Opinion
EDITORIAL
Does Natalizumab Therapy Benefit Patients With Multiple Sclerosis? Olaf Stüve, MD, PhD; Gary R. Cutter, PhD
Figure. Patients With Multiple Sclerosis Experience a Meaningful Reduction in Disease Activity During Natalizumab Therapy Before Natalizumab Therapy
After Natalizumab Therapy
During Natalizumab Therapy
Progression of Neurologic Disability
A
Time
Progression of Neurologic Disability
B
Time C
Progression of Neurologic Disability
Doesnatalizumabtherapybenefitpatientswithmultiplesclerosis (MS)? The obvious answer is yes. Natalizumab was approved for patients with relapsing forms of MS by regulatory agencies based on the results of 2 phase 3 clinical trials that showed substantial benefits with regard to clinical and paraclinical outcomes.1,2 Post hoc analyses suggest that many who adhere to natalizumab therapy have a high likelihood of being disease free for many years.3 Based on these efficacy data, patients should perhaps be treated with natalizumab indefinitely or until they seem to have transitioned to secondary progressive MS. However, shortly after its initial approval, it was determined that natalizumab use is associated with progressive multifocal encephalopathy (PML), an opportunistic infection of the central nervous system that is caused by the human polyomavirus John Cunningham virus (JCV). It is unclear why natalizumab increases the risk of PML, but its mechanism of antagonizing α4 integrin–mediated cell migration likely diminishes immune surveillance of the brain and spinal cord. While debatably low, this risk is cause for concern among physicians and at various times for some patients based on their risk tolerance. Almost since its approval, attempts have been Related article page 954 made to determine whether discontinuation of natalizumab is safe, in whom the agent should be discontinued, and how. Although the pathogenic events leading to natalizumab-associated PML remain opaque, the following 3 factors are associated with the overall risk of this infection: a positive serostatus for anti–JCV antibodies, the utilization of immunosuppressants before initiating natalizumab use, and the duration of natalizumab therapy (alone or in combination).4 If all 3 risk factors are present, the risk of natalizumab-associated PML is approximately 1 in 90, which seems unacceptably high given that PML is associated with a high morbidity and mortality and that alternative therapies exist. The development of an assay to identify patients who are positive for JCV and the identification of the other known risk factors represent a major plus for initiating therapy, but when a patient becomes positive for JCV or has been on a natalizumab regimen for a substantial amount of time and desires to stop therapy, the path is less clear. Consequently, neurologists have been investigating how to transition patients who want to cease natalizumab to other therapies.5,6 The goal of a treatment change is 2-fold, namely, to lower the risk of PML and to prevent MS disease reactivation. The risk of PML is thought to be absent or negligible for any of the other approved therapies, whereas it remains elevated at least for a period after natalizumab is discontinued.7 The risk of disease reactivation is high, and it occurs within 3 to 6 months after the last natalizumab dose is administered.8
Time
It is unknown whether beneficial effects of natalizumab are sustained in the long term (A), whether reactivation of disease after discontinuation results in neurologic disability similar to that of untreated patients (B), or whether eventually there is increased disease progression (C). The black line represents no treatment, and the red line represents natalizumab treatment.
jamaneurology.com
JAMA Neurology August 2014 Volume 71, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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945
Opinion Editorial
In this issue of JAMA Neurology, Clerico and colleagues9 report the results of a spontaneous, observational, prospective multicenter study among 124 patients to compare the efficacy of various approved disease-modifying MS therapies on the disease relapse rate, the accumulation of neurologic disability as measured by the Expanded Disability Status Scale, and the paraclinical disease biomarkers based on magnetic resonance imaging activity during 1 year after 24 doses of natalizumab. The investigators confirm what was previously shown, namely, that discontinuation of natalizumab allows reactivation of disease activity, confirming the drug’s efficacy in suppressing disease but also documenting the return of disease events on its withdrawal. One patient in the study developed PML. Based on these results, the authors advise the readers to discontinue natalizumab use only in patients at high risk of PML. Unfortunately, the attempt by Clerico et al9 is not the first that has failed at identifying a safe exit strategy for patients with MS receiving natalizumab, one that minimizes the return of disease activity and progression and lowers the risk of PML. Therefore, it is difficult to assess the risk-benefit equation of switching to another therapy in patients with MS at lower (1 risk factor) or intermediate (2 risk factors) risk of natalizumab-associated PML. To make a rational decision on the recommendation by the authors, the following important information is unavailable to patients and their neurologists: are the reductions in disease activity and therapeutic benefits gained during natalizumab therapy maintained in the long term and, most important, after treatment cessation? As stated above, it is difficult to observe disease activity in many ARTICLE INFORMATION Author Affiliations: Veterans Affairs Medical Center, Neurology Section, Medical Service Dallas, Veterans Affairs North Texas Health Care System, Dallas (Stüve); Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas (Stüve); Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (Stüve); Associate Editor, JAMA Neurology (Stüve); Section on Research Methods and Clinical Trials, Department of Biostatistics, University of Alabama at Birmingham (Cutter). Corresponding Author: Olaf Stüve, MD, PhD, Veterans Affairs Medical Center, Neurology Section, Medical Service Dallas, Veterans Affairs North Texas Health Care System, 4500 S Lancaster Rd, Dallas, TX 75216 ([email protected]). Published Online: June 30, 2014. doi:10.1001/jamaneurol.2014.1201. Conflict of Interest Disclosures: Dr Stüve reported serving on the editorial boards of Multiple Sclerosis Journal, Clinical and Experimental Immunology, and Therapeutic Advances in Neurological Disorders; participating in data and safety monitoring committees for Pfizer and sanofi-aventis; and receiving grant support from Teva. Dr Cutter reported being employed as president of Pythagoras, Inc, a private consulting company in Birmingham, Alabama; serving on the editorial board of Multiple Sclerosis Journal and as a statistical and contributing editor for Neurology Clinical Practice; and receiving funding from numerous National Institutes of Health grants and from the Department of Defense. In the past 24 946
natalizumab responders. Consequently, it is conceivable that the disease burden remains diminished compared with patients not treated with natalizumab even after disease activity returns (Figure, A), adding disability-free years gained equal to the time on therapy. Alternatively, it is possible that natalizumab has no lasting effect on pathogenic mechanisms that perpetuate MS disease activity and disability, and that eventually there are no detectable long-term beneficial effects on disease activity that we can measure (Figure, B and C), which would translate to fewer disability-free years gained. The second scenario would be analogous to the effects of pregnancy on MS, in which patients are protected from disease activity during the second and third trimesters, but whereby any benefit seems to vanish in the postpartum months.10 In the case of natalizumab, these changes in disease activity may take years, and this is why long-term data are needed to capture potential long-term benefits if they exist, as well as to be able to calculate discounts to these benefits if there is an accelerated decline after treatment cessation. Natalizumab therapy has had a positive effect on the lives of many patients with MS. Its beneficial effects do not seem to be limited to the parameters we measure routinely in clinical trials or neurologic practice, but they also include quality-of-life outcomes.11 These outcomes are relevant even if they are time limited and cannot be sustained. However, further research is urgently needed to answer the questions of whom to treat, how long to treat, how to initiate sequential therapies to maintain these benefits, and whether disease reactivation after natalizumab cessation is a risk factor for increased long-term disability.
months, Dr Cutter reported participating in data and safety monitoring committees for Apotek, Ascendis, Biogen-Idec, Cleveland Clinic, GlaxoSmithKline Pharmaceuticals, Gilead Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Neuren, PCT Bio, Teva, Vivus, National Institute of Neurological Disorders and Stroke, National Multiple Sclerosis Society, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Units Network), and National Heart, Lung, and Blood Institute (protocol review committee). In the past 24 months, Dr Cutter reported participating in consulting, speaking engagements, and advisory board and data and safety monitoring board commitments for Alexion, Allozyne, Bayer, Consortium of MS Centers (grant), Klein-Buendel Incorporated, Genzyme, Medimmune, Novartis, Nuron Biotech, Receptos, Revalesio, sanofi-aventis, Spiniflex Pharmaceuticals, Somahlution, Teva, and Xenoport. REFERENCES 1. Polman CH, O’Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 2. Rudick RA, Stuart WH, Calabresi PA, et al; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-923. 3. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis. Lancet Neurol. 2009;8(3):254-260.
4. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880. 5. Berger JR, Centonze D, Comi G, et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis. Ann Neurol. 2010;68(3):409-411. 6. Rossi S, Motta C, Studer V, et al. A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation. Mult Scler. 2013;19(1):59-68. 7. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014; 75(1):108-115. 8. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858-1865. 9. Clerico M, Schiavetti I, De Mercanti SF, et al. Treatment of relapsing-remitting multiple sclerosis after 24 doses of natalizumab: evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP study) [published online June 30, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.1200. 10. Vukusic S, Hutchinson M, Hours M, et al; Pregnancy in Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study). Brain. 2004;127(pt 6):1353-1360. 11. Rudick RA, Miller D, Hass S, et al; AFFIRM and SENTINEL Investigators. Health-related quality of life in multiple sclerosis. Ann Neurol. 2007;62(4):335-346.
JAMA Neurology August 2014 Volume 71, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Purdue University User on 05/22/2015
jamaneurology.com
EDITORIAL
Does Natalizumab Therapy Benefit Patients With Multiple Sclerosis? Olaf Stüve, MD, PhD; Gary R. Cutter, PhD
Figure. Patients With Multiple Sclerosis Experience a Meaningful Reduction in Disease Activity During Natalizumab Therapy Before Natalizumab Therapy
After Natalizumab Therapy
During Natalizumab Therapy
Progression of Neurologic Disability
A
Time
Progression of Neurologic Disability
B
Time C
Progression of Neurologic Disability
Doesnatalizumabtherapybenefitpatientswithmultiplesclerosis (MS)? The obvious answer is yes. Natalizumab was approved for patients with relapsing forms of MS by regulatory agencies based on the results of 2 phase 3 clinical trials that showed substantial benefits with regard to clinical and paraclinical outcomes.1,2 Post hoc analyses suggest that many who adhere to natalizumab therapy have a high likelihood of being disease free for many years.3 Based on these efficacy data, patients should perhaps be treated with natalizumab indefinitely or until they seem to have transitioned to secondary progressive MS. However, shortly after its initial approval, it was determined that natalizumab use is associated with progressive multifocal encephalopathy (PML), an opportunistic infection of the central nervous system that is caused by the human polyomavirus John Cunningham virus (JCV). It is unclear why natalizumab increases the risk of PML, but its mechanism of antagonizing α4 integrin–mediated cell migration likely diminishes immune surveillance of the brain and spinal cord. While debatably low, this risk is cause for concern among physicians and at various times for some patients based on their risk tolerance. Almost since its approval, attempts have been Related article page 954 made to determine whether discontinuation of natalizumab is safe, in whom the agent should be discontinued, and how. Although the pathogenic events leading to natalizumab-associated PML remain opaque, the following 3 factors are associated with the overall risk of this infection: a positive serostatus for anti–JCV antibodies, the utilization of immunosuppressants before initiating natalizumab use, and the duration of natalizumab therapy (alone or in combination).4 If all 3 risk factors are present, the risk of natalizumab-associated PML is approximately 1 in 90, which seems unacceptably high given that PML is associated with a high morbidity and mortality and that alternative therapies exist. The development of an assay to identify patients who are positive for JCV and the identification of the other known risk factors represent a major plus for initiating therapy, but when a patient becomes positive for JCV or has been on a natalizumab regimen for a substantial amount of time and desires to stop therapy, the path is less clear. Consequently, neurologists have been investigating how to transition patients who want to cease natalizumab to other therapies.5,6 The goal of a treatment change is 2-fold, namely, to lower the risk of PML and to prevent MS disease reactivation. The risk of PML is thought to be absent or negligible for any of the other approved therapies, whereas it remains elevated at least for a period after natalizumab is discontinued.7 The risk of disease reactivation is high, and it occurs within 3 to 6 months after the last natalizumab dose is administered.8
Time
It is unknown whether beneficial effects of natalizumab are sustained in the long term (A), whether reactivation of disease after discontinuation results in neurologic disability similar to that of untreated patients (B), or whether eventually there is increased disease progression (C). The black line represents no treatment, and the red line represents natalizumab treatment.
jamaneurology.com
JAMA Neurology August 2014 Volume 71, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a Purdue University User on 05/22/2015
945
Opinion Editorial
In this issue of JAMA Neurology, Clerico and colleagues9 report the results of a spontaneous, observational, prospective multicenter study among 124 patients to compare the efficacy of various approved disease-modifying MS therapies on the disease relapse rate, the accumulation of neurologic disability as measured by the Expanded Disability Status Scale, and the paraclinical disease biomarkers based on magnetic resonance imaging activity during 1 year after 24 doses of natalizumab. The investigators confirm what was previously shown, namely, that discontinuation of natalizumab allows reactivation of disease activity, confirming the drug’s efficacy in suppressing disease but also documenting the return of disease events on its withdrawal. One patient in the study developed PML. Based on these results, the authors advise the readers to discontinue natalizumab use only in patients at high risk of PML. Unfortunately, the attempt by Clerico et al9 is not the first that has failed at identifying a safe exit strategy for patients with MS receiving natalizumab, one that minimizes the return of disease activity and progression and lowers the risk of PML. Therefore, it is difficult to assess the risk-benefit equation of switching to another therapy in patients with MS at lower (1 risk factor) or intermediate (2 risk factors) risk of natalizumab-associated PML. To make a rational decision on the recommendation by the authors, the following important information is unavailable to patients and their neurologists: are the reductions in disease activity and therapeutic benefits gained during natalizumab therapy maintained in the long term and, most important, after treatment cessation? As stated above, it is difficult to observe disease activity in many ARTICLE INFORMATION Author Affiliations: Veterans Affairs Medical Center, Neurology Section, Medical Service Dallas, Veterans Affairs North Texas Health Care System, Dallas (Stüve); Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas (Stüve); Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (Stüve); Associate Editor, JAMA Neurology (Stüve); Section on Research Methods and Clinical Trials, Department of Biostatistics, University of Alabama at Birmingham (Cutter). Corresponding Author: Olaf Stüve, MD, PhD, Veterans Affairs Medical Center, Neurology Section, Medical Service Dallas, Veterans Affairs North Texas Health Care System, 4500 S Lancaster Rd, Dallas, TX 75216 ([email protected]). Published Online: June 30, 2014. doi:10.1001/jamaneurol.2014.1201. Conflict of Interest Disclosures: Dr Stüve reported serving on the editorial boards of Multiple Sclerosis Journal, Clinical and Experimental Immunology, and Therapeutic Advances in Neurological Disorders; participating in data and safety monitoring committees for Pfizer and sanofi-aventis; and receiving grant support from Teva. Dr Cutter reported being employed as president of Pythagoras, Inc, a private consulting company in Birmingham, Alabama; serving on the editorial board of Multiple Sclerosis Journal and as a statistical and contributing editor for Neurology Clinical Practice; and receiving funding from numerous National Institutes of Health grants and from the Department of Defense. In the past 24 946
natalizumab responders. Consequently, it is conceivable that the disease burden remains diminished compared with patients not treated with natalizumab even after disease activity returns (Figure, A), adding disability-free years gained equal to the time on therapy. Alternatively, it is possible that natalizumab has no lasting effect on pathogenic mechanisms that perpetuate MS disease activity and disability, and that eventually there are no detectable long-term beneficial effects on disease activity that we can measure (Figure, B and C), which would translate to fewer disability-free years gained. The second scenario would be analogous to the effects of pregnancy on MS, in which patients are protected from disease activity during the second and third trimesters, but whereby any benefit seems to vanish in the postpartum months.10 In the case of natalizumab, these changes in disease activity may take years, and this is why long-term data are needed to capture potential long-term benefits if they exist, as well as to be able to calculate discounts to these benefits if there is an accelerated decline after treatment cessation. Natalizumab therapy has had a positive effect on the lives of many patients with MS. Its beneficial effects do not seem to be limited to the parameters we measure routinely in clinical trials or neurologic practice, but they also include quality-of-life outcomes.11 These outcomes are relevant even if they are time limited and cannot be sustained. However, further research is urgently needed to answer the questions of whom to treat, how long to treat, how to initiate sequential therapies to maintain these benefits, and whether disease reactivation after natalizumab cessation is a risk factor for increased long-term disability.
months, Dr Cutter reported participating in data and safety monitoring committees for Apotek, Ascendis, Biogen-Idec, Cleveland Clinic, GlaxoSmithKline Pharmaceuticals, Gilead Pharmaceuticals, Modigenetech/Prolor, Merck/Ono Pharmaceuticals, Merck, Neuren, PCT Bio, Teva, Vivus, National Institute of Neurological Disorders and Stroke, National Multiple Sclerosis Society, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Obstetric-Fetal Pharmacology Research Units Network), and National Heart, Lung, and Blood Institute (protocol review committee). In the past 24 months, Dr Cutter reported participating in consulting, speaking engagements, and advisory board and data and safety monitoring board commitments for Alexion, Allozyne, Bayer, Consortium of MS Centers (grant), Klein-Buendel Incorporated, Genzyme, Medimmune, Novartis, Nuron Biotech, Receptos, Revalesio, sanofi-aventis, Spiniflex Pharmaceuticals, Somahlution, Teva, and Xenoport. REFERENCES 1. Polman CH, O’Connor PW, Havrdova E, et al; AFFIRM Investigators. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 2. Rudick RA, Stuart WH, Calabresi PA, et al; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911-923. 3. Havrdova E, Galetta S, Hutchinson M, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis. Lancet Neurol. 2009;8(3):254-260.
4. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880. 5. Berger JR, Centonze D, Comi G, et al. Considerations on discontinuing natalizumab for the treatment of multiple sclerosis. Ann Neurol. 2010;68(3):409-411. 6. Rossi S, Motta C, Studer V, et al. A genetic variant of the anti-apoptotic protein Akt predicts natalizumab-induced lymphocytosis and post-natalizumab multiple sclerosis reactivation. Mult Scler. 2013;19(1):59-68. 7. Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol. 2014; 75(1):108-115. 8. O’Connor PW, Goodman A, Kappos L, et al. Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858-1865. 9. Clerico M, Schiavetti I, De Mercanti SF, et al. Treatment of relapsing-remitting multiple sclerosis after 24 doses of natalizumab: evidence from an Italian spontaneous, prospective, and observational study (the TY-STOP study) [published online June 30, 2014]. JAMA Neurol. doi:10.1001/jamaneurol.2014.1200. 10. Vukusic S, Hutchinson M, Hours M, et al; Pregnancy in Multiple Sclerosis Group. Pregnancy and multiple sclerosis (the PRIMS study). Brain. 2004;127(pt 6):1353-1360. 11. Rudick RA, Miller D, Hass S, et al; AFFIRM and SENTINEL Investigators. Health-related quality of life in multiple sclerosis. Ann Neurol. 2007;62(4):335-346.
JAMA Neurology August 2014 Volume 71, Number 8
Copyright 2014 American Medical Association. All rights reserved.
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