REVIEW

C URRENT
OPINION New drugs for multiple sclerosis: new treatment
algorithms
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Bruce A.C. Cree a, Hans-Peter Hartung b,c,d,e, and Michael Barnett c,f
CywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2023

Purpose of review
To discuss recent changes in the multiple sclerosis (MS) treatment algorithm and to present therapies
currently in MS clinical trials.
Recent findings
High efficacy disease modifying therapies are optimally beneficial when used in the early, inflammatory
phase of MS. Bruton’s tyrosine kinase has emerged as an important therapeutic target for both relapsing
and progressive forms of MS. Multiple therapies targeting remyelination failed to provide conclusive
evidence of broad therapeutic benefit; however, more targeted approaches offer hope that myelin repair
might be achieved resulting in specific clinical improvements. Strategies targeting chronic Epstein--Barr
virus infection and dysbiosis of the gut microbiome are the first to link microbial risk factors for MS and
therapeutic interventions.
Summary
A striking number of diverse treatments under investigation bodes well for development of better and more
effective therapies in MS.
Keywords
Bruton’s tyrosine kinase, clinical trials, disease modifying therapies, multiple sclerosis, remyelination

INTRODUCTION platform therapies, and high efficacy agent treat-

The last 25 years have seen remarkable progress in
the development of multiple sclerosis (MS) treat-
ments [1,2]. Although many therapies employing
different mechanisms of action are available for
relapsing forms of MS (RMS), therapies proven to
be effective for progressive RMS are limited. Thera-
pies intended to enhance remyelination have yet to
receive regulatory approval and other strategies
directed at enhancing recovery from chronic injury
have yet to show benefit. Therefore, great unmet
needs persist in MS both for treatments that can
arrest progressive disability worsening and restore
function following central nervous system (CNS)
injury. This purpose of this review is two-fold. First,
a major change in the treatment philosophy of
relapsing RMS is underway. Second, this review will
showcase MS therapies that are currently being
evaluated in clinical trials.
A SEA CHANGE IN THE MULTIPLE
SCLEROSIS TREATMENT ALGORITHM
MS disease modifying agents are commonly divided
into drugs of moderate effectiveness, also termed
ments (HEATs). Two strategies were proposed for MS
treatment: first, the treat-to-target or tiered escala-
tion approach that begins with lower initial treat-
ment efficacy (LITE) and reserves HEAT for
breakthrough disease and second, high efficacy
frontline treatment (HEFT) that begins with HEAT
a
Department of Neurology, UCSF Weill Institute for Neurosciences,
University of California, San Francisco, San Francisco, California, USA,
b
Department of Neurology, Heinrich Heine University D€ usseldorf,
D€usseldorf, Germany, cBrain and Mind Centre, University of Sydney,
Sydney, New South Wales, Australia, dDepartment of Neurology, Med-
ical University of Vienna, Vienna, Austria, eDepartment of Neurology,
Palacky University Olomouc, Olomouc, Czech Republic and fSydney
Neuroimaging Analysis Centre, Sydney, New South Wales, Australia
Correspondence to Bruce A.C. Cree, MD, PhD, MAS, Professor of
Clinical Neurology, Department of Neurology, UCSF Weill Institute for
Neurosciences, University of California, San Francisco, San Francisco,
CA, USA. Tel: +1 415 514 2466; e-mail: Bruce.Cree@ucsf.edu
Curr Opin Neurol 2022, 35:262–270
DOI:10.1097/WCO.0000000000001063
This is an open access article distributed under the terms of the Creative
Commons Attribution-Non Commercial-No Derivatives License 4.0
(CCBY-NC-ND), where it is permissible to download and share the
work provided it is properly cited. The work cannot be changed in any
way or used commercially without permission from the journal.

www.co-neurology.com Volume 35
Number 3
June 2022

 New drugs for multiple sclerosis, new treatment algorithms Cree et al.
KEY POINTS

High efficacy frontline treatment uses highly potent
therapies at clinical onset to maximize treatment benefit
during a window of opportunity in which anti-
inflammatory therapies are optimally beneficial.

Bruton’s tyrosine kinase has emerged as an important
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therapeutic target for both relapsing and progressive
forms of MS.
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Multiple therapies targeting remyelination failed to
provide conclusive evidence of broad therapeutic
benefit with this strategy whereas more targeted
approaches offer hope that repair might be achieved.

Strategies targeting chronic Epstein--Barr virus infection
and dysbiosis of the gut microbiome are the first to link
microbial risk factors for MS and therapeutic
intervention.
early in the disease course. LITE involves initiation
of treatment with drugs such as interferons, glatir-
amer, teriflunomide or fumarates, careful monitor-
ing of the treatment response, and switching to
HEAT (natalizumab, anti-CD20 monoclonal anti-
bodies, alemtuzumab, S1P receptor modulators or
cladribine) when ongoing disease activity or pro-
gressive disability becomes apparent. This approach
was driven by safety concerns related to two earlier
HEAT therapies: mitoxantrone, which can cause
cardiac toxicity and leukemia, and natalizumab
which can cause progressive multifocal leukoence-
phalopathy. The development of risk mitigation
strategies for natalizumab and HEATs with more
favorable safety profiles such as B-cell-depleting
treatments allows for potential use of HEAT early
in RMS.
Whereas LITE was the dominant treatment strat-
egy in MS for the last 2 decades, accumulating data
from both relatively short-term randomized trials
[3–7] and results from population-based studies
suggest that HEFT provides greater long-term bene-
& &
fit to MS patients [8–15,16 ]. However, definite
conclusions about whether either LITE or HEFT is
superior to the other requires head-to-head compar-
ison of these therapeutic strategies in prospective
randomized controlled trials. Both the Traditional
verses Early Aggressive Therapy for MS trial (TREAT-
MS, NCT03500328) and the Determining the Effec-
tiveness of Early Intensive verses Escalation
Approaches for the Treatment of Relapsing-remit-
ting MS trial (DELIVER-MS, NCT03535298) are
designed to address this question. The primary out-
comes are disability progression for TREAT-MS and
brain volume loss for DELIVER-MS. Hopefully, these
1350-7540 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
studies will yield consistent results. For now, avail-
able data provide some evidence for wider use of
HEFT. HEFT offers a therapeutic approach of choos-
ing highly potent therapies at the earliest stages of
the disease to capitalize on a theoretical window of
opportunity for maximal anti-inflammatory bene-
fit. In contrast, LITE embodies a fix-on-fail philos-
ophy that guarantees irreversible injury for at least
some patients.
NEW TREATMENTS IN DEVELOPMENT FOR
MULTIPLE SCLEROSIS
Bruton's tyrosine kinase inhibitors
Bruton’s tyrosine kinase (BTK) is a cytoplasmic Tec
family kinase expressed in all hematopoietic cell
lines except for T cells and terminally differentiated
plasma cells [17,18] (Table 1). BTK is a critical signal-
ing node for peripheral myeloid cells, B cells and
CNS microglia. B-cell receptor activation results in
intracellular signaling through this kinase with
downstream transcriptional regulation governing
diverse processes including chemotaxis, trafficking,
adhesion, maturation, antibody production and
cytokine secretion [19]. Inhibition of BTKs is a
proved treatment for lymphoma and is under inves-
tigation in diverse autoimmune disorders [20]. As
small molecules, BTK inhibitors (BTKIs) could have
advantages over biologics since they are less likely to
trigger antibody mediated responses and have the
potential for CNS penetrance. Many BTKIs were
developed to covalently bind their receptor thereby
reducing the steady-state concentration needed for
pharmacologic effect. Additional factors to consider
are target specificity for BTK relative to other tyro-
sine kinases and the degree of CNS penetrance.
Evobrutinib was the first BTKI to show therapeu-
tic potential in a phase 2 study in RMS [21] and is
now being investigated in twinned phase 3 study
(NCT04338022, NCT04338061). Tolebrutinib was
developed to be a CNS penetrant BTKI [22] and
showed activity on gadolinium-DPTA lesion forma-
tion in RMS [23 ]. Three phase 3 trials with tolebru-
tinib are underway in RMS, primary progressive MS
(PPMS) and secondary progressive MS (SPMS)
(NCT04879628, NCT04544449, NCT04411641).
Fenebrutinib is a peripherally acting, reversibly bind-
ing BTKI that is under investigation in twinned phase
3 studies in RMS as well as a phase 3 study in PPMS
(NCT04586023, NCT04586010, NCT04544449).
Remibrutinib is a peripherally acting, covalent bind-
ing BTKI being compared head-to-head versus teri-
flunomide in a phase 3 study in RMS (NCT05156281).
Orelabrutinib is a CNS penetrant BTKI under inves-
tigation in a phase 2 study, placebo-controlled trial in
www.co-neurology.com 263
 Multiple sclerosis

Table 1. Drug therapies currently under investigation in multiple sclerosis

Medication-based therapies in development
Compound Phase NCT number Sponsor Study population Enrollment target

EBV
ATA-188 1/2 NCT03283826 Atara Nonrelapsing progressive 225
Autologous EBV reactive T cells 1 NCT02912897 University of Nantes Clinically isolated syndrome 7
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Tenofovir alafenamide 2 NCT04880577 Gilead Clinically definite 60

fumarate
Bruton’s tyrosine kinase inhibitors
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Evobrutinib 3 NCT04338022 Merck Serono Relapsing 930

NCT04338061 930
Tolebrutinib 3 NCT04410978 Sanofi Relapsing 900
NCT04410991 Relapsing 900
NCT04458051 Primary progressive 990
NCT04411641 Non-relapsing secondary 1290
progressive
Fenebrutinib 2 NCT05119569 Hoffmann-La Roche Relapsing 120
3 NCT04586023 Relapsing 736
3 NCT04586010 Relapsing 736
3 NCT04544449 Primary Progressive 946
Remibrutinib 3 NCT05156281 Novartis Relapsing 800
Orelabrutinib 2 NCT04711148 Beijing InnoCare Relapsing 160
Pharma Tech Co., Ltd./Biogen
Remyelinating strategies
Clemastine fumarate 2 NCT02521311 UCSF Acute optic neuritis in 90
relapsing MS
Bazedoxifene acetate 2 NCT04002934 UCSF Postmenopausal women with 50
relapsing MS
CNM-Au8 2 NCT03536559 Clene Chronic optic neuropathy in 150
relapsing MS
BIIB061 2 NCT04079088 Biogen Relapsing 300
Immune suppressants
Vidofludimus calcium (IMU- 3 NCT05134441 Immunic AG Relapsing 1050
838) NCT05201638 Relapsing 1050
NCT05054140 Progressive 450
Anakinra 1/2 NCT04025554 NIH MS 10
Foralumab 2 NCT05029609 Tiziana Life Sciences Secondary progressive 55
Imatinib 2 NCT03674099 Swedish Research Council Relapsing 200
SAR441344 2 NCT04879628 Sanofi Relapsing 120
Simvastatin 2 NCT03896217 University College of London Secondary Progressive 40
3 NCT03387670 MS Society 1180
EK-12 3b NCT03283397 Bosnalijek D.D. Relapsing 400
Hul001 1 NCT04540770 HuniLife Biotechnology, Inc. Healthy volunteers and MS 24
Humoral immune system
Belimumab 2 NCT04767698 Glaxo Smith Kline/Johns Relapsing 40
Hopkins University
Ixazomib 2 NCT03783416 Takeda Pharmaceuticals All forms of MS 72
Queen Mary University of
London
Immune tolerance
ANK-700 1 NCT04602390 Anokion Relapsing MS 33
Tol-Dec 2 NCT04530318 Institut d’Investigacions Relapsing MS 45
Biomediques August Pi i
Sunyer
Neurovax 2 NCT02149706 Immune Response BioPharma, Secondary progressive 150
NCT02057159 Inc. Pediatric 200
NCT02200718 12
Neural protection and antioxidation
N-acetyl cysteine 2 NCT05122559 University of California San Progressive MS 98
Francisco
Department of Defense
Lipoic acid 2 NCT03161028 Veterans Administration Office Progressive MS 118
of Research and
Development

EBV, Epstein--Barr virus; MS, multiple sclerosis.

264 www.co-neurology.com Volume 35
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 New drugs for multiple sclerosis, new treatment algorithms Cree et al.
RMS (NCT04711148). Several other BTKIs are being
considered for clinical trials in MS including two CNS
penetrant molecules GB5121 and GB7208 from Gos-
samer Bio and BIIB091, a peripherally acting BTKI
from Biogen. Clearly with so many BTKIs in develop-
ment, differentiating between these products will be
challenging if efficacy and safety profiles for the more
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peripherally acting BTKIs are similar. The CNS pen-
etrant BTKIs have a potential advantage over the
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peripherally acting products in that the CNS pene-
trant BTKis could interact directly with microglial
cells. Whether modulation of microglial activation
is beneficial in MS is unknown but hypothetically
could be important especially for progressive RMS.
Myelin repair
Myelin repair offers hope for restoration of deficits
caused by MS demyelination. Histopathology sug-
gests that oligodendroglial precursor cells are
present in MS plaques but are unable to remyelinate
due to inhibitory signals [24] (Table 1). Stimulating
oligodendrocyte precursor cells (OPCs) to remyeli-
nate denuded axons could restore saltatory axonal
conduction thereby potentially reversing conduc-
tion block associated neurological deficits and pro-
moting neuronal survival through renewed trophic
support of previously demyelinated axons. Strat-
egies to promote remyelination include overcoming
inhibitory signals, stimulating OPC differentiation
or providing cofactors for myelin forming enzymes.
Opicinumab is a monoclonal antibody directed
against leucine rich repeat and Immunoglobin-like
domain-containing protein 1 (LINGO-1), an inhib-
itory signaling molecule that prevents remyelina-
tion. Three opicinumab clinical trials proved
unsuccessful and further development seems doubt-
ful [25,26]. Similarly disappointing results were
reported for elezanumab, an inhibitor of repulsive
guidance molecule A, another inhibitory factor for
myelination and axonal sprouting [27]. A phase 1
study was conducted for RHIgM22a, a putative mye-
lin inducing monoclonal antibody, that although
detectable in cerebrospinal fluid, showed no dis-
cernible effect on gadolinium enhancing lesions
[28]. Small molecules with putative myelin repair
properties also were investigated. MD-1003, phar-
maceutical grade, high-dose, biotin is a cofactor for
acetyl-CoA carboxylases that are involved in fatty
acid metabolism and underlie myelin production as
well as carboxylases that generate intermediates for
the tricarboxylic acid cycle. Despite a successful
phase 2 study that showed significant reversal MS
disability, replication of these findings fell short in
phase 3 study [29]. These studies used composite
endpoints designed to detect overall improvements
1350-7540 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
in function; however, because MS disability is not
only caused by demyelination but also by axonop-
athy and neuronal loss it is perhaps not surprising
that these studies were unsuccessful [30].
Several small molecules with indications other
than in MS are being repurposed to stimulate myelin
repair. Bexarotene, a small molecule retinoic acid
RXR-gamma receptor agonist that stimulate myeli-
nation in preclinical models was investigated in a
phase 2 study in RMS and not only failed to meet its
primary endpoint but also demonstrated poor toler-
ability [31]. A study of domperidone, a therapy used
in some countries to alleviate constipation in Par-
kinson’s disease that also stimulates prolactin secre-
tion and therefore might promote remyelination, in
SPMS failed to reach its primary endpoint [32].
Clemastine fumarate, an antihistamine, was identi-
fied in an in-vitro screen to promote myelin forma-
tion and showed physiologic effects consistent with
remyelination in a phase 2 study of chronic optic
neuropathy [33,34]. This study’s design that tar-
geted a specific neuroanatomic deficit known to
be caused by demyelination likely contributed to
its success. Clemastine fumarate is being studied in
an acute optic neuritis trial (NCT02521311) and in
combination with metformin, a commonly used
diabetes medication that may help condition OPCs
for remyelination (NCT05131828). Bazedoxifene
acetate, a selective estrogen receptor modulator
used in combination with conjugated estrogens to
prevent postmenopausal osteoporosis, was identi-
fied in an in-vitro screen to promote myelin differ-
entiation and is being studied in a phase 2 study in
postmenopausal women with MS. Somewhat anal-
ogous to bazedoxifene in women, testosterone
undecanoate is being studied as a potential remyeli-
nating and neuroprotective therapy in men with
RMS (NCT03910738).
CNM-Au8, nanocrystalline gold, catalyzes the
oxidation of nicotinamide adenine dinucleotide
hydride to the energetic cofactor NADþ and may
stimulate demanding cellular respiratory processes
such as myelin production, potentially accounting
for its remyelinating properties in preclinical mod-
els [35]. CNM-Au8 is being studied in a phase 2
trial of chronic optic neuropathy in RMS
(NCT03536559). Thyroid hormone promotes mye-
lination during development and in preclinical
models of remyelination. Liothyronine was inves-
tigated in a phase 1 study in RMS (NCT02760056)
[36]. Follow-up studies with this product have not
been registered possibly due to concern about thy-
roid hormone toxicity in euthyroid participants.
BIIB061 is an oral small molecule that induces
OPC growth and thereby potentially promote mye-
lin repair. A phase II, add-on study will be conducted
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 Multiple sclerosis
in participants already treated with interferons and
glatiramer acetate (NCT04079088).
Epstein–Barr virus
Epstein–Barr virus (EBV) infection is a well recog-
&&
nized MS risk factor [37,38 ] (Table 1). Although
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this is a common infection in adults and children,
evidence of prior EBV infection is found in virtually
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every MS patient. Although EBV infection functions
as a trigger for MS it remains unclear to what extent,
if any, latent EBV infection contributes to MS patho-
genesis [39]. In MS, both humoral and cellular
immune responses are altered compared with unaf-
fected controls. Children with MS have increased
EBV shedding consistent with frequent EBV reacti-
vation [40]. A recent study pointed to possible
mechanism in which antibodies directed against
EBV antigens cross-react with CNS antigens suggest-
ing molecular mimicry as an underlying mechanism
[41]. Autoreactive EBV-infected B cells are present in
ectopic follicular like structures that are found in the
meninges of MS patients and are a unique histopa-
thological feature of the disease [42,43]. Latent EBV
infection might contribute to MS pathogenesis and
might have a role in progressive disease.
Based on these observations, autologous EBV-
reactive CD8 T cells were used to treat progressive
MS patients in a pilot study that showed improve-
&
ment in chronic disability [44 ]. A larger phase 1/2
randomized, placebo-controlled clinical trial in
nonrelapsing, progressive MS using heterologous,
HLA-matched EBV-reactive CD8 T cells (ATA-188)
is underway (NCT03283826). A single-center, phase
1 study using autologous EBV-reactive CD8 T cells in
participants who experienced a first demyelinating
event (clinically isolated syndrome) is underway
(NCT02912897). A phase 2 study is planning to
investigate whether the antiviral, tenofovir alafena-
mide fumarate, could improve fatigue and other
outcomes in MS (NCT04880577).
New immune suppressants and immune
modulators
Autoimmune demyelination in MS is mediated by T
and B lymphocytes and successfully developed ther-
apeutics target multiple immunologic processes [2]
(Table 1). Several strategies that build upon the prior
successes of immune directed therapies are in devel-
opment. Teriflunomide, an inhibition of dihydro-
orotate dehydrogenase (DHODH) a mitochondrial
enzyme in the de novo pyrimidine synthesis path-
way impairs DNA synthesis in actively proliferating
T and B lymphocytes without causing cell death, is
indicated in adults and children (in Europe) with
266 www.co-neurology.com
relapsing MS [45]. However, teriflunomide has off-
target activity against protein kinases, including the
epidermal growth factor receptor tyrosine kinase,
leading to antiproliferative side effects such as neu-
tropenia, alopecia and diarrhea [46]. Vidofludimus
calcium (IMU-838) is a next-generation small mol-
ecule inhibitor of DHODH with improved target
specificity that may lead to a better side effect
profile relative to teriflunomide [47]. Vidofludimus
calcium is a more potent inhibitor of DHODH and
is more effective at inhibiting T-cell proliferation
compared with teriflunomide. Vidofludimus cal-
cium was successfully studied in a phase 2 trial in
RMS (NCT03846219) and is in development in
twinned, phase 3 studies in RMS (NCT05134441,
NCT05201638) and in a single trial in nonrelapsing
progressive RMS (NCT05054140). Vidofludimus
calcium also has antiviral activity including anti-
coronavirus activity, an appealing property given
the Covid-19 pandemic [48].
Anakinra is recombinant interleukin receptor-1
antagonist and is used for treatment of deficiency of
interleukin receptor-1 antagonist, refractory rheu-
matoid arthritis, cryopyrin-associated periodic syn-
dromes including neonatal-onset multisystem
inflammatory disease, familial Mediterranean fever
and Still’s disease. Anakinra is being studied in a
phase 1/2 study to determine whether it has an
impact on chronically inflamed brain lesions (para-
magnetic rim lesions identified on 7T MRI) in MS
(NCT04025554).
Imatinib mesylate is an inhibitor of the Bcr-Abl
tyrosine kinase and is used as an antioncologic for
several cancers. Imatinib showed benefit in a pre-
clinical model of MS [49] and is being compared
with methylprednisolone in a phase 2 study of MS
relapses (NCT03674099). Imatinib’s known toxicity
may limit application.
Masitinib is a selective tyrosine kinase inhibitor
targeting microglia and mast cells. A recently pub-
lished phase 3 trial (NCT01433497) demonstrated
clinical efficacy in slowing disease progression in
primary progressive and clinically inactive SPMS.
On the contrary, MRI was not performed [50]. A
new phase 3 trial including magnetic resonance
outcomes is being planned.
Foralumab (TZLS-401) is a human, anti-CD3
monoclonal antibody that modulates CD3 function
without inducing lymphopenia and is delivered in a
stabilized liquid form intranasally. Foralumab is
under investigation in a phase 1 study of SPMS
(NCT05029609).
SAR441344 is a monoclonal antibody that anta-
gonizes the CD40 ligand, a costimulatory molecule
of the immunologic synapse, and is under inves-
tigation in a phase 2 study in RMS (NCT04879628).
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 New drugs for multiple sclerosis, new treatment algorithms Cree et al.
CD40 ligand inhibition was previously studied in
MS [51].
Simvastatin is an HMG-CoA reductase inhibitor
that is proposed to have neural protective and anti-
inflammatory effects in MS [52]. Following the suc-
cess of a multicenter study in SPMS [53] a multicenter,
placebo controlled, phase 3 trial of simvastatin in
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SPMS is investigating the impact of simvastatin on
disability worsening (NCT03387670). It is possible
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that simvastatin exerts a beneficial property in SPMS
through effects other and by reducing inflammation.
A phase 2, placebo-controlled, study in SPMS is inves-
tigating the effect of simvastatin on a noninvasive
measure of cerebral blood flow (NCT03896217).
EK-12 is a neuropeptide combination of meten-
kefalin (an endogenous endorphin) and tridecactide
(alpha-1–13-corticotropin) and is being compared
with subcutaneous interferon beta-1a in a head-to-
head phase 3 study (NCT03283397). Significantly,
although this study is described as a phase 3 clinical
trial, there do not appear to be earlier phase studies
of this neuropeptide combination in MS.
Hul001 is an antienolase monoclonal anti-
body that is being investigated in a phase 1 study
in healthy volunteers and MS participants
(NCT04540770). In addition to being an intracel-
lular enzyme involved in glycolysis enolase is a
plasminogen receptor displayed on the surface of
activated monocytes and may block ENO1-bearing
monocytes from CNS entry.
B-cell-targeting therapies
The profound reduction of neuroinflammation in
MS by anti-CD20 monoclonal antibodies shows that
B cells have a critical role in MS pathogenesis [2,54]
(Table 1). Several approaches are in development
that seek to build upon the success of B-cell deple-
tion. Belimumab is a B-cell-activating factor that is
being developed as an add-on treatment to ocreli-
zumab in a phase 2 study of RMS (NCT04767698).
The concept behind this study is that belimumab in
combination with a short course of ocrelizumab will
be equally effective as ongoing ocrelizumab treat-
ment but will be associated with less immune sup-
pression and improved responses to pneumococcal
vaccination.
Ixazomib is a site-specific proteasome inhibitor
that targets plasma cells and is approved for treat-
ment of multiple myeloma. Ixazomib is being
studied to determine whether treatment will reduce
the presence of oligoclonal bands in the cerebrospi-
nal fluid in MS (NCT03783416).
Self-tolerance
Perhaps one of the most appealing concepts in MS
treatment is the notion that the breach in self-
1350-7540 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
tolerance which underlies autoimmune injury could
be reversed through induction of antigen-specific
immune tolerance (Table 1). This approach could
address the underlying pathophysiology in MS with-
out the side effects of more broadly acting immune
therapies [55]. ANK-700 is a myelin antigen thought
to be involved in MS pathogenesis, designed to restore
self-tolerance by delivery to the liver where it is
intended to reprogram the immune system for self-
tolerance. ANK-700 is being investigated in a phase 1
study in RMS (NCT04602390).
Autologous tolerogenic dendritic cells from
peripheral blood are being studied in a phase 2 clinical
trial as an intravenous add-on to moderately effective
treatments (NCT04530318). Tolerogenic dendritic
cells are loaded with immunogenic peptides and
interact with antigen-specific T lymphocytes to
induce regulatory T cells. Another phase 1, single
arm study will investigate the safety of autologous
monocyte-derived dendritic cells tolerized with vita-
min-D3 and pulsed with myelin peptides adminis-
tered by intranodal injection (NCT02903537).
NeuroVax is a T cell receptor (TCR) peptide
vaccine that is being studied in placebo-controlled,
phase 2 clinical trials in secondary progressive
(NCT02149706, NCT02057159) and pediatric MS
(NCT02200718).
Microbiome
The microbial composition of the intestines inter-
acts with dendritic cells and lymphocytes in the
lamina propria (Table 1). Different commensal
microorganisms can elicit proinflammatory and
anti-inflammatory responses in the host. Therefore,
it is possible that the gut microbiome could be
involved in triggering and perpetuating MS and
manipulation of the gut microbiota could be
another MS therapeutic strategy [56]. Taurourso-
deoxycholic acid (TUDCA) is a bile acid present as
a minor constituent in humans but is in abundance
in bears. TUDCA is used as a natural remedy in
traditional Chinese medicine. TUDCA is proposed
for use as a neuroprotective agent, an anti-inflam-
matory agent, and an apoptosis inhibitor, and may
have bone density conservation and cardioprotec-
tive properties. A phase 1/2 study in progressive MS
is investigating the impact of TUDCA treatment on
metabolomics, gut microbiota and immunopheno-
typing (NCT03423121).
The association of gut microflora with MS
among other neurological disorders naturally led
to the hypothesis that altering the gut microflora
might be beneficial in MS [57]. A single-arm, pilot
study is investigating the safety and tolerability of
oral fecal matter transplantation (FMT) in MS
www.co-neurology.com 267
 Multiple sclerosis

(NCT04096443). A large, single-arm study of FMT in
multiple indications including MS is also underway
(NCT04014413). Assessment of outcomes other
than safety and perhaps immunology will be chal-
lenging given the uncontrolled nature of these stud-
ies. A phase 2, blinded, placebo-controlled study of
allogenic versus autologous FMT that also involves
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show a beneficial impact on measures of brain and
spinal cord atrophy (NCT05122559). Lipoic acid is a
commonly used antioxidant that may have neural
protective properties and is being investigated in a
phase 2 study of progressive RMS to determine
whether lipoic acid can help preserve ambulation
and brain volume (NCT03161028).

preconditioning with amoxicillin/clavulanate (or

matched placebo) followed by a bowel cleanse with
CywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2023

PEGLYTE prior to FMT will assess the efficacy of FMT
on MRI measures of disease activity in untreated
RMS (NCT04150549).
Neural protection
Strategies aimed at preventing oligodendrocyte and
neuronal injury in MS independent of antineural
inflammatory mechanisms might be particularly
beneficial in progressive RMS wherein neurodegen-
eration occurs without overt inflammatory injury
[57] (Table 1). N-acetyl cysteine (NAC) is a gluta-
thione precursor with antioxidant properties that
was previously studied in progressive MS but found
no benefit on fatigue [58]. NAC is being investigated
in a phase 2 study of progressive MS whose goal is to
Stem cells therapies
Eradicating memory cells in MS by intensive immune
suppression with subsequent repopulation of naı̈ve
stem cells may induce sustained remission in relaps-
ing MS [59] (Table 2). Several trials are following up on
a large body of observational evidence studying hem-
atopoietic stem cell transplantation as a treatment in
MS [60–62]. Some of these studies are observational
(NCT04674280, NCT05029206) or single arm with
safety measures being the primary outcome
(NCT03113162, NCT00716066, NCT04203017).
Autologous hematopoietic stem cell transplantation
(AHSCT) is being compared with alemtuzumab in a
rater-blinded, single-center study (NCT03477500).
Lastly, AHSCT is also being compared against best
available therapy (B-cell depletion, cladribine,

Table 2. Stem-cell-based therapies currently under investigation in multiple sclerosis

Stem-cell-based therapies in development
Compound Phase NCT number Sponsor Study population Enrollment target

AHSCT Observational NCT04674280 European Society for Blood All forms of MS 50

and Marrow Transplantation
AHSCT Observational NCT05029206 Uppsala University, Sweden Relapsing MS 200
Reduced intensity Single arm NCT03113162 Makati Medical Center Progressive MS 15
immunoablation and AHSCT
High-dose immune suppressive 2 NCT00716066 Fred Hutchinson Cancer Treatment refractory 40
treatment and AHSCT Research Center neurological
autoimmune disease
(including MS)
AHSCT plus allogeneic fecal 1 NCT04203017 St. Petersburg State Pavlov Treatment refractory MS 20
microbiota transplant Medical University
AHSCT versus alemtuzumab 3 NCT03477500 Haukeland University Hospital Relapsing MS 100
AHSCT versus best available 3 NCT04047628 National Institute of Allergy Relapsing MS 156
therapy and Infectious Diseases
(NIAID)
Allogeneic adult umbilical cord 1 NCT05003388 The Foundation for All forms of MS 15
derived MSC Orthopaedics and
Regenerative Medicine
Intrathecal autologous MSC- Expanded access NCT03822858 Tisch Multiple Sclerosis Progressive MS Unspecified
neural progenitor cells Research Center of New
York
Intravenous MSC (IMS001) 1 NCT04956744 ImStem Biotechnology All forms of MS 30
Donated human umbilical cord 1 NCT04943289 Duke University Primary progressive MS 20
blood mononuclear cells
Intrathecal MSC 1/2 NCT04749667 Haukeland University Hospital Secondary progressive or 18
primary progressive MS
Adipose derived mesenchymal 2 NCT05116540 Hope Biosciences Stem Cell Relapsing MS 24
stem cells (autologous) Research Foundation

AHSCT, autologous hematopoietic stem cell transplantation; MS, multiple sclerosis; MSC, mesenchymal stem cell.

268 www.co-neurology.com Volume 35
Number 3
June 2022

 New drugs for multiple sclerosis, new treatment algorithms Cree et al.
alemtuzumab or natalizumab) in a phase 3 random-
ized, rater-blinded trial in rigorously defined treat-
ment-resistant relapsing RMS (NCT04047628). The
more rigorously designed, randomized trials hope-
fully will provide clearly interpretable results.
Several uncontrolled, single-arm trials are
studying mesenchymal stem cells either through
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intrathecal transplantation or intravenous infusion
as a neuroregenerative or neuroprotective or treat-
CywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 04/16/2023
ment in MS (NCT05003388, NCT03822858,
NCT04956744, NCT04943289). It is unclear what
value these small, uncontrolled studies will add to
the present understanding of either intrathecal or
intravenous administered stem cells. Two clinical
trials utilize control groups and have the potential
to demonstrate therapeutic benefits. One is a phase 1/
2 study using a blinded, cross-over study design will
assess evoked potentials in progressive RMS
(NCT04749667) and the other is a phase 2, random-
ized, blinded, placebo-controlled trial will assess
the impact of intravenously infused adult-derived,
mesenchymal stem cells on MS quality of life
(NCT05116540).
CONCLUSION
A diagnosis that once carried dismal prospects for
many is now a treatable disease with a much-
improved prognosis. MS relapses can be almost
completely eliminated and progressive disability
at least partially slowed. Irreversible end-organ
injury resulting in brain atrophy might be prevent-
able with HEFT. Taken together these breakthroughs
are a wonderful achievement of modern medicine
and one of the most important advances in clinical
neurobiology of the century. The incredible number
of diverse treatments under investigation bodes well
for development of better and more effective thera-
pies. Nonetheless, there are fundamental deficits in
our understanding of the molecular and cellular
mechanisms that underlie disease progression. Until
the precise mechanisms that cause irreversible dis-
ability are understood, it seems unlikely that defin-
itive treatments to arrest this most vexing aspect of
MS will be definitively developed. Further, our
understanding of the inhibitory mechanisms that
prevent neuronal CNS repair need elucidation.
Thus, much work in the basic science of MS is
needed to propel a next generation of treatments
forward.
Acknowledgements
None.
Financial support and sponsorship
None.
1350-7540 Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.
Conflicts of interest
B.A.C.C. received personal compensation for consulting
from Alexion, Atara, Autobahn, Avotres, Biogen, EMD
Serono, Gossamer Bio, Horizon, Neuron23, Novartis,
Sanofi, TG Therapeutics and Therini and received
research support from Genentech. H.-P.H. received per-
sonal compensation for serving on steering and data
monitoring committees from BayerHealthcare, Biogen,
BMS Celgene, GeNeuro, Merck KG Darmstadt, Novartis,
Roche, TG Therapeutics, VielaBio. M.B. received per-
sonal compensation for consulting from Novartis and
Autobahn Therapeutics and research support from Bio-
gen, Novartis, Sanofi-Genzyme, Merck, Alexion and
Bristol Myers Squibb and is Research Director at the
Sydney Neuroimaging Analysis Centre.
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[Online ahead of print]
Volume 35
Number 3
June 2022