The Current Clinical Arena of Progressive Multiple Sclerosis

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1 The Current Clinical Arena of Progressive Multiple Sclerosis Carrie M. Hersh, DO Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio Abstract The majority of patients with multiple sclerosis (MS) develop a progressive phase of disease characterized by the insidious accumulation of neurologic disability. More therapies for relapsing-remitting MS are becoming available; however, treatment options for primary progressive MS (PPMS) and secondary progressive MS (SPMS) are still limited. Global efforts have addressed this crucial unmet challenge via diverse collaborative efforts, such as the International Progressive MS Alliance and the MS Outcome Assessments Consortium. Ongoing phase 3 clinical trials of potential therapies for progressive forms of MS include the ASCEND study of natalizumab in patients with SPMS; other studies are investigating early neuronal damage in the spinal cord of patients with PPMS and potential predictive markers of progressive MS. The strides we have made and will continue to make in evaluating the pathogenesis of PPMS and SPMS will gauge the ongoing efforts to develop safe and effective treatments for progressive MS. T he definition of progressive multiple sclerosis (MS) is unique to different disciplines. The neurologist characterizes it as progressive myelopathy or cognitive impairment. The imager judges the extent of disease based upon progressive atrophy on conventional magnetic resonance imaging (MRI), decreasing magnetization transfer ratio (MTR) or N-acetyl aspartate (NAA) levels, or the results of fractional anisotropy. The pathologist describes it as axonal or oligodendrocyte pathology. The physiatrist defines it as loss of function or worsening symptoms. And the patient understands it as loss of independence and function and the inability to work. Historically, the majority of untreated Dr. Hersh is a Neuroimmunology Fellow in the Mellen Center for Multiple Sclerosis Treatment and Research, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. patients with relapsing-remitting multiple sclerosis (RRMS) eventually develop secondary progressive MS (SPMS). 1 Currently, strong imaging biomarkers to screen new anti-inflammatory therapies and as many as 10 different diseasemodifying therapies for treating patients with relapsing MS are available. However, the treatment of progressive MS remains a crucial, unmet challenge. 2 n DEFINING AND UNDERSTANDING Many international research teams are working to better understand progressive MS and to develop targeted treatment options. Efforts to redefine the clinical course are being led by the European Committee for Treatment and Research in Multiple Sclerosis/National Multiple Sclerosis Society (ECTRIMS/NMSS) International Advisory Committee on Clinical Trials in Multiple Sclerosis. The Multiple Sclerosis Outcome Assessments Consortium (MSOAC), a conglomerate of industry, academic, regulatory, and patient representatives, strives to develop and support the adoption of new clinical outcome assessment tools for use in future MS clinical trials. The International Collaborative on Progressive MS 3 has identified five key priority areas for research: 1. Discovery of experimental models that reproduce the key clinical and pathologic features of primary progressive MS (PPMS) and SPMS. 2. Identification and validation of biologic targets and opportunities to repurpose existing MS medications for use in treating progressive MS. 3. Recognition and validation of proof-of-concept clinical trial outcomes. 4. Development of precise, reproducible, and broad-based clinical outcome measures that are both sensitive to change and predictive over time. 5. Optimization of symptom-management and rehabilitation strategies that can help to reduce the impact of disability and improve the quality of life of patients affected by progressive and relapsing MS. At present, there are no validated phase 2 outcomes that identify adequate models in defining progressive MS. Whole-brain atrophy currently is recommended, but it is limited by one measure per brain; further, imaging quality varies from scan to scan, is affected by a low signal-to-noise ratio, and changes slowly. Some alternative measures that have been proposed are segmented atrophy (eg, cortical gray matter atrophy), MTR, diffusion tensor imaging, spectroscopy, functional MRI, and optical coherence tomography; however, their usefulness in defining or measuring progressive MS remains unknown. Limitations and possible confounders include the degree of reliability, responsiveness over time, predictive ability of measur- 12 T H E N E U R O L O G Y R E P O R T V o l u m e 6 N u m b e r 1

2 ing disability and treatment response, and multicenter implementation in both cross-sectional and longitudinal studies. Identifying Validated Models and Drug Therapies A myriad of efforts currently are addressing the identification of good, validated models and potential drug therapies for progressive forms of MS. The International Progressive MS Alliance is an expanding global alliance of MS organizations that seeks to expedite the development of therapies for effective modification and symptom management of progressive MS. This alliance currently involves the United States, the United Kingdom, Italy, Denmark, Spain, and Canada and is in its early stages, but its status is rapidly progressing. Since April 2012, this collaboration has been organized via working groups in priority areas, the development of research support mechanisms, and an international call in September 2013 for research proposals ( n POTENTIAL THERAPEUTICS FOR Despite the increasing availability of novel and effective treatments for RRMS, therapeutic options for patients with PPMS and SPMS are still lacking. 4 Most MS patients initially are diagnosed with a disease course defined by periodic relapses with full or partial recovery of neurologic function; immunopathologically, MS is defined by active inflammation. The majority of patients subsequently develop a progressive accumulation of disability dominated by neurodegeneration and fewer superimposed relapses. The pathology of progressive MS can involve widespread, compartmentalized inflammation; cortical lesions reflecting meningeal inflammation; and normalappearing inflammation of the white matter. These pathologic changes correlate with neuronal and axonal damage and disease progression. 5 7 The results of histopathologic studies suggest that inflammation and neurodegeneration occur simultaneously throughout the disease course, not in a stepwise fashion. Such findings further complicate the classification of progressive MS forms as RRMS with incomplete remissions versus SPMS with superimposed relapses versus a gradual progression of disease from the outset (PPMS). Disease progression over time tends to be smooth, and the dividing line between these three phases is often blurred. Clinical Trials Disease-modifying therapies for RRMS prevent disability and neurologic impairment, but their ability to prevent insidious disease progression remains unclear. Limited data from randomized, controlled studies support the effectiveness of any therapy currently approved for RRMS or Despite the increasing availability of novel and effective treatments for RRMS, therapeutic options for patients with progressive forms of the disease are still lacking. SPMS in slowing the progression of disability in SPMS. 8 The OLYMPUS study examined the usefulness of rituximab-induced B- cell depletion in patients with PPMS. 9 Analysis of the data from this clinical trial suggested that placebo-treated patients experienced faster disease progression than did those given rituximab, although this finding was not statistically significant. A subgroup analysis of younger patients with PPMS showed that those with gadolinium-enhancing lesions seemed to benefit from rituximab therapy; however, it remains unknown whether the mechanism of action involves peripherally circulating B cells or those within the central nervous system (CNS). Other clinical trials have focused on various factors that could impede the MS process. A recent study measured cerebrospinal fluid (CSF) levels of osteopontin, a marker for neurofilament damage, to further characterize the role of intrathecal immune activation in progressive MS. 10 Neuroprotective trials involving treatment with lamotrigine 11 or tetrahydrocannabinol 12 in patients with progressive MS did not meet their primary endpoints. Statin treatment slowed the development of brain atrophy and progression of the Expanded Disability Status Scale (EDSS) in the ECTRIMS MS-STAT trial, 13 although the underlying mechanism remains unknown. Another recent study showed an improvement in visual function resulting from the intravenous (IV) infusion of autologous mesenchymal stem cells in a small cohort of patients affected with SPMS. 14 A study of the potassium-sparing diuretic amiloride, which has been shown in experimental models of MS to block ph-dependent neurodegeneration in inflammatory lesions, demonstrated a neuroprotective effect in a few PPMS patients, as revealed by diffusion-weighted imaging. 15 Treatments in the Pipeline MS-SMART ( a placebo-controlled phase 2 trial based in the United Kingdom, is studying three potential therapies (riluzole, amiloride, and ibudilast) that have shown promise in patients with SPMS. Primary outcome measures are the degree of cortical atrophy (as measured by clinical observations and advanced imaging studies in a subgroup of patients) and CSF changes. SPRINT-MS ( nn102-sprint-ms) is a phase 2 clinical trial based in the United States. Investigators are using the National Institutes of Healthsponsored phase 2 trial network Neuro- NEXT to compare the use of ibudilast versus placebo in patients with PPMS and SPMS. Outcomes, including the degree of cortical atrophy, are being assessed via standardized advanced imaging modalities at all sites and considering all clinical measures. Investigators are using head-tohead comparisons of imaging measures and longitudinal validation of clinical T H E N E U R O L O G Y R E P O R T W i n t e r

3 outcomes to predict treatment response and to determine the reliability of therapy in slowing the progression of disability. Summary Investigators have shown a relationship between systemic and intrathecal immune activation and inflammation in progressive MS, and the relationship between inflammation and neuronal and axonal damage is being explored in clinical trials. Positive trial results are beginning to emerge from this research effort, with three ongoing phase 3 studies currently investigating the usefulness of ocrelizumab, fingolimod, and natalizumab in treating progressive MS. Now that we have a strong foothold on RRMS treatment, we must refocus attention on neuroprotective treatments and target the reduction of neuronal and axonal loss. Significant strides in developing regenerative treatments that improve remyelination are being made. Mesenchymal stem cells may be useful in treating progressive MS, and we must focus on the role of neural stem cells in modifying disease progression. n EARLY SPINAL NEURONAL DAMAGE AS A POTENTIAL PREDICTOR OF PPMS Most patients with PPMS reach a high level of disability in the first years after disease onset, and the rate of progression may vary from one patient to the next. Pathologic changes in the gray and white matter are associated with disability and predict disease progression. 16 The spinal cord has been studied less often with advanced MRI technology. Abdel-Aziz and colleagues 17 used spinal-cord magnetic resonance spectroscopy in a small cohort of patients with progressive MS. They investigated the differences in metabolite concentrations between healthy controls and individuals with early PPMS, observing the relationship between metabolites and disability in the latter. Ultimately, they hoped to provide insights into the pathologic changes underlying disability in PPMS. The investigators used total NAA levels as a marker of axonal integrity and metabolic function, myoinositol as a marker of astrocytic activation and proliferation, and glutamate plus glutamine (Glx) levels as a marker of neuronal integrity and neurotransmitter pool. Clinical measures were assessed using the EDSS, Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25-FW), 12-Item MS Walking Scale (MSWS-12), Ashworth spasticity scale, grip strength, vibration sense testing, and static posturography. Linear-regression models were used to investigate differences between groups, and regression models (EDSS, T25-FW, 9HPT) and multivariate analysis (static posturography) were used to explore correlations. Covariates were corrected for gender, age, cord area, brain white- and gray-matter fractions, and T2 lesion load. Results showed lower total NAA (P = 0.03) and Glx peaks (P = 0.03) on magnetic resonance spectroscopy in PPMS patients when compared with placebocontrolled participants, with the former correlating with higher EDSS scores (P = 0.03); greater rolling on static posturography (P = 0.005); and worse posterior column sensory function, as measured by vibration sense testing (P = 0.003). Lower total NAA and Glx levels in this cohort of PPMS patients suggested a role for neuronal loss and metabolic dysfunction in the glutamatergic pathway in the spinal cord. Additionally, the association between total NAA and Glx levels indicated that these pathologic abnormalities may contribute to disability. n RADIOLOGICALLY ISOLATED SYNDROME AND PROGRESSIVE FORMS OF MS Previous studies suggested that the onset of progressive MS is age-sensitive and independent of the disease course prior to disease progression. 18,19 Cranial and spinal cord MRI findings at the time of PPMS diagnosis can be remarkably similar to those of SPMS, and the asymptomatic pre-progression disease course in PPMS is difficult to study systematically. Kantarci and colleagues 20 sought to define the pre-progression period in PPMS, hypothesizing that MRI characteristics of the pre-progression phase would be similar to that of bout-onset progressive MS (SPMS + progressive MS following a single clinical attack of progressive MS, or SAPMS). They reported PPMS development after a longitudinal follow-up of a robust multicenter radiologically isolated syndrome (RIS) cohort. Investigators defined RIS as incidental white matter changes on MRI that suggest[ed] demyelinating disease and fulfill[ed] three out of four Barkhof criteria 21 ; symptomatic conversion as an acute or progressive demyelinating event following the RIS course ; and progression from the onset of the event following the RIS course as the development of a clinical symptom with the temporal profile revealing at least a 12-month history of neurologic worsening. Among 20 multicenter databases, investigators retrospectively identified and prospectively followed 451 participants. In all, 34% of the initial cohort developed symptomatic MS after 5 years, with 9% of the initial cohort ultimately being classified as having PPMS, as indicated by the 2010 Revised Multiple Sclerosis criteria. The reasons for obtaining an initial MRI varied widely among the PPMS cohort and included the investigation of a primary headache disorder (n = 5); trauma (n = 4); low back/radicular pain (n = 2); and one instance each of spell, tumor screen, and childhood epilepsy. Overall, the incidence of PPMS (9%) and sex ratio (43% female) in this RIS cohort mirrored population-based studies. The CSF findings were positive in 83% of RIS patients who developed PPMS. These patients had a notably higher cervical and thoracic cord lesion load than did other symptomatic patients. Further, pre-progression MRI findings in PPMS patients appeared to be similar to pre-progression MRI findings in patients with SPMS, but a comparative MRI study is needed to better qualify these observations. n IMPACT OF RELAPSES ON NEUROLOGIC DISABILITY IN Approximately 75% of patients with MS experience disease progression, characterized by an insidious accumulation of neurologic disability that may be present from the time of clinical onset and may 14 T H E N E U R O L O G Y R E P O R T V o l u m e 6 N u m b e r 1

4 follow a relapsing-remitting phase. The determinants of MS progression are incompletely understood: not all patients develop the progressive phase of disease, age distribution at the onset of disease progression varies, and the accumulation of neurologic disabilities ranges widely among patients. The onset of progression is age-dependent and has an equivalent mean and distribution across clinical phenotypes. 22 An EDSS score of 6.0 serves as a robust disability milestone. These findings provide a uniform starting point for factors that affect the cadence of progression. Paz Soldan and coworkers 23 investigated the impact of relapses on post-progression disability accrual. They hypothesized that patients experiencing clinical relapses accumulate disability faster during the progressive phase of MS. The researchers studied a population- and clinic-based cohort of patients that fulfilled the 2010 McDonald diagnostic criteria for MS. Disease progression was defined as an insidious, irreversible worsening of neurologic disease lasting 1 year. This definition included brain, brainstem-cerebellar, and spinal cord syndromes and excluded progressive, purely sensory symptoms. The progressive disease course was classified as PPMS, SPMS, or SAPMS. Disability was assigned based on the patient s Kurtzke EDSS score. Kaplan-Meier analysis was used to generate survival curves from the onset of progressive MS to reaching an EDSS score of 6.0. The presence of pre-progression relapses predicted a shorter time from onset of disease progression to an EDSS score of 6.0. Post-progression disability accumulation was slowest in patients with PPMS (50% of patients in 10 years) and SAPMS (50% of patients in 7 years) and fastest in those with SPMS (50% of patients in 4 years; P < ). Post-progression relapses were more common in patients with SPMS (29.5%) than in those with SAPMS (10.7%) or PPMS (3.1%), reflecting the pre-progression relapse status in these groups. Ongoing relapses following the onset of progressive disease independently predicted a shorter time (~ 2 years) from onset of disease progression to an EDSS score of 6.0 (P = ). Most post-progression relapses occurred within 5 years (91.6%) after the onset of progression and before age 55 years (95.2%). This study showed that relapses prior to or following the onset of disease progression increase the rate of accumulation of post-progression disability and that gender and age at the onset of progressive disease have minor influences on disability accumulation. In this context, continued immunomodulation 5 years after the onset of progressive MS, or at least until age 55 years, may be a reasonable approach for managing SPMS. However, due to a paucity of findings, these approaches may not be indicated in SAPMS or PPMS. n EFFICACY OF NATALIZUMAB ON REDUCING DISABILITY PROGRESSION IN SPMS Natalizumab, a recombinant humanized anti-α4 integrin antibody, is an approved therapy for relapsing forms of MS. It reduces CNS inflammation by preventing the migration of mononuclear leukocytes across the blood-brain barrier. Additionally, natalizumab may suppress chronic compartmentalized CNS inflammation, as indicated by a reduction in the levels of proinflammatory mediators in the CSF, including C-X-C motif chemokine 13 and osteopontin. 10,24 Results of recent retrospective studies of clinical data have suggested that natalizumab therapy may reduce disease progression in SPMS. 25 The ASCEND trial is an international, multicenter, randomized, double-blinded, placebo-controlled, phase 3 study of the efficacy of natalizumab in reducing disability progression in patients with SPMS. 26 Interim data as of August 2013 included over 800 enrolled patients from various countries with baseline functional disability test scores consistent with MS progression. About 62% of the study participants were classified as low EDSS (EDSS score of ), and 38% were classified as high EDSS (EDSS score of ). The patients were randomized 1:1 to receive 300 mg of natalizumab or placebo IV every 4 weeks for 2 years. The primary endpoint of the study is the percentage of patients experiencing confirmed progression of disability in one or more of the following measures: EDSS, T25-FW, or 9HPT. Once completed, ASCEND will provide data on the effect of natalizumab on progression of disability in patients having SPMS not attributable to relapses. ASCEND substudies will explore the effects of natalizumab on cognitive impairment using MS-COG, a novel composite measure to assess cognitive function in patients with SPMS. 27 The use of composite measures, as opposed to a single modality, offers many potential advantages: lower error rates, improved sensitivity and reliability of collected data, and greater simplicity in assessing treatment effects and clinical meaningfulness of the observed data The components of the MS-COG assess two domains: learning/ memory and processing speed. Baseline data are currently available for 112 participants, most of whom have changed their occupation because of MS. Overall, average performances on tests of memory and processing speed and on the total MS-COG composite were lower than were those found among the patients given placebo. Approximately 75% of study participants had at least mild cognitive impairment (z score 0.5), and about 20% had evidence of severe cognitive impairment (z score 2.0). At the conclusion of the study, the researchers intend to provide evidence supporting the validity and feasibility of the MS-COG to measure treatment effects on cognitive function in MS clinical trials. n CONCLUSION Furthering our understanding of the aspects of human pathology relevant to disease progression in MS will necessitate validation of a preclinical model that emulates human pathology and development of high-throughput screening tools. It is also crucial to develop and validate an outcome biomarker; we can accomplish this critical task by using clinical trials to advance methodologies. Finally, we must develop accepted clinical outcome measures to better understand progressive MS pathology and to guide development of targeted disease-mod- T H E N E U R O L O G Y R E P O R T W i n t e r

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