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2020 Edition RESEARCH MS U P D A T E
MS
Written and compiled by
Tom Garry and Pete Kelly
Reviewed by Barry Hendin, MD,
MSAA Chief Medical Officer
RESEARCH
UPDATE
Edited by Susan Courtney,
MSAA Senior Writer
The Multiple Sclerosis Association of America (MSAA) is pleased to present this 2020
edition of its MS Research Update. The Update highlights important new data on
approved and experimental treatments for MS, and is provided to serve as a
comprehensive resource for the entire MS community. Please note that the MS Research
Update focuses on research related to approved and experimental medications and
therapies for the long-term treatment of multiple sclerosis. It does not include
information on symptom-management medications or therapies.
For additional information about MS, symptoms and symptom management, as well as
MSAA’s programs and services, please visit mymsaa.org or call (800) 532-7667. Also,
please note that due to the timing of national and international MS conferences, study
data from 2020 conferences generally could not be included in the Update. Information
in this publication includes data presented at 2019 conferences, as well as important
updates that occurred in the early months of 2020. Please visit MSAA’s website
at mymsaa.org for future summaries of 2020 conference highlights.
The 2020 MS Research Update is made possible through contributions in honor of:
Dr. Jules Kernan and Ms. Hannah Dennehy Lee and an anonymous supporter
Multiple Sclerosis Association of America
National Headquarters
375 Kings Highway North
Cherry Hill, New Jersey 08034
Website: mymsaa.org
Toll-free phone: (800) 532-7667
Email: msaa@mymsaa.org
CONTENTS
Introduction ............................................................................................2
FDA-APPROVED MEDICATIONS: RECENTLY APPROVED
Zeposia® (ozanimod) ........................................................................7
Bafiertam™ (monomethyl fumarate) ................................................9
Vumerity® (diroximel fumarate) ......................................................10
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS The Multiple Sclerosis Association
of America (MSAA) is a leading
INFUSED MEDICATIoNS ....................................................................13 resource for the entire MS
ocrevus® (ocrelizumab) ..................................................................13 community, improving lives today
Tysabri® (natalizumab)......................................................................15
through vital services and support.
Lemtrada® (alemtuzumab) ..............................................................17
oRAL MEDICATIoNS ..........................................................................19 MSAA publications are intended
Mayzent® (siponimod)......................................................................19 to inform and educate those with
Mavenclad® (cladribine) ..................................................................21 MS and their families. MSAA does
Tecfidera® (dimethyl fumarate) ......................................................22 not endorse or recommend any
Aubagio® (teriflunomide) ................................................................24 specific products, services,
Gilenya® (fingolimod) ......................................................................25 therapies, or activities mentioned
in articles or advertisements that
INJECTABLE MEDICATIoNS ..............................................................27 appear in MSAA publications.
Rebif® (interferon beta-1a) ..............................................................27 MSAA, its staff, and those affiliated
Plegridy® (peginterferon beta-1a) ..................................................27 with the writing of this publication
cannot be held responsible for
EXPERIMENTAL MEDICATIONS any unintentional errors.
MoNoCLoNAL ANTIBoDIES............................................................29
ofatumumab......................................................................................29 MSAA strives to provide useful,
Ublituximab........................................................................................30 up-to-date information on matters
opicinumab ......................................................................................31 of concern to MS patients and
Rituxan® (rituximab) ..........................................................................32 their families. This material is
Temelimab ........................................................................................33 intended for general informational
purposes only, and it does not
S1P RECEPToR MoDULAToRS ........................................................34 constitute medical advice. You
Ponesimod ........................................................................................34 should not use the information
presented as a means of
ADMINISTERED oRALLY ....................................................................35
diagnosis or for determining
Evobrutinib ........................................................................................35
treatment. For diagnosis and
Ibudilast (also known as MN-166) ..................................................35
treatment options, you are urged
CNM-Au8 ..........................................................................................36
MD1003..............................................................................................37 to consult your physician.
NEW DIRECTIONS IN MS RESEARCH Copyright © Multiple Sclerosis
Association of America, 2020. All
Stem Cell Therapies ..........................................................................38 rights reserved. No part of this
Diet and MS ......................................................................................41 publication may be reproduced,
Gut Microbiome ................................................................................43
stored in a retrieval system, or
Vitamin D ............................................................................................45
transmitted in any form or by any
Biomarkers ........................................................................................46
means, electronic, mechanical,
Genetics..............................................................................................47
photocopying, recording, or
Closing Notes ......................................................................................50 otherwise, without prior written
permission from MSAA.
References ............................................................................................51
Multiple Sclerosis Association of America 1 MS RESEARCH UPDATE 2020
MS
RESEARCH
UPDATE
Introduction report. Rather, the items presented here were
selected for their relevance to current or
The 2020 MS Research Update reviews future patient care, and with a view toward
new data and findings on: showcasing the breadth of work being done
• Disease-modifying therapies (DMTs) to understand and treat MS. The information
approved by the FDA, including recently that follows is drawn from a variety of sources,
approved medications and those that have including journal literature on MS and its
been available for several years management, a review of ongoing clinical
• Experimental drugs under investigation trials, and presentations at major national
for the long-term treatment of multiple and international conferences.
sclerosis (MS) Please note that this MS Research
Update reports on the most recent study
• New therapeutic approaches and treatment
results available at the time of publication.
targets, such as stem cell therapy and the
gut microbiome While every effort has been made to provide
meaningful, timely, and balanced information,
• Promising areas of inquiry that are keeping the amount of information equal for
enhancing researchers’ and clinicians’ each medication covered is not possible.
understanding of MS, such as genetics and Please understand that the different degree
biomarkers of coverage given to the various therapies
While this 2020 edition of MSAA’s MS should in no way be considered as favoritism
Research Update provides a comprehensive toward any one medication or treatment
overview of important areas of inquiry and approach. Additionally, references have been
study findings, it is not an exhaustive cited only for newer study results.
compilation of all relevant data released in the While medications for management of MS
past year. There is – fortunately – far too much symptoms are beyond the scope of this
ongoing research for summation in a single report, information on the specific symptoms
Multiple Sclerosis Association of America 2 MS RESEARCH UPDATE 2020
INTRODUCTION
of MS and their treatment is available in the biotechnology company investigating the
symptoms section of MSAA’s website. monoclonal antibody temelimab for use in
Providing these resources is at the heart of primary- and secondary-progressive MS, in
MSAA’s mission of being a leading resource March announced the postponement of a
for the entire MS community, improving lives planned Phase II trial of the medication in
today through vital services and support. order to “prioritize healthcare resources
Feedback and thoughts on the 2020 MS behind the fight of CoVID-19 and to reduce
Research Update are welcomed. These can the risk for MS patients.” 1 Meanwhile,
be directed to MSAA at editor@mymsaa.org. MediciNova, the company developing the
oral medication ibudilast for potential use in
Overview of MS Research Progress relapsing forms of MS, announced in April that
Never before have so many people been it also will study the medication for use in
so keenly aware of the importance of medical acute respiratory distress syndrome (ARDS)
research. With the arrival of the CoVID-19 caused by CoVID-19. 2
pandemic in early 2020, people who just a While some temporary delays, detours,
few months earlier had only a passing and distractions may be part of the near-term
familiarity with the drug-development impact of CoVID-19 on the MS research
process, now understand more about the agenda, the long-term effect hopefully will
different trial phases. include an enduring commitment to funding
This widespread appreciation for research against the full range of conditions –
therapeutic innovation is just one of many acute and chronic – that harm health and
ways the coronavirus has changed life for all threaten lives. Meanwhile, investigators in
people. For those with MS, however, the clinics, hospitals, and laboratories around the
pandemic brings additional concerns and world continue to explore the biological
considerations. Does taking a disease- processes that lead to MS onset and
modifying therapy (DMT) that affects the progression, and the treatment approaches
immune system increase the risk of that can reduce or even halt disease activity.
contracting CoVID-19? Does having a chronic There is abundant evidence that this
condition, such as MS, suggest more severe research effort is making progress on many
symptoms and worse outcomes should a fronts. one of the most tangible markers of
person become infected? For information on success is the expanding array of disease-
those topics and related issues, visit the modifying therapies (DMTs) available to treat
Coronavirus and MS section of MSAA’s MS.
website. Since the publication of MSAA’s 2019 MS
Beyond its impact on the daily lives of Research Update, the FDA has approved three
people with MS, the CoVID-19 pandemic also more DMTs. In April 2020, Bafiertam™
is affecting the course of multiple sclerosis (monomethyl fumarate) received approval for
research. For example, GeNeuro, a use in relapsing forms of MS. The Banner Life
Multiple Sclerosis Association of America 3 MS RESEARCH UPDATE 2020INTRODUCTION
Sciences’ medication is an oral agent taken March 2020, the FDA approved the
twice daily. It is a fumarate-type medication, sphingosine 1-phosphate (S1P1)-receptor
as is Biogen’s Tecfidera® (dimethyl fumarate). modulator for use in relapsing forms of MS.
Bafiertam obtained FDA approval after Banner Two other S1P1-receptor modulators,
Life Sciences showed that the medication is a Gilenya® (fingolimod) and Mayzent®
“bioequivalent alternative” to Tecfidera, (siponimod), also are FDA-approved for MS.
meaning that the active ingredient and site of How this class of medication exerts a
action do not differ significantly between the therapeutic effect in MS is not completely
two medications.3 Because Tecfidera can understood. However, the mechanism of
cause gastrointestinal (GI) effects – including action may involve reducing the number of
nausea, vomiting, and diarrhea – in some lymphocytes – white blood cells involved in
patients,4 biopharmaceutical companies have immune function – that migrate to the central
explored formulations of fumarate medications nervous system (CNS), where they may
that would have efficacy against MS – as contribute to damaging the myelin sheath
Tecfidera has demonstrated – with fewer GI that protects nerves. 7
side effects. In the case of Bafiertam, this goal Turning from medications approved by
is being pursued through use of a daily dose the FDA to those now being evaluated by
lower than that for Tecfidera. 4, 5 However, the FDA, Janssen/Johnson & Johnson is
whether or not Bafiertam causes fewer GI side requesting that another S1P1-receptor
effects has not yet been determined and has modulator, ponesimod, be approved for
not been evaluated in clinical trials in people treating adults with relapsing forms of MS. 8
with relapsing forms of MS. The request is based on data from the Phase
Another of the three recently approved III oPTIMUM trial, in which patients treated
medications pursues the same goal of with ponesimod had lower average
reducing GI side effects by other means. In annualized relapse rates than those receiving
october 2019, the FDA authorized use of an already approved DMT, Aubagio®
Vumerity® (diroximel fumarate) in relapsing (teriflunomide). 9, 10
forms of MS. Also an oral medication taken Meanwhile, the FDA is conducting a
twice daily, Vumerity was developed by priority review of ofatumumab for the
Biogen – which markets Tecfidera – and the treatment of relapsing forms of MS. Novartis,
Irish pharmaceutical company Alkermes plc. In which markets the agent collaboratively with
this case, the chemical structure of Vumerity Genmab, says ofatumumab could be
differs from that of Tecfidera, and the recently approved as early as this summer. 11 The
approved medication has been shown to monoclonal antibody, which already is
cause fewer GI side effects than Tecfidera. 6 indicated for treating chronic lymphocytic
The third medication recently approved by leukemia,12 binds to the CD20 molecule
the FDA is Zeposia® (ozanimod), a once-daily located on the surface of lymphocytes, a type
oral medication from Bristol Myers Squibb. In of white blood cell. Lymphocytes trigger the
Multiple Sclerosis Association of America 4 MS RESEARCH UPDATE 2020INTRODUCTION
abnormal immune response that damages the -10 inhibitor that suppresses pro-inflammatory
protective sheath (myelin) surrounding nerve molecules and promotes nerve-growth
cells in the brain and spinal cord. By binding factors.17
to CD20, the lymphocytes are destroyed and on another research front, investigators
neuronal damage is prevented or delayed. continue to assess previously approved
ofatumumab is self-injected medications, examining their long-term
subcutaneously once a month, allowing for at- effectiveness and safety, both in the overall
home administration.13 Novartis and Genmab MS population and in specific groups of
are seeking approval for use of ofatumumab people with MS. This MS Research Update
in MS based on data from the Phase III reports on studies evaluating the impact of
ASCLEPIoS I and ASCLEPIoS II trials, in which starting specific DMTs earlier rather than later
ofatumumab outperformed Aubagio in following diagnosis, and of switching from
slowing disease progression in RMS. 11 one DMT to another. Inquiries are also
Phase III trials, which generate the main examining how approved DMTs are affecting
data used to pursue FDA approval, are under efficacy measures beyond relapse rates and
way or planned for other potential MS MRI findings, such as confirmed disability
treatments. TG Therapeutics hopes to provide progression, and the need for wheelchair use.
results later this year from two simultaneous In terms of safety, research is examining the
Phase III trials assessing the safety and frequency and nature of adverse events with
effectiveness of its monoclonal antibody multi-year use, how DMTs affect maternal and
ublituximab in relapsing forms of MS.15 EMD fetal outcomes when used during pregnancy,
Serono will evaluate its oral investigational and whether altering dosing schedules can
agent evobrutinib in patients with relapsing reduce the incidence of adverse effects.
MS in the Phase III EVoLUTIoN RMS 1 and Beyond evaluating pharmacologic agents,
EVoLUTIoN RMS 2 studies.16 Evobrutinib a plethora of research is probing the
inhibits Bruton's tyrosine kinase (BTK), an therapeutic potential of interventions ranging
enzyme that contributes to the development from stem cell therapy and dietary
and function of B lymphocytes, a type of white adjustments, to Vitamin D supplementation
blood cell that can attack and destroy the and altering the gut microbiome. other
neuroprotective myelin sheath that surrounds studies are looking at the role genetics and
nerve cells.16 other factors may play in the development
MediciNova is organizing a Phase III trial and course of MS, and at how biomarkers
that will determine whether its oral medication such as serum neurofilament light (NfL) can
ibudilast, also known as MN-166, can slow help in monitoring MS status and informing
disease progression in more-severe, non- treatment decisions. All of these topics are
relapsing MS. Ibudilast is a small molecule addressed in the sections that follow.
macrophage migration inhibitory factor (MIF) In short, thousands of clinicians and
inhibitor and phosphodiesterase (PDE) -4 and researchers around the world are exploring
Multiple Sclerosis Association of America 5 MS RESEARCH UPDATE 2020INTRODUCTION INTRODUCTION
various aspects of MS, and their collective understand, more effectively manage, and
efforts promise even further progress in the one day defeat multiple sclerosis. If you
years just ahead. It is important to remember, already are counted among their ranks, you
however, that the work of these physicians, have our deepest gratitude. If you have not
nurses, biochemists, pharmacologists, and participated to date, we would encourage
others would not be possible without the interested readers to ask their providers about
selfless participation of even larger numbers possible opportunities to become involved in
of people with MS. The patients who enroll in MS research. For more information about
clinical trials, submit data to registries, and participating in clinical trials for the treatment
otherwise contribute to research, play an of MS and its symptoms, readers may
invaluable role in the effort to better visit mymsaa.org/clinicaltrials.
Editor’s note: Initial study results for therapeutic agents under investigation should be
considered preliminary because additional studies and/or evaluations may be needed to
determine the long-term safety and efficacy of these agents. MSAA does not endorse or
recommend any specific products or therapies. Readers are advised to consult their physician
before making any changes to their medication, diet, exercise, or other treatment regimen.
TRIAL PHASES FOR INVESTIGATING TREATMENTS
Phase I Phase II Phase III Phase IV
Phase I studies are once a drug has been In a Phase III study, a Phase IV clinical trials
primarily concerned shown to be safe, it must drug is usually tested in are conducted after a
with assessing the be tested for efficacy. This several hundred to drug has been
drug’s safety. This second phase of testing several thousand approved.
initial phase of testing may last from several patients, usually in Participants are
in humans is done in a months to two years, and multiple medical enrolled to further
small number of involve up to several facilities around the monitor safety and
healthy volunteers, hundred patients. Phase II world. Phase III studies side effects, while
and is designed to studies are often “double- typically last two or evaluating long-term
determine what blinded,” meaning that more years. only after a efficacy.
happens to the drug the participants, medical Phase III study is
in the human body – staff, and investigators are successfully completed
how it is absorbed, not told who is receiving can a pharmaceutical
metabolized, and the drug and who is company request FDA
excreted. receiving the placebo. approval for marketing
the drug.
Multiple Sclerosis Association of America 6 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
Medications Recently Approved
Three more medications have joined the ranks of FDA-approved therapies for MS since the
2019 MS Research Update was posted. They are: Zeposia® (ozanimod), approved in March
2020; Bafiertam™ (monomethyl fumarate), approved in April 2020; and Vumerity® (diroximel
fumarate), approved in october 2019. To follow is information on these medications, their
approved uses and dosages, and their clinical data.
Zeposia® (ozanimod) to the term “multiple sclerosis.”
Two other S1P1-receptor modulators,
Company: Bristol Myers Squibb Gilenya® (fingolimod) and Mayzent®
n Starting dose: 0.23 mg orally once daily on (siponimod) are also approved by the FDA for
Days 1-4, followed by 0.46 mg orally on treating MS. Additionally, Janssen/Johnson &
Days 5-7 Johnson has asked the FDA to approve
another medication in this class, ponesimod,
n Maintenance dose: 0.92 mg orally once for the treatment of relapsing forms of MS in
daily on Day 8 and thereafter adults.
n Approved in March 2020 for relapsing Zeposia is an oral medication taken once
forms of MS, including clinically isolated daily. The initial dose of 0.23 mg on Days 1-4 is
followed by a dose of 0.46 mg on Days 5-7,
syndrome, relapsing-remitting disease, and
with a once-daily dose of 0.92 mg starting on
active secondary-progressive disease, in
Day 8 and continuing thereafter.7 This
adults.
approach to increasing the starting dose over
Zeposia® (ozanimod) is a sphingosine a few days, which clinicians call “up-titration,”
1-phosphate (S1P1)-receptor modulator, is necessary because some people starting
meaning that it binds to two receptors – S1P1 Zeposia may experience initial but temporary
and S1P5 – on the surface of cells.7 While the decreases in heart rate and delays in the way
exact mechanism by which Zeposia exerts a electrical signals are transmitted in the heart.7
therapeutic effect in MS is not completely Before beginning Zeposia, people should
understood, the medication’s impact may have a complete blood count (CBC), an
involve reducing the number of lymphocytes electrocardiogram (ECG), and liver function
that migrate to the central nervous system tests (which involve analyzing a sample of
(CNS), where lymphocytes may contribute to blood that can be obtained from the same
damaging the myelin sheath that protects blood draw performed for the CBC).
nerves. This damage results in lesions, or areas Physicians are advised to consider what other
of sclerosis (scarring/hardening), at different medications a person is taking in order to be
locations along the myelin sheath, giving rise aware of any potential interactions between
Multiple Sclerosis Association of America 7 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
those medications and Zeposia. They also number of T1-weighted gadolinium-
need to conduct an eye examination in enhanced brain lesions more than Avonex
patients with a history of certain (0.16 vs 0.43), which is a relative reduction of
ophthalmologic problems, and to vaccinate 63%, and reduced the number of new or
patients against varicella zoster virus (VZV) if enlarging T2 lesions (1.47 vs. 2.84), which is a
their blood does not contain antibodies relative reduction of 48%. 7, 20 At two years,
against that virus, which causes chickenpox Zeposia achieved a 53% relative reduction in
and shingles. T1-weighted gadolinium-enhanced brain
Zeposia is contraindicated in people who lesions and a 42% relative reduction in new
in the last six months experienced a heart or enlarging T2 lesions, compared to the
attack, stroke, coronary-related chest pain, interferon-based therapy. 7, 19
or certain other cardiovascular conditions.7 However, in two other measures examined
Unlike other approved S1P1-receptor in the trials – impact on three-month and six-
modulators, however, the FDA-approved month confirmed disability progression (CDP),
prescribing information for Zeposia does not there was not a statistically significant
direct that people taking the medication be difference between patients in the Zeposia
monitored after their first dose for possible group and those in the Avonex group over
cardiac issues.18 the course of two years.7
The FDA’s approval of Zeposia is based on In the Phase III clinical trials, the most
data from two large Phase III trials, SUNBEAM common adverse reactions (occurring in 4%
and RADIANCE Part B, which together or more of people receiving Zeposia) were
enrolled more than 2,600 people with MS. upper respiratory infection, liver enzyme
Both trials examined the safety and efficacy of elevations, a fall in blood pressure upon
Zeposia relative to Avonex® (interferon beta- standing (orthostatic hypotension), urinary
1a). This interferon-based treatment is one of tract infection, back pain, and hypertension.
the first therapies approved for multiple Please note that in clinical trials, all adverse
sclerosis.18 effects reported by study subjects are
In the two studies, people taking Zeposia recorded; these events may or may not be
had an annualized relapse rate (ARR) – a related to the medication. This is why control
measure of the average number of relapses or placebo groups are used to compare with
a group of patients will experience over the groups receiving the experimental medication
course of 12 months – of 0.18 at one year being studied.7
compared to 0.35 for Avonex, and of 0.17 People who participated in SUNBEAM,
versus 0.28 for Avonex over two years. Those RADIANCE Part B, and earlier, Phase II studies
rates translate into Zeposia providing a relative of Zeposia were eligible to enter an extension
reduction in ARR of 48% at one year and 38% study assessing the long-term safety and
at two years compared to Avonex.7, 19, 20 efficacy of the medication. Researchers
Further, at one year, Zeposia reduced the recently reported on an interim analysis of
Multiple Sclerosis Association of America 8 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
data on almost 2,500 patients who Bafiertam™ (monomethyl fumarate) is an
participated in that extension trial. oral medication taken twice daily for relapsing
Among patients who took 1 mg of Zeposia forms of MS. It is a fumarate-type medication,
in any of the earlier trials and who then as is Tecfidera® (dimethyl fumarate). Bafiertam
continued that dose over an average of 19.2 secured FDA approval after its developer,
months in the follow-up study, the ARR was Banner Life Sciences, demonstrated that the
0.126. Meanwhile, people who had taken an medication is a “bioequivalent alternative” to
interferon-based medication in an earlier trial Biogen’s Tecfidera, meaning that the active
and then switched to Zeposia in the extension ingredient and site of action do not differ
study, had a very similar annualized relapse significantly between the two medications.3, 5
rate – 0.123 – over an average of 18.3 months The issue of bioequivalence is important
in the follow-up study. because Tecfidera has demonstrated efficacy
The incidence and nature of adverse in treating relapsing forms of MS but can
events were similar to those seen in the cause significant gastrointestinal (GI) effects –
Phase III studies. The most common adverse including nausea, vomiting, and diarrhea – in
event during the extension study was some patients.4 As a result, drug developers
nasopharyngitis (a cold or sore throat), which have sought to find formulations of fumarate
was reported by 11.3% of participants. Just medications that offer similar efficacy but have
under 6% of participants reported a serious fewer GI side effects. These efforts include
treatment-emergent adverse event, and just Biogen partnering with Ireland-based
over 1% of participants stopped participating Alkermes to develop the recently approved
in the study due to an adverse event.21 Vumerity® (diroximel fumarate), as detailed
below, and Banner Life Science’s
development of Bafiertam.
Bafiertam™ The starting and maintenance doses of
(monomethyl fumarate) Bafiertam are lower than those for Tecfidera.4, 5
With the daily doses assumed to be
Company: Banner Life Sciences
equivalent in terms of their efficacy, the hope
n Starting dose: 95 mg twice a day, orally, for is that the reduced amount of Bafiertam will
7 days result in fewer GI side effects while providing
n Maintenance dose after 7 days: 190 mg similar benefit against relapses and other
(administered as two 95 mg capsules) twice manifestations of MS. Although not studied
a day, orally in MS patients, a recent study compared the
gastrointestinal tolerability of Bafiertam to
n Approved in April 2020 for relapsing forms Tecfidera in 210 healthy adults without MS.
of MS, including clinically isolated syndrome, The five-week study has been completed,
relapsing-remitting disease, and active but results were not posted at the time of this
secondary-progressive disease, in adults. writing.22, 23
Multiple Sclerosis Association of America 9 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
The exact mechanism of action by which thereafter (as well as when clinically
fumarate medications exert their therapeutic indicated).5
effect in MS is not completely understood. According to Banner, Bafiertam may
However, the monomethyl fumarate molecule cause flushing, which may be experienced as
is thought to activate an antioxidant protein warmth, redness, itching, and/or a burning
that reduces oxidative stress, which in turn sensation. In clinical trials with Tecfidera,
slows damage to protective nerve fibers in 40% of treated patients experienced flushing,
the brain. Clinical trials with Tecfidera showed which in most cases was mild to moderate in
a reduction in relapse rate, a delay in severity. As noted earlier, other common side
progression of physical disability, and a effects include: redness, itching, or rash;
slowing in the development of brain lesions, nausea, vomiting, diarrhea, stomach pain, or
as compared to placebo. indigestion. Flushing and stomach problems
According to the prescribing information are the most common reactions, especially at
for Bafiertam, the starting dose is one 95-mg the start of therapy, and may decrease over
oral capsule taken twice daily for the first time.3
seven days. The maintenance dose after seven
days is two 95-mg capsules (for a total of 190 Vumerity® (diroximel fumarate)
mg) taken twice daily. The prescribing
Company: Biogen Inc. and Alkermes plc
information also warns not to crush, chew, or
mix contents of the delayed-release oral n Starting dose: 231 mg twice a day, orally, on
capsules with food. However, Bafiertam may Days 1-7
be taken with or without food.
n Maintenance dose after seven days: 462 mg
Warnings, side effects, and adverse events
(administered as two 231-mg capsules) twice
are similar to those listed for Tecfidera. a day, orally
Bafiertam is contraindicated in patients with
known hypersensitivity to monomethyl n Approved in October 2019 for relapsing
fumarate, dimethyl fumarate, diroximel forms of MS, including clinically isolated
fumarate, or to any of its inactive ingredients. syndrome, relapsing-remitting disease, and
Allergic reactions, PML (progressive multifocal active secondary-progressive disease, in
leukoencephalopathy), herpes zoster and adults
other serious opportunistic infections, Vumerity® (diroximel fumarate) is a
decreases in white blood cell counts, and liver fumarate agent, as is Biogen’s Tecfidera®
injury, are among the potential serious (dimethyl fumarate). However, it has a
adverse events that could occur. Blood tests, chemical structure that is distinct from
including a complete blood count (CBC) and Tecfidera, and has been shown to cause fewer
lymphocyte count, need to be performed gastrointestinal (GI) side effects – such as
prior to starting treatment, six months after diarrhea, nausea, vomiting, and abdominal
starting treatment, and every six to 12 months pain – than Tecfidera. The exact mechanism of
Multiple Sclerosis Association of America 10 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
action by which diroximel fumarate exerts its compared the GI tolerability of Vumerity with
therapeutic effect in MS is not completely that of Tecfidera. 24
understood. However, upon entering the EVoLVE-MS-2 was a multi-center, double-
body, the medication is rapidly converted into blind, active-controlled, five-week study
the molecule monomethyl fumarate. The involving 506 patients with relapsing forms of
converted molecule is thought to activate an MS. The primary endpoint was the number of
antioxidant protein that reduces oxidative days patients reported GI symptoms with a
stress, which in turn slows damage to symptom intensity score ≥2 on the Individual
protective nerve fibers in the brain.6 Gastrointestinal Symptom and Impact Scale
The FDA’s october 2019 approval of (IGISIS) rating scale. Secondary endpoints
Vumerity was based on a new drug included the number of days (relative to
application (NDA) that included data from exposure) that patients reported GI symptoms
pharmacologic studies comparing Vumerity with IGISIS intensity scores of ≥1 or ≥3 in the
and Tecfidera. By demonstrating that the two overall population. Patients who completed
agents were similar in many key respects, or the five-week treatment period were eligible
had “bioequivalence,” Biogen and Alkermes to enroll in EVoLVE-MS-1, the 96-week, open-
were able to ask the FDA to consider findings label, safety study referenced above.
on the safety and efficacy of Tecfidera as part Results for the primary endpoint showed
of the evidence supporting Vumerity.6 that patients treated with Vumerity reported
The application also included interim 46% fewer days with intensity scores of ≥2 on
exposure and safety findings from EVoLVE- the IGISIS, compared to Tecfidera.
MS-1, an ongoing, Phase III, single-arm, The EVoLVE-MS-2 results also found that
open-label, two-year safety study evaluating compared to people taking Tecfidera, patients
Vumerity in patients with relapsing-remitting receiving Vumerity had:
MS. Interim results from EVoLVE-MS-1 at the
• Lower discontinuations due to GI adverse
time the application was submitted included
events (0.8% vs. 4.8%).
a low overall rate of Vumerity treatment
discontinuation due to adverse events • Fewer days with IGISIS intensity scores of ≥1
(6.3%), which included less than 1% of and ≥3 (29% relative reduction and 44%
patients discontinuing Vumerity due to relative reduction, respectively).
gastrointestinal (GI) adverse events. • Fewer days with a self-reported intensity
Additional exploratory efficacy endpoints in score of ≥1 (30% reduction on the Global
the ongoing EVoLVE-MS-1 study showed Gastrointestinal Symptom and Impact Scale
changes in clinical and radiological measures [GGISIS], which assessed the overall intensity
compared to baseline. 6 of GI symptoms, their impact on daily
A few weeks after the FDA approved activities and how bothersome they were).
Vumerity, Biogen presented data from another Fewer days with GGISIS intensity scores of
Phase III study, EVoLVE-MS-2, that directly ≥2 and ≥3 were also observed.
Multiple Sclerosis Association of America 11 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
RECENTLY APPROVED
• A gradual decline in worst IGISIS intensity adverse effects were mild or moderate in
scores over the five-week treatment period. severity. overall, 1.6% of patients receiving
These findings that use the patient- Vumerity and 5.6% of those taking Tecfidera
assessed symptom intensity scales were experienced adverse effects that caused
supported by lower investigator-reported them to stop participating in the study.
incidences of GI adverse events with Among those patients who discontinued
Vumerity (34.8%) compared to Tecfidera due to any adverse effect, 0.8% in the
(49.0%). overall, adverse events occurred in Vumerity group stopped due to GI effects,
78.3% of patients receiving Vumerity and as compared to 4.8% in the Tecfidera
83.7% taking Tecfidera, but most of those group.24
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MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
Please note that not all of the approved treatments for MS have been included in this section.
For a full listing, please see MSAA’s treatment chart giving an overview of the approved DMTs.
INFUSED MEDICATIONS
Ocrevus® (ocrelizumab) of ocrevus in RRMS, researchers said.
During the oPERA trials, ocrevus showed
Company: Genentech and Roche Pharma AG superiority over an interferon-based
n Starting dose: 300 mg given via IV medication in slowing disease activity and
infusion, followed two weeks later by a progression over 96 weeks.25 Patients who
second 300-mg infusion completed the 96-week, double-blind
n Subsequent doses: 600 mg given via IV comparison trial entered a four-year, open-
infusion every six months label extension phase, during which they
either stayed with or switched to ocrevus.
n Approved in 2017 for relapsing forms of
Among patients who switched from the
MS (RMS) and primary-progressive MS
interferon medication to ocrevus, adjusted
(PPMS)
annualized relapse rates (ARR) fell from 0.20
ocrevus® (ocrelizumab) is a humanized in the year before the switch to 0.04 at Year 4
monoclonal antibody, meaning that it is an of the open-label phase. Patients who stayed
antibody from a non-human species whose on ocrevus after the comparison phase also
protein sequences have been modified to saw a decrease in ARR during the same
increase their similarity to antibodies period, from 0.13 to 0.05.26
produced naturally in humans. ocrevus works Another analysis suggests that early and
by destroying the CD20 receptor, a molecule intensive intervention with ocrevus may
that helps B cells receive messages from provide meaningful benefit for people with
throughout the body. Destroying the CD20 MS who suffer early severe disability.
depletes the B cells that can trigger Researchers performed a post-study
neurodegeneration in MS. analysis of the oPERA I, oPERA II, and
A recent study found that people with oRAToRIo trials, in which ocrevus showed
relapsing-remitting MS (RRMS) who start efficacy in slowing disease activity and
ocrevus early and respond to the progression in patients with relapsing-
monoclonal antibody may continue to benefit remitting MS over 96 weeks, and in patients
from the medication many years later. The with primary-progressive MS (PPMS) over 120
findings, from an open-label extension of the weeks or longer. Drawing on data from those
oPERA I and oPERA II Phase III clinical trials, trials, investigators identified 882 patients
offer solid evidence for sustained first-line use with baseline Expanded Disability Status
Multiple Sclerosis Association of America 13 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
Scale (EDSS) scores of 4.0 or greater, 92 effects 10 patients would suffer in 10 years.
patients with baseline EDSS scores >5.0, and A total of 4,501 people with MS received
88 patients with baseline EDSS scores >6.0. ocrevus in the clinical trials, amounting to
(on the EDSS scale, a higher score indicates a 12,559 patient years of exposure. Side-effect
greater degree of disability.) The patients had rates per 100 patient years were:
received ocrevus or a comparator –
interferon beta-1a in oPERA or placebo in • Adverse events: 255
oRAToRIo. • Serious adverse events: 7.52
The researchers found that the incidence • Infections: 77.1
of EDSS score increases over a given 24-week • Serious infections: 2.01
period were significantly lower among • Malignancies: 0.47
patients who received ocrevus compared • Adverse events prompting treatment
with those who received interferon beta-1a or discontinuation: 1.15
placebo. ocrevus-treated patients from the
oRAToRIo trial who had high baseline EDSS Using United States’ claims data and
scores also saw significant reductions in number of vials sold, the researchers then
disability compared with placebo. 27 estimated that as of April 2019, 96,000
Another team of investigators recently patients in the general population with MS
examined the safety of ocrevus in had received ocrevus, and that the
widespread, “real world” use. Researchers prevalence of adverse events in this “real
regularly compare clinical trial data on a world” group is similar to the data reported
medication’s safety with data collected after for the clinical trials group.13
the medication has been approved by the Turning from safety assessments to
FDA and prescribed by clinicians across the measures of effectiveness, investigators in the
country. The purpose is to ensure that no Phase III oPERA I, oPERA II, and oRAToRIo
new “safety signals” or other concerns clinical trials measured serum and plasma
emerge as a medication that had been tested neurofilament light (Nfl) levels in study
in hundreds or thousands of patients in subjects. Nfl levels are an important marker
clinical trials now is given to a much larger of disability and disease progression in MS,
number of people. with those levels tending to be higher in
In one such study of ocrevus, researchers patients experiencing progressive disability
analyzed safety outcomes data from the than in patients with stable disease.28
medication’s Phase II and Phase III trials, and After 96 weeks, NfL levels were
from related open-label extension periods significantly lower among patients who
and sub-studies. Because length of exposure received ocrevus relative to levels in the
to ocrevus varied among participants, rates studies’ comparator groups. Among 621
of adverse events were calculated per 100 people with either RRMS or PPMS whose
patient years, or the number of adverse baseline NfL levels were above the 90th
Multiple Sclerosis Association of America 14 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
percentile of normal, a higher proportion of identified in patients taking the medication.
individuals treated with ocrevus saw their NfL Tysabri became available again in 2006,
decrease to normal levels, compared with based on the implementation of a
those who received interferon beta-1a (81.4% comprehensive risk-management program
vs 58.9% in RRMS) or placebo (40.4% vs that includes testing potential Tysabri users to
16.6% in PPMS). Higher baseline NfL levels see if they have anti-JC virus antibodies.30
also predicted increased disability In an attempt to reduce the risk of PML,
progression in PPMS, and were linked to some clinicians are extending the interval
worse outcomes for patients with RRMS between Tysabri doses, adopting a
treated with interferon beta-1a, as evidenced personalized dosing strategy that has been
by changes in Expanded Disability Status used to mitigate the adverse effects of extra-
Scale, Nine-Hole Peg Test, and Timed 25-Foot strength antibiotics and other medications.31
Walk scores.29 As more physicians stretch out the time
between doses beyond the recommended
Tysabri® (natalizumab) four weeks, researchers decided to assess
how this risk-reduction approach affects the
Company: Biogen medication’s therapeutic effects. 4, 31
n 300 mg given via one-hour IV infusion Investigators leading a two-year study are
every four weeks recording several measures of disease
progression in 61 adults with MS who had
n Approved in 2004 for relapsing forms of
no disease activity in the 12 months before
MS
enrollment. Treatment intervals are being
Tysabri® (natalizumab) is a monoclonal adjusted to maintain the lowest therapeutic
antibody that acts against a molecule concentration of Tysabri (10 mcg/mL) for
involved in the activation and function of each patient before the next dose is given.
lymphocytes, immune system cells produced At the time interim study results were
to fight infection and disease. Tysabri also released, the 10 mcg/mL level had been
acts against the passage of lymphocytes into maintained with extended dosing intervals of
the central nervous system (CNS), which five to seven weeks in 84% of patients. No
consists of the brain, spinal cord, and optic gadolinium-enhanced lesions or new or
nerves. enlarging T2 lesions had been reported.
The FDA approved Tysabri in 2004 based Also, Expanded Disability Status Scale and
on positive results in the Phase III AFFIRM MS Functional Composite scores had not
trial. Tysabri was voluntarily withdrawn from increased, and serum levels of neurofilament
the market in 2005, after three cases of light, an important indicator of MS disease
progressive multifocal leukoencephalopathy activity, had remained low.
(PML), a rare but potentially fatal brain While biomarkers suggested some
infection caused by the JC virus, were degree of disease activity among a subset of
Multiple Sclerosis Association of America 15 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
patients, the findings suggest that Tysabri early had fewer relapses (1.91 vs 3.2) and
dosing intervals can be safely expanded on modestly higher SDMT scores (52 vs 50) in
a patient-by-patient basis.31 the year before starting Tysabri early,
other researchers recently found greater compared with late-treated patients.32
cognitive improvement among people who Tysabri has long-term effectiveness in
started Tysabri early in the course of their MS delaying relapses and slowing disability
than in individuals whose treatment was progression among people with relapsing-
delayed. The findings suggest that the earlier remitting MS, another ongoing study
treatment can be started, the greater the suggests.
chances of maintaining a patient’s cognitive The Tysabri observational Program (ToP),
function, researchers said. begun by the medication’s manufacturer after
A total of 2,069 patients with relapsing MS Tysabri was approved by the FDA in 2004, is
who were treated with Tysabri for at least 12 an open-label, multinational, prospective
months were followed at 58 neurology clinics study that assesses the efficacy and safety of
across Sweden. The participants were divided Tysabri in real-world clinical settings. As of
into two groups: those who started treatment November 2017, the continuing study
within three years after MS onset, and those included 6,148 patients with RRMS who
who started treatment later. Symbol Digit received or are still receiving Tysabri. Median
Modalities Test (SDMT) scores were collected exposure to the medication was 3.3 years,
at the start of Tysabri therapy, at six months and nearly 500 patients received Tysabri for
and at one year after the start of treatment, eight years or longer. Median follow-up was
and annually thereafter. 62 months as of the November 2017 review.
SDMT scores improved overall in During the analysis, the annualized relapse
both groups across the median 72-month rate (ARR) for patients on Tysabri fell from
follow-up, but the rate of improvement was 1.99 in the year before treatment initiation to
an average of 0.38 points per year lower in 0.15. of note, ARRs for individuals taking
the late-treatment group compared with Tysabri were significantly lower among
patients who started treatment early. patients with baseline Expanded Disability
When SDMT scores were examined by Status Scale scores of 3.0 or less, having taken
age, no difference in score trajectory was two or fewer prior disease-modifying
noted among patients younger than age 36 therapies, or no more than one relapse in
years, regardless of when they started the year prior to treatment.
treatment. Among patients aged 36 and Additionally, EDSS scores were stable
older, however, SDMT score improvements throughout the analysis. At 10 years, the
were on average 0.45 points lower per year cumulative probability of 24-week
of follow-up among late-treated patients vs. confirmed disability worsening was 27.8%,
early-treated subjects. and the cumulative probability of 24-week
of note, individuals who started Tysabri confirmed disability improvement was 33.1%.
Multiple Sclerosis Association of America 16 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
of the 5,179 patients with baseline EDSS groups. No differences in mean gestational
scores of 2.0 or higher, 1,210 (23.4%) age or birthweight were found. However,
experienced a confirmed disability major and minor malformations were
improvement event. reported in seven infants in Groups 1 and 2
The safety profile of Tysabri was consistent (women who stopped natalizumab in early
with adverse events (AE) reported in clinical pregnancy or continued throughout),
trials. one or more serious AE was reported compared with one in Group 0 (women who
in 829 patients (13.5%). Infection was the stopped before pregnancy). Anemia was
most common AE, reported by 4.1% of found in five newborns from mothers in
patients. PML occurred in 53 patients (0.9%), Group 2, including three infants who were
while breast cancer and other malignancies born prematurely.
occurred in 1.1%.33 The researchers commented that
Meanwhile, a recent Italian study found continuing Tysabri during pregnancy “is
that use of Tysabri during pregnancy is associated with lower risk of relapses
associated with a lower risk of relapse but a
compared to wash-out and early interruption.
greater incidence of newborn anemia
No worrisome adverse events emerged in
compared to stopping the agent before
newborns. occurrence of anemia is
conceiving.
consistent with previous findings and may
Researchers followed 84 expectant
be biased by prematurity.”34
mothers who were receiving Tysabri at 19 MS
Please note that women who are pregnant
centers. Participants were divided into three
or are planning to become pregnant, while
groups: women whose last Tysabri infusion
occurred before their last menstrual period considering or taking a DMT, are advised to
(Group 0), those who were last infused during consult their physician.
the first trimester of pregnancy (Group 1), and
those who continued treatment throughout Lemtrada® (alemtuzumab)
pregnancy (Group 2).
Company: Sanofi Genzyme
Annualized relapse rates (ARR) during
pregnancy were 1.06 among Group 0 n Intravenous infusion over four hours for
expectant mothers, 0.49 for those in Group 2, two treatment courses:
and 0.09 for women in Group 3. Among the
women who restarted Tysabri after giving n First course: 12 mg/day on five
birth, ARRs 12 months postpartum were 0.39 consecutive days;
for women in Group 0 and 0.23 for women in n Second course: At one year, 12 mg/day on
Group 1.
three consecutive days;
Researchers also analyzed data on the 94
infants who were born during the study and n Approved in 2014 for relapsing forms of
compared pregnancy outcomes among MS
Multiple Sclerosis Association of America 17 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
Lemtrada (alemtuzumab) is a monoclonal original CARE-MS I study, 75% stayed in the
antibody formulated to slow or prevent the study through the entire five-year extension
immune system's destruction of the phase, and 55% required no additional
neuroprotective myelin sheath by killing treatment with Lemtrada or another disease-
white blood (immune) cells. The United modifying therapy.
States’ prescribing information for the After the full nine-year study period:
medication describes the risk of serious • 68% of patients showed no signs of
and potentially fatal adverse events with confirmed disability progression over a
use of the medication, including stroke, given six-month period, and 41% showed
autoimmune conditions, infusion reactions, improvement after confirmed six-month
and certain cancers.35 disability progression.
The EMA made the recommendations
after its drug-safety monitoring committee • The mean increase Expanded Disability
received reports of cardiovascular issues – Status Score (EDSS) was 0.10, suggesting
including heart attacks and strokes – as well as overall minimal disability progression.
immune complications in people with MS Also, 77% of patients had improved or
taking Lemtrada.36 Because of the potential stable EDSS scores.
toxicity associated with Lemtrada, the • 89% of patients showed no gadolinium-
manufacturer advises using the agent only in enhanced lesions, and 68% were free of
"patients who have had an inadequate new or enlarging T2 lesions. Also, 68%
response to two or more [DMTs].”35 showed no disease activity after magnetic
Meanwhile, findings from a recent long- resonance imaging.
term analysis suggest that people receiving
Lemtrada for relapsing-remitting MS may • Median cumulative brain volume loss
retain function nearly a decade after starting (BVL) was 1.97%. Also, median annual BVL
treatment. was 0.22% or less in Years 3 through 9.
over the course of four years, Lemtrada Lemtrada also maintained a consistent
significantly improved clinical and imaging safety profile throughout the extended nine-
outcomes in the CARE-MS I clinical trial and a year period. The cumulative incidence of
subsequent extension study. An additional thyroid-related adverse events was 46%, and
five-year extension trial, ToPAZ, assessed the incidence of immune thrombocytopenia
participants' continuing function and disease (an uncommon disorder marked by reduced
progression. Patients could receive Lemtrada platelet counts) was 2%. overall, the
or another disease-modifying therapy as incidence of drug-related adverse events
needed at the investigators’ discretion. and infections declined over the nine-year
Among Lemtrada-treated patients in the period.37
Multiple Sclerosis Association of America 18 MS RESEARCH UPDATE 2020FDA-APPRoVED MEDICATIoNS:
NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS
ORAL MEDICATIONS
Mayzent® (siponimod) Mayzent was the first FDA-approved oral
drug to treat secondary-progressive MS in
Company: Novartis adults experiencing active disease. Mayzent is
n Starting dose for most patients: 0.25 mg also approved for use in clinically isolated
orally on Day 1, increasing in 0.25-mg syndrome (CIS) and relapsing-remitting MS
increments over five days to 1.25 mg. (RRMS).39
A recent study found that Mayzent may
n For patients with CYP2C9*1/*3 or *2/*3 delay or prevent wheelchair dependence in
genotype, 0.25 mg on Days 1 and 2, some people with secondary-progressive MS
increasing to 0.5 mg on Day 3 and 0.75 on (SPMS). In the Phase III EXPAND study that
Day 4. led to Mayzent receiving FDA approval, the
medication delayed disability progression
n Maintenance dose: 2 mg daily orally for and cognitive decline among those with
most patients; 1 mg daily orally for SPMS.
patients with CYP2C9*1/*3 or *2/*3 Investigators subsequently performed
genotype two analyses on data for participants in the
EXPAND active treatment and placebo
n Approved in 2019 for relapsing forms of
groups. The first analysis measured time to
MS
wheelchair dependence in 412 patients with
Mayzent® (siponimod) is a sphingosine 1- a baseline Expanded Disability Status Scale
phosphate (S1P)-receptor modulator, (EDSS) score of 6.5, which indicates
meaning that it binds to two receptors, called dependence on a walking device and high
S1P1 and S1P5, on the surface of cells. By risk of progression to a wheelchair. In that
binding to these receptors, Mayzent blocks group, EDSS scores increased to 7.0
lymphocytes (a type of white blood cell) from (indicating wheelchair dependence) in 19.8%
leaving the lymph nodes and entering the of Mayzent-treated patients, compared with
peripheral blood. While the mechanism by 26.1% of those in the placebo group.
which Mayzent exerts its effects in MS is not In the second analysis, researchers split
fully understood, it may involve reduction of the overall EXPAND population of 1,645
lymphocyte migration into the central participants into three groups by EDSS score
nervous system (CNS).25 Further, Mayzent range: 5.0 or lower; 5.5 to 6.0; and 6.5. The
binds to S1P1 and S1P5 receptors on investigators then calculated the time each
oligodendrocytes and astrocytes, cells within patient stayed in an EDSS range before
the CNS, which are thought to promote moving to another, and used that information
remyelination and prevent inflammation.38 to predict time to wheelchair dependence for
Multiple Sclerosis Association of America 19 MS RESEARCH UPDATE 2020You can also read
