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ARTICLES: J. P. Thompson, K. Noyes, E. R. Dorsey, S. R. Schwid, and R. G. Holloway Quantitative risk-benefit analysis of natalizumab Neurology 2008; 71: 357-364 [Abstract] [Full text] [PDF]

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Quantitative risk-benefit analysis of natalizumab

Israel Steiner   (11 September 2008)

Reply from the authors

Robert G. Holloway, Joel P. Thompson, Katia Noyes, E. Ray Dorsey, Steven R. Schwid, Robert G. Holloway   (11 September 2008)

Quantitative risk-benefit analysis of natalizumab 11 September 2008
Israel Steiner, Neurological Sciences Unit Hadassah University Hospital, Mount Scopus, P.O. Box 24035, Jerusalem, 91240, Israel Send Correspondence to journal: Re: Quantitative risk-benefit analysis of natalizumab isteiner{at}cc.huji.ac.il Israel Steiner	I read with interest the analysis by Thompson et al. that assessed the risks and benefits of natalizumab in relapsing multiple sclerosis (MS). [1] The study is based on an incorrect assumption and does not consider another fatal complication besides progressive multifocal leukoencephalopathy (PML). Following reports of the development of PML under natalizumab therapy, it is currently approved in a subgroup of MS patients who "have had an inadequate response to, or are unable to tolerate, alternate therapies." [2] However, this indication is based on the observed effect of natalizumab in two studies that did not examine its impact in the selective subgroup of MS patients who already had not responded to immuno-suppressive therapy. [3] Ironically, it seems that natalizumab is indicated for a clinical setting in which it was not tested. The current therapeutic approach in MS is based on the unproven assumption that relapses in MS are due to acute CNS inflammation and therefore immuno-modulating or immuno-suppressive therapies are aimed at preventing the immune response. The hypothesis that an immuno-suppressive agent will work where others have failed requires proof. If MS is a syndrome and not a single disease entity, failure to respond to several immuno-modulating therapies may render the usage of another agent futile. [4] Thus, extrapolating the findings observed in previous studies to this analysis is irrelevant to the current indications of natalizumab use and therefore cannot be used in the proposed model. Natalizumab has been associated with a fatal case of herpes encephalitis, herpes meningitis [5], several cases of recurrent herpes zoster, and herpes labialis. [6] Consequently, another potential fatal complication of natalizumab was not discussed in this analysis. References 1. Thompson JP, Noyes K, Dorsey ER, Schwid SR, Holloway RG. Quantitative risk-benefit analysis of natalizumab. Neurology. 2008;71:357-364 2. http://www.tysabri.com/tysbProject/tysb.portal 3. Ropper AH. Selective treatment of multiple sclerosis. N Engl J Med. 2006;354:965-967 4. Steiner I, Sriram S. The "one virus, one disease" model of multiple sclerosis is too constraining. Ann Neurol. 2007;62:529. 5. Ransohoff RM. Natalizumab for multiple sclerosis.N Engl J Med. 2007;35:2622-2629. 6. Kister I, Herbert J. Three cases of herpes reactivation in MS patients on natalizumab monotherapy. The 23rd Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS), Prague 2007. Disclosure: The authors report no disclosures.
Reply from the authors 11 September 2008
Robert G. Holloway, University of Rochester University of Rochester Medical Center, 601 Elmwood Ave, Box 673, Rochester, NY 14642, Joel P. Thompson, Katia Noyes, E. Ray Dorsey, Steven R. Schwid, Robert G. Holloway Send Correspondence to journal: Re: Reply from the authors Robert_Holloway{at}urmc.rochester.edu Robert G. Holloway, et al.	We thank Dr. Steiner for his interest in our work. His first point regarding the inconsistency between the AFFIRM trial population and the sub-population of MS patients most likely to be treated with natalizumab is an acknowledged limitation to our model. Only a well-designed trial can definitively assess the effects of natalizumab in the sub-population of patients for which it is indicated. However, U.S. Food and Drug Administration approval of natalizumab for patients not responding to other therapies indicates that they accept similar efficacy between this sub-population and the original trial participants. In our model, we assessed cohorts with increased baseline disability and increased risk of disability progression and found that those factors did not significantly change the results. We prefer this approach rather than stating that existing data are inadequate. We also agree with Dr. Steiner that there may be new information about the risks of natalizumab arising over time. However, while Dr. Steiner considers this a weakness of our model, we consider it a strength. An advantage of this model is that it can accommodate new risk information as it emerges, whether it is to refine PML risk (now estimated to be 2 per 6,600 patients treated over 18 months or more) [7] or to incorporate new risks (e.g., the development of other serious infectious complications such as herpes encephalitis). We believe that our model can help clinicians, patients, and regulators incorporate this new information into their decision-making. Reference 7. National Multiple Sclerosis Society. Two New Cases of PML Develop in People with MS Taking Tysabri. Available at http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=260. Accessed August 12, 2008. Disclosures: 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.