CoMMeNT
Towards treating progressive multiple
sclerosis
Alan Thompson    ✉ and Olga Ciccarelli
Following extensive progress in the treatment of relapsing multiple sclerosis, the major challenge in
the field is now to develop effective therapies for progressive forms of multiple sclerosis. As the first
signs of success emerge, now is the time to consider the research needed to move the field forward.
Few neurological conditions have seen such a rapid
the field increase in treatment options as multiple sclerosis (MS).
needs to reflect However, this progress has largely benefitted patients
on what we with relapsing MS, and the great challenge now is to
develop effective treatments that target the neuro­
know about degeneration responsible for progression of disability.
progressive Implicit within this challenge is the need for a deeper
MS and what understanding of the underlying mechanisms to enable
identification of treatment targets and redefinition of
research is clinical phenotypes. At this point, the field needs to
needed reflect on what we know about progressive MS and what
research is needed.
Clinical descriptions
One fundamental difficulty that has hampered research
in progressive MS is confusion around the terms ‘pro­
gression’ and ‘worsening’. In 2020, the descriptors of
progressive phenotypes were clarified. The current
recom­mendations are to reserve the terms ‘progressing’ or
‘disease progression’ to refer to the progressive phase of
MS and accrual of disability independent of relapses,
and use the term ‘worsening’ to describe any increase in
disability, whether from residual deficits after a relapse
or increasing disability during the progressive phase.
In addition, it is recommended that progression is evalu­
ated annually1. This clarification facilitates communica­
tion and provides an important foundation for the field
to move forward.
Predicting progression
Ongoing identification of imaging biomarkers is pro­
viding greater insights into progression and helping to
identify patients who are at risk. Studies have shown
that MRI measures available in routine clinical practice,
Queen Square Multiple including gadolinium enhancing brain and spinal cord
Sclerosis Centre, UCL Queen lesions, are predictors of long-​term disease outcomes2.
Square Institute of Neurology, Measures that are not routinely obtained in clinical
Faculty of Brain Sciences,
London, UK.
practice, including slowly expanding lesions and tissue
✉e-​mail: alan.thompson@ loss, are promising biomarker candidates. In addition,
ucl.ac.uk atrophy of specific grey matter regions3 is strongly asso­
https://doi.org/10.1038/ ciated with clinical progression, and cortical atrophy is
s41582-020-00421-4 accelerated in progressive MS.
Nature Reviews | Neurology
Some non-​MRI biomarkers could also predict progres­
sion. Use of optical coherence tomography has demon­
strated that the rate of retinal thinning could identify
progressive MS and predict disability progression4. Blood
levels of serum neurofilament light could predict which
patients will enter the progressive phase and the rate of
progression, though this marker requires validation5.
Biomarkers are essential for reliable identification
of progressive MS and prediction of which patients
will experience progression to enable earlier treatment
with more effective medications. The biomarkers being
identified need to be validated and consolidated for
translation into reliable clinical tools.
Therapy
Recent trials in progressive MS have revealed modest
benefits of ocrelizumab in primary progressive MS and
siponimod in secondary progressive MS. Furthermore,
the FDA has ruled that all agents that are effective for
relapsing MS can be used for treatment of secondary
progressive MS with evidence of activity, defined as
clinical relapses, but not new MRI activity (Fig. 1).
Further success has come from repurposing of
approved drugs, such as simvastatin and ibudilast,
which reduce brain atrophy in secondary progres­
sive MS. Combined drug repurposing and innovative
trial designs are likely to reduce timeframes and costs
in drug develop­ment. This approach has been proven
feasible with the MS-​SMART trial, in which three repur­
posed agents were tested, although the findings were
emphatically negative6.
Despite these innovations, truly effective therapies for
progressive MS will need to target mechanisms involved
in the accumulation of disability. A few agents that target
these mechanisms are being studied (Fig. 1), but greater
focus on this area is needed.
Mechanisms of progression
Critical for the development of treatments for progressive
MS is a complete understanding of the biological dyna­
mics that lead to the progressive phase7. Knowledge of
inflammatory mechanisms has driven the development
Comment

of many disease-​modifying therapies for relapsing MS, require targeting of neuroprotective and repair mecha­
effective and we know that inflammation is also important in pro­ nisms, a challenging but very active field of research8.
therapies ... will gressive MS, but its nature differs. Inflammation associ­ The need for identification of new therapeutic targets
ated with progression is characterized by inflammatory in progressive MS has led to the establishment of the
need to target
processes within the parenchyma behind a (partly) Progressive MS Alliance to stimulate research, which
mechanisms closed or repaired blood–brain barrier, and by the pres­ is already driving progress; for example, work funded
involved in the ence of chronic active and/or slowly expanding lesions by the Alliance has identified epigenetic modifiers as
accumulation of with resident inflammatory microglia at the edges7. candidate targets to suppress the pathogenic activity of
However, the mechanisms of progressive MS go astrocytes in MS9.
disability beyond inflammation. For example, progression seems to
involve failure of repair mechanisms, including impaired Symptomatic management
remyelination7. At a macrostructural level, abnormal Rehabilitation and symptomatic management is also
communication between brain regions seems to contri­ important in MS, particularly progressive MS. A focus
bute to cognitive dysfunction, and exhaustion of brain on the effects of exercise in MS has revealed benefits
reserve could lead to functional deficits. for motor function and cognitive function. An ongoing
Greater insight into these non-​inflammatory mecha­ international study will provide detailed insight into
nisms is needed for identification of therapeutic targets. the effects of aerobic exercise on cognitive function10.
Truly effective therapy for progressive MS is likely to Studies of the effects of exercise have shown that, besides
the clinical efficacy of the interventions, such studies are
feasible and cost-​effective, so should continue to estab­
Progressive MS treatments and pipeline
lish best clinical practice for slowing progression and for
Phase I Phase II Phase III Approved rehabilitation in those with existing disability.
♦Interferons
♦Glatiramer acetate Approved Conclusion
♦Natalizumab indication
♦Dimethyl fumarate expanded to
Progress in the field of progressive MS is encouraging,
♦Fingolimod include but the challenge of understanding the mechanisms that
♦Teriflunomide active SPMS underpin progression remains. Until this challenge is
♦Ozanimod in the USA overcome, we will struggle to develop effective treatments.
♦Cladribine These mechanisms must, therefore, be the main focus for
♦Ofatumumab Approved for the next 5 years, and this research will be facili­tated by
♦Siponimod active SPMS collaborations and organizations, such as the Progressive
♦Ocrelizumab Approved for MS Alliance.
♦SAR442168 (PPMS) PPMS and
♦SAR442168 (SPMS) active SPMS 1. Lublin, F. D. et al. The 2013 clinical course descriptors for multiple
sclerosis: a clarification. Neurology 94, 1088–1092 (2020).
Fenebrutinib 2. Brownlee, W. J. et al. Early imaging predictors of long-​term outcomes
Simvastatin in relapse-​onset multiple sclerosis. Brain 142, 2276–2287 (2019).
♦Biotin 3. Eshaghi, A. et al. Progression of regional grey matter atrophy in
multiple sclerosis. Brain 141, 1665–1677 (2020).
Cladribine (upper-limb) 4. Martinez-​Lapiscina, E. H. et al. Retinal thickness measured with
♦Masinitib optical coherence tomography and risk of disability worsening in
multiple sclerosis: a cohort study. Lancet Neurol. 15, 574–584
Ibudilast
(2016).
Lipoic acid 5. Kapoor, R. et al. Serum neurofilament light as a biomarker in
Domperidone progressive multiple sclerosis. Neurology https://doi.org/10.1212/
WNL.0000000000010346 (2020).
Estriol
6. Chataway, J. et al. Efficacy of three neuroprotective drugs in
Quetiapine secondary progressive multiple sclerosis (MS-​SMART): a phase 2b,
N-acetylcysteine multiarm, double-​blind, randomised placebo-​controlled trial. Lancet
Neurol. 19, 214–225 (2020).
Hydroxychloroquine 7. Absinta, M., Lassmann, H. & Trapp, B. D. Mechanisms underlying
Oxacarbazepine progression in multiple sclerosis. Curr. Opin. Neurol. 33, 277–285
Mesenchymal stem cells (2020).
8. Neumann, B. et al. Problems and pitfalls of identifying remyelination
Bile acid supplement in Multiple Sclerosis. Cell Stem Cell 26, 617–619 (2020).
Dimethyl fumarate 9. Wheeler, M. A. et al. MAFG-​driven astrocytes promote CNS
♦Elezanumab inflammation. Nature 578, 593–599 (2020).
10. Feinstein, A. et al. CogEx Research Team. Study protocol: improving
Intranasal insulin cognition in people with progressive multiple sclerosis: a multi-​arm,
Melatonin randomized, blinded, sham-​controlled trial of cognitive rehabilitation
ACTH and aerobic exercise (COGEx). BMC Neurol. 20, 204 (2020).
COGEx Competing interests
Human neural stem cells A.J.T. has served on scientific advisory boards and received honoraria from
Fetal neural stem cells Eisai and Abbvie; has received support for travel from the International
Progressive Multiple Sclerosis Alliance as chair of their Scientific Steering
♦ATA-188 Committee, and from the National Multiple Sclerosis Society as a member
Functional electric ♦Industry-led programs of their Research Programs Advisory Committee; receives an honorarium
stimulation from SAGE Publishers as Editor-​in-​Chief of Multiple Sclerosis Journal; is an
editorial board member for Lancet Neurology; and receives research sup-
port from NIHR and the NIHR UCLH Biomedical Research Centre. O.C. has
Fig. 1 | Agents that are currently being studied for treatment of progressive MS. served on scientific advisory boards and has received honoraria and sup-
Active secondary progressive multiple sclerosis (SPMS) is defined by new clinical relapses port for travel from Merck, Novartis and Roche; is Deputy Editor for
but not new MRI activity. Biotin was tested in a placebo-​controlled phase III trial, but the Neurology; serves on the editorial board for Multiple Sclerosis Journal;
receives research support from EPSRC, MS Society of GB and NI, National
primary and secondary end points of this trial were not met, indicated by the cross. Image MS Society, NIHR, the NIHR UCLH/UCL Biomedical Research Centre and
courtesy of Timothy Coetzee, National MS Society. PPMS, primary progressive MS. the Rosetrees Trust.

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