Multiple Sclerosis and Related Disorders (2013) 2, 65–67

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Editors’ welcome and a working definition for a multiple sclerosis cure Welcome to the first issue of the New Year; turning one is an important milestone in the life of a new journal. Most importantly, we can now be reviewed by the Literature Selection Technical Review Committee of the U.S. National Library of Medicine so that articles published in MSARD can be indexed in PubMed. This will allow us to be given an official citation rating, which will dramatically improve our academic appeal. One reason why 2012 will be noteworthy is the recent publication of two phase 3 clinical trials of alemtuzumab in relapsing-remitting MS (Cohen and Coles, 2012; Coles and Twyman, 2012) and the regulatory submission of alemtuzumab to European Medicines Agency (EMA) and the Food and Drug Administration (FDA) (Genzyme, 2012). On page 92 of this issue of the journal Chaudhuri and Behan (2013) comment on what lessons we have learnt from the clinical development programme of alemtuzumab. They raise concerns about the use of alemtuzumab in MS and query whether or not the risks, both defined and undefined, outweigh its benefits (Chaudhuri and Behan, 2013). Chaudhuri and Behan have concerns about the ‘‘leap of faith that is driving the development of alemtuzumab and similar biological therapies in MS’’ on the premise that MS is an autoimmune disease (Chaudhuri and Behan, 2013). They hypothesise that MS is primarily a neurodegenerative disease with the inflammatory component being a secondary response to what is causing the disease. The experiment to test this hypothesis is underway. If a significant number of people with MS treated with alemtuzumab, early in the course of their disease, develop secondary progressive MS, despite being rendered relapse and MRI disease activity free, the neurodegenerative hypothesis will gain the upper hand. If on the other hand this population of treated MS patients do not develop secondary progressive MS will Chaudhuri and Behan accept that MS is an autoimmune disease and that alemtuzumab treatment is a cure? Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of 2211-0348/$ - see front matter & 2012 Elsevier B.V. All rights reserved.

detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual end point. In addition, the median time to the onset of secondary progressive MS is 10.4 years (Kremenchutzky and Rice, 2006) and is well within the 15 years time window of our proposed definition of a cure. At present NEDA is defined using a composite of (a) no relapses, or (b) no EDSS progression, or (c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova and Galetta, 2009; Giovannoni and Cook, 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova and Galetta, 2009; Giovannoni and Cook, 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future it will almost certainly include patientrelated outcomes (PROs or PROMS), grey matter disease activity and an index of brain atrophy. Although Chaudhuri and Behan allude to a poorly, or a yet to be, defined long-term risk-benefit ratio of alemtuzumab therapy they avoid discussing the issue of who should make the decision to use alemtuzumab (Chaudhuri and Behan, 2013). Should the decision to prescribe alemtuzumab be made by neurologists, people with MS, regulators or thirdparty payers? The latter is relevant—Chaudhuri and Behan (2013) express concern about the high cost of alemtuzumab – a factor which will diminish its availability. In the current era of the expert patient and democratisation of knowledge via the internet, people with MS are becoming increasingly empowered, and actively involved in the decision-making process. It will be interesting to observe how much this will impact upon individual clinicians’ perception of their role in the management of the disease. Regulators, at least in Europe, may have the final say. For example, natalizumab and fingolimod in Europe, are handcuffed with relatively well-defined criteria for treatment within their licences.

66 Unlike other licensed disease-modifying therapies for MS, with the possible exception of mitoxantrone (Hartung and Gonsette, 2002), alemtuzumab may be the first induction therapy to be licensed for MS. Alemtuzumab is administered as a course of five daily infusions at the beginning of year one and three daily infusions at the beginning of year two (Cohen and Coles, 2012; Coles and Twyman, 2012). It is being proposed that people with MS will only be offered a third course, or retreatment, if their disease is active, i.e. if they have a relapse or have evidence of disease activity on MRI. Another challenge will be the mandatory active surveillance for early detection of delayed-onset autoimmune complications of alemtuzumab treatment, some of which may be life threatening (Coles and Compston, 2008). Immune thrombocytopenic purpura (ITP) and Goodpasture’s syndrome will probably require a monthly full blood count and urinalysis. Who will be responsible for insuring that this monitoring takes place; the patient with MS or the clinician who administered the treatment? Bundling the licensing of drugs with an intensive post-marketing risk mitigation programme is not new. Clozapine, for the treatment of schizophrenia, was successfully coupled with the routine monitoring of blood counts (Gerson, 1993). This did not deter psychiatrists from prescribing the drug; obviously the benefits of clozapine for the treatment of schizophrenia out-weighed the risks of agranulocytosis. Since Chaudhuri’s and Behan’s commentary was submitted the manufacturer of alemtuzumab, Genzyme-Sanofi, have controversially withdrawn the alemtuzumab oncology product, Campath or Mabcampath, from the market, citing safety concerns with the off-label prescribing of the drug for MS as the reason (Sanofi, 2012). This has generated a backlash from the MS community (Laurance, 2012). What about paediatric MS? All licensed drugs for adult-MS come with a mandatory condition that the company has to undertake clinical trials in children within 7 years of licensing. Alemtuzumab targets the CD52 molecule that is ubiquitously expressed on leucocytes including populations of lymphocytes within the thymus. Alemtuzumab not only reduces thymic emigrants, the number of lymphocytes leaving the thymus, but theoretically induces premature immune senescence. The potential impact this may have on an immature, or developing, immune system will need to be taken into account when designing the paediatric trial programme. Alemtuzumab, analogous to the introduction of clozapine for the treatment of schizophrenia, will challenge many of our current practices. Importantly, this new drug has the potential to answer fundamental questions concerning the biology of MS. This issue contains two timely review articles. In the first review Toro et al. (2013) discuss the emerging problem of MS in Latin America and the difficulties of treating MS in this region. In the second review Gelfand and colleagues, highlight the problem of migraine in MS (Gelfand et al., 2013). They review the epidemiological literature and concede that although an association exists between migraine and MS, the magnitude of the association is small and a causal relationship has not been demonstrated (Gelfand et al., 2013). They provide a helpful guide on the evaluation and treatment of migraine in people with MS (Gelfand et al., 2013). In a technical paper, Taheria et al., (2013), describe a method to quantify blood-brain-barrier (BBB) disruption in

Editorial MS lesions and non-lesion brain areas. They quantified and index or BBB transfer rate in white matter lesions, normal appearing white matter and the full-brain of people with MS and identified an increase in full-brain BBB transfer rate in MS, which they interpret to mean global vascular involvement (Taheria et al., 2013). Interestingly, white matter vasculature was less involved than the global vasculature (Taheria and Rosenberg, 2013). Could this indicate MS is a disease predominantly of grey matter? They propose their technique could be applied to evaluate and monitor the effectiveness of MS treatments (Taheria et al., 2013). Ramachandrana and colleagues, describe an interesting method to study slow or fast progression in MS (Ramachandrana et al., in press). They define a variable based on dividing the population relative to the median time from MS onset to reaching a single EDSS value as a way to define slow or fast progressors (Ramachandrana et al., 2013). They then apply this variable to the relationship of several items concerned with progression (Ramachandrana et al., 2013). It will be interesting to see if other investigators adopt this method. Kearney et al. (2013) in a pilot study describe a method to delineate the involvement of grey and white matter spinal cord structures in MS. Their technique was good at depicting white tract involvement, but was less successful in delineating central grey matter involvement (Kearney et al., 2013). In a qualitative study, Shapiro et al. (2013), highlight the problem of various forms of physical, sexual, and disabilityspecific abuse to which MS patients are susceptible. Rather surprising is the finding that, all denied any form of abuse in a focus group setting despite study subjects having been identified as recipients, or perpetrators of mistreatment (Shapiro et al., 2013). They conclude that attitudes toward mistreatment or abuse differ between genders; male caregivers may disclose abuse as a cry for help, whereas female caregivers may feel such behaviour is justified because of the perceived ‘‘provocations’’ of the person with MS. Women with MS appeared reluctant to acknowledge abuse because they feared loss of their primary relationship; while men with MS calculated that putting up with a certain amount of mistreatment was worthwhile (Shapiro et al., 2013). These results highlight the difficulties researchers have in studying mistreatment or abuse of people with MS. Magyari and colleagues, from Copenhagen, report the results of the REPAIR study; in short those with neutralising antibodies to interferon-beta retain an in vivo biological response to interferon-alpha (Magyarin et al., 2013). The investigators suggest that interferon-alpha as a possible therapeutic option in people with MS with neutralising antibodies (NABs) to interferon-beta (Magyarin et al., 2013). This seems unlikely in view of the recent emergence of several licensed alternative biological and small molecule therapies to treat MS. Daniel Reich and colleagues, performed a detailed post-hoc study on 26 people with MS who were treated at the NIH with daclizumab (anti-CD25) and compared them to 44 subjects with MS who had not been treated with the drug (Borges et al., 2013). Using mixed-effects multivariable linear regression models they were able to show that daclizumab therapy reduced the rates of brain-volume change compared to

Editorial subjects that were predominantly treated with interferon-beta (Borges et al., 2013). These results support the recently presented data showing a surprisingly large impact of daclizumab on confirmed disease progression in relapsing-remitting MS (Giovannoni et al., 2012). We are heartened by the interest you have shown in the content of our new journal and your continuing support. We are now confident that the journal will thrive and go from strength-to-strength.

Conflict of interest Gavin Giovannoni received research grant support from Bayer-Schering Healthcare, Biogen-Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva and Sanofi-Aventis. He received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Bayer-Schering Healthcare, Biogen-Idec, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals. In the past 5 years Christopher Hawkes received royalties from the Massachusetts Medical Society and Cambridge University Press, and also he has received an honorarium from Teva Pharmaceuticals and educational support from Sanofi Genzyme.

References Borges I, Shea C, et al. The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis. Multiple Sclerosis and Related Disorders 2012;2:33–140. Chaudhuri A, Behan P. Lessons from clinical trials of alemtuzumab in multiplesclerosis. Multiple Sclerosis and Related Disorders 2013;2:92–5. Cohen JA, Coles AJ, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 2012;380(9856):1819–28. Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. The New England Journal of Medicine 2008;359(17):1786–801. Coles AJ, Twyman CL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 2012;380(9856): 1829–39. Gelfand A, Gelf J, et al. Migraine and multiple sclerosis: epidemiology and approach to treatment. Multiple Sclerosis and Related Disorders 2013;2:73–9. Genzyme. Genzyme submits applications to FDA and EMA for approval of LEMTRADATM (alemtuzumab) for multiple sclerosis. 2012:1–3. Gerson SL. Clozapine–deciphering the risks. The New England Journal of Medicine 1993;329(3):204–5.

67 Giovannoni G, Cook S, et al. Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis. The Lancet Neurology 2011;10(4):329–37. Giovannoni G, Gold R, et al. Primary results of the SELECTION trial of daclizumab HYP in relapsing multiple sclerosis. Multiple Sclerosis and Related Disorders 2012;18(S4):514. Hartung HP, Gonsette R, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet 2002;360(9350):2018–25. Havrdova E, Galetta S, et al. Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the natalizumab safety and efficacy in relapsingremitting multiple sclerosis (AFFIRM) study. Lancet Neurology 2009;8(3):254–60. Kearney H, Miszkiel K, et al. A pilot MRI study of white and grey matter involvement by multiple sclerosis spinal cord lesions. Multiple Sclerosis and Related Disorders 2013;2:103–8. Kremenchutzky M, Rice GP, et al. The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease. Brain 2006;129(Pt 3):584–94. Laurance J. Neurologists appeal to health secretary over withdrawal of drug for MS patients. British Medical Journal 2012;345:e7449. Magyarin M, Søndergaard H, et al. Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIRstudy). Multiple Sclerosis and Related Disorders 2013;2:141–6. Ramachandrana S, Strangea R, et al. Progression of disability in multiple sclerosis : a study of factors in fluencing median time to reach an EDSS value. Multiple Sclerosis and Related Disorder 2013;2:109–16. Sanofi. Discontinuation of licensed supplies of alemtuzumab (Mabcampath), In press. Shapiro J, Wiglesworth A, et al. Views on disclosing mistreatment: a focus group study of differencesbetween people with MS and their caregivers. Multiple Sclerosis and Related Disorders 2013;2:96–102. Taheria S, Rosenberg G, et al. Quantification of blood-to-braintransfer rate in multiple sclerosis. Multiple Sclerosis and Related Disorders 2013;2:124–32. Toro J, Cardenas S, et al. Multiple sclerosis in Colombia and other Latin American Countries. Multiple Sclerosis and Related Disorders 2013;2:80–9.

Chief Editors Brenda Banwell, MD Gavin Giovannoni, MD Christopher Hawkes, MD Fred Lublin, MD

Corresponding author.

Editors' welcome and a working definition for a multiple sclerosis cure.

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