel to medical meetings. Dr. Miller has received personal compensation for activities with Accordant Health Services, Acorda, Alkermes, Biogen, EMD Serono, Genentech, , Novartis, Roche, and Sanofi-Genzyme,. Dr. Miller has received personal compensation in an editorial capacity for Continuum Audio. Dr. Miller has received research support from Biogen, Genentech/Roche, Sanofi Genzyme, Novartis, and Mallinckrodt. Dr. Sellebjerg has received personal compensation for activities with Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis, and Teva. Dr. Sellebjerg has received research support from Biogen, EMD Serono, Genzyme, Lundbeck, Merck Serono, Novartis, and Teva. Dr. Li has received personal compensation for activities with Biogen as an employee. Dr. Li holds stock and/or stock options in Biogen, which sponsored research in which Dr. Li was involved as an investigator. Employee of Biogen Idec,,,,Holds stock and/or stock options in Biogen,, Dr. Cadavid has received personal compensation for activities with Biogen as a holder of stock and/or stock options and as an employee. Dr. Campbell has received personal compensation for activities with Biogen as an employee. Dr. Ho has received personal compensation for activities with Biogen as an employee. Dr. Ho holds stock and/or stock options in Biogen. Dr. Steiner has nothing to disclose.