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Quantitative risk-benefit analysis of natalizumab

From the Departments of Neurology (J.P.T., E.R.D., S.R.S., R.G.H.) and Community and Preventive Medicine (K.N., R.G.H.), University of Rochester, NY.

Address correspondence and reprint requests to Dr. Robert G. Holloway, University of Rochester Medical Center, 601 Elmwood Ave., Box 673, Rochester, NY 14642 robert_holloway{at}urmc.rochester.edu

Objective: To model the long-term risks and benefits of natalizumab in individuals with relapsing multiple sclerosis (MS).

Methods: We created a Markov model to evaluate treatment effects on reducing relapses and slowing disease progression using published natural history data and clinical trial results. Health changes, measured in quality-adjusted life-years (QALYs), were based on patient health preferences. Patient cohorts treated with no disease-modifying treatment, natalizumab, subcutaneous interferon β-1a, and a theoretical "perfect" MS treatment were modeled. Sensitivity analysis was used to explore model uncertainty, including varying risks of developing progressive multifocal leukoencephalopathy (PML).

Results: Treatment with natalizumab resulted in 9.50 QALYs over a 20-year time horizon, a gain of 0.80 QALYs over the untreated cohort and 0.38 QALYs over interferon β-1a. The health loss due to PML was small (–0.06 QALYs). To offset natalizumab’s incremental health gain over interferon β-1a, the risk had to increase from 1 to 7.6 PML per 1,000 patients treated over 17.9 months. The "perfect" MS treatment accumulated 10.59 QALYs over the 20-year time horizon, 1.89 QALYs above the untreated cohort. Interferon β-1a resulted in greater QALY gains compared with natalizumab if natalizumab’s relative relapse reduction was reduced from 68% to 35% or if interferon β-1a’s relative reduction was increased from 32% to 65%.

Conclusions: A more than sevenfold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab’s health gain below that of interferon β-1a, and there remains considerable room for additional gains in health (>50%) beyond those already achieved with current therapies.

Abbreviations: AFFIRM = Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis; EDSS = Expanded Disability Status Scale; FDA = Food and Drug Administration; IFN = interferon; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; PRISMS = Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis; QALY = quality-adjusted life-year; TOUCH = Tysabri Outreach: Unified Commitment to Health; TYGRIS = Tysabri Global Observation Program in Safety.

Disclosure: K.N., R.G.H., and S.R.S. were supported in part by contract HC0071 from the National Multiple Sclerosis Society. K.N. was supported in part by research grant K01 AG 20980 from the National Institute on Aging. E.R.D. was supported in part by an American Academy of Neurology Clinical Research Training Fellowship. R.G.H. was supported in part by grant K24 NS4 2098 from the National Institute of Neurological Disorders and Stroke. S.R.S. has received research funding from Biogen, Serono, and Teva and honoraria for educational and consulting activities from Berlex, Biogen, Serono, and Teva. The project described was partially supported by grant number 1 UL1 RR024160-01 from the National Center for Research Resources (NCRR), a component of the NIH and the NIH Roadmap for Medical Research, and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Information on NCRR is available at http://www.ncrr.nih.gov/. Information on Re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational.asp.

Received August 23, 2007. Accepted in final form April 1, 2008.

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