`
`Multiple Sclerosis Therapeutics
`
`Fourth Edition
`
`Edited by
`Jeffrey A. Cohen, MD
`Jmlo: Lx|::rmv:n'.J|
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`.. 3'5 CAMBRIDGE
`UNIVERSITY PRESS
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`CAMBRIDGE UNIVERSITY PRESS
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`
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`
`Library of Congress Cataloging in Publication data
`Multiple sclerosis therapeutics / edited by Jeffrey A. Cohen,
`Richard A. Rudick. — 4th ed.
`p.
`;
`cm.
`
`Includes bibliographical references and index.
`ISBN 978-0-521-76627-2 (hardback)
`I. Cohen, Jeffrey A. (Jeffrey Alan). 1954-
`III. Title.
`
`II. Rudick, Richard A.
`
`2. Clinical Trials as Topic —
`[DNLM: 1. Multiple Sclerosis - therapy.
`methods.
`3. Magnetic Resonance Imaging.
`4. Multiple Sclerosis ~
`pathology.
`5. Outcome Assessment (Health Care) WL 360]
`LC classification not assigned
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`2011030483
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`ISBN 978-0-521-76627-2 Hardback
`
`Cambridge University Press has no responsibility for the persistence
`or accuracy of URLs for external or third-party internet websites
`referred to in this publication, and does not guarantee that any
`content on such websites is, or will remain, accurate or appropriate.
`
`Every effort has been made in preparing this book to provide accurate
`and up-to«date information which is in accord with accepted
`standards and practice at the time ofpublication. Although case
`histories are drawn from actual cases, every effort has been made to
`disguise the identities of the individuals involved. Nevertheless, the
`authors, editors and publishers can make no warranties that the
`information contained herein is totally free from error, not least
`because clinical standards are constantly changing through research
`and regulation. The authors, editors and publishers therefore disclaim
`all liability for direct or consequential damages resulting from the use
`ofmaterial contained in this book. Readers are stronglyadvised to pay
`careful attention to information provided by the manufacturer ofany
`drugs or equipment that they plan to use.
`
`Page 2 of 16
`
`

`

`
`
`l l
`
`Measurement of CNS atrophy
`Elizabeth Fisher
`
`128
`
`Axonal pathology in patients with multiple
`sclerosis: Evidence from in vivo proton
`magnetic resonance spectroscopy
`150
`
`Sridar Narayanan, Zografos Caramanos, Paul M.
`Matthews, and Douglas L. Arnold
`
`Imaging of gray matter lesions in multiple
`sclerosis
`165
`
`Mike P. Wattjcs, Jerocn I.G. Geurts, and Frederik Barkhof
`
`Functional imaging in multiple sclerosis
`Kyle C. Kern and Nancy L. Sicotte
`
`175
`
`Diffusion imaging in multiple sclerosis
`
`186
`
`Stephen
`
`lones and Michael D. Phillips
`
`The use of MRI in multiple sclerosis clinical
`trials
`198
`
`Robert A. Bermel, Elizabeth Fisher, Peter B. lmrey,
`and Jeffrey A. Cohen
`
`Optical coherence tomography to monitor
`axonal and neuronal integrity in multiple
`sclerosis
`213
`
`Kristin M. Galetta and Laura]. Balcer
`
`The process of drug development and
`approval in the United States, the European
`Union, and Asia
`225
`
`Nadine Cohen, Ann Dodds-Frerichs, Tammy
`Phinncy, and Paula Sandler
`
`Selection, interpretation, and development of
`end-points in multiple sclerosis clinical trials
`Marc K. Walton
`
`232
`
`The challenge of demonstrating long-term
`benefit of disease-modifying therapies in
`multiple sclerosis
`244
`Maria Trojano
`
`l6
`
`l8
`
`I9
`
`20
`
`Contents
`
`List ofcontribulors
`Abbreviationslist
`Foreword
`xv
`
`page viii
`xiii
`
`Stephen C. Reingold
`Preface
`xvii
`
`Section I — Introduction
`
`Aspects of multiple sclerosis that relate to
`experimental therapeutics
`1
`Richard A. Rudick and Jeffrey A. Cohen
`
`The pathology of multiple sclerosis
`Ranjan Dutta and Bruce D. Trapp
`
`12
`
`The immunology of multiple sclerosis
`Amit Bar-Or and Peter]. Darlington
`
`20
`
`35
`The genetics of multiple sclerosis
`Iorge R. Oksenberg, Sergio E. Baranzini, and
`Stephen L. Hauser
`
`The epidemiology of multiple sclerosis
`Ruth Ann Marric and Helen Tremlett
`
`46
`
`Section II — Clinical trial methodology
`
`Measures of neurological impairment and
`disability in multiple sclerosis
`56
`
`Gary R. Cutter, Charity J. Morgan, Amber R.
`Salter, Stacey S. Coiield, and Laura J. Balcer
`
`Assessment of neuropsychological function in
`multiple sclerosis
`65
`Stephen M. Rao
`
`Health-related quality of life assessment in
`multiple sclerosis
`79
`Deborah M. Miller, i\/Iichael W. Kattan, and Alex 7.. F11
`
`Ki‘!
`
`6)
`
`Measures of acute and chronic lesions
`
`visualized by conventional magnetic
`resonance imaging
`91
`lack H. Simon and Jerry S. Wolinsky
`
`10
`
`Measures of magnetization transfer
`Massimo Filippi, Ioscph C. McGowan. and
`Maria A. Rocca
`
`112
`
`
`
`Page 3 of 16
`
`

`

`"l
`
`I Contents
`
`
`
`_i
`
`37
`
`38
`
`39
`
`40
`
`Use of immunosuppressants to treat multiple
`sclerosis
`436
`
`James M. Stankiewicz and Howard L. Wciner
`
`intravenous immunoglobulin to treat multiple
`sclerosis
`444
`
`Franz Fazekas, Siegrid Fuchs, Per Soelberg
`Srzirensen, and Ralf Gold
`
`Plasma exchange treatment for CNS
`454
`inflammatory demyelinating disease
`Brian G. Weinshenker, B. Mark Keegan, leffrey L.
`Winters, Ichiro Nakashima, and Kazuo Fujihara
`
`465
`Statins in multiple sclerosis
`Martin S. Weber, Emmanuelle Waubant, and Scott
`S. Zamvil
`
`/ll
`
`42
`
`43
`
`44
`
`45
`
`46
`
`47
`
`48
`
`49
`
`50
`
`T-cell-based therapies for multiple
`sclerosis
`472
`
`Tanuja Chitnis and Samia I. Khoury
`
`B-cell-based therapies for multiple
`sclerosis
`483
`
`Emmanuelle Waubant and Amit Bar-Or
`
`Sex hormones and other pregnancy-related
`factors with therapeutic potential in multiple
`sclerosis
`498
`Rhonda R. Voskuhl
`
`Hematopoietic stem cell transplantation to
`treat multiple sclerosis
`508
`
`Richard K. Burt and Francesca Milanetti
`
`Mesenchymal stem cell transplantation to
`treat multiple sclerosis
`520
`Don Mahad, Sarah M. Planchon, and Ieffrey A. Cohen
`
`Neuroprotection in multiple sclerosis
`Avindra Nath and Peter A. Calabresi
`
`535
`
`Combination therapy in multiple
`sclerosis
`547
`
`Michelle Fabian and Fred D. Lublin
`
`Dalfampridine in multiple sclerosis
`Andrew D. Goodman
`
`557
`
`Complementary and alternative treatments in
`multiple sclerosis
`562
`
`Vijayshree Yadav, Lynne Shinto, and Dennis N.
`Bourdette
`
`The role of chronic cerebrospinal venous
`insufficiency in multiple sclerosis
`574
`Devon Conway, Soo Hyun Kim, and Alexander
`Rae—Grant
`
`21
`
`22
`
`23
`
`24
`
`The growing need for alternative clinical trial
`designs for multiple sclerosis
`253
`Stephen C. Reingold, Henry F. McFarland, and
`A. John Petkau
`
`Ethical considerations in multiple sclerosis
`clinical trials
`261
`
`Aaron E. Miller, Nada Gligorov, and Stephen C. Krieger
`Pharmacogenomics and related
`discovery-driven approaches in multiple
`sclerosis
`272
`
`Paulo Fontoura and David Leppert
`
`Neutralizing antibodies directed against
`biologic agents to treat multiple sclerosis
`Per Soelberg Sorensen
`
`287
`
`25
`
`26
`
`27
`
`28
`
`29
`
`30
`
`31
`
`32
`
`33
`
`34
`
`35
`
`36
`
`Section III — Clinical trials of multiple
`sclerosis therapies
`
`Interferon beta to treat multiple sclerosis
`Richard A. Rudick
`
`300
`
`Glatiramer acetate to treat multiple
`sclerosis
`315
`
`Jenny Guerre and Corey C. Ford
`
`330
`Natalizumab to treat multiple sclerosis
`Chris H. Polman, Ioep Killestein, and Richard A. Rudick
`
`Mitoxantrone to treat multiple sclerosis
`Gilles Edan and Emmanuelle Le Page
`
`344
`
`Cladribine to treat multiple sclerosis
`Gavin Giovannoni and Stuart D. Cook
`
`358
`
`Fingolimod to treat multiple sclerosis
`Ieifrey A. Cohen
`
`370
`
`Dimethyl fumarate to treat multiple sclerosis
`Robert J. Fox and Ralf Gold
`
`387
`
`Alemtuzumab to treat multiple sclerosis
`Orla Tuohy and Alasdair I. Coles
`
`393
`
`Dacllzumab to treat multiple sclerosis
`Iaume Sastre-Garriga and Xavier Montalban
`
`399
`
`Laqulnimod to treat multiple sclerosis
`Douglas R. Ielfery
`
`405
`
`Teriflunomide to treat multiple sclerosis
`Paul W. O'Connor
`
`410
`
`High-dose methylprednisolone to treat
`multiple sclerosis
`418
`Robert]. Fox and R. Philip Kinkel
`
`vi
`
`Page 4 of 16
`
`

`

`51
`
`52
`
`53
`
`54
`
`55
`
`56
`
`Section IV — Therapy in clinical practice
`
`Disease-modifying therapy for multiple
`sclerosis in clinical practice
`583
`Jeffrey A. Cohen and Andrew D. Goodman
`
`Treatment for patients with primary
`progressive multiple sclerosis
`604
`Zhaleh Khaleeli and Alan J. Thompson
`
`Diagnosis, pathogenesis, and treatment of
`neuromyelitls optica (NMO) spectrum
`disorders
`614
`
`Sean J. Pittock
`
`Management of pediatric multiple
`sclerosis
`632
`
`F.. Ann Yeh and Bianca Weinstock-Guttman
`
`Use of MRI in the clinical management of
`multiple sclerosis
`645
`
`I. Theodore Phillips and Lacl A. Stone
`
`Multiple sclerosis-associated fatigue
`Lauren B. Krupp and Dana J. Serafin
`
`654
`
`Contents /I
`
`57
`
`58
`
`60
`
`61
`
`62
`
`666
`Management of spastlcity
`Francois A. Bethoux and Matthew Sutliff
`
`Management of bladder and sexual
`dysfunction in multiple sclerosis
`676
`Natasha Frost, Jessica Szpak, Scott Litwiller, and
`Alexander Rae-Grant
`
`Depression in multiple sclerosis
`Adam I. Kaplin and Ryan E. Stagg
`
`696
`
`Assessment and treatment of pain disorders
`in multiple sclerosis
`707
`Jahangir Maleki and Amy Sullivan
`
`Management of medical comorbidities in
`patients with multiple sclerosis
`714
`John R. Scagnelli and Myla D. Goldman
`
`Rehabilitation in multiple sclerosis
`Francois A. Bethoux and Matthew Sutliff
`
`724
`
`Index
`
`731
`
`Color plates appear between p. 398 and 399
`
`Page 5 of 16
`
` ~
`
`vii
`
`

`

`
`
`w Introduction
`
`Chapter
`
`Aspects of multiple sclerosis that relate to
`experimental therapeutics
`
`Richard A. Rudick and Jeffrey A. Cohen
`
`The purpose of this chapter is to discuss key features of multi-
`ple sclerosis (MS) that relate to clinical trial design or treatment.
`The emphasis will be on aspects of the disease that create chal-
`lenges for developing effective therapies, and for using them in
`practice. These include the subclinical nature of early-stage MS,
`phenotypic and disease heterogeneity, and complexities related
`to measuring disease severity. Many of these topics are covered
`in greater detail throughout the book. This chapter will end with
`a brief discussion about current controversies in the MS exper-
`imental therapeutics field.
`
`Disease features relevant to clinical trials
`
`MS pathology is largely subclinical in early MS
`Relapsing remitting MS (RRMS) patients have periodic relapses
`occurring at variable rates, but generally less than one per year.
`Serial MRI demonstrates many more new lesions than clin-
`ical relapses, with most studies demonstrating a rate of new
`MRI lesions about 10-20-fold higher than clinical relapses.” In
`some patients, MRI shows active disease for years with no clin-
`ical relapses, indicating that MS disease activity may be entirely
`subclinical in some patients during the early stage ofthe disease.
`New inflammatory lesions in white matter begin with gadolini-
`ium (Gd) enhancement, marking sites of inllammatory lesions
`(Chapter 9).5’5 Approximately 50% of untreated RRMS patients
`have Gd—enhancing lesions on a cranial MRI scan obtained
`when the disease is inactive clinically.“ Even the number of
`Gd-positive lesions drastically underestimates disease activity,
`however. First, gray matter pathology is present in MS patients,
`even early in the disease (Chapters 2, II, and I3), and Gd-
`enhancement rarely occurs in gray matter lesions. Second, dis-
`ease in normal appearing white matter is well recognized, and
`correlates with progressive atrophy. Therefore, Gd-enhancing
`lesions, themselves mostly asymptomatic, are just the “tip of the
`iceberg" with respect to MS pathology.
`There are several implications of this for clinical trials. First,
`relapse counts are meaningful clinical outcomes in RRMS, but
`inherently insensitive, and it is difficult to measure clinical dis-
`ability in RRMS patient groups, because RRMS patients don’t
`generally get disabled during the time-frame of a clinical trial.
`Second, insensitivity of clinical outcomes in RRMS drives up
`
`sample sizes, which become prohibitive in active arm designs
`(Chapter 21). 'Ihird, the subclinical nature of disease activity in
`RRMS forms the basis for screening putative therapies using
`MRI outcomes, including MRI parameters as secondary out-
`comes, and potentially using MRI as a primary outcome mea-
`sure in RRMS trials. In that regard, Sormani and colleagues
`conducted a pooled analysis of 23 clinical trials that included
`MRI lesion measurements, to test the effect of interventions
`on lesions and relapse rate.” The effect of the intervention on
`MRI lesions was strongly correlated with the effect of the inter-
`vention on relapses, accounting for over 80% of the total vari-
`ance. This indicates that formation of new lesions in RRMS is
`clinically relevant, and supports the argument that MRI disease
`activity could be used as a primary outcome for RRMS trials.
`While many have advocated for this, use of MRI as a primary
`outcome measure has not achieved regulatory agency accep-
`tance (Chapter 18).
`
`Progressive destructive pathology starts early
`in the disease
`
`The rationale for early intervention in MS is the presence of
`widespread tissue damage at
`the earliest stages of the dis-
`ease."‘ " Once RRMS is established, residual clinical disability
`is usually minimal or absent early in the disease, yet there is
`ongoing tissue damage, as evidenced by accumulation of T2-
`bright MRI lesions,‘ T1-hypointense lesions,” and brain atro-
`phy (Chapter II).”‘"'’ Gray matter lesions are frequent in MS
`autopsy material.” Although these lesions are not visualized
`with standard MRI methods, gray matter atrophy has been doc-
`umented early in the disease.”“9 It is widely believed that the
`ongoing destructive pathology sets the stage for later conver-
`sion to secondary progressive MS (SPMS), in which disability
`accumulates. According to this model, tissue destruction pro-
`ceeds without frank neurological disability progression until a
`threshold is surpassed. Beyond that stage, progressive neurolog-
`ical disability ensues. 'lhe threshold hypothesis was supported
`by studies correlating retinal nerve fiber layer (RNFI.) thickness
`with visual acuity?" Visual acuity was maintained until RNFL
`thickness declined to about 75 microns, and then fell off rapidly
`with further loss of RN FL thickness. The implication of this for
`
`Multiple Sclerosis Therapeutics, Fourth Edition, ed. Jeffrey A. Cohen and Richard A. Rudick. Published by Cambridge University Press.
`© Cambridge University Press 2011.
`
`Page 6 of 16
`
` r
`
`

`

`Section I: Introduction
`
`clinical trials is that disease-modifying drug therapy should be
`viewed as providing secondary neuroprotection, i.e. treatment
`prevents neuroclegeneration by inhibiting inflammation, and
`thereby decreases the amount of brain injury and delays or pre-
`vents SPMS.
`
`Disease manifestations are heterogeneous
`Another factor complicating MS clinical
`trials is disease
`heterogeneity, which is one of the hallmarks of MS. Patients
`manifest varying patterns of clinical features, variable clinical
`course, and variable disease severity. This creates hurdles
`for clinical
`trials,
`as heterogeneity complicates outcomes
`assessment, and increases required sample sizes. The myriad
`clinical manifestations include neuropsychological impairment
`(itself multifaceted), visual loss, eye movement abnormalities,
`weakness, spasticity, incoordination, imbalance, sensory loss,
`paresthesias, gait impairment, bowel and bladder dysfunction,
`sexual dysfunction,
`fatigue, and paroxysmal phenomena.
`Individuals manifest these features in varying combinations,
`and the symptoms change over time. Even within multi-
`ply affected families, there is striking clinical heterogeneity
`between affected family members. Disease heterogeneity is
`poorly understood in MS, as genome—wide association studies
`have mostly focused on disease susceptibility genes, rather
`than disease modifying genes (Chapter 4).
`Managing the wide variety of MS symptoms is crucially
`important for patient well-being, but is increasingly challenging
`with increasing complexity and emphasis on disease modifying
`drug therapy. Heterogeneity in clinical manifestations also
`presents significant challenges for the design of clinical trials.
`Subjects in separate trials and treatment arms within a given
`trial exhibit variable admixtures of clinical manifestations that
`
`are not necessarily evenly matched between study groups. Mul-
`tidimensional clinical outcome measures are needed to capture
`the range of ways in which MS affects patients (Chapter 6). The
`traditional clinical outcome measure — Expanded Disability
`Status Scale (BDSS) - is heavily weighted to motor impairment,
`particularly gait dysfunction. Common symptoms such as cog-
`nitive dysfunction, sphincter disturbances, pain, and fatigue
`have significant effects on functional status and quality of life
`(QOL), but may not correlate well with measures of physical
`impairment and disability. This forms a strong rationale for
`including patient-reported outcomes in clinical
`trials as a
`measure of the impact of intervention on disease-related
`symptoms (Chapter 8). It is possible that therapies may have
`different effects on specific disease manifestations, i.e. benefit
`for some with no effect or deleterious effects on others. This is
`
`an under-explored area.
`
`Evolution of the MS disease process —
`the ”MS categories”
`Because the clinical course of MS evolves over decades, there
`has been interest in subcategorizing MS into discrete groupings.
`
`The current classification system was based on clinical phe-
`nomenology of the clinical disease course.“ not on the under-
`lying biological mechanisms. According to this classification,
`MS begins with a clinically isolated syndrome (CIS), defined
`as an initial clinical episode with features typical for inflam-
`matory demyelination (e.g. optic neuritis, partial transverse
`myelitis). With additional clinical episodes, CIS evolves to clin-
`ically definite RRMS. Even in the absence of a second relapse. a
`patient meets criteria for clinically definite MS when new MRI
`lesions are observed during follow-up.” RRMS then evolves to
`SPMS in many but not all patients. About 15% of patients have
`primary progressive MS (PPMS), meaning that progressive dis-
`ability ensues without prior relapses. In RRMS patients, peri-
`odic relapses occur at irregular and unpredictable intervals,
`averaging approximately one per year, but declining with dis-
`ease duration. Episodic attacks of neurological dysfunction are
`followed by partial or complete recovery, separated by clini-
`cally stable intervals. Relapses become less conspicuous over the
`years, and over 60% of RRMS patients transition to SPMS. Dur-
`ing this stage physical and cognitive disability gradually wors-
`ens, and disease worsening is refractory to known treatment.
`RRMS and SPMS present different challenges in study
`design. In RRMS, relapses are infrequent, occur at irregular
`intervals, and pose significant measurement challenges, and
`disability progression tends to be minimal during the course
`of a clinical trial. There seems to be some “drift” in MS sever-
`
`ity in the direction of more benign disease. This may be driven
`by increased awareness of MS and widespread use of MRI scan-
`ning for patients with non-specific symptoms such as fatigue,
`paresthesias, or headache.” The SPMS stage of the disease is
`also difficult to study, but for different reasons. Deterioration
`occurs slowly over the course of years, and there is significant
`within-patient and between-patient variability. Further, while
`trials tend to restrict patients by disease category, transition
`from RRMS to SPMS does not occur at a precise point in time.
`Clinical relapses become less distinct, recovery becomes less
`complete, and gradual worsening in the absence of relapses
`eventually becomes apparent. Transition to the SPMS stage,
`which commonly occurs during the fourth and fifth decade of
`life, can be estimated only in retrospect, once it is clear that the
`patient has gradually worsened in the absence of acute relapses.
`Because of the indistinct boundary between RR and SPMS,
`many patients could be entered into either a RRMS or a SPMS
`clinical trial, depending on how the clinician chooses to classify
`the individual patient.
`A consensus has emerged that PPMS (Chapter 52) should
`be considered separately for clinical trials. This is based on the
`uncertainty about the etiological relationship between PPMS
`and SPMS. Prototypical PPMS patients have symptom onset at
`a later age, typically between ages 40 and 60, and the female
`preponderance seen with relapsing forms of MS is not evi-
`dent. These patients commonly present with insidiously pro-
`gressive spastic weakness, imbalance, and sphincter dysfunc-
`tion; diffuse and less nodular T2—hyperintense lesions on cranial
`MRI; few if any Gd-enhancing lesions; and less indication of
`
`Page 7 of 16
`
`
`
`

`

`?*
`
`L__
`
`inflammation in cerebrospinal fluid (CSF).“ PPMS may be less
`dependent on inflammation, and neurodegenerative mecha-
`nisms may underlie the disease. Some PPMS patients have clini-
`cal, MRI, and CSF findings similar to SPMS. These patients may
`be similar to SPMS. but without clinically distinct relapses dur-
`ing the early disease stage. This is probably also true of another
`clinical category — progressive relapsing MS (PRMS) - in which
`there is gradual neurological progression from onset but with
`subsequent superimposed relapses. Thus, studies in PPMS are
`problematic for two reasons. These cases are relatively uncom-
`mon, and clinical trial groups contain admixtures of disease eti-
`ologies. It is unknown whether “SPMS—lil<e PPMS” and “pure
`PPMS” patients have similar pathogenic mechanisms driving
`disease progression, or whether they would respond similarly
`to treatment intervention.
`
`Common practice has been to select relatively homoge-
`neous patient groups for inclusion in clinical trials by enter-
`ing patients with a specified disease category, and creating dis-
`ability limits based on the EDSS.” As a result of widespread
`acceptance of the disease categories, separate trials have been
`conducted for patients with C18, RRMS, SPMS, and PPMS.
`This strategy aims to reduce between—patient variability and to
`increase the power to show therapeutic effects with a given sam-
`ple size. However, there are some drawbacks. Narrow entry cri-
`teria impede recruitment; it may not be clear whether the results
`of a trial enrolling a highly selected cohort of patients can be
`extrapolated to other groups of MS patients; and the distinc-
`tion between clinical disease categories is imprecise and based
`on clinical features that are disconnected from underlying dis-
`ease mechanisms. Conversely, different clinical trials that nom-
`inally studied the same patient population almost certainly con-
`tain different mixes of patients. This point is well illustrated by
`the European and North American trials of interferon beta-lb
`(IFNB—lb) in SPMS. These two trials used similar entry crite-
`ria, but enrolled distinct patient populations that yielded differ-
`ent results with the same therapeutic agent.“ The problem of
`classifying patients is most problematic at the interface between
`RRMS and SPMS. as discussed above. Biological markers for the
`different MS categories would be valuable, but are not currently
`available.
`
`Disease severity can not be accurately predicted in
`individuals or groups
`Because of the highly variable future course for newly diag-
`nosed MS patients, there is a compelling need for prognos-
`tic markers for treatment decision—making at the individual
`patient level. Prognostic markers would not only serve the
`need for better clinical decision-making, but also would help
`with informative enrollment into clinical trials. Data from the
`
`pre—therapeutic era suggested that 50% of MS patients were
`unable to carry out household and employment responsibilities
`10 years after disease onset, 50% required an assistive device to
`walk after 15-20 years, and 50% were unable to walk at all after
`
`Chapter 1:Chal|enges in experimental therapies
`
`l
`
`25 years.” About 10% of patients have an unusually severe dis-
`ease course, deteriorating to severe disability in only a few years,
`while 10%—20% exhibit mild disease with minimal disability
`decades after symptom onset. Distinguishing these severe and
`mild cases early after symptom onset has proved difficult.
`Selective enrollment has been attempted in clinical trials.
`The approach has been to enroll patients at risk for disease activ-
`ity, excluding patients not likely to change during the trial. In
`groups of patients, milder disease has been associated with sen-
`sory symptoms or optic neuritis at onset, good recovery from
`relapses and infrequent relapses early in the disease course.”' 15
`Conversely, symptom onset at an older age, progressive disease
`from onset, and poor relapse recovery mark a relatively worse
`prognosis. Clinical features have not been useful for informa-
`tive enrollment, however. The presence of multiple white matter
`lesions at the time of first MS symptom has proven very useful,
`as it is associated with much higher risk of disease activity in
`the next 5 years." Also, the amount of T2 lesion accrual during
`the initial 5 years after onset is a modest predictor of EDSS 20
`years later.” Despite this, T2 lesion load has not been used for
`informative enrollment strategies in clinical trials.
`Most trials employ relapses or progression during a speci-
`fied time period prior to the trial, or Gd-enhancing lesions on
`screening MRIs to identify patients with increased likelihood
`of disease activity during the trial. This is supported by a study
`showing that relapse rate prior to the trial and disease duration
`were the best predictors of on-study relapse rate.” In that study,
`disease course and Gd-enhancement status did not provide
`additional information. That study used a pooled data set from
`natural history studies and the placebo groups of randomized
`clinical trials, with a substantially larger sample size compared
`with previous analyses. A second study examined factors
`that predicted on-study Gd—enhancement, a common efficacy
`end-point in Phase 2 studies.“ A combination of younger
`age at onset, shorter disease duration, recent relapses, and T2
`lesion volume predicted Gd-enhancement. In other studies,
`the presence of Gd—enhancing lesions at baseline predicted
`frequency of clinical relapses, as well as increased T2 lesion
`volume and brain atrophy progression over the subsequent two
`years.”'32 However, all of the identified predictors, alone or in
`combination, are only modestly predictive of disease activity
`during a trial. The advantages of informative enrollment need
`to be balanced against the difficulty of finding eligible patients,
`and the problem of generalizing results when the entry criteria
`are restrictive.
`
`Heterogeneity in pathological mechanisms
`Studies of a large number of biopsy and autopsy specimens
`suggested that the mechanisms leading to tissue damage differ
`from patient to patient.”‘3“ Four distinct patterns of pathol-
`ogy were proposed. Analogous to experimental autoimmune
`encephalomyelitis,
`in patterns I and II
`the myclin sheath
`appears to be the target of the destructive process, mediated
`by macrophages in pattern I and antibody and complement
`
`,..—n-mm.-..
`
`Page 8 of 16
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`I
`
`Section I: Introduction
`
`deposition in pattern 11. Pattern III is characterized by an
`ill-defined lesion border with early loss of adaxonal myelin-
`associated glycoprotein. This pattern is similar to that seen
`in some viral encephalitides and in cerebral ischemia. In pat-
`tern IV, there is a sparse inflammatory reaction, with pron1i-
`nent non-apoptotic degeneration of oligodendrocytes in the
`periplaque white matter. At present, pathologically distinct MS
`subgroups cannot be defined on the basis of biomarkers, or
`functional assays. However, most now recognize neuromyeli-
`tis optica (NMO) as a distinct disorder (Chapter 53). It has
`long been known that NMO differs from typical MS clinically,
`by imaging features, pathology,” and response to MS disease-
`modifying drugs. But the watershed event was the observa-
`tion that NMO is associated with antibodies to aquaporin—4,
`an astrocyte water channel.”‘'” Presumably, better understand-
`ing of MS pathological heterogeneity will lead to more rationale
`approaches to personalized use of disease—modifying drugs.
`
`(omplexities related to measurement tools
`that impact clinical trials
`Clinical measures: relapses, physical function,
`neuropsychological performance (Chapters 6-8)
`The annualized relapse rate or the number of relapses are the
`most common primary outcome measure for RRMS clinical
`trials. Relapse frequency was the primary outcome measure
`in pivotal trials of two of the three IFNB products,‘l""” the
`glatiramer acetate trial,“ and the natalizumab trials.43““ These
`studies led to world-wide approval by regulatory agencies, and
`marketing of the products. Relapses are considered clinically
`relevant by regulatory agencies, because they are defined by new
`neurological symptoms and signs and are therefore assumed to
`have clinical impact. The relationship between relapse number
`and future disability is weak, however.“ Relapses may be sub-
`jective, and influenced by bias, over- or under-reporting, and
`treatment unmasking. There are no accepted methods to quan-
`tify relapse severity or recovery from relapse. Lastly, the amount
`of relapse rate reduction considered “clinically important” has
`never been defined. The rate of relapse in MS clinical trial pop-
`ulations has fallen over time. This indicates that n1ore recent tri-
`
`als have enrolled patients with less active disease, lowering the
`power of recent trials to show treatment arm differences, and
`making comparison across trials completely impractical.
`The EDSS is an ordinal scale ranging from O to 10 that classi-
`fies disability severity according to 19 steps.” A score of0 means
`a normal neurological examination; a score of 3.5 is computed
`when there is moderate disability in more than one functional
`system (e.g. visual, motor, cerebellar, sensory, bowel, bladder,
`etc.), but the patient is able to walk an unlimited distance with-
`out assistance. A score between 4.0 and 6.0 indicates limited dis-
`
`tance walking. Level 6.0 indicates the need for unilateral assis-
`tance to walk, 6.5 bilateral assistance, and 37.0 measures sever-
`
`ity in non-ambulatory patients. There is debate whether the
`EDSS measures disability accurately at the low end, because it
`
`has been very difficult to standardize the scoring for the func-
`tional system scales a11d small changes within the functional
`systems have unclear clinical relevance; and the middle and
`high ranges are insensitive to change, and so lower the power
`of clinical trials. Despite criticism, the EDSS has been the stan-
`dard measure of neurologic disability in nearly all MS clinical
`trials.
`
`Since the mid-1990s, the EDSS has been used to deter-
`
`mine “disability progression,” by identifying patients with con-
`firmed worsening from the baseline score. The proportion of
`patients in different treatment arms are compared directly, or
`using survival curves. The most common definition of “disabil-
`ity progression” in RRMS trials is worsening from baseline by at
`least 1.0 EDSS point, confirmed at the next three-month study
`visit. A minority of trials have required six-month confirma-
`tion. The EDSS may revert to baseline more commonly if the
`three-month definition is used,“ probably because of residual
`effects of relapses still present at three-months. The relevance
`of confirmed EDSS worsening in the early stages of MS remains
`controversial. One study showed a strong observed correlation
`between six-month confirmed EDSS worsening and clinical
`outcome eight years later.” There are no similar studies using
`three-month confirmation. A pooled analysis of multiple clini-
`cal trials demonstrated a strong association between treatment
`effect on relapse rate, and treatment effect on confirmed EDSS
`worsening, suggesting these two measures are i11ter-related in
`RRMS patients.” Despi