1059766 research-article20212021 MSJ0010.1177/13524585211059766Multiple Sclerosis JournalAJ Thompson, W Carroll MULTIPLE SCLEROSIS MSJ JOURNAL Future Perspectives Charting a global research strategy for Multiple Sclerosis Journal 2022, Vol. 28(1) 16­–28 progressive MS—An international progressive DOI: 10.1177/ https://doi.org/10.1177/13524585211059766 13524585211059766 https://doi.org/10.1177/13524585211059766 MS Alliance proposal © The Author(s), 2021. Article reuse guidelines: sagepub.com/journals- Alan J Thompson , William Carroll , Olga Ciccarelli, Giancarlo Comi, Anne Cross , permissions Alexis Donnelly, Anthony Feinstein , Robert J Fox , Anne Helme, Reinhard Hohlfeld, Robert Hyde, Pamela Kanellis, Douglas Landsman, Catherine Lubetzki, Ruth Ann Marrie , Julia Morahan, Xavier Montalban, Bruno Musch, Sarah Rawlings, Marco Salvetti , Finn Sellebjerg, Caroline Sincock, Kathryn E Smith, Jon Strum, Paola Zaratin and Timothy Coetzee Abstract Correspondence to: T Coetzee Background: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. National Multiple Sclerosis Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progres- Society, 733 Third Avenue, 3rd Floor, New York, NY sive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have 10017, USA. been mixed. The recent introduction of the term ‘active’ secondary progressive MS into the therapeutic timothy.coetzee@nmss.org lexicon has introduced potential confusion to disease description and thereby clinical management. Alan J Thompson Objective: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf University College London, London, UK of the International Progressive MS Alliance, a global research strategy for progressive MS. William Carroll Methods: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search The University of Western terms “progressive multiple sclerosis”, “primary progressive multiple sclerosis”, “secondary progressive Australia, Perth, WA, Australia MS”. Proposed strategies were developed through a series of in-person and virtual meetings of the Inter- Olga Ciccarelli national Progressive MS Alliance Scientific Steering Committee. University College London, London, UK Results: Sustaining and accelerating progress will require greater understanding of underlying mecha- Giancarlo Comi nisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of Vita-Salute San Raffaele University, Milan, Italy clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative Anne Cross interventions are starting to address ongoing challenges experienced by people with progressive MS. Washington University in St. Louis, St. Louis, MO, USA Conclusion: We need to manage these challenges and realise the opportunities in the context of a global Alexis Donnelly research strategy, which will improve quality of life for people with progressive MS. International Progressive MS Alliance, Dublin, Ireland Anthony Feinstein Keywords: Multiple sclerosis, progressive, progression, progressive multiple sclerosis Sunnybrook Research Institute, Toronto, ON, Canada Date received: 23 August 2021; revised: 29 September 2021; accepted: 5 October 2021 Robert J Fox Cleveland Clinic, Cleveland, Introduction within 25 years of initial diagnosis.2–5 In addition, it is OH, USA Multiple Sclerosis (MS) is a growing global neurologi- estimated that 15% of individuals are diagnosed with Anne Helme MS International Federation, cal challenge affecting 2.8 million individuals world- PPMS.6 Taken together it is reasonable to conclude that London, UK wide.1 A large proportion of these individuals either in excess of one million individuals globally currently Reinhard Hohlfeld Munich Cluster for Systems live with a relapsing form (RMS) and/or a progres- live with one of the progressive forms of the disease. Neurology, Ludwig sive form of MS—the latter either Primary Progressive Maximilian University of Munich, Munich, Germany MS (PPMS) which is progressive from the outset, or Since publication of the International Progressive MS Robert Hyde Secondary Progressive MS (SPMS). Arriving at a pre- Alliance’s initial scientific strategy statement in 2012, we Biogen, Cambridge, MA, cise global estimate of the prevalence of progressive have seen the achievement of a significant milestone— USA forms of MS remains difficult. Prior to the availability approval of the first MS treatments for progressive disease, Pamela Kanellis MS Society of Canada, of disease-modifying treatments, natural history studies ocrelizumab (for PPMS) and siponimod (for active Toronto, ON, Canada of MS estimated that 50% of individuals diagnosed SPMS).7–9 While these agents demonstrated modest effi- with RMS would transition to SPMS within 10 years of cacy with respect to confirmed time to disability progres- initial diagnosis and 90% would transition to SPMS sion, their addition to the clinician’s toolbox nonetheless 16 journals.sagepub.com/home/msj AJ Thompson, W Carroll et al. Douglas Landsman National Multiple Sclerosis Society, New York, NY, USA Catherine Lubetzki Salpêtrière Hospital, Paris, France Ruth Ann Marrie University of Manitoba, Winnipeg, MB, Canada Julia Morahan MS Research Australia, North Sydney, NSW, Australia Xavier Montalban Hospital Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain Bruno Musch Genentech, San Francisco, CA, USA Sarah Rawlings MS Society, London, UK Marco Salvetti Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University of Rome, Rome, Italy/Istituto Neurologico Figure 1. Pathways influencing development of progressive MS: The accumulation of disability and development of Mediterraneo (INM) progressive MS likely reflects a combination of factors including damage arising from inflammatory disease mechanisms, Neuromed, Pozzilli, Italy neurodegenerative mechanisms, and biological aging. These processes are likely attenuated by compensatory mechanisms Finn Sellebjerg and reserve during the early- to mid-stages of the disease, but over time these compensatory processes are depleted. Copenhagen University Hospital—Rigshospitalet, Moderators such as sex, gender, socioeconomic status, and DMT utilization likely exert positive and negative influences Glostrup, Denmark on progression and the development of progressive MS. Caroline Sincock International Progressive MS Alliance, Glasgow, UK Kathryn E Smith signals a hopeful start to a potential new therapeutic era— toolbox of pharmacological and non-pharmacologi- International Progressive MS similar to that previously seen in relapsing MS. In addition, cal interventions.7,13 Alliance, Lyme, CT, USA observational studies support the possibility that interven- Jon Strum International Progressive tion with disease-modifying treatments can reduce the risk In this paper, we review recent progress, highlight MS Alliance, Los Angeles, of transition from RMS to SPMS and improve disability continued knowledge, and propose, on behalf of CA, USA outcomes in patients with active SPMS.10,11 Together, the International Progressive MS Alliance, a global Paola Zaratin Italian Multiple Sclerosis these developments point to the prospect that therapeutic research strategy for progressive MS. Foundation, Genoa, Italy interventions can alter the natural history of the disease and improve outcomes for those individuals concerned about developing or living with SPMS. Progressive MS—a persistent clinical challenge Identifying the onset of progressive MS in the indi- Despite positive developments in the field, major vidual patient remains a clinical challenge. Currently, gaps persist in both the treatment and management this determination is made retrospectively using a of progressive disease.12 Over the past 5 years, the combination of assessments by a skilled clinician.14,15 emergence of global engagement and collaboration Currently, we lack effective tools to prospectively of many stakeholders to address these challenges has assess if and when an individual transitions from been a welcome development. Collective efforts by relapsing to progressive MS but there are emerging the International Progressive MS Alliance, national efforts to leverage large patient databases to develop patient organizations, government, and industry algorithmic tools to aid clinicians.16,17 Moreover, together with researchers and clinicians have drawn advances in our understanding of the pathophysiolog- much needed attention to the challenges of progres- ical mechanisms of the disease suggest that multiple sive MS. Although this effort has catalyzed scien- pathogenic mechanisms are present in an individual tific progress, much work remains to address the patient at any given time and that these mechanisms remaining scientific gaps so that people with pro- are expressed clinically with some variability. Thus, gressive MS can have access to a robust therapeutic in an individual patient, the onset of progressive MS journals.sagepub.com/home/msj 17 Multiple Sclerosis Journal 28(1) most likely begins close to a confluence of two major factors such as the role of complement genes, biologi- factors: (1) the accumulation of CNS damage, due to cal aging as reflected in telomere shortening, and inflammatory disease mechanisms, combined with microstructural changes in the spinal cord are also (2) an accumulation of neuroaxonal damage that being considered.18,36,37 Gray matter damage has also overwhelms extant CNS compensatory mechanisms been implicated to the onset of the progressive phase (Figure 1). The precise point at which an individual and the development of disability.21,38–41 patient enters clinically apparent progressive disease and the rate of progression will vary, depending on a number of moderating factors. These include bio- Tools—biomarkers, imaging modalities, logical sex, gender, race, comorbidities, possibly functional measures genetic factors, and utilization of disease modifying Another challenge is the absence of biomarkers sign- treatments (DMTs) along with the aging process.18,19 aling progression that are scientifically sensitive and There is also some evidence that the onset of pro- specific enough to justify their use in phase II and gression does not take place at the same time in differ- phase III clinical trials. A major difficulty is disen- ent central nervous system pathways and areas, nor do tangling how much of a change of a given biomarker we fully appreciate how sustained immunotherapy is due to neurodegenerative mechanisms underlying influences this process.10,20,21 progression or to acute inflammation driven by peripheral immune mechanisms. Several imaging markers have been explored to good effect in the Recent progress Phase II trial of ibudilast, which evaluated gray mat- ter atrophy and whole brain atrophy, along with Pathophysiological mechanisms advanced MRI measures including magnetization A better understanding of the mechanisms underpin- transfer imaging and diffusion tensor imaging.42,43 ning or moderating progression is fundamental to Recent studies have identified some potential bio- expanding the therapeutic repertoire. Recent efforts have markers of progression: imaging biomarkers include revealed important new insights in aspects of immune- slowly expanding lesions on brain MRI (which could mediated inflammation and neurodegeneration. It is be a correlate of smoldering demyelination and axonal thought that in MS there are two types of inflamma- loss in chronic active lesions) and changes in N-acetyl tion.22 One is characterized by acute focal invasion of aspartate concentration, which indicates neuroaxonal immune cells giving rise to active demyelinated plaques integrity and mitochondrial function.39,44 Other in the white matter, and the other by slow formation of approaches, including OCT and a revisiting of visual immune cell aggregates in connective tissues spaces evoked potentials, are also being explored.45,46 such as the meninges and perivascular spaces. The latter type of inflammation gradually increases with disease The measurement of serum neurofilament light (NfL) duration and patient age. It is associated with subpial has been assessed in a number of recent studies look- demyelinated lesions in the cortex, slowly expanding ing at both acute and chronic changes in MS.47–50 An lesions in the white matter, and diffuse neurodegenera- association with the development of disability has tion in the white and gray matter.22–25 been described. The growing body of evidence asso- ciated with NfL has also stimulated global efforts to The role of the innate immune system is of interest determine its utility as a tool for drug discovery and with a particular focus on the control of pathological clinical management of the disease.51,52 A critical astrocytes by microglia.26–32 Recently, NOD-leucine aspect of this work is the need for longitudinal exami- rich repeat and pyrin containing protein 3 (NLRP3) nation of patient cohorts to examine the utility of NfL inflammasome has been shown to be overactive in in measuring progression independent of relapse monocytes in PPMS, and canonical NLRP3 inflam- activity. Recent work in natalizumab-treated patients masome activation with a combination of ATP plus illustrates this complexity and the need for careful lipopolysaccharide was associated with increased consideration of NfL as a tool in clinical management IL1-Beta production.31,33 The mechanisms underpin- of progressive MS.53 ning progression, however, go far beyond inflamma- tion and likely involve failure of normal maintenance and repair mechanisms, including remyelination. Clinical trials of investigational drugs Mechanisms driving neurodegeneration include Recent Phase III trials in progressive MS demon- axonal loss and involve the interrelationship between strated that ocrelizumab in PPMS and siponimod in demyelination, astrocyte pathology mitochondrial SPMS modestly reduced the risk of confirmed disa- dysfunction, and neuronal vulnerability.30,34,35 Other bility progression, while trials of the water soluble B 18 journals.sagepub.com/home/msj AJ Thompson, W Carroll et al. Figure 2. Progressive MS treatments in clinical development. Active clinical trials evaluating agents in progressive MS and registered with ClinicalTrials.gov or World Health Organization International Clinical Trials Registry Platform as of April 2021 are illustrated. Trials are positioned based on their stage of development and agent or intervention profile (disease modification or symptom management/quality of life). Phase 0/I studies are in the outermost ring, with Phase II and III studies reflected in the inner rings. Phase I/II and II/III studies are placed on the borders of the respective rings. vitamin, biotin, in PPMS and SPMS, and natali- Rehabilitation and symptom management zumab in SPMS and fingolimod in PPMS, were Evaluating interventions in the fields of symptomatic unequivocally negative.54–58 However, if we are to management and rehabilitation in progressive MS have a major impact on progression we need to remains a major challenge—as noted recently in a call develop agents that provide neuroprotection and/or for action by a work group convened by the International encourage repair, and here the picture is less clear. Progressive MS Alliance.62 People with progressive There have been a number of phase II trials of puta- MS are looking for rapidly translatable approaches that tive neuroprotective agents. The innovative multi- treat their disease now, while the longer term disease- arm MS-SMART trial evaluated three agents, modifying treatments are developed. Fortunately, there amiloride, fluoxetine, and riluzole, but showed no have been well constructed studies demonstrating for benefit of any of the therapies. An earlier study of example the benefits to motor function from a very fluoxetine was also negative.59,60 However, a practical standing frame program; along with careful recent study of ibudilast showed positive results studies examining the benefits of exercise on fatigue as on several imaging outcomes (see earlier sec- well as cognition.63–66 The last of these areas is cur- tion).42,43 Very recently, masitinib, an oral tyrosine rently being evaluated in an innovative multi-center kinase inhibitor that selectively targets mast cell international clinical trial.67 activity and microglia activity, was reported to sig- nificantly reduce the risk of disability progression in a double-blind placebo controlled phase III study.61 Three areas requiring renewed focus and effort In addition to these advances, a review of ClinicalTrials.gov and World Health Organization Understand progression International Clinical Trials Registry Platform (as of A fundamental challenge in progressive MS is the April 2021) found a number of ongoing clinical tri- continued poor understanding of the mechanisms ini- als (Phase 0/I to Phase III) of agents and interven- tiating and perpetuating disease progression. This tions in progressive MS. Given the considerable limitation hampers efforts to identify biologically attrition associated with drug development, more tri- plausible treatment targets that are essential for effi- als would be desirable, but, nonetheless, this augurs cient drug discovery. Continued exploration of the well for the future (Figure 2). journals.sagepub.com/home/msj 19 Multiple Sclerosis Journal 28(1) fundamental mechanisms of disease, using both com- similarly powerful tool(s) is needed in progressive putational systems, animal models and human stud- MS. Volumetric imaging measures such as whole ies, will be required. This work would be stimulated brain atrophy or volumetric MRI percentage brain vol- by the establishment of robust data sharing platforms ume change are being used in clinical trials but these that leverage machine learning and related artificial require long studies, typically 96 weeks, to detect intelligence tools to develop new insights into bio- measurable changes. Such lengthy timelines when logical pathways contributing to progressive disease. compared to the shorter intervals required in relapsing Drug discovery networks—whether existing or new trials (typically 24 weeks for a trial measuring reduc- efforts—can build on these insights to identify new or tion in gadolinium enhancing lesions) pose a signifi- repurposed agents with potential to treat progressive cant challenge for investigators and companies MS. Furthermore, the pipeline of new therapeutic seeking to move agents into Phase 3 trials in progres- agents may be expanded by careful, innovative design sive MS.43,59,74 of short, efficient exploratory human clinical trials to provide insights into disease progression. They may The development and validation of fluid biomarkers also serve as an initial proving ground for agents suit- such as NfL as well as other imaging modalities able for later stage clinical trial strategies which can should lead to shorter studies which accelerate and further expand the pipeline of agents to be tested in enable progress.49,52,75,76 Moreover, efforts such as the larger clinical trials.68 An additional consideration Multiple Sclerosis Outcomes Assessment Consortium would be the development of more biologically based (MSOAC), the global Patient Reported Outcomes descriptors of the clinical course of the disease. Initiative for MS (PROMS), and the proposed EDSS Efforts in this area are under way under the auspices plus will contribute to development of new or modi- of the International Advisory Committee on Clinical fied outcome measures, but additional efforts are Trials in MS.15 needed.77–81 An intriguing possibility is the use of smartphone sensor-based digital outcome assess- ments. While still in the early stages, recent work Accelerate clinical trials demonstrated that an app-based tool—Floodlight Study design is a critical consideration for acceler- PoC—along with a smartwatch accurately captured ating clinical trials of progressive MS treatments. reliable and clinically relevant measures of functional The current two-arm clinical trial paradigm—while impairment in MS, in this area points to a future largely reasonable for relapsing MS agents—poses where ubiquitous digital tools could be leveraged to significant challenges for progressive MS trials, given enhance research and clinical care.82,83 the large numbers of patients that must be enrolled and the long duration required to ascertain a clinical Finally, the ongoing challenge of phenotypic classifi- effect, using conventional clinical outcome meas- cation of the disease continues to impact clinical trials ures (e.g. Expanded Disability Status Scale).69 One of progressive MS agents. This challenge introduced solution may be the use of adaptive, multi-arm, and a measure of confusion due to the differing applica- multi-stage trial designs to evaluate multiple agents tions of the 2013 clinical course descriptors used in simultaneously and in a potentially more cost effec- the review and approval of ocrelizumab and siponi- tive manner.68 Encouraging examples of this are the mod by both the US Food and Drug Administration MS-SMART trial of three agents in progressive MS (FDA) and the European Medicines Agency and and the recently launched OCTOPUS trial.59,70,71 A compounded by the FDA’s retroactively expanding very recent innovation is the use of Simon (2 stage) approval of agents for RMS to include active trial designs to screen compounds for non-futility.72,73 SPMS.9,15,84 Coordination among regulatory authori- This approach, while far from a definitive demonstra- ties and the MS patient and clinician community, in tion of effect, can act as an efficient screen to identify relation to disease phenotypes, is essential if we are to promising therapeutic candidates relatively quickly. avoid undue complexity and confusion in patient Such efforts are welcome, perhaps even overdue, and recruitment, trial design, and subsequent treatment should inspire similar efforts globally. approvals. Another critical barrier is the lack of a validated bio- marker or outcome measure to enable shorter phase 2 Improving wellbeing clinical trials. The development of treatments for The final area for global prioritization is improving relapsing forms of MS was revolutionized by the the wellbeing of persons with progressive MS. adoption of reduction in gadolinium enhancing lesions Unfortunately, this area remains poorly addressed as a proof-of-concept measure in Phase 2 trials. A with considerable gaps in the development of novel 20 journals.sagepub.com/home/msj AJ Thompson, W Carroll et al. Figure 3. Quality-of-life intervention targets. Potential targets for quality-of-life interventions in progressive MS span several inter-related domains. While some are directly associated with disease mechanisms (e.g. cognition, pain) others are associated with other disease indications (e.g. hypertension) or social support mechanisms (e.g. care providers, housing) that affect quality of life. rehabilitative and symptomatic interventions that can is a cause for hope. Clinical trials of approved treat- meaningfully enhance quality of life for persons with ments for progressive MS as well as those with nega- progressive MS. There are, nevertheless, an abun- tive outcomes are providing valuable insights and dance of potential interventional targets in the domains experience for the design and conduct of future trials. of physical and cognitive health, emotional wellbeing, Moreover, there is growing appreciation of the impor- social support, and comorbidities (Figure 3). A tance of quality-of-life interventions in enabling welcome development is the recently launched CogEx patients with progressive MS to participate fully in clinical trial—the first multi-country, multi-arm, ran- society leading full and productive lives. While sig- domized, blinded, sham-controlled trial of cognitive nificant challenges remain, there are opportunities for rehabilitation and aerobic exercise.67 Continued pro- impact provided the community prioritizes efforts to gress in these areas will require development of a understand progression, accelerate clinical trials, and coordinated global rehabilitation and symptom man- to enhance well-being of those with progressive MS agement research strategy with targeted initiatives (Table 1). in areas that have appropriate scientific readiness. Foundational efforts will also be needed to address All parties—people affected by progressive MS, areas requiring further development (e.g. methodo- patient groups, funders, academia, industry, regula- logical or workforce gaps).62 tory authorities—have a role to play and ideally should be engaged, coordinated, and encouraged to work together (Figure 4).85 Perspectives of people Critical steps going forward affected by Progressive MS must be incorporated The research and clinical progress, together with the across the research continuum to ensure proper focus raised profile of progressive MS, over the last 5 years on what matters to them. Engaging people with journals.sagepub.com/home/msj 21 Multiple Sclerosis Journal 28(1) Table 1. Recommendations for areas of global research focus. Priority Area Potential Strategies Understand Data sharing to facilitate identification of pathophysiological mechanisms and potential new targets progression Drug discovery networks Exploratory clinical studies of new agents targeting new biologic pathways Accelerate Innovation in clinical trial design clinical trials Clinical trial data sharing to facilitate trial design, validation of outcome measures, and discovery and validation of imaging and functional biomarkers Development of imaging and functional biomarkers for use in clinical trials and clinical care Development of fluid biomarkers for use in clinical trials and clinical care Improve Development of a global targeted rehabilitation and symptom management research strategy well-being Global coordination of rehabilitation research Development of a robust pipeline of rehabilitation researchers and programs Figure 4. Stakeholders in the progressive MS agenda. Addressing the challenges of MS is a multi-stakeholder effort spanning patient organizations, clinical professionals, government, and industry. Progressive MS, as a key stakeholder, in research and funding decisions and/or other parts of the research measuring impact on outcome that matter most to continuum. A recent example of such inclusion is the them, will give research the direction to make all the EU-funded MULTI-ACT initiative that has developed relevant stakeholders co-accountable for social and a framework to incorporate the perspectives of people wellbeing needs related to progressive MS.79 This with brain diseases in setting research agendas and in involvement can take many forms, such as inclusion evaluating research impact.86 These endeavors and of people with MS in establishing research agendas, others point to a future where patients contribute dis- contributing to design of clinical trials, planning for tinctively and meaningfully to the development trans- and communicating research results, and informing formational treatments. 22 journals.sagepub.com/home/msj AJ Thompson, W Carroll et al. Funders will need to sustain investments in ongoing Declaration of Conflicting Interests programs and consider new ways of catalyzing pro- The author(s) declared the following potential con- gress. The impact of these investments will be further flicts of interest with respect to the research, author- enhanced by meaningful coordination of research ship, and/or publication of this article: Thompson agendas at the national and international levels. et al Conflict of Interest Disclosures. Global multi-disciplinary and multi-stakeholder col- AJ Thompson reports personal fees paid to his insti- laborative efforts like the International Progressive tution from Eisai Ltd; is an editorial board member MS Alliance and a number of related strategic alli- for The Lancet Neurology receiving a free subscrip- ances (e.g. International Advisory Committee on tion; is Editor-in-Chief for Multiple Sclerosis Journal Clinical Trials in MS, imaging networks in Europe receiving an honorarium from SAGE Publications; and North America—MAGNIMS and NAIMS, receives support for travel as Chair, Scientific respectively—and the UK MS Society multi-arm clin- Advisory Committee, International Progressive MS ical trial platform—OCTOPUS—among others) will Alliance, and from the National MS Society (USA) be critically important in directing efforts to refine as member, NMSS Research Programs Advisory our descriptions of progressive MS, accelerating Committee. drug discovery, and ensuring efficient conduct of WM Carroll reports honoraria and travel assistance clinical trials. Finally, robust efforts must be under- for participation in industry sponsored meetings taken to ensure knowledge translation and implemen- from and has provided advice to Biogen, Novartis, tation of interventions by health systems and clinicians. Genzyme, Sanofi, Aventis, Merck, and Celgene and Fortunately, the field of implementation science points has received travel support from the International the way to success in such endeavors.87 The well- Progressive MS Alliance, PACTRIMS and the World established Quality Enhancement Research Initiative Federation of Neurology. (QUERI) led by the US Veterans Administration is O Ciccarelli is Deputy Editor for Neurology and has one pertinent illustration of how quality of care can acted as a Consultant for Merck and Biogen. be improved with a sustained focus on measuring the RAM receives research funding from CIHR, the MS health, economic, and cultural impacts of scientific Society of Canada, Research Manitoba, the CMSC, investments.88,89 Without similar efforts, we risk National MS Society, US Department of Defense, and advancing knowledge without concomitant benefits Crohn’s and Colitis Canada. She is supported by the being realized by people with progressive MS. Waugh Family Chair in Multiple Sclerosis. She is a co-investigator on studies funded by Biogen Idec and Roche. Conclusion G. Comi has received compensation for consulting Addressing the needs of people with progressive services for Bristol Myers Squibb, Janssen, Novartis, MS remains a central challenge for the MS com- Teva, Sanofi, Genzyme, Merck, Biogen, Excemed, munity. While there has been considerable pro- Roche, Almirall, Chugai, Receptos, and Forward gress in understanding the pathophysiological Pharma and compensation for speaking activities for mechanisms of progressive MS, much remains to Novartis, Teva, Sanofi, Genzyme, Merck, Biogen, be understood. Moreover, the emergence of mod- Excemed, and Roche. estly effective treatments for progressive forms of A. Cross has done paid consulting for Biogen, Bristol the disease—while a source of hope—are just a Myers Squibb (Celgene), EMD Serono, Genentech/ beginning. Continued and coordinated efforts by the Roche, Greenwich Biosciences, Horizon Therapeutics, global scientific, clinical, and patient advocacy Janssen, Novartis, and TG Therapeutics and has community will be critical to ensure sustained pro- contracted research funded by EMD Serono and gress toward a future where fewer individuals are Genentech. affected by progressive MS and where those with A. Feinstein is on an Advisory Board for Akili progressive MS have access to a suite of compre- Interactive and reports grants from the MS Society of hensive and effective treatments. The International Canada, book royalties from Johns Hopkins University Progressive MS Alliance and its member organiza- Press, Cambridge University Press and Amadeus Press tions and many supporters affirm their commitment and speaker’s honoraria from Novartis, Biogen, to invest in the proposed research strategy and call Roche, and Sanofi-Genzyme. on the global research community to join in these C. Lubetzki reports grants from Biogen and personal collective efforts to find solutions and deliver hope fees for participation to advisory boards and/or symposia to those affected by progressive MS. from Biogen, Merck Serono, Roche, Rewind, and Ipsen. journals.sagepub.com/home/msj 23 Multiple Sclerosis Journal 28(1) A Donnelly receives support for travel and subsist- C Sincock receives support for travel and subsistence ence as a member, Scientific Advisory Committee, as a member of the Scientific Advisory Committee, International Progressive MS Alliance. International Progressive MS Alliance. RJ Fox reports personal consulting fees from AB K Smith receives consulting fees for project work from Science, Biogen, Celgene, EMD Serono, Genentech, the International Progressive MS Alliance, and travel Genzyme, Greenwich Biosciences, Immunic, Janssen, support from the Alliance as a member of the Scientific Novartis, Sanofi, and TG Therapeutics; has served Steering Committee and the National MS Society as a on advisory committees for AB Science, Biogen, member of their Scientific Advisory Committee. Genzyme, Immunic, Janssen, Novartis, Sanofi, and F Sellebjerg has served on scientific advisory boards TG Therapeutics; and receives clinical trial contract for, served as consultant for, received support for and research grant funding from Biogen, Novartis, congress participation or received speaker honoraria and Sanofi. from Alexion, Biogen, Bristol Myers Squibb, Merck, Anne Helme has no personal pecuniary interests to Novartis, Roche, and Sanofi Genzyme. His laboratory disclose, other than being an employee of the MS has received research support from Biogen, Merck, International Federation (MSIF), which receives Novartis, Roche, and Sanofi Genzyme. income from a range of corporate sponsors, recently J Strum is the host of the RealTalk MS podcast. He including: Biogen, Bristol Myers Squibb (formerly has received podcast sponsorship fees from the Celgene), Genzyme, Med-Day, Merck, Mylan, National MS Society, EMD Serono, and Janssen Novartis, Roche. MSIF is a managing member of the Pharmaceuticals. As a speaker, he has received hono- International Progressive MS Alliance. raria from Novartis, Auburn University, European MS P Kanellis is an employee of the Multiple Sclerosis Platform, and Can-Do MS. As co-lead investigator for Society of Canada, a member of the International caregiver research projects, he has received compen- Progressive MS Alliance sation from the Accelerated Cure Project for MS. He R Hohlfeld received consultancy fees from Novartis, has also received support for travel to conferences Sanofi, Biogen, Merck, Janssen/Johnson&Johnson, and meetings from the National MS Society, the and Roche. International Progressive MS Alliance, and the R. Hyde is an employee of Biogen and co-chair of the Accelerated Cure Project for MS. International Progressive MS Alliance Industry P Zaratin is an employee of the Italian Multiple Forum. Sclerosis Society, a managing member of the D Landsman is an employee of the National Multiple International Progressive MS Alliance and has no Sclerosis Society, a managing member of the conflict of interest. International Progressive MS Alliance and has no T Coetzee is an employee of the National Multiple conflict of interest. Sclerosis Society, a managing member of the X Montalban received speaking honoraria and travel International Progressive MS Alliance and has no expenses for participation in scientific meetings, has conflict of interest. been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the Funding past years with Abbvie, Actelion, Alexion, Bayer, The author(s) disclosed receipt of the following finan- Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, cial support for the research, authorship, and/or publi- Genzyme, Hoffmann-La Roche, Immunic, Janssen cation of this article: This work was supported by the Pharmaceuticals, Medday, Merck, Mylan, Nervgen, International Progressive MS Alliance. The funder Novartis, Sanofi-Genzyme, Teva Pharmaceutical, TG provided financial support for convening activities of Therapeutics, Excemed, MSIF, and NMSS. the authors to inform development of research strate- JM Morahan is an employee of Multiple Sclerosis gies discussed in this paper. Australia, a managing member of the International Progressive MS Alliance. ORCID iDs B. Musch is an employee of Genentech, a subsidiary Alan J Thompson https://orcid.org/0000-0002 of Roche AG. -4333-8496 M. Salvetti reports speaking honoraria and research William Carroll https://orcid.org/0000-0002-5088 support from Merck, Sanofi, Novartis, Biogen, Roche, -548X Bristol Myers Squibb. Anne Cross https://orcid.org/0000-0003-0829 S Rawlings is an employee of the MS Society UK, a -7569 managing member of the International Progressive Anthony Feinstein https://orcid.org/0000-0002 MS Alliance. -0132-0909 24 journals.sagepub.com/home/msj AJ Thompson, W Carroll et al. 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