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Natalizumab reduces visual loss in patients with relapsing multiple sclerosis

From the Departments of Neurology and Ophthalmology (L.J.B., S.L.G.), University of Pennsylvania School of Medicine, Philadelphia, PA; Department of Neurology (P.A.C.), The Johns Hopkins University School of Medicine, Baltimore, MD; Hôpital Neurologique (C.C.), Lyon, France; Institute of Neurology (G.G.), London, UK; General Teaching Hospital (E.H.), Prague, Czech Republic; St. Vincent's University Hospital (M.H.), Dublin, Ireland; University Hospital Basel (L.K., E.W.R.), Basel, Switzerland; Mt. Sinai School of Medicine (F.D.L.), New York, NY; St. Michael's Hospital (P.W.O.), Toronto, Ontario, Canada; Multiple Sclerosis Center at Texas Neurology (J.T.P.), Dallas, TX; Vrije Universiteit Medical Center (C.H.P.), Amsterdam, the Netherlands; Mellen Center for Multiple Sclerosis Research (R.A.R), Cleveland Clinic Foundation, Cleveland, OH; MS Center of Atlanta (W.H.S.), Atlanta, GA; Silesian Medical University (A.W.), Katowice, Poland; Baird Multiple Sclerosis Center (B.W.G.), State University of New York at Buffalo, Buffalo, NY; Consultants in Neurology (D.R.W.), Multiple Sclerosis Center, Northbrook, IL; Biogen Idec (F.L., M.A.P.), Cambridge, MA.

Address correspondence and reprint requests to Dr. Laura J. Balcer, University of Pennsylvania School of Medicine, 3 East Gates Building, 3400 Spruce Street, Philadelphia, PA 19104; e-mail: lbalcer{at}mail.med.upenn.edu

Objective: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS).

Methods: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%).

Results: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups.

Conclusions: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the April 17 issue to find the title link for this article.

All investigators who participated in the AFFIRM study are listed in appendix E-1 on the Neurology Web site.

This study was supported by Biogen Idec and Elan.

Disclosure: Dr. Balcer has received support for consulting on the development of visual outcome measures for multiple sclerosis clinical trials from Biogen Idec, Centocor, Serono, Incyte, and Novartis. Dr. Galetta has received consulting fees, lecture fees, and grant support from Biogen Idec. Dr. Calabresi has received the following: consulting fees from Biogen Idec, Teva, Schering AG, Eisai, Amgen, Millenium, and Novartis; lecture fees from Biogen Idec, Serono, and Teva; and grant support from Biogen Idec, Teva, and Genentech. Prof. Confavreux has received consulting and lecture fees from Biogen Idec, Sanofi-Aventis, Schering AG, Serono, and Teva. Prof. Giovannoni received consulting fees from Biogen Idec, Serono, Teva, and Schering AG, and grant support from Biogen Idec, GlaxoSmithKline, and Teva. Prof. Havrdova has received consulting fees from Biogen Idec, Schering, Teva, Pfizer, and Serono. Prof. Hutchinson has received consulting fees from Biogen Idec and grant support from Serono, Schering AG, and Biogen Idec. Prof. Kappos has received grant support from Biogen Idec, Schering AG, Wyeth, Novartis, Serono, Teva, Sanofi-Aventis, and GlaxoSmithKline. Dr. Lublin received grant support from Biogen Idec, Teva, Acorda, and Merck and consulting/lecture fees from Biogen Idec, Berlex, Teva, Novartis, Schering Plough, Serono, Pfizer, Amgen, and Antisense Therapeutics. Prof. Miller has received grant support from Biogen Idec, Elan, Schering, and GlaxoSmithKline for performance of MRI analyses in clinical trials and honoraria for advisory or consultancy work, lectures, and related travel expenses from Aventis, Biogen Idec, Bristol-Myers Squibb, GlaxoSmithKline, Schering, Serono, UCB Pharma, and Wyeth. Dr. O'Connor has received consulting fees from Biogen Idec, Bristol-Myers, Sanofi-Aventis, Novartis, Serono, Schering, and Wyeth, and grant support from Biogen Idec, Novartis, Sanofi-Aventis, Schering, BioMS, Bristol-Myers, and Genentech. Dr. Phillips has received consulting fees from Biogen Idec, Teva, and Genzyme. Prof. Polman has received consulting fees from Biogen Idec, Schering AG, Teva, Serono, Novartis, GlaxoSmithKline, and Antisense Therapeutics, and grant support from Biogen Idec, Schering AG, Wyeth, Novartis, and GlaxoSmithKline. Prof. Radue has received lecture fees from Biogen Idec. Dr. Rudick reports having received consulting fees, lecture fees, and grant support from Biogen Idec. Dr. Stuart has received consulting fees, lecture fees, and grant support from Biogen Idec. Prof. Wajgt has nothing to disclose. Dr. Weinstock-Guttman has received lecture fees from Biogen Idec and Teva, and grant support from Biogen Idec. Dr. Wynn has received consulting fees from Biogen Idec, Teva, Serono, and Avanir Pharmaceuticals, and lecture fees from Biogen Idec, Teva, Pfizer, and Serono. Ms. Lynn and Dr. Panzara have equity interests and are employees of Biogen Idec.

Received June 21, 2006. Accepted in final form December 14, 2006.

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