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2020 Edition

RESEARCHU P D A T EMS

The Multiple Sclerosis Association of America (MSAA) is pleased to present this 2020edition of its MS Research Update. The Update highlights important new data onapproved and experimental treatments for MS, and is provided to serve as acomprehensive resource for the entire MS community. Please note that the MS ResearchUpdate focuses on research related to approved and experimental medications andtherapies for the long-term treatment of multiple sclerosis. It does not includeinformation on symptom-management medications or therapies.

For additional information about MS, symptoms and symptom management, as well asMSAA’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, studydata from 2020 conferences generally could not be included in the Update. Informationin this publication includes data presented at 2019 conferences, as well as importantupdates that occurred in the early months of 2020. Please visit MSAA’s websiteat mymsaa.org for future summaries of 2020 conference highlights.

Written and compiled by Tom Garry and Pete Kelly

Reviewed by Barry Hendin, MD, MSAA Chief Medical Officer

Edited by Susan Courtney, MSAA Senior Writer

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MS

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Introduction ............................................................................................2

FDA-APPROVED MEDICATIONS: RECENTLY APPROVEDZeposia® (ozanimod) ........................................................................7Bafiertam™ (monomethyl fumarate) ................................................9Vumerity® (diroximel fumarate) ......................................................10

NEW DATA ON PREVIOUSLY APPROVED MEDICATIONSINFUSED MEDICATIoNS ....................................................................13

ocrevus® (ocrelizumab) ..................................................................13Tysabri® (natalizumab)......................................................................15Lemtrada® (alemtuzumab) ..............................................................17

oRAL MEDICATIoNS ..........................................................................19Mayzent® (siponimod)......................................................................19Mavenclad® (cladribine) ..................................................................21Tecfidera® (dimethyl fumarate) ......................................................22Aubagio® (teriflunomide) ................................................................24Gilenya® (fingolimod) ......................................................................25

INJECTABLE MEDICATIoNS ..............................................................27Rebif® (interferon beta-1a) ..............................................................27Plegridy® (peginterferon beta-1a) ..................................................27

EXPERIMENTAL MEDICATIONSMoNoCLoNAL ANTIBoDIES............................................................29

ofatumumab......................................................................................29Ublituximab........................................................................................30opicinumab ......................................................................................31Rituxan® (rituximab) ..........................................................................32Temelimab ........................................................................................33

S1P RECEPToR MoDULAToRS ........................................................34Ponesimod ........................................................................................34

ADMINISTERED oRALLY ....................................................................35Evobrutinib ........................................................................................35Ibudilast (also known as MN-166) ..................................................35CNM-Au8 ..........................................................................................36MD1003..............................................................................................37

NEW DIRECTIONS IN MS RESEARCHStem Cell Therapies ..........................................................................38Diet and MS ......................................................................................41Gut Microbiome ................................................................................43Vitamin D............................................................................................45Biomarkers ........................................................................................46Genetics..............................................................................................47

Closing Notes ......................................................................................50

References ............................................................................................51

The Multiple Sclerosis Associationof America (MSAA) is a leadingresource for the entire MScommunity, improving lives todaythrough vital services and support.

MSAA publications are intendedto inform and educate those withMS and their families. MSAA doesnot endorse or recommend anyspecific products, services,therapies, or activities mentionedin articles or advertisements thatappear in MSAA publications.MSAA, its staff, and those affiliatedwith the writing of this publicationcannot be held responsible forany unintentional errors.

MSAA strives to provide useful,up-to-date information on mattersof concern to MS patients andtheir families. This material isintended for general informationalpurposes only, and it does notconstitute medical advice. Youshould not use the informationpresented as a means ofdiagnosis or for determiningtreatment. For diagnosis andtreatment options, you are urged to consult your physician.

Copyright © Multiple SclerosisAssociation of America, 2020. Allrights reserved. No part of thispublication may be reproduced,stored in a retrieval system, ortransmitted in any form or by anymeans, electronic, mechanical,photocopying, recording, orotherwise, without prior writtenpermission from MSAA.

CONTENTS

1Multiple Sclerosis Association of America MS RESEARCH UPDATE 2020

IntroductionThe 2020 MS Research Update reviews

new data and findings on: • Disease-modifying therapies (DMTs)approved by the FDA, including recentlyapproved medications and those that havebeen available for several years

• Experimental drugs under investigation for the long-term treatment of multiplesclerosis (MS)

• New therapeutic approaches and treatmenttargets, such as stem cell therapy and thegut microbiome

• Promising areas of inquiry that areenhancing researchers’ and clinicians’understanding of MS, such as genetics andbiomarkers

While this 2020 edition of MSAA’s MSResearch Update provides a comprehensiveoverview of important areas of inquiry andstudy findings, it is not an exhaustivecompilation of all relevant data released in thepast year. There is – fortunately – far too muchongoing research for summation in a single

report. Rather, the items presented here wereselected for their relevance to current orfuture patient care, and with a view towardshowcasing the breadth of work being doneto understand and treat MS. The informationthat follows is drawn from a variety of sources,including journal literature on MS and itsmanagement, a review of ongoing clinicaltrials, and presentations at major nationaland international conferences.

Please note that this MS ResearchUpdate reports on the most recent studyresults available at the time of publication.While every effort has been made to providemeaningful, timely, and balanced information,keeping the amount of information equal foreach medication covered is not possible.Please understand that the different degreeof coverage given to the various therapiesshould in no way be considered as favoritismtoward any one medication or treatmentapproach. Additionally, references have beencited only for newer study results.

While medications for management of MSsymptoms are beyond the scope of thisreport, information on the specific symptoms

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of MS and their treatment is available in thesymptoms section of MSAA’s website.

Providing these resources is at the heart ofMSAA’s mission of being a leading resourcefor the entire MS community, improving livestoday through vital services and support.Feedback and thoughts on the 2020 MSResearch Update are welcomed. These canbe directed to MSAA at [email protected].

Overview of MS Research ProgressNever before have so many people been

so keenly aware of the importance of medicalresearch. With the arrival of the CoVID-19pandemic in early 2020, people who just afew months earlier had only a passingfamiliarity with the drug-developmentprocess, now understand more about thedifferent trial phases.

This widespread appreciation fortherapeutic innovation is just one of manyways the coronavirus has changed life for allpeople. For those with MS, however, thepandemic brings additional concerns andconsiderations. Does taking a disease-modifying therapy (DMT) that affects theimmune system increase the risk ofcontracting CoVID-19? Does having a chroniccondition, such as MS, suggest more severesymptoms and worse outcomes should aperson become infected? For information onthose topics and related issues, visit theCoronavirus and MS section of MSAA’swebsite.

Beyond its impact on the daily lives ofpeople with MS, the CoVID-19 pandemic alsois affecting the course of multiple sclerosisresearch. For example, GeNeuro, a

biotechnology company investigating themonoclonal antibody temelimab for use inprimary- and secondary-progressive MS, inMarch announced the postponement of aplanned Phase II trial of the medication inorder to “prioritize healthcare resourcesbehind the fight of CoVID-19 and to reducethe risk for MS patients.” 1 Meanwhile,MediciNova, the company developing theoral medication ibudilast for potential use inrelapsing forms of MS, announced in April thatit also will study the medication for use inacute respiratory distress syndrome (ARDS)caused by CoVID-19. 2

While some temporary delays, detours,and distractions may be part of the near-termimpact of CoVID-19 on the MS researchagenda, the long-term effect hopefully willinclude an enduring commitment to fundingresearch against the full range of conditions –acute and chronic – that harm health andthreaten lives. Meanwhile, investigators inclinics, hospitals, and laboratories around theworld continue to explore the biologicalprocesses that lead to MS onset andprogression, and the treatment approachesthat can reduce or even halt disease activity.

There is abundant evidence that thisresearch effort is making progress on manyfronts. one of the most tangible markers ofsuccess is the expanding array of disease-modifying therapies (DMTs) available to treatMS.

Since the publication of MSAA’s 2019 MSResearch Update, the FDA has approved threemore DMTs. In April 2020, Bafiertam™(monomethyl fumarate) received approval foruse in relapsing forms of MS. The Banner Life

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Sciences’ medication is an oral agent takentwice daily. It is a fumarate-type medication,as is Biogen’s Tecfidera® (dimethyl fumarate).Bafiertam obtained FDA approval after BannerLife Sciences showed that the medication is a“bioequivalent alternative” to Tecfidera,meaning that the active ingredient and site ofaction do not differ significantly between thetwo medications.3 Because Tecfidera cancause gastrointestinal (GI) effects – includingnausea, vomiting, and diarrhea – in somepatients,4 biopharmaceutical companies haveexplored formulations of fumarate medicationsthat would have efficacy against MS – asTecfidera has demonstrated – with fewer GIside effects. In the case of Bafiertam, this goalis being pursued through use of a daily doselower than that for Tecfidera. 4, 5 However,whether or not Bafiertam causes fewer GI sideeffects has not yet been determined and hasnot been evaluated in clinical trials in peoplewith relapsing forms of MS.

Another of the three recently approvedmedications pursues the same goal ofreducing GI side effects by other means. Inoctober 2019, the FDA authorized use ofVumerity® (diroximel fumarate) in relapsingforms of MS. Also an oral medication takentwice daily, Vumerity was developed byBiogen – which markets Tecfidera – and theIrish pharmaceutical company Alkermes plc. Inthis case, the chemical structure of Vumeritydiffers from that of Tecfidera, and the recentlyapproved medication has been shown tocause fewer GI side effects than Tecfidera. 6

The third medication recently approved bythe FDA is Zeposia® (ozanimod), a once-dailyoral medication from Bristol Myers Squibb. In

March 2020, the FDA approved thesphingosine 1-phosphate (S1P1)-receptormodulator for use in relapsing forms of MS.Two other S1P1-receptor modulators,Gilenya® (fingolimod) and Mayzent®(siponimod), also are FDA-approved for MS.How this class of medication exerts atherapeutic effect in MS is not completelyunderstood. However, the mechanism ofaction may involve reducing the number oflymphocytes – white blood cells involved inimmune function – that migrate to the centralnervous system (CNS), where they maycontribute to damaging the myelin sheaththat protects nerves. 7

Turning from medications approved bythe FDA to those now being evaluated bythe FDA, Janssen/Johnson & Johnson isrequesting that another S1P1-receptormodulator, ponesimod, be approved fortreating adults with relapsing forms of MS. 8The request is based on data from the PhaseIII oPTIMUM trial, in which patients treatedwith ponesimod had lower averageannualized relapse rates than those receivingan already approved DMT, Aubagio®(teriflunomide). 9, 10

Meanwhile, the FDA is conducting apriority review of ofatumumab for thetreatment of relapsing forms of MS. Novartis,which markets the agent collaboratively withGenmab, says ofatumumab could beapproved as early as this summer. 11 Themonoclonal antibody, which already isindicated for treating chronic lymphocyticleukemia,12 binds to the CD20 moleculelocated on the surface of lymphocytes, a typeof white blood cell. Lymphocytes trigger the

INTRODUCTION


abnormal immune response that damages theprotective sheath (myelin) surrounding nervecells in the brain and spinal cord. By bindingto CD20, the lymphocytes are destroyed andneuronal damage is prevented or delayed.

ofatumumab is self-injectedsubcutaneously once a month, allowing for at-home administration.13 Novartis and Genmabare seeking approval for use of ofatumumabin MS based on data from the Phase IIIASCLEPIoS I and ASCLEPIoS II trials, in whichofatumumab outperformed Aubagio inslowing disease progression in RMS. 11

Phase III trials, which generate the maindata used to pursue FDA approval, are underway or planned for other potential MStreatments. TG Therapeutics hopes to provideresults later this year from two simultaneousPhase III trials assessing the safety andeffectiveness of its monoclonal antibodyublituximab in relapsing forms of MS.15 EMDSerono will evaluate its oral investigationalagent evobrutinib in patients with relapsingMS in the Phase III EVoLUTIoN RMS 1 andEVoLUTIoN RMS 2 studies.16 Evobrutinibinhibits Bruton's tyrosine kinase (BTK), anenzyme that contributes to the developmentand function of B lymphocytes, a type of whiteblood cell that can attack and destroy theneuroprotective myelin sheath that surroundsnerve cells.16

MediciNova is organizing a Phase III trialthat will determine whether its oral medicationibudilast, also known as MN-166, can slowdisease progression in more-severe, non-relapsing MS. Ibudilast is a small moleculemacrophage migration inhibitory factor (MIF)inhibitor and phosphodiesterase (PDE) -4 and

-10 inhibitor that suppresses pro-inflammatorymolecules and promotes nerve-growthfactors.17

on another research front, investigatorscontinue to assess previously approvedmedications, examining their long-termeffectiveness and safety, both in the overallMS population and in specific groups ofpeople with MS. This MS Research Updatereports on studies evaluating the impact ofstarting specific DMTs earlier rather than laterfollowing diagnosis, and of switching fromone DMT to another. Inquiries are alsoexamining how approved DMTs are affectingefficacy measures beyond relapse rates andMRI findings, such as confirmed disabilityprogression, and the need for wheelchair use.

In terms of safety, research is examining thefrequency and nature of adverse events withmulti-year use, how DMTs affect maternal andfetal outcomes when used during pregnancy,and whether altering dosing schedules canreduce the incidence of adverse effects.Beyond evaluating pharmacologic agents,a plethora of research is probing thetherapeutic potential of interventions rangingfrom stem cell therapy and dietaryadjustments, to Vitamin D supplementationand altering the gut microbi ome. otherstudies are looking at the role genetics andother factors may play in the developmentand course of MS, and at how biomarkerssuch as serum neurofilament light (NfL) canhelp in monitoring MS status and informingtreatment decisions. All of these topics areaddressed in the sections that follow.

In short, thousands of clinicians andresearchers around the world are exploring

INTRODUCTION


TRIAL PHASES FOR INVESTIGATING TREATMENTSPhase I Phase II Phase III Phase IV

Phase I studies areprimarily concernedwith assessing thedrug’s safety. Thisinitial phase of testingin humans is done in asmall number ofhealthy volunteers,and is designed todetermine whathappens to the drugin the human body –how it is absorbed,metabolized, andexcreted.

once a drug has beenshown to be safe, it mustbe tested for efficacy. Thissecond phase of testingmay last from severalmonths to two years, andinvolve up to severalhundred patients. Phase IIstudies are often “double-blinded,” meaning thatthe participants, medicalstaff, and investigators arenot told who is receivingthe drug and who isreceiving the placebo.

In a Phase III study, adrug is usually tested inseveral hundred toseveral thousandpatients, usually inmultiple medicalfacilities around theworld. Phase III studiestypically last two ormore years. only after aPhase III study issuccessfully completedcan a pharmaceuticalcompany request FDAapproval for marketingthe drug.

Phase IV clinical trialsare conducted after adrug has beenapproved.Participants areenrolled to furthermonitor safety andside effects, whileevaluating long-termefficacy.

various aspects of MS, and their collectiveefforts promise even further progress in theyears just ahead. It is important to remember,however, that the work of these physicians,nurses, biochemists, pharmacologists, andothers would not be possible without theselfless participation of even larger numbersof people with MS. The patients who enroll inclinical trials, submit data to registries, andotherwise contribute to research, play aninvaluable role in the effort to better

understand, more effectively manage, andone day defeat multiple sclerosis. If youalready are counted among their ranks, youhave our deepest gratitude. If you have notparticipated to date, we would encourageinterested readers to ask their providers aboutpossible opportunities to become involved inMS research. For more information aboutparticipating in clinical trials for the treatmentof MS and its symptoms, readers mayvisit mymsaa.org/clinicaltrials.

Editor’s note: Initial study results for therapeutic agents under investigation should beconsidered preliminary because additional studies and/or evaluations may be needed todetermine the long-term safety and efficacy of these agents. MSAA does not endorse orrecommend any specific products or therapies. Readers are advised to consult their physicianbefore making any changes to their medication, diet, exercise, or other treatment regimen.

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INTRODUCTION

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Zeposia® (ozanimod) Company: Bristol Myers Squibbn Starting dose: 0.23 mg orally once daily onDays 1-4, followed by 0.46 mg orally onDays 5-7

n Maintenance dose: 0.92 mg orally oncedaily on Day 8 and thereafter

n Approved in March 2020 for relapsingforms of MS, including clinically isolatedsyndrome, relapsing-remitting disease, andactive secondary-progressive disease, inadults.Zeposia® (ozanimod) is a sphingosine

1-phosphate (S1P1)-receptor modulator,meaning that it binds to two receptors – S1P1and S1P5 – on the surface of cells.7 While theexact mechanism by which Zeposia exerts atherapeutic effect in MS is not completelyunderstood, the medication’s impact mayinvolve reducing the number of lymphocytesthat migrate to the central nervous system(CNS), where lymphocytes may contribute todamaging the myelin sheath that protectsnerves. This damage results in lesions, or areasof sclerosis (scarring/hardening), at differentlocations along the myelin sheath, giving rise

to the term “multiple sclerosis.” Two other S1P1-receptor modulators,

Gilenya® (fingolimod) and Mayzent®(siponimod) are also approved by the FDA fortreating MS. Additionally, Janssen/Johnson &Johnson has asked the FDA to approveanother medication in this class, ponesimod,for the treatment of relapsing forms of MS inadults.

Zeposia is an oral medication taken oncedaily. The initial dose of 0.23 mg on Days 1-4 isfollowed by a dose of 0.46 mg on Days 5-7,with a once-daily dose of 0.92 mg starting onDay 8 and continuing thereafter.7 Thisapproach to increasing the starting dose overa few days, which clinicians call “up-titration,”is necessary because some people startingZeposia may experience initial but temporarydecreases in heart rate and delays in the wayelectrical signals are transmitted in the heart.7

Before beginning Zeposia, people shouldhave a complete blood count (CBC), anelectrocardiogram (ECG), and liver functiontests (which involve analyzing a sample ofblood that can be obtained from the sameblood draw performed for the CBC).Physicians are advised to consider what othermedications a person is taking in order to beaware of any potential interactions between

Medications Recently ApprovedThree 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 March2020; Bafiertam™ (monomethyl fumarate), approved in April 2020; and Vumerity® (diroximelfumarate), approved in october 2019. To follow is information on these medications, theirapproved uses and dosages, and their clinical data.


FDA-APPRoVED MEDICATIoNS: RECENTLY APPROVED

those medications and Zeposia. They alsoneed to conduct an eye examination inpatients with a history of certainophthalmologic problems, and to vaccinatepatients against varicella zoster virus (VZV) iftheir blood does not contain antibodiesagainst that virus, which causes chickenpoxand shingles.

Zeposia is contraindicated in people whoin the last six months experienced a heartattack, stroke, coronary-related chest pain,or certain other cardiovascular conditions.7Unlike other approved S1P1-receptormodulators, however, the FDA-approvedprescribing information for Zeposia does notdirect that people taking the medication bemonitored after their first dose for possiblecardiac issues.18

The FDA’s approval of Zeposia is based ondata from two large Phase III trials, SUNBEAMand RADIANCE Part B, which togetherenrolled more than 2,600 people with MS.Both trials examined the safety and efficacy ofZeposia relative to Avonex® (interferon beta-1a). This interferon-based treatment is one ofthe first therapies approved for multiplesclerosis.18

In the two studies, people taking Zeposiahad an annualized relapse rate (ARR) – ameasure of the average number of relapsesa group of patients will experience over thecourse of 12 months – of 0.18 at one yearcompared to 0.35 for Avonex, and of 0.17versus 0.28 for Avonex over two years. Thoserates translate into Zeposia providing a relativereduction in ARR of 48% at one year and 38%at two years compared to Avonex.7, 19, 20

Further, at one year, Zeposia reduced the

number of T1-weighted gadolinium-enhanced brain lesions more than Avonex(0.16 vs 0.43), which is a relative reduction of63%, and reduced the number of new orenlarging T2 lesions (1.47 vs. 2.84), which is arelative reduction of 48%. 7, 20 At two years,Zeposia achieved a 53% relative reduction inT1-weighted gadolinium-enhanced brainlesions and a 42% relative reduction in newor enlarging T2 lesions, compared to theinterferon-based therapy. 7, 19

However, in two other measures examinedin the trials – impact on three-month and six-month confirmed disability progression (CDP),there was not a statistically significantdifference between patients in the Zeposiagroup and those in the Avonex group overthe course of two years.7

In the Phase III clinical trials, the mostcommon adverse reactions (occurring in 4%or more of people receiving Zeposia) wereupper respiratory infection, liver enzymeelevations, a fall in blood pressure uponstanding (orthostatic hypotension), urinarytract infection, back pain, and hypertension.Please note that in clinical trials, all adverseeffects reported by study subjects arerecorded; these events may or may not berelated to the medication. This is why controlor placebo groups are used to compare withgroups receiving the experimental medicationbeing studied.7

People who participated in SUNBEAM,RADIANCE Part B, and earlier, Phase II studiesof Zeposia were eligible to enter an extensionstudy assessing the long-term safety andefficacy of the medication. Researchersrecently reported on an interim analysis of



data on almost 2,500 patients whoparticipated in that extension trial.

Among patients who took 1 mg of Zeposiain any of the earlier trials and who thencontinued that dose over an average of 19.2months in the follow-up study, the ARR was0.126. Meanwhile, people who had taken aninterferon-based medication in an earlier trialand then switched to Zeposia in the extensionstudy, had a very similar annualized relapserate – 0.123 – over an average of 18.3 monthsin the follow-up study.

The incidence and nature of adverseevents were similar to those seen in thePhase III studies. The most common adverseevent during the extension study wasnasopharyngitis (a cold or sore throat), whichwas reported by 11.3% of participants. Justunder 6% of participants reported a serioustreatment-emergent adverse event, and justover 1% of participants stopped participatingin the study due to an adverse event.21

Bafiertam™ (monomethyl fumarate)Company: Banner Life Sciencesn Starting dose: 95 mg twice a day, orally, for7 days

n Maintenance dose after 7 days: 190 mg(administered as two 95 mg capsules) twicea day, orally

n Approved in April 2020 for relapsing formsof MS, including clinically isolated syndrome,relapsing-remitting disease, and activesecondary-progressive disease, in adults.

Bafiertam™ (monomethyl fumarate) is anoral medication taken twice daily for relapsingforms of MS. It is a fumarate-type medication,as is Tecfidera® (dimethyl fumarate). Bafiertamsecured FDA approval after its developer,Banner Life Sciences, demonstrated that themedication is a “bioequivalent alternative” toBiogen’s Tecfidera, meaning that the activeingredient and site of action do not differsignificantly between the two medications.3, 5

The issue of bioequivalence is importantbecause Tecfidera has demonstrated efficacyin treating relapsing forms of MS but cancause significant gastrointestinal (GI) effects –including nausea, vomiting, and diarrhea – insome patients.4 As a result, drug developershave sought to find formulations of fumaratemedications that offer similar efficacy but havefewer GI side effects. These efforts includeBiogen partnering with Ireland-basedAlkermes to develop the recently approvedVumerity® (diroximel fumarate), as detailedbelow, and Banner Life Science’sdevelopment of Bafiertam.

The starting and maintenance doses ofBafiertam are lower than those for Tecfidera.4, 5With the daily doses assumed to beequivalent in terms of their efficacy, the hopeis that the reduced amount of Bafiertam willresult in fewer GI side effects while providingsimilar benefit against relapses and othermanifestations of MS. Although not studiedin MS patients, a recent study compared thegastrointestinal tolerability of Bafiertam toTecfidera in 210 healthy adults without MS.The five-week study has been completed,but results were not posted at the time of thiswriting.22, 23



The exact mechanism of action by whichfumarate medications exert their therapeuticeffect in MS is not completely understood.However, the monomethyl fumarate moleculeis thought to activate an antioxidant proteinthat reduces oxidative stress, which in turnslows damage to protective nerve fibers inthe brain. Clinical trials with Tecfidera showeda reduction in relapse rate, a delay inprogression of physical disability, and aslowing in the development of brain lesions,as compared to placebo.

According to the prescribing informationfor Bafiertam, the starting dose is one 95-mgoral capsule taken twice daily for the firstseven days. The maintenance dose after sevendays is two 95-mg capsules (for a total of 190mg) taken twice daily. The prescribinginformation also warns not to crush, chew, ormix contents of the delayed-release oralcapsules with food. However, Bafiertam maybe taken with or without food.

Warnings, side effects, and adverse eventsare similar to those listed for Tecfidera.Bafiertam is contraindicated in patients withknown hypersensitivity to monomethylfumarate, dimethyl fumarate, diroximelfumarate, or to any of its inactive ingredients.Allergic reactions, PML (progressive multifocalleukoencephalopathy), herpes zoster andother serious opportunistic infections,decreases in white blood cell counts, and liverinjury, are among the potential seriousadverse events that could occur. Blood tests,including a complete blood count (CBC) andlymphocyte count, need to be performedprior to starting treatment, six months afterstarting treatment, and every six to 12 months

thereafter (as well as when clinicallyindicated).5

According to Banner, Bafiertam maycause flushing, which may be experienced aswarmth, redness, itching, and/or a burningsensation. In clinical trials with Tecfidera,40% of treated patients experienced flushing,which in most cases was mild to moderate inseverity. As noted earlier, other common sideeffects include: redness, itching, or rash;nausea, vomiting, diarrhea, stomach pain, orindigestion. Flushing and stomach problemsare the most common reactions, especially atthe start of therapy, and may decrease overtime.3

Vumerity® (diroximel fumarate)Company: Biogen Inc. and Alkermes plcn Starting dose: 231 mg twice a day, orally, onDays 1-7

n Maintenance dose after seven days: 462 mg(administered as two 231-mg capsules) twicea day, orally

n Approved in October 2019 for relapsingforms of MS, including clinically isolatedsyndrome, relapsing-remitting disease, andactive secondary-progressive disease, inadultsVumerity® (diroximel fumarate) is a

fumarate agent, as is Biogen’s Tecfidera®(dimethyl fumarate). However, it has achemical structure that is distinct fromTecfidera, and has been shown to cause fewergastrointestinal (GI) side effects – such asdiarrhea, nausea, vomiting, and abdominalpain – than Tecfidera. The exact mechanism of



action by which diroximel fumarate exerts itstherapeutic effect in MS is not completelyunderstood. However, upon entering thebody, the medication is rapidly converted intothe molecule monomethyl fumarate. Theconverted molecule is thought to activate anantioxidant protein that reduces oxidativestress, which in turn slows damage toprotective nerve fibers in the brain.6

The FDA’s october 2019 approval ofVumerity was based on a new drugapplication (NDA) that included data frompharmacologic studies comparing Vumerityand Tecfidera. By demonstrating that the twoagents were similar in many key respects, orhad “bioequivalence,” Biogen and Alkermeswere able to ask the FDA to consider findingson the safety and efficacy of Tecfidera as partof the evidence supporting Vumerity.6

The application also included interimexposure and safety findings from EVoLVE-MS-1, an ongoing, Phase III, single-arm,open-label, two-year safety study evaluatingVumerity in patients with relapsing-remittingMS. Interim results from EVoLVE-MS-1 at thetime the application was submitted includeda low overall rate of Vumerity treatmentdiscontinuation due to adverse events(6.3%), which included less than 1% ofpatients discontinuing Vumerity due togastrointestinal (GI) adverse events.Additional exploratory efficacy endpoints inthe ongoing EVoLVE-MS-1 study showedchanges in clinical and radiological measurescompared to baseline. 6

A few weeks after the FDA approvedVumerity, Biogen presented data from anotherPhase III study, EVoLVE-MS-2, that directly

compared the GI tolerability of Vumerity withthat of Tecfidera. 24

EVoLVE-MS-2 was a multi-center, double-blind, active-controlled, five-week studyinvolving 506 patients with relapsing forms ofMS. The primary endpoint was the number ofdays patients reported GI symptoms with asymptom intensity score ≥2 on the IndividualGastrointestinal Symptom and Impact Scale(IGISIS) rating scale. Secondary endpointsincluded the number of days (relative toexposure) that patients reported GI symptomswith IGISIS intensity scores of ≥1 or ≥3 in theoverall population. Patients who completedthe five-week treatment period were eligibleto enroll in EVoLVE-MS-1, the 96-week, open-label, safety study referenced above.

Results for the primary endpoint showedthat patients treated with Vumerity reported46% fewer days with intensity scores of ≥2 onthe IGISIS, compared to Tecfidera.

The EVoLVE-MS-2 results also found thatcompared to people taking Tecfidera, patientsreceiving Vumerity had:• Lower discontinuations due to GI adverse

events (0.8% vs. 4.8%).• Fewer days with IGISIS intensity scores of ≥1

and ≥3 (29% relative reduction and 44%relative reduction, respectively).

• Fewer days with a self-reported intensityscore of ≥1 (30% reduction on the GlobalGastrointestinal Symptom and Impact Scale[GGISIS], which assessed the overall intensityof GI symptoms, their impact on dailyactivities and how bothersome they were).Fewer days with GGISIS intensity scores of≥2 and ≥3 were also observed.



• A gradual decline in worst IGISIS intensityscores over the five-week treatment period.

These findings that use the patient-assessed symptom intensity scales weresupported by lower investigator-reportedincidences of GI adverse events withVumerity (34.8%) compared to Tecfidera(49.0%). overall, adverse events occurred in78.3% of patients receiving Vumerity and83.7% taking Tecfidera, but most of those

adverse effects were mild or moderate inseverity. overall, 1.6% of patients receivingVumerity and 5.6% of those taking Tecfideraexperienced adverse effects that causedthem to stop participating in the study.Among those patients who discontinueddue to any adverse effect, 0.8% in theVumerity group stopped due to GI effects,as compared to 4.8% in the Tecfideragroup.24

12MS RESEARCH UPDATE 2020


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Ocrevus® (ocrelizumab)Company: Genentech and Roche Pharma AGn Starting dose: 300 mg given via IVinfusion, followed two weeks later by asecond 300-mg infusion

n Subsequent doses: 600 mg given via IVinfusion every six months

n Approved in 2017 for relapsing forms ofMS (RMS) and primary-progressive MS(PPMS)ocrevus® (ocrelizumab) is a humanized

monoclonal antibody, meaning that it is anantibody from a non-human species whoseprotein sequences have been modified toincrease their similarity to antibodiesproduced naturally in humans. ocrevus worksby destroying the CD20 receptor, a moleculethat helps B cells receive messages fromthroughout the body. Destroying the CD20depletes the B cells that can triggerneurodegeneration in MS.

A recent study found that people withrelapsing-remitting MS (RRMS) who startocrevus early and respond to themonoclonal antibody may continue to benefitfrom the medication many years later. Thefindings, from an open-label extension of theoPERA I and oPERA II Phase III clinical trials,offer solid evidence for sustained first-line use

of ocrevus in RRMS, researchers said. During the oPERA trials, ocrevus showed

superiority over an interferon-basedmedication in slowing disease activity andprogression over 96 weeks.25 Patients whocompleted the 96-week, double-blindcomparison trial entered a four-year, open-label extension phase, during which theyeither stayed with or switched to ocrevus.

Among patients who switched from theinterferon medication to ocrevus, adjustedannualized relapse rates (ARR) fell from 0.20in the year before the switch to 0.04 at Year 4of the open-label phase. Patients who stayedon ocrevus after the comparison phase alsosaw a decrease in ARR during the sameperiod, from 0.13 to 0.05.26

Another analysis suggests that early andintensive intervention with ocrevus mayprovide meaningful benefit for people withMS who suffer early severe disability.

Researchers performed a post-studyanalysis of the oPERA I, oPERA II, andoRAToRIo trials, in which ocrevus showedefficacy in slowing disease activity andprogression in patients with relapsing-remitting MS over 96 weeks, and in patientswith primary-progressive MS (PPMS) over 120weeks or longer. Drawing on data from thosetrials, investigators identified 882 patientswith baseline Expanded Disability Status

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


FDA-APPRoVED MEDICATIoNS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

https://mymsaa.org/PDFs/Treatment_Chart.pdf

Scale (EDSS) scores of 4.0 or greater, 92patients with baseline EDSS scores >5.0, and88 patients with baseline EDSS scores >6.0.(on the EDSS scale, a higher score indicates agreater degree of disability.) The patients hadreceived ocrevus or a comparator –interferon beta-1a in oPERA or placebo inoRAToRIo.

The researchers found that the incidenceof EDSS score increases over a given 24-weekperiod were significantly lower amongpatients who received ocrevus comparedwith those who received interferon beta-1a orplacebo. ocrevus-treated patients from theoRAToRIo trial who had high baseline EDSSscores also saw significant reductions indisability compared with placebo. 27

Another team of investigators recentlyexamined the safety of ocrevus inwidespread, “real world” use. Researchersregularly compare clinical trial data on amedication’s safety with data collected afterthe medication has been approved by theFDA and prescribed by clinicians across thecountry. The purpose is to ensure that nonew “safety signals” or other concernsemerge as a medication that had been testedin hundreds or thousands of patients inclinical trials now is given to a much largernumber of people.

In one such study of ocrevus, researchersanalyzed safety outcomes data from themedication’s Phase II and Phase III trials, andfrom related open-label extension periodsand sub-studies. Because length of exposureto ocrevus varied among participants, ratesof adverse events were calculated per 100patient years, or the number of adverse

effects 10 patients would suffer in 10 years.A total of 4,501 people with MS received

ocrevus in the clinical trials, amounting to12,559 patient years of exposure. Side-effectrates per 100 patient years were:

• Adverse events: 255• Serious adverse events: 7.52• Infections: 77.1• Serious infections: 2.01• Malignancies: 0.47• Adverse events prompting treatment

discontinuation: 1.15

Using United States’ claims data andnumber of vials sold, the researchers thenestimated that as of April 2019, 96,000patients in the general population with MShad received ocrevus, and that theprevalence of adverse events in this “realworld” group is similar to the data reportedfor the clinical trials group.13

Turning from safety assessments tomeasures of effectiveness, investigators in thePhase III oPERA I, oPERA II, and oRAToRIoclinical trials measured serum and plasmaneurofilament light (Nfl) levels in studysubjects. Nfl levels are an important markerof disability and disease progression in MS,with those levels tending to be higher inpatients experiencing progressive disabilitythan in patients with stable disease.28

After 96 weeks, NfL levels weresignificantly lower among patients whoreceived ocrevus relative to levels in thestudies’ comparator groups. Among 621people with either RRMS or PPMS whosebaseline NfL levels were above the 90th



15

percentile of normal, a higher proportion ofindividuals treated with ocrevus saw their NfLdecrease to normal levels, compared withthose who received interferon beta-1a (81.4%vs 58.9% in RRMS) or placebo (40.4% vs16.6% in PPMS). Higher baseline NfL levelsalso predicted increased disabilityprogression in PPMS, and were linked toworse outcomes for patients with RRMStreated with interferon beta-1a, as evidencedby changes in Expanded Disability StatusScale, Nine-Hole Peg Test, and Timed 25-FootWalk scores.29

Tysabri® (natalizumab)Company: Biogenn 300 mg given via one-hour IV infusionevery four weeks

n Approved in 2004 for relapsing forms ofMSTysabri® (natalizumab) is a monoclonal

antibody that acts against a moleculeinvolved in the activation and function oflymphocytes, immune system cells producedto fight infection and disease. Tysabri alsoacts against the passage of lymphocytes intothe central nervous system (CNS), whichconsists of the brain, spinal cord, and opticnerves.

The FDA approved Tysabri in 2004 basedon positive results in the Phase III AFFIRMtrial. Tysabri was voluntarily withdrawn fromthe market in 2005, after three cases ofprogressive multifocal leukoencephalopathy(PML), a rare but potentially fatal braininfection caused by the JC virus, were

identified in patients taking the medication.Tysabri became available again in 2006,based on the implementation of acomprehensive risk-management programthat includes testing potential Tysabri users tosee if they have anti-JC virus antibodies.30

In an attempt to reduce the risk of PML,some clinicians are extending the intervalbetween Tysabri doses, adopting apersonalized dosing strategy that has beenused to mitigate the adverse effects of extra-strength antibiotics and other medications.31As more physicians stretch out the timebetween doses beyond the recommendedfour weeks, researchers decided to assesshow this risk-reduction approach affects themedication’s therapeutic effects. 4, 31

Investigators leading a two-year study arerecording several measures of diseaseprogression in 61 adults with MS who hadno disease activity in the 12 months beforeenrollment. Treatment intervals are beingadjusted to maintain the lowest therapeuticconcentration of Tysabri (10 mcg/mL) foreach patient before the next dose is given.

At the time interim study results werereleased, the 10 mcg/mL level had beenmaintained with extended dosing intervals offive to seven weeks in 84% of patients. Nogadolinium-enhanced lesions or new orenlarging T2 lesions had been reported.Also, Expanded Disability Status Scale andMS Functional Composite scores had notincreased, and serum levels of neurofilamentlight, an important indicator of MS diseaseactivity, had remained low.

While biomarkers suggested somedegree of disease activity among a subset of


Multiple Sclerosis Association of America MS RESEARCH UPDATE 2020

16

patients, the findings suggest that Tysabridosing intervals can be safely expanded ona patient-by-patient basis.31

other researchers recently found greatercognitive improvement among people whostarted Tysabri early in the course of their MSthan in individuals whose treatment wasdelayed. The findings suggest that the earliertreatment can be started, the greater thechances of maintaining a patient’s cognitivefunction, researchers said.

A total of 2,069 patients with relapsing MSwho were treated with Tysabri for at least 12months were followed at 58 neurology clinicsacross Sweden. The participants were dividedinto two groups: those who started treatmentwithin three years after MS onset, and thosewho started treatment later. Symbol DigitModalities Test (SDMT) scores were collectedat the start of Tysabri therapy, at six monthsand at one year after the start of treatment,and annually thereafter.

SDMT scores improved overall inboth groups across the median 72-monthfollow-up, but the rate of improvement wasan average of 0.38 points per year lower inthe late-treatment group compared withpatients who started treatment early.

When SDMT scores were examined byage, no difference in score trajectory wasnoted among patients younger than age 36years, regardless of when they startedtreatment. Among patients aged 36 andolder, however, SDMT score improvementswere on average 0.45 points lower per yearof follow-up among late-treated patients vs.early-treated subjects.

of note, individuals who started Tysabri

early had fewer relapses (1.91 vs 3.2) andmodestly higher SDMT scores (52 vs 50) inthe year before starting Tysabri early,compared with late-treated patients.32

Tysabri has long-term effectiveness indelaying relapses and slowing disabilityprogression among people with relapsing-remitting MS, another ongoing studysuggests.

The Tysabri observational Program (ToP),begun by the medication’s manufacturer afterTysabri was approved by the FDA in 2004, isan open-label, multinational, prospectivestudy that assesses the efficacy and safety ofTysabri in real-world clinical settings. As ofNovember 2017, the continuing studyincluded 6,148 patients with RRMS whoreceived or are still receiving Tysabri. Medianexposure to the medication was 3.3 years,and nearly 500 patients received Tysabri foreight years or longer. Median follow-up was62 months as of the November 2017 review.

During the analysis, the annualized relapserate (ARR) for patients on Tysabri fell from1.99 in the year before treatment initiation to0.15. of note, ARRs for individuals takingTysabri were significantly lower amongpatients with baseline Expanded DisabilityStatus Scale scores of 3.0 or less, having takentwo or fewer prior disease-modifyingtherapies, or no more than one relapse inthe year prior to treatment.

Additionally, EDSS scores were stablethroughout the analysis. At 10 years, thecumulative probability of 24-weekconfirmed disability worsening was 27.8%,and the cumulative probability of 24-weekconfirmed disability improvement was 33.1%.


Multiple Sclerosis Association of America MS RESEARCH UPDATE 2020

of the 5,179 patients with baseline EDSSscores of 2.0 or higher, 1,210 (23.4%)experienced a confirmed disabilityimprovement event.

The safety profile of Tysabri was consistentwith adverse events (AE) reported in clinicaltrials. one or more serious AE was reportedin 829 patients (13.5%). Infection was themost common AE, reported by 4.1% ofpatients. PML occurred in 53 patients (0.9%),while breast cancer and other malignanciesoccurred in 1.1%.33

Meanwhile, a recent Italian study foundthat use of Tysabri during pregnancy isassociated with a lower risk of relapse but agreater incidence of newborn anemiacompared to stopping the agent beforeconceiving.

Researchers followed 84 expectantmothers who were receiving Tysabri at 19 MScenters. Participants were divided into threegroups: women whose last Tysabri infusionoccurred before their last menstrual period(Group 0), those who were last infused duringthe first trimester of pregnancy (Group 1), andthose who continued treatment throughoutpregnancy (Group 2).

Annualized relapse rates (ARR) duringpregnancy were 1.06 among Group 0expectant mothers, 0.49 for those in Group 2,and 0.09 for women in Group 3. Among thewomen who restarted Tysabri after givingbirth, ARRs 12 months postpartum were 0.39for women in Group 0 and 0.23 for women inGroup 1.

Researchers also analyzed data on the 94infants who were born during the study andcompared pregnancy outcomes among

groups. No differences in mean gestationalage or birthweight were found. However,major and minor malformations werereported in seven infants in Groups 1 and 2(women who stopped natalizumab in earlypregnancy or continued throughout),compared with one in Group 0 (women whostopped before pregnancy). Anemia wasfound in five newborns from mothers inGroup 2, including three infants who wereborn prematurely.

The researchers commented thatcontinuing Tysabri during pregnancy “isassociated with lower risk of relapsescompared to wash-out and early interruption.No worrisome adverse events emerged innewborns. occurrence of anemia isconsistent with previous findings and maybe biased by prematurity.”34

Please note that women who are pregnantor are planning to become pregnant, whileconsidering or taking a DMT, are advised toconsult their physician.

Lemtrada® (alemtuzumab)Company: Sanofi Genzymen Intravenous infusion over four hours fortwo treatment courses:

n First course: 12 mg/day on fiveconsecutive days;

n Second course: At one year, 12 mg/day onthree consecutive days;

n Approved in 2014 for relapsing forms ofMS



Lemtrada (alemtuzumab) is a monoclonalantibody formulated to slow or prevent theimmune system's destruction of theneuroprotective myelin sheath by killingwhite blood (immune) cells. The UnitedStates’ prescribing information for themedication describes the risk of serious and potentially fatal adverse events with use of the medication, including stroke,autoimmune conditions, infusion reactions,and certain cancers.35

The EMA made the recommendationsafter its drug-safety monitoring committeereceived reports of cardiovascular issues –including heart attacks and strokes – as well asimmune complications in people with MStaking Lemtrada.36 Because of the potentialtoxicity associated with Lemtrada, themanufacturer advises using the agent only in"patients who have had an inadequateresponse to two or more [DMTs].”35

Meanwhile, findings from a recent long-term analysis suggest that people receivingLemtrada for relapsing-remitting MS mayretain function nearly a decade after startingtreatment.

over the course of four years, Lemtradasignificantly improved clinical and imagingoutcomes in the CARE-MS I clinical trial and asubsequent extension study. An additionalfive-year extension trial, ToPAZ, assessedparticipants' continuing function and diseaseprogression. Patients could receive Lemtradaor another disease-modifying therapy asneeded at the investigators’ discretion.Among Lemtrada-treated patients in the

original CARE-MS I study, 75% stayed in thestudy through the entire five-year extensionphase, and 55% required no additionaltreatment with Lemtrada or another disease-modifying therapy.

After the full nine-year study period:• 68% of patients showed no signs of

confirmed disability progression over agiven six-month period, and 41% showedimprovement after confirmed six-monthdisability progression.

• The mean increase Expanded DisabilityStatus Score (EDSS) was 0.10, suggestingoverall minimal disability progression.Also, 77% of patients had improved orstable EDSS scores.

• 89% of patients showed no gadolinium-enhanced lesions, and 68% were free ofnew or enlarging T2 lesions. Also, 68%showed no disease activity after magneticresonance imaging.

• Median cumulative brain volume loss(BVL) was 1.97%. Also, median annual BVLwas 0.22% or less in Years 3 through 9.Lemtrada also maintained a consistent

safety profile throughout the extended nine-year period. The cumulative incidence ofthyroid-related adverse events was 46%, andthe incidence of immune thrombocytopenia(an uncommon disorder marked by reducedplatelet counts) was 2%. overall, theincidence of drug-related adverse eventsand infections declined over the nine-yearperiod.37



Mayzent® (siponimod)Company: Novartisn Starting dose for most patients: 0.25 mgorally on Day 1, increasing in 0.25-mgincrements over five days to 1.25 mg.

n For patients with CYP2C9*1/*3 or *2/*3genotype, 0.25 mg on Days 1 and 2,increasing to 0.5 mg on Day 3 and 0.75 onDay 4.

n Maintenance dose: 2 mg daily orally formost patients; 1 mg daily orally forpatients with CYP2C9*1/*3 or *2/*3genotype

n Approved in 2019 for relapsing forms ofMSMayzent® (siponimod) is a sphingosine 1-

phosphate (S1P)-receptor modulator,meaning that it binds to two receptors, calledS1P1 and S1P5, on the surface of cells. Bybinding to these receptors, Mayzent blockslymphocytes (a type of white blood cell) fromleaving the lymph nodes and entering theperipheral blood. While the mechanism bywhich Mayzent exerts its effects in MS is notfully understood, it may involve reduction oflymphocyte migration into the centralnervous system (CNS).25 Further, Mayzentbinds to S1P1 and S1P5 receptors onoligodendrocytes and astrocytes, cells withinthe CNS, which are thought to promoteremyelination and prevent inflammation.38

Mayzent was the first FDA-approved oraldrug to treat secondary-progressive MS inadults experiencing active disease. Mayzent isalso approved for use in clinically isolatedsyndrome (CIS) and relapsing-remitting MS(RRMS).39

A recent study found that Mayzent maydelay or prevent wheelchair dependence insome people with secondary-progressive MS(SPMS). In the Phase III EXPAND study thatled to Mayzent receiving FDA approval, themedication delayed disability progressionand cognitive decline among those withSPMS.

Investigators subsequently performedtwo analyses on data for participants in theEXPAND active treatment and placebogroups. The first analysis measured time towheelchair dependence in 412 patients witha baseline Expanded Disability Status Scale(EDSS) score of 6.5, which indicatesdependence on a walking device and highrisk of progression to a wheelchair. In thatgroup, EDSS scores increased to 7.0(indicating wheelchair dependence) in 19.8%of Mayzent-treated patients, compared with26.1% of those in the placebo group.

In the second analysis, researchers splitthe overall EXPAND population of 1,645participants into three groups by EDSS scorerange: 5.0 or lower; 5.5 to 6.0; and 6.5. Theinvestigators then calculated the time eachpatient stayed in an EDSS range beforemoving to another, and used that informationto predict time to wheelchair dependence for

ORAL MEDICATIONS

19 Multiple Sclerosis Association of America MS RESEARCH UPDATE 2020


patients at any EDSS range. Based on this analysis, the researchers

found that Mayzent reduced the risk ofprogression from an EDSS of 5 or less toEDSS 5.5 or 6 by 21%, and reduced the riskof worsening from an EDSS of 6.5 to 7.0 by28%, compared with placebo. Assuming thatthe effect of Mayzent would remain stableover time, the researchers predicted thatMayzent may extend the median time towheelchair dependence by 4.3 years in theoverall study population, compared withplacebo.40

Another analysis of EXPAND data by aseparate team of investigators found furtherevidence that Mayzent reduces the risk ofconfirmed disability progression (CDP) inpeople with active SPMS. The researchersevaluated data on 779 EXPAND studyparticipants with active SPMS, which wasdefined as having suffered one or morerelapses in the two years before screening,or having one or more T1 gadolinium-enhancing lesions at baseline. A total of 516patients in the active-disease group receivedMayzent, while 263 received placebo.

The analysis found that Mayzent reducedthe risk of three-month CDP by 31% and therisk of six-month CDP by 37%, compared withplacebo. Among patients in the treatmentgroup, Mayzent also:

• Lowered the annualized relapse rate by46%.

• Reduced T1 gadolinium-enhancinglesions by 85%, and new or enlarging T2lesions by 80%. Also, T2 lesions weresmaller at 12 months and 24 months in the

treatment group, compared withplacebo.41

Meanwhile, a six-year analysis of Mayzent-treated patients uncovered no major safetyconcerns or increased incidence of adverseevents (AEs), but underscored the need tomonitor patients for tolerability issues. Itshould be noted that just because a personexperiences an adverse event while taking amedication, it does not necessarily mean thatthe medication caused that event.Researchers record all adverse events to lookfor patterns that may suggest an associationbetween the medication and the event.

Researchers typically perform long-termstudies of medications to determine theirsafety and tolerability in real-world practice. Inthis analysis, researchers studied two groupsof patients: a “controlled pool” of 1,755people who received Mayzent or placeboduring the medication’s core clinical trials,and a “long-term pool” of 1,737 people whoreceived at least one 2-mg or 10-mg dose ofMayzent in either the core or extension trialphases. Mean exposure to Mayzent was 17.7months in the controlled pool and 27.8months in the long-term pool, and 127people in the long-term pool receivedMayzent for five years or longer.

In the long-term pool, 90% of patients hadat least one adverse event, 20.7% had at leastone serious adverse event (AE), and 9.6% hadAEs that led to study discontinuation. Rates ofinfection in the long-term and controlledpools were 43.2 and 48.9, respectively, per100 patient years (the number of infections10 patients would suffer in 10 years). By



comparison, the infection rate in the placebogroup within the controlled pool was 53.8 per100 patient years. Also, between 42.3% and53% of Mayzent-treated patients with lowlevels of lymphocytes (an infection-fightingtype of white blood cell) contractedinfections, but these percentages were similarto those in the placebo group and did notindicate an increased infection ratecompared with previous data.

The most common AEs in both groupswere headache, urinary tract infection, falls,high blood pressure, and the common cold.The incident rates ranged from 4.9 to 11.3per 100 patient years, and were similarbetween both patient pools.42

A new six-month, multicenter, open-labelstudy called EXCHANGE will examine thesafety of switching patients currently takinganother disease-modifying therapy (DMT) toMayzent. The study will recruit 300 patientswith relapsing-remitting MS from 80 MStreatment centers throughout the UnitedStates. Individuals with the CYP2C9*3/*3genotype are ineligible, as this genotypeslows the body’s ability to process Mayzentand increases the risk of medication-relatedadverse effects.

Study participants will switch from theircurrent DMT to Mayzent within 24 hours ofstudy entry. Patients who have been takingAubagio, which is metabolized more slowlythan other DMTs,43 will stop Aubagio andwait 14 days before starting Mayzent.Participants will start Mayzent at a low dose,and then be titrated over five days to 2 mgdaily at Day 6. Participants will be monitoredfor adverse effects throughout the six-month

analysis, as well as for treatment satisfaction,treatment adherence after switching, andcardiac safety. 29

Mayzent is contraindicated in those whoexperienced a cardiovascular event or whowere diagnosed with severe heart failure inthe past six months. Physicians are advised toperform an echocardiogram and check foruse of other medications that affect heartfunction before starting Mayzent.39

Mavenclad® (cladribine)Company: EMD Seronon 3.5 mg/kg divided into two yearlytreatment courses of 1.75 mg/kg

n Approved in 2019 for relapsing forms ofMSMavenclad® (cladribine) is an

antimetabolite that reduces the number oflymphocytes, which are white blood cells thatare part of the immune system. It long hasbeen used to treat hairy cell leukemia, andregulatory authorities in other countriesapproved it to treat MS several years beforethe FDA granted its approval in 2019. TheFDA acted later than other regulatoryagencies in part because of concerns aboutMavenclad potentially increasing the risk ofcancer in some patients. Indeed, theprescribing information for Mavencladincludes a boxed warning that the medicationmay increase risk for malignancy, addingthat clinicians should weigh the benefits andrisks of treatment on an individual basis,considering a patient’s specific history of,or risks for, cancer.



The prescribing information also notesthat, due to its safety profile, “use ofMavenclad is generally recommended forthose who have had an inadequate responseto, or are unable to tolerate, an alternate drugindicated for treatment of MS.” Mavencladalso is contraindicated in pregnant women,and in men and women of reproductivepotential who do not plan to use effectivecontraception. This contraindication stemsfrom concerns about potential birth defects.44

However, new findings provide reassuringnews regarding both the safety of Mavencladand its ability to slow disease progression inpeople with MS.

Researchers reviewed safety data for 211patients who received between one andthree cycles of Mavenclad. The patients hadeither relapsing-remitting or progressive MS,and showed disease activity based onmagnetic resonance imaging (MRI) scans andmeasurement of neurofilament light chains(NfL) in cerebrospinal fluid. Patients receivedthree to four 10-mg Mavenclad doses at thestart of the study, plus as many as three more10-mg doses five weeks later if theirlymphocytes (a type of infection-fightingwhite blood cell) were at normal levels.Mavenclad can diminish lymphocytes todangerously low levels; the manufactureradvises regular blood testing before andduring treatment.44

A total of 154 patients completed anothercycle of treatment 11 months after the initialcycle. overall, Mavenclad was well tolerated.Severe lymphopenia (shortage oflymphocytes) occurred in less than 3% ofparticipants, and 12 patients had skin

reactions that resolved shortly after treatment.one patient survived a heart attack, andanother was diagnosed with breast cancer.Two patients died, but neither death wasbelieved by investigators to be medication-related.

Mavenclad also showed efficacy inslowing MS disease progression. The rate ofno evidence of disease activity (NEDA) was71% among patients with RRMS, and the rateof no evidence of progression or activedisease (NEPAD) was 38% among patientswith progressive MS. of 23 patients withelevated NfL initially, 22 had normal levelsat follow-up.45

Tecfidera® (dimethyl fumarate)Company: Biogenn Starting dose: 120 mg twice a day, orallyfor seven days; ongoing dose: 240 mgtwice a day, orally

n Approved in 2013 for RMSThe exact means by which Tecfidera®

(dimethyl fumarate) exerts its effects in MS isnot known. The medication has been shownto activate a pathway involved in the cellularresponse to oxidative stress, which is inducedby inflammation. However, it is unclearwhether this pathway activation plays a role inTecfidera’s impact on the MS diseaseprocess.4

In 2017, the prescribing information forTecfidera was revised to include direction toobtain a complete blood cell count and tomeasure liver enzymes and other valuesbefore initiating the medication. Additionally,



warnings were added to the prescribinginformation noting that progressive multifocalleukoencephalopathy (PML), a rare butserious brain infection, and liver injury, haveoccurred in people taking Tecfidera.4

A recent study found that patients withrelapsing-remitting MS (RRMS) respond wellto Tecfidera and generally adhere totreatment, regardless of whether theyswitched from a previous disease-modifyingtherapy or were being treated for the firsttime. The findings offer a glimpse into thereal-world efficacy of Tecfidera, and mayguide physicians’ use of the oral agent atvarious stages of RRMS.

Researchers reviewed the records of 456people with RRMS at six MS treatment centersin Italy. These individuals either had startedtreatment with Tecfidera or switched to themedication from another DMT. Two of everythree patients studied were women, and thegroup had a mean Expanded Disability StatusScale (EDSS) score of 2.5, indicating mild tomoderate disability for many of theseindividuals. The participants’ mean age was40 years, and mean MS disease duration wasnine years.

The annualized relapse rate was reducedby 75% from baseline among those treatedwith Tecfidera. However, study participantswith an elevated pre-treatment EDSS score(suggesting more-severe disability) weremore likely to discontinue the medication,compared to those who had mild tomoderate disability before treatment. Also,patients who de-escalated from a strongerbut potentially more-toxic second-linetherapy to Tecfidera faced an increased risk

of relapse. Among the other findings:

• EDSS scores were stable in 88% ofpatients.

• The younger the patient, the lower the riskof relapse.

• The shorter patients’ disease duration,the greater their chance of achieving noevidence of disease activity (NEDA) overa three-month period.46Meanwhile, an analysis of 665 people with

MS in Denmark and Switzerland sought tomeasure real-world discontinuation rates forTecfidera and determine why patients stopthe medication. The average length ofTecfidera use among the study subjects was15.3 months. The researchers found that 200patients (30.1% of the study population)discontinued Tecfidera, with 115 of themciting adverse events as the main reason.Lymphopenia (a shortage of an infection-fighting white blood cell), gastrointestinal(GI) discomfort, and flushing were the mostcommon adverse effects reported. Diseaseactivity and pregnancy were also commonreasons for discontinuation.

Among those who discontinued Tecfiderawithin three months after starting treatment,GI discomfort was the most common reasoncited. Lymphopenia, GI effects, and diseaseactivity were common reasons among thosewho stopped after three to 12 months, whilelymphopenia and disease activity drovediscontinuation after one year.47

Pregnancy is a common reason forstopping Tecfidera and other DMTs, as



reflected in the findings from the study justcited. While clinical trials and post-marketingdata have not found evidence that exposureto delayed-release Tecfidera duringpregnancy poses safety concerns for themother or unborn child, the medication’smanufacturer advises that the agent maycause fetal harm based on animal studies.4However, recent research may providereassurance for women who are weighing therisks and benefits of taking Tecfidera duringpregnancy. As noted earlier, women who arepregnant or planning on becoming pregnant,and who are taking or considering a DMT,should consult with their physician.

Researchers reviewed data from anongoing registry of women with MS who tookTecfidera one day before their last menstrualperiod, before conception, or duringpregnancy. Data were obtained atenrollment, at six to seven months ofgestation, at four weeks after estimateddelivery date, and at four, 12, and 52 weeksafter birth. Mean duration of fetal exposure todimethyl fumarate was 5.7 weeks.

As of october 2018, a total of 194 birthswere reported, including 177 live births and17 fetal deaths (16 miscarriages and onestillbirth). No ectopic or molar pregnancies,nor infant or maternal deaths, occurred. ofthe 174 infants for whom gestational age wasknown, 160 were born full-term and 14 werepremature. of the 144 infants for whomgestational size was recorded, 119 wereappropriately sized, 13 were small, and 12were large. Birth defects were reportedamong seven (4%) of the 194 births.48

Aubagio® (teriflunomide)Company: Sanofi Genzyme n Starting dose: 7 mg once daily n Approved in 2012; indicated for relapsingforms of MSAs is the case with many other disease-

modifying therapies (DMTs) used to treat MS,the exact mechanism by which Aubagio®(teriflunomide) exerts its therapeutic effecthas not yet been fully determined. In the caseof Aubagio, the mechanism may involvereducing the number of activatedlymphocytes – immune-system cells – in thecentral nervous system. The medication hasanti-inflammatory properties and has beenshown to inhibit the synthesis of pyrimidine,an organic compound involved with variouscells and processes throughout the body.43

Recently reported study results indicatethat Aubagio may alleviate the fatigue thatcommonly afflicts individuals with relapsing-remitting MS (RRMS).

Teri-FAST, an observational studyconducted in France, followed 210 patientswith RRMS who were receiving 14 mg dailyof Aubagio. of these patients, 110 had notreceived a disease-modifying therapy (DMT)prior to Aubagio, and 100 had switched toAubagio from another DMT. Fatigue wasmeasured using EMIF-SEP, the French versionof the Modified Fatigue Impact Scale. Data onfatigue and medication adherence werecollected at baseline and at six months, oneyear, and two years after treatment initiation.

After two years, the overall meanreduction from baseline in EMIF-SEP scores



was 1.5 points, suggesting a decrease infatigue with Aubagio. Significant mean two-year EMIF-SEP score reductions were alsoreported among those previously treatedwith other DMTs, suggesting that Aubagiomay reduce fatigue regardless of the patient’streatment history. At the two-year point, 126patients were still taking Aubagio, with 123 ofthese patients taking the medication daily.Adverse events were reported in 27.5% of thetotal patient population.49

Another study showed that Aubagiohelped patients maintain quality of life overtwo years, even though adverse effects (AEs)with the medication were common.

The Teri-LIFE study followed 200 adults inScandinavia treated with Aubagio 14 mgdaily for RRMS. Patients’ quality of lifeassessed was every six months with the ShortForm-36 (SF-36) questionnaire. Slightly morethan seven of 10 participants were women.The mean age for all participants was 44.1years, and the mean time since diagnosis atstudy entry was 3.6 years. The medianExpanded Disability Status Scale score was2.0, suggesting that many patients had mildto moderate disability at study initiation.

Mean SF-36 scores remained stable frombaseline through Year 2, ranging from 46.5 to47.7 for the physical component and from46.6 to 48.8 for the mental component. Theon-treatment annualized relapse rate was0.17, and 79% of patients experienced norelapses.

At the two-year mark, 118 individuals(59%) were still taking Aubagio; 22% haddiscontinued because of adverse events(AEs), 9% stopped due to lack of efficacy,

and 10% discontinued for other reasons.The most common AEs reported were hairthinning (26.5%), diarrhea (23%), and fatigue(20%). Serious AEs were reported by 11% ofpatients. These percentages, were similar tothe prevalence of AEs reported in clinicaltrials of Aubagio.50

Gilenya® (fingolimod)Company: Novartis n Starting dose: 0.5 mg once daily forpatients weighing more than 88.2 lbs (40kg); 0.25 once daily for patients weighing88.2 lbs (40 kg) or less

n Approved in 2010; indicated for clinicallyisolated syndrome (CIS), relapsingmultiple sclerosis (RMS), and activesecondary-progressive multiple sclerosis(SPMS) in patients aged 10 years andolderGilenya® (fingolimod) was the first

sphingosine 1-phosphate (S1P)-receptormodulator approved for the treatment of MS.In 2018, the FDA expanded the approveduses of Gilenya to include treatment ofchildren ages 10 years and older withrelapsing forms of MS, clinically isolatedsyndrome, and active secondary-progressiveMS. Gilenya is similar in structure to anaturally occurring component of cell-surfacereceptors on white blood cells. (White bloodcells are produced by the immune system tofight infection and disease.) Gilenya blockspotentially damaging T cells from leavinglymph nodes, lowering their number in theblood and tissues. It may reduce damage to




the central nervous system (CNS) andenhance the repair of damaged nerves withinthe brain and spinal cord.51

A study comparing Gilenya with aninterferon-based medication in pediatricpatients found that Gilenya was moreeffective in slowing disease progression inchildren and adolescents with MS.

The study assigned 215 children andadolescents ages 10 to 18 years to receiveeither Gilenya at 0.25 or 0.5 daily dependingon body weight, or interferon beta at 30 mcgper week. Magnetic resonance imaging (MRI)scans were taken every six months for twoyears or until treatment was stopped.

After two years, the children receivingGilenya had a 66% lower annualized rate offormation of gadolinium-enhancing T1lesions, compared with the interferon group.Annualized rates of new or enlarging T2lesions were 52.6% lower in the Gilenyagroup, and rates of T1 hypointense andcombined unique active lesions were 62.8%and 60.7% lower, respectively, with Gilenyathan with interferon. T2 and gadolinium-enhancing T1 lesion volumes also were loweramong youths receiving Gilenya. of note,approximately 77% of children treated withGilenya showed no gadolinium-enhancinglesions after the study, compared with 54%of the interferon group.52

While Gilenya demonstrated its efficacy inthe clinical trials that led to its approval,French researchers wanted to know moreabout its effectiveness and safety over thelong term in real-world clinical settings, wherepatients may be in poorer overall health and

receive less-intensive managementcompared with a controlled trial setting.53

The VIRGILE trial, a multicenter,observational study, observed 1,052 adultswith highly active RRMS who received Gilenyabetween 2014 and 2016. For comparison,researchers also studied 331 patients treatedwith Tysabri, the intravenously administereddisease-modifying therapy (DMT) throughoutthe same period. All participants wereanalyzed every six months. A total of 1,064patients from either group completed twoyears of follow-up; 923 of them completedthree years, and some patients in the Gilenyagroup continued treatment in an additionaltwo-year extension study.

Annualized relapse rates (ARRs) atbaseline were 1.0 in the Gilenya group and2.1 among patients treated with Tysabri. TheARRs decreased to 0.3 in both groups aftertwo years and three years, and ARRs for theGilenya patients were 0.2 after 4 years. Also,mean Expanded Disability Status Scale(EDSS) scores remained stable for bothgroups, changing from 2.7 to 3.0 over fouryears for Gilenya patients and from 3.2 to 2.9over three years in the Tysabri group. Thefindings suggest that oral Gilenya may be analternative to second-line IV therapy in thosewith active MS, the researchers said.

over the entire study period, 59.4% of theGilenya group and 52.3% of Tysabri patientsreported one or more adverse events (AEs).one or more serious AEs were reported in13.5% and 7.9% of Gilenya and Tysabripatients, respectively. The AE incidencewas similar to that seen in clinical trials.53


Rebif® (interferon beta-1a)Company: EMD Seronon Dose: 22 mcg or 44 mcg injectedsubcutaneously three times per week

n Approved in 1996 for relapsing forms of MSRebif® is an interferon medication.

Interferons are a group of proteins thatsignal the body’s immune system to respondto threats, such as a virus. While the exactmeans by which Rebif and other interferon-based medications exercise their therapeuticeffects in multiple sclerosis is not known,interferons are among the earliest disease-modifying therapies (DMTs) used to treat MS.

A recent head-to-head comparison ofRebif and the oral disease-modifying therapy(DMT) Aubagio showed no significantdifferences between the two medications interms of slowing MS disease progressionover the course of two years.

A total of 932 patients with relapsing-remitting MS (RRMS) were started on Rebif orAubagio, and were followed for two yearsregardless of whether they discontinuedeither medication. Relapse rates and lesionactivity were measured during that period,and disability progression was calculatedbased on Expanded Disability Status Scale(EDSS) scores. Individuals who were pregnantor who had RRMS for 10 years or longer wereexcluded from the study.

After two years, the prevalence ofdisability progression was low but similar

among both treatment groups (8.5% withRebif vs 11.4% with Aubagio). The percentageof participants who suffered one or morerelapses in two years was lower in the Rebifgroup (39.4%) than in the Aubagio group(49.2%). Also, a higher proportion ofindividuals in the Rebif group were free ofdisease activity over a given three-monthperiod (73.1%) vs Aubagio (55.1%).

The researchers warned, however, thatdifferences in baseline EDSS scores and pastdisease-free periods were not consideredwhen the percentages were calculated, so theresults are not definitive.54 Ultimately,individual response, patient preference,tolerability, and accessibility to medication gofar toward determining which patients arebest suited to a specific DMT.

Plegridy® (peginterferon beta-1a)Company: Biogenn Dose: 125 micrograms injectedsubcutaneously every 14 days

n Approved in 2014 for relapsing forms of MSPlegridy is a form of interferon beta-1a

that is pegylated, meaning that its chemicalstructure allows for longer duration of themedication’s effect. Like other interferon-basedagents used in multiple sclerosis, however, theexact means by which Plegridy exercises itstherapeutic effect in MS is not fully understood.

An evaluation of the long-term safety andeffectiveness of Plegridy in adults with


INJECTABLE MEDICATIONS



relapsing forms of MS has yielded reassuringfindings, researchers reported recently.

The Plegridy observational Program(PoP) is an initiative sponsored by Biogen,the company that markets Plegridy. It is a five-year project involving patients in 14 countrieswho are taking Plegridy. The effort is a “post-marketing study,” meaning that it collectsdata on real-world use of a medicationfollowing the medication’s approval byregulatory authorities.

The study includes a safety analysisinvolving 1,126 patients, plus an effectivenessanalysis that examines data on 1,125 patients.Results for both analyses are groupedaccording to whether individuals are newlydiagnosed (those diagnosed with MS withinone year before consenting to the study) andthose who were previously diagnosed. Thenewly diagnosed individuals are younger(mean age 38.0 vs 45.9 years), have less MS-related disability, and have a higher rate ofrelapse before entering the study (mean

relapses: 0.9 vs 0.3) than those diagnosedmore than one year before entering the study.

As of September 11, 2018, annualizedrelapse rates were similar between the newlyand previously diagnosed patients (0.12 vs0.14). Serious adverse events were reportedin 5.3% of those who were newly diagnosed,compared with 7.0% of previously diagnosedindividuals. Transient, post-injection flu-likesymptoms were common in both groups(reported in 47.7% of newly diagnosed and38.6% of previously diagnosed patients) aswere injection-site reactions (35.8% vs 38.6%).of note, newly diagnosed individuals had asignificantly shorter MS-treatment history(mean duration 21.5 months), comparedwith non-newly diagnosed individuals (meanduration 87.3 months).

No birth defects, premature births, orectopic or molar pregnancies relating toPlegridy exposure were reported amongexpectant mothers in the study. Nineteen livebirths and two miscarriages were recorded.55


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OfatumumabCompany: Novartis and Genmabn Injected subcutaneously, being studied at20 mg monthly

n Being studied in RMS The Food and Drug Administration (FDA)

is conducting a priority review of the cancermedication ofatumumab for the treatmentof relapsing forms of MS (RMS). Executivesat Novartis, which markets ofatumumabcollaboratively with Genmab, say themedication could be approved as early asmid-2020. The European Medicines Agency(EMA), the drug regulatory agency for theEuropean Union, is also reviewingofatumumab and may approve themedication in early 2021. 56

ofatumumab, a monoclonal antibody

used for treating chronic lymphocyticleukemia,12 binds to the CD20 moleculelocated on the surface of lymphocytes, a typeof white blood cell. Lymphocytes arebelieved to trigger the abnormal immuneresponse that damages the protective sheath(myelin) surrounding nerve cells in the brainand spinal cord. By binding to CD20, thelymphocytes are destroyed and neuronaldamage is prevented or delayed. 57

This treatment approach is similar to thatof ocrelizumab, a monoclonal antibody that isFDA-approved for RMS and primary-progressive MS, as well as rituximab, which isoften used off-label to treat MS. But whileocrelizumab and rituximab are administeredintravenously, ofatumumab is self-injectedsubcutaneously (under the skin) once amonth. For this reason, ofatumumab couldprovide the benefits of a CD20 monoclonal

About Monoclonal AntibodiesMonoclonal antibodies are medications derived from identical cells that are cloned from

a single cell and then replicated. They are produced from animal tissue, most commonlylaboratory mice. Humanized monoclonal antibodies are antibodies from non-human species,again, commonly a mouse, whose protein sequences have been modified to increase theirsimilarity to antibodies produced naturally in humans.

Monoclonal antibodies can be extremely powerful and effective, as they can specificallytarget a certain segment of one of the body’s systems – such as the immune system – whileleaving the other parts of the system unaffected. This can be very desirable when trying toimpact a structure as complex as the immune system.

The names of all monoclonal antibodies end with “mab,” including alemtuzumab(Lemtrada®), ocrelizumab (ocrevus®), and natalizumab (Tysabri®), which are already approvedfor MS. Several other monoclonal antibodies have shown promise in MS, and five of these arereviewed in this section.


EXPERIMENTAL MEDICATIoNS:MONOCLONAL ANTIBODIES

antibody with convenient at-home dosing,and could be an option for individualslooking for an alternative to periodic infusionsor frequent self-injections. 13

The application for FDA approval to useofatumumab in MS is supported by data fromthe Phase III ASCLEPIoS I and ASCLEPIoS IItrials, in which ofatumumab outperformedAubagio in slowing disease progression inRMS.56 A total of 1,881 adults with RMS inthe two simultaneous trials received asubcutaneous 20-mg injection ofofatumumab plus an oral placebo tablet, ororal Aubagio at 14 mg once daily plus a sham(placebo) injection, for up to 2½ years.Neither the investigators nor the participantsknew which treatment was active and whichwas placebo. Those who received activeofatumumab injections received loadingdoses of 20 mg upon study entry and thenseven and 14 days later before switching tomonthly dosing.13

At the end of the two trials, annualizedrelapse rates were 50.5% and 58.5% lower,respectively, among ofatumumab-treatedindividuals compared with the Aubagiogroup (0.11 vs. 0.22) and (0.10 vs 0.25). Thosetreated with ofatumumab also showed arelative risk reduction of 34.4% in confirmeddisability progression (CDP) over threemonths, and a 32.5% reduced risk of six-month CDP, compared with Aubagio.

Additionally, ofatumumab-treated patientsshowed fewer gadolinium-enhancing T1lesions on magnetic resonance imagingcompared with those treated with Aubagio,suggesting that ofatumumab suppressesinflammatory activity.56

UblituximabCompany: TG Therapeutics

n Given via IV infusionn Being studied in RMS

Results from two simultaneous Phase IIIclinical trials testing the effectiveness ofublituximab for slowing disease progressionin people with relapsing forms of MS (RMS)are expected to be released later in 2020.15

The ULTIMATE I and ULTIMATE II studiesare randomized, double-blind, 2-year studiesinvolving 1,094 adults with RMS. The studypopulation reflects the typical real-worldcaseload of individuals with MS based on itshistory of relapse and existence of lesionsshown via magnetic resonance imaging(MRI). Participants range in age from 18 to 55years, and approximately two-thirds arewomen. 58, 21, 15

Participants have been receiving a one-hour IV infusion of ublituximab at 450milligrams every 24 weeks plus a dailyplacebo tablet, or oral Aubagio at 14milligrams daily plus a twice-yearly sham(placebo) IV infusion. Neither the researchersnor the participants know which of the twotreatments is active and which is placebo.Improvements in annualized relapse rates,a commonly used measurement of diseaseactivity, will be used to determine theeffectiveness of ublituximab in slowing orpreventing neurologic damage.59

Similar to the disease-modifying therapies(DMTs) ocrevus and Rituxan, ublituximab is amonoclonal antibody that targets the CD20antigen on the surface of B lymphocytes, a



type of white blood cell. Lymphocytes cantrigger an abnormal immune response thatdamages the protective sheath (myelin) thatprotects nerve cells in the brain and spinalcord. By binding to CD20, ublituximab isbelieved to initiate a process that destroyslymphocytes and slows neuronal damage.59Ublituximab employs antibody-dependentcellular cytotoxicity (ADCC), a type ofimmune reaction where target cells arecoated with antibodies that attract whiteblood cells, which then kill the target cells.60Ublituximab can be administered lessfrequently (twice annually) than other DMTs,and can be infused in one hour.15

Ublituximab showed robust efficacy in aprior Phase II clinical trial that tested sixdifferent dosages and infusion durations in 48individuals with RMS. Forty-five participantsfrom the Phase II clinical trial were thenenrolled in a subsequent open-labelextension. Among the findings:

• B cells were depleted by a median of 99%at four weeks into the original Phase IIstudy and stayed at reduced levelsthroughout the trial.

• Infusion-related reactions occurred in onlyfive patients (11%) in the extension study,and all reactions were mild.

• An annualized relapse rate of 0.07 wasobserved, and 93% of study participantswere relapse-free at Week 48.

• Gadolinium-enhancing T1 lesions wereeliminated at the initial study’s halfwaypoint, and the volume of new or enlargingT2 lesions was reduced by 10% at study’send.15, 58

Opicinumab Company: Biogenn Given via IV infusionn Being studied in RMS

Researchers are investigating whether themonoclonal antibody opicinumab reversesneurologic damage and disability whenadded to existing therapy in select patientswith relapsing forms of MS (RMS).

If the ongoing AFFINITY clinical trial showsa significant benefit for opicinumab as add-on therapy, the results could be the first steptoward a breakthrough that could givephysicians an option for restoring functionaland neurologic loss in MS, rather than justslowing or preventing further decline.However, opicinumab did not show ameaningful benefit in a previous Phase IIstudy, called SYNERGY, which examined theuse of concomitant opicinumab with anotherdisease-modifying therapy.61

MS can manifest when the myelin sheath,the protective fibers around nerve cells inthe brain and spinal cord, is damaged byan abnormal autoimmune response.opicinumab is formulated to promotemyelin sheath repair by blocking the effectsof LINGo-1, a protein that hindersdevelopment of myelin-generating cellscalled oligodendrocytes. It is hoped thatallowing oligodendrocytes to proliferatewill restore damaged myelin, offering thepotential for opicinumab to prevent andpossibly reverse disability.62 opicinumabhas been shown in animal studies to restoremyelin, and investigators hope to replicate



that effect in humans. In the Phase II SYNERGY trial, 418 adults

with RMS received interferon beta-1a at 30micrograms per week, plus IV opicinumabevery four weeks or a placebo infusion.opicinumab was dosed at 3, 10, 30, or 100milligrams per kilogram (about 2.2 pounds)of body weight. After 72 weeks, disability waslessened in between 40% and 65% of thoseindividuals who received opicinumab at anydosage. Similar benefits, however, were seenin 49% of the other group. The investigatorsfound no overall dose-related benefit withopicinumab, but found an increased rate ofdiscontinuation with the higher doses. 61

However, a later analysis of theSYNGERGY findings showed more-robusttreatment responses in a subgroup ofindividuals whose first MS symptom camewithin the past 20 years. These patients alsohad magnetic resonance imaging (MRI)findings that indicated that some nerve fibersremained intact despite myelin damage,suggesting that more nerve fibers andmyelin may have been preserved. A lowerproportion of people in this subgroupshowed confirmed disability worsening withthe 10 mg/kg dosage of opicinumab, andmore of these individuals showed positiveeffects on exploratory biomarkers of centralnervous system repair. These findingsprompted Biogen, the developer ofopicinumab, to continue assessing themedication’s potential effects on myelinreconstruction.

The AFFINITY trial is following 263 peoplewith RMS who are being treated withinterferon-based DMTs, Tecfidera, or Tysabri.

Participants will receive intravenousopicinumab at 750 mg or a placebo IVinfusion every four weeks as an add-on totheir current therapy for 72 weeks.63 Severaltests will be performed throughout the trialto measure treatment effect on participants’cognitive and physical function. Studycompletion is scheduled for May 2022.63

Rituxan® (rituximab)Company: Genentech/Rochen Given via IV infusionn Being studied in RMS

Rituxan is a monoclonal antibody thatbinds to a receptor, known as CD20, on thesurface of B cells. These cells are thendestroyed, and their levels in the circulationare decreased. Rituxan is approved for use inthe treatment of lymphomas, leukemias, andautoimmune disorders. It is not approved bythe FDA for use in MS, but many neurologistsprescribe it for that purpose.

A recent analysis of electronic medicalrecords found no increased risk of cancerwith several disease-modifying therapies(DMTs), including Rituxan. The impact ofDMTs on cancer incidence is a concernbecause the medications suppress theimmune system to counteract theabnormal inflammatory immune responsethat harms the nervous system in MS. Thisimmunosuppression, however, can increasethe risk of cancer. 64

A total of 4,340 people with MS whoreceived Rituxan were identified from theKaiser Permanente Southern California health



system’s electronic records and the SwedishNational Cancer Registry. Seven women(0.2%) had breast cancer, translating to abreast cancer rate of 1.2 per 1,000 personyears. Breast cancer rates were similar amongwomen taking other DMTs, and in acomparison group of women without MS,suggesting a low risk of cancer with thesemedications.65

TemelimabCompany: GeNeuro n Given via IV infusionn Being studied in SPMS and PPMSn Studies are postponed due to the COVID-19 pandemicA Phase II clinical trial to assess the efficacy

of temelimab in progressive, non-relapsingforms of MS has been put on hold so thatinvestigators can instead focus on developingsolutions against CoVID-19. Trial organizersalso expressed concern about exposingindividuals with MS to increased risk of viralinfection during the pandemic.

The one-year clinical trial, when initiated,will test the efficacy of temelimab in slowingdisability progression in severe, progressiveforms of MS.1 Temelimab, a monoclonalantibody, is formulated to slow diseaseprogression by targeting a humanendogenous retrovirus (HERV), a proteinthat is either replicated from a host cell, iscaused by a germ, or is hereditary.

The HERV protein activates immune cellsthat cause inflammation in the brain anddestruction of the protective sheath (myelin)surrounding the nerve cells in the brain andspinal cord. The protein also inhibitsdevelopment of myelin-generating cellscalled oligodendrocytes. It is hoped thatneutralizing HERV will halt both the abnormalinflammatory immune response andneurologic deterioration and diseaseprogression. This treatment approach isunlike that of currently approved DMTs.66

Temelimab showed efficacy in a previousPhase II clinical trial, called ANGEL-MS. Thestudy enrolled 219 individuals with relapsing-remitting MS who had completed an earlier48-week, Phase IIb trial, CHANGE-MS.Participants in ANGEL-MS were followed forup to 48 weeks, or 96 weeks after the start ofCHANGE-MS. At study’s end, those whoreceived monthly infusions of temelimab at18 milligrams per kilogram (or approximately2.2 pounds) of body weight showed lowervolume of T1 hypointense lesions, whichindicate severe damage to the centralnervous system (CNS), compared with theplacebo-treated group from CHANGE-MS.

No clinically relevant effect was seen onmeasures of CNS inflammation, however.67In the previous CHANGE-MS trial, the 18mg/kg dose was significantly more effectivein slowing lesion development and CNSdamage than two lower doses of themedication.66 Temelimab overall was welltolerated, and no dose-related safety issueswere reported.67



EXPERIMENTAL MEDICATIoNS:S1P RECEPTOR MODULATORS

PonesimodCompany: Janssen/Johnson & Johnsonn Oral medication being studied at 20mg/day

n Being studied in RMSJanssen/Johnson & Johnson has applied

to the United States Food and DrugAdministration (FDA) and European MedicinesAgency (EMA) for approval of its selectivesphingosine-1-phosphate receptor 1 (S1P1)immunomodulator ponesimod for treatingadults with relapsing forms of MS (RMS).

The applications for approval aresupported by data from a multicenter, double-blind, Phase III clinical trial (oPTIMUM), inwhich ponesimod outperformed anotherdisease-modifying therapy, Aubagio, in ahead-to-head comparison among 1,133adults with relapsing MS.10 Participantsreceived ponesimod 20 mg or Aubagio 14mg once daily for approximately two years.Ponesimod was started at 2 mg daily, thenincreased gradually to 20 mg daily to preventeffects on heart rate that can result with S1Preceptor modulators.9

After two years, the annualized relapserate was 30% lower in the ponesimod group(0.2) compared with individuals who receivedAubagio (0.29). Also, the number of combinedunique active lesions (gadolinium-enhancingT1 and new or enlarging T2 lesions) detectedby magnetic resonance imaging was 56%lower in the ponesimod group, compared withthose receiving Aubagio.10

Additionally, scores on the FatigueSymptoms and Impacts Questionnaire -Relapsing Multiple Sclerosis (FSIQ-RMS) – a20-item patient survey that measures MS-related fatigue symptoms and their impacton quality of life – were a mean of 3.57 pointslower in the ponesimod group.10 This findingsuggests that ponesimod may alleviatefatigue, an often-debilitating symptom thataffects roughly 80% of people with MS.

Ponesimod also displayed the same levelof tolerability shown in previous clinical trials.The most common treatment-related adverseeffects were colds, headache, upperrespiratory tract infections, and an increase inalanine amino transferase, an enzyme that atelevated levels could signal liverdysfunction.10

About S1P Receptor ModulatorsSphingosine-1-phosphate receptor (S1P) modulators confine certain immune cells in thelymph nodes so that they cannot reach the central nervous system (CNS) and contribute to theformation of the lesions that are hallmarks of MS. Two FDA-approved disease-modifyingtherapies (DMTs), Gilenya® and Mayzent®, work in this manner, and other S1P receptormodulators are being evaluated for a possible role in treating MS. The company developingone of those investigational medications, ponesimod, recently asked the FDA and theEuropean regulators to authorize use of its medication in relapsing forms of MS based on theresults of the following study.8


EvobrutinibCompany: EMD Serono

n Oral medication being studied at 75 mgonce and twice daily

n Being studied in RMS

Two simultaneous Phase III clinical trials –EVoLUTIoN RMS 1 and EVoLUTIoN RMS 2 –will be testing the efficacy of the oralinvestigational medication evobrutinib fordelaying neurologic and functional decline inpeople with relapsing forms of MS (RMS).

In a previous Phase II trial, evobrutinibreduced the total cumulative number of T1gadolinium-enhancing (Gd+) lesionscompared with placebo. The reduction inGd+ T1 lesions was seen at 12 weeks andmaintained through 48 weeks withevobrutinib 75 mg once or twice daily.Reductions in relapse rates were alsoobserved at week 24 and were maintainedthrough 48 weeks.16

Evobrutinib is a highly selective inhibitorof Bruton's tyrosine kinase (BTK), a non-receptor enzyme. BTK contributes to thedevelopment and function of B lymphocytes,a type of white blood cell that can attack anddestroy the neuroprotective myelin sheaththat surrounds nerve cells in the brain andspinal cord. Evobrutinib is formulated toinhibit the primary B cell actions that lead toabnormal immune responses and, ultimately,neurodegeneration. It is hoped that throughthis mechanism of action, neurologic andfunctional decline will be delayed or evenprevented.16

In another Phase II clinical trial, evobrutinibat different dosages did not appreciablyreduce total B cells or immunoglobulin levels.This finding suggests that BTK inhibition,which is often employed to treat certaincancers, may not kill enough myelin-damaging cells and proteins to effectivelycombat MS.37 Still, however, the preliminaryfindings that point to evobrutinib’s effect onlesions and relapses give investigators reasonto hope.

EVoLUTIoN RMS 1 and 2 are two-year,randomized, double-blind studies comparingtwice-daily evobrutinib with interferon beta-1a (given intramuscularly once weekly).Researchers in both studies will recordchanges in annualized relapse rates, time tofirst occurrence of 12- and 24-week confirmeddisability progression, and total number oflesions based on magnetic resonanceimaging readings.16 Study completion forevaluation of primary results is expectedsometime in 2023.68

Ibudilast (also known as MN-166)Company: MediciNovan Oral medication being studied at up to100 mg (50 mg twice daily)

n Being studied in RMSAn upcoming Phase III clinical trial will

examine whether ibudilast effectively slowsdisease progression in more-severe, non-relapsing MS. Ibudilast is a small molecule(specifically, a macrophage migrationinhibitory factor [MIF] inhibitor andphosphodiesterase [PDE] -4 and -10 inhibitor)

EXPERIMENTAL MEDICATIoNS:ADMINISTERED ORALLY


that suppresses pro-inflammatory moleculesand promotes nerve-growth factors.69

In a Phase IIb trial, this oral medication,also known as MN-166, slowed brain-volumeloss and reduced the risk of confirmeddisability progression (CDP) by 46% relativeto placebo among individuals withsecondary-progressive MS (SPMS).69, 2

Ibudilast suppresses the pro-inflammatorycytokines that can cause neurologic damagein MS and supports the nurturing of nervecells. It also prevents glial cells, which helpregenerate the protective myelin sheatharound nerve cells in the brain and spinalcord, from becoming overactive andtriggering inflammation that can damagemyelin.69, 2 For the Phase III trial, researcherswill measure time to CDP across threemonths, a marker of long-term disability inMS, as measured with the ExpandedDisability Status Scale.69

Meanwhile, MediciNova, thebiopharmaceutical company developingibudilast, announced in April 2020 that it willalso study the medication for use in acuterespiratory distress syndrome (ARDS) causedby CoVID-19. 2

CNM-Au8Company: Clene Nanomedicinen Oral medication being studied at up to30 mg per day

n Being studied in RMS Researchers are investigating the efficacy

and safety of the oral suspension medicationCNM-Au8 for repairing central nervous

system damage in people with relapsingforms of MS (RMS) who experience visualimpairment.

A Phase II clinical trial is under way, withfull results expected in mid-2021. Preliminaryresults showed a median improvement invisual function among 34 patients across 36weeks, based on performance on the LowContrast Letter Acuity (LCLA), a vision test forindividuals with MS. Physical and cognitivefunction also improved, based on severalpatient surveys commonly used to measureMS-related functional decline.

Preliminary results also indicate that CNM-Au8 is safe and well tolerated. All reportedadverse events (AEs) were mild in severity,with headache, upper respiratory infection,and sore throat being the most commonlyreported AEs with either the 15 mg per dayor 30 mg per day dosage, according to thecompany developing the medication.70, 71

CNM-Au8 consists of nanocrystalline goldparticles formulated to promote normalcellular function while decreasing abnormal,destructive activity. It is hoped that thistreatment approach will not only preventfurther damage to myelin (the protectivesheath surrounding neurons), but will repairpreviously damaged myelin and, in theprocess, restore lost function in MS.70

In preclinical studies, CNM-Au8prolonged survival of nerve cells in thecentral nervous system and showedeffectiveness in regenerating myelin.CNM-Au8 also showed safety and tolerabilityin Phase I studies that involved healthyvolunteers. Clene Nanomedicine, thebiopharmaceutical company developing



CNM-Au8, has received FDA approval toconduct clinical studies of this experimentalmedication for reversing remyelination failurein patients with MS.70

MD1003Company: MedDay Pharmaceuticalsn Oral medication being studied at up to300 mg per day

n Being studied in SPMS and PPMSThe oral biotin-based medication

MD1003 did not significantly affect disabilityprogression in patients with secondary- orprimary-progressive MS (SPMS, PPMS) in apivotal Phase III clinical trial, according to thecompany developing MD1003. Those resultsrun counter to a previous small pilot study,which showed evidence that biotin at highdoses might slow disability and progressionin MS.72

Biotin is a B-group vitamin (vitamin B7)

commonly found in over-the-countersupplements. Biotin activates enzymesinvolved in energy production anddevelopment of myelin, the protective sheatharound the nerve cells of the brain and spinalcord. Researchers are examining whetherhigh-dose biotin can promote myelin repairby activating an enzyme involved in myelinsynthesis and by enhancing energyproduction in damaged nerves.

MD1003, formulated as a capsule takenthree times daily, is a highly concentratedformulation of biotin. The dosages beingtested in clinical trials (100 to 300 milligramsdaily) are several thousand times therecommended daily intake of biotin. TheFood and Drug Administration (FDA) setsthe recommended daily allowance for biotinat 0.3 milligrams per day.73

MedDay Pharmaceuticals, the companydeveloping MD1003, says it will continue toevaluate the data and confer with regulatorsin assessing potential next steps.72



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MRI Please visit mymsaa.org/mri or call (800) 532-7667, ext. 120 for more information.

MSAA’s MRI Access Fund is made possible with support from Biogen and Sanofi Genzyme.

MSAA’s MRI Access Fund:• Assists with the payment of cranial (brain) and

cervical-spine (upper back) magnetic resonanceimaging (MRI) scans

• For qualified individuals who have no medicalinsurance or cannot afford their insurance costs

• Exam must be required to help determine adiagnosis of multiple sclerosis (MS) or evaluatecurrent MS disease progression

Stem Cell TherapiesResearchers around the world continue

to explore the role of stem cells in treatingmultiple sclerosis (MS).

Most stem cell research in MS focuses onautologous hematopoietic stem celltransplantation, or aHSCT. The term“autologous” means that the cells are takenfrom the patient’s own body. Hematopoieticstem cells have the ability to generate newimmune cells and blood cells.

The goal of stem cell transplantation in MSis to “re-boot” the immune system so that itstops the mounting inflammatory responsesharmful to the brain and spinal cord.Physicians pursue this goal through asophisticated process that typically beginswith giving a patient several days ofchemotherapy. This treatment prompts thebone marrow to produce stem cells andrelease them into the blood. Blood containingthese stem cells is then drawn from a vein andstored.

Next, the patient is given another set ofchemotherapy drugs to suppress or evenentirely wipe out his or her immune system.

The patient is carefully monitored during andafter this phase of treatment to guard againstinfection and other risks associated withreduced immunity. The stem cells takenfrom the patient’s blood earlier are thentransplanted back into the patient byintravenous infusion.

These stem cells begin to re-build thebody’s immune function over the course ofa few months, with the hope being that thenewly constituted immune system will“tolerate” the brain and spinal cord rather thangenerate an inflammatory response, whichleads to the myelin sheath damage andoutward symptoms that are the hallmark ofMS. The transplantation process typicallyinvolves a prolonged hospital stay.

Just a few weeks before the CoVID-19pandemic came to dominate his every wakingmoment, Anthony S. Fauci, MD, announcedthat the government’s National Institutes ofHealth (NIH) had launched a clinical trial to testaHSCT against the best available biologictherapies for severe forms of relapsing MS.74In announcing the trial in early January, Dr.Fauci said, “aHSCT has the potential to halt theprogress of relapsing MS, eliminate the need

IntroductionWhile the development of new disease-modifying therapies (DMTs) remains a major focus ofmultiple sclerosis research, considerable attention is also being devoted to other avenues ofinquiry. These include stem cell therapy, the role of diet and vitamin supplementation in theonset and management of MS, the impact of genetics, and the significance of variousbiomarkers in tracking disease onset, progression, and response to therapy. (Examples ofbiomarkers include substances in the blood or cerebrospinal fluid, as well as findings onimaging). This section of the 2020 MS Research Update reports on several interesting studiesaddressing these topics.


NEW DIRECTIONS IN MS RESEARCH

for a person to take life-long medication, andallow the body to partially regain function.However, we need to be certain that thebenefits of this form of treatment outweighits serious risks.”

The NIH noted that prior studies havesuggested that aHSCT may be an effectiveand durable treatment for people with MS, butthe therapy has never been formallycompared head-to-head with relatively newer,so-called “third-line” MS medications, whichthe government agency noted are highlyeffective but can have harsh side effects.Treatment with aHSCT also carries the risksof serious side effects, and even death.

Given these risks and benefits, the NIHcontinued, investigators will seek to determinewhether aHSCT is an appropriate treatmentoption for people with severe forms ofrelapsing MS who would otherwise receiveone of the best available third-line biologicdrugs. The trial is sponsored by the NationalInstitute of Allergy and Infectious Diseases(NIAID), the division of the NIH that Dr. Faucileads.

The trial is called BEAT-MS (BEst AvailableTherapy versus autologous hematopoieticstem cell transplant for Multiple Sclerosis).It is being conducted by the NIAID-fundedImmune Tolerance Network (ITN) incollaboration with the Blood and MarrowTransplant Clinical Trials network (BMT CTN).The BMT CTN is funded by the National Heart,Lung, and Blood Institute and the NationalCancer Institute, both components of NIH. Thetrial is being led by Jeffrey A. Cohen, MD, aprofessor of neurology at the Cleveland Clinic

Lerner College of Medicine and the directorof the Experimental Therapeutics Program inthe Mellen Center for Multiple SclerosisTreatment and Research at the ClevelandClinic.

BEAT-MS will enroll 156 adults ages 18 to55 years at 19 sites in the United States andthe United Kingdom. Participants will berandomly assigned to receive either aHSCT orone of the best available high-efficacy biologicdrugs, and will be followed for six years. Theneurologists who periodically examine theparticipants and assess their level of disabilitywill not know which type of treatment theywere assigned.

The main outcome investigators willmeasure is how much time elapses betweena participant’s assignment to a treatmentstrategy and MS relapse or death from anycause, if either of these occur, during the firstthree years of the follow-up period. Theresearchers will also examine the mechanismsof action of the two treatment strategies andwill compare the newly developing immunesystems of participants who receive aHSCTwith the immunologic features of studyparticipants who receive the best availablebiologic drugs. In addition, investigators willcompare the effects of the two treatmentstrategies on other measures of diseaseactivity and severity, cost-effectiveness interms of health care costs and individualproductivity, and participants’ quality of life.74

At the September 2019 annual meeting ofthe European Committee for Treatment andResearch in Multiple Sclerosis (ECTRIMS) inStockholm, Sweden, several other teams of



researchers reported on their experience withstem cell transplantation. one of the largeststem cell transplantation studies reported atECTRIMS yielded disappointing results interms of its primary endpoint, but offeredsome potentially encouraging newsnonetheless.

The Phase II MESEMS trial was a multi-center, international study that included 144people with MS. The trial was double-blinded,meaning that neither the physician nor patientknew whether or when the patient wasreceiving transplanted stem cells or placebo.The study also had a “cross-over” design,meaning that one group of participantsreceived transplanted stem cells at the start ofthe trial, was observed for 24 weeks, and thenreceived placebo for 24 weeks.

Participants in the other group receivedplacebo for 24 weeks and then underwenttransplantation, after which they wereobserved for 24 weeks. The purpose of this“cross-over” approach is to see how allpatients do on six months of placebo andduring the six months after transplantation.The patients were treated with their ownmesenchymal stem cells. Mesenchymal stemcells are adult cells derived from bone marrowthat have the ability to develop into manykinds, but not every kind, of human cell.

The primary endpoint of the MESEMS trialwas reduction in the number of gadolinium-enhancing lesions on imaging compared toplacebo. on this foremost measure, there wasnot a statistically significant differencebetween stem cell transplantation andplacebo. However, the results of a secondary

endpoint, annualized relapse rate (ARR), weremore promising. Although the study did notshow statistical significance based on thecriteria specified at the outset of the trial, stemcell transplantation showed a 36% reductionin the ARR relative to placebo. While theresults have to be interpreted with cautionbecause they did not achieve statisticalsignificance, one of the study’s investigatorstermed them a “strong signal.”75

The results of the MESEMS trial reinforcethe fact that while medical research inexorablymoves forward, it rarely does so in a perfectlystraight line, or at the pace and with the near-term results that clinicians and patients wouldwish.

Investigators from Uppsala UniversityHospital in Sweden reported that 93% ofpeople with MS who underwent aHSCT attheir institution, between 2004 and early 2019,had no disease progression over an average3.9 years of follow-up. Further, 87% of the 81people studied had no relapses during thatfollow-up period, and 74% had no new lesionsappear on MRI.76 The study included 56women and 25 men, and 95% of theparticipants had relapsing forms of MS. Theirmedian age at transplantation was 29 years,and the average disease duration prior to theprocedure was six years. Study participantshad received a median of two MS therapiesprior to aHSCT. Roughly three-quarters ofthese individuals received a low-intensitychemotherapy regimen prior totransplantation, while the remainderreceived an intermediate intensity-conditioning regimen.



The group’s annualized relapse rate (ARR)declined from 2.2 in the year precedingtransplant to 0.0022 afterwards. Further, 63%of participants saw an improvement in theirExpanded Disability Status Scale (EDSS)scores. Another 35% of those taking part inthe study had an unchanged EDSS score,while 2% worsened. No patients died duringthe follow-up period.76

A study examining outcomes in 30 peoplewith relapsing forms of MS who underwentstem cell transplantation in Norway, between2015 and early 2018, reported similarlyfavorable results. The study’s primary outcomemeasure was the percentage of people whoachieved “No Evidence of Disease Activity-3”(NEDA-3), which was defined as no clinicalrelapse, no MRI activity, and no ExpandedDisability Status Scale (EDSS) progressionpost-transplant.77

Eighty-three percent of the participantsachieved this NEDA-3 status. Additionally,43% had a sustained improvement in theirEDSS score, 33% were working full-time aftertransplantation as compared to only 3%beforehand, and no patients received disease-modifying treatment after stem cell transplant.

While no individuals in the study died, andno serious treatment-related complicationswere reported, 17% of those treated werediagnosed with autoimmune thyroid diseasefollowing transplantation, and 43% of thewomen in the study reported not having amenstrual period for more than 12 monthsafter transplant.77

Meanwhile, investigators in Hamburg,Germany used a prospective case-control

approach to compare outcomes betweenaHSCT and the disease-modifying therapy(DMT) Lemtrada® (alemtuzumab) in 40 peoplewith highly inflammatory MS. Nineteen of thepatients received aHSCT. of the people in thatgroup, 12 had relapsing forms of MS, whileseven had progressive MS. Five of the 21individuals receiving Lemtrada had anunderlying chronic disease.

The two groups were similar in terms ofgender, age, EDSS score, number of priortherapies, and other factors. Disease duration,however, was longer in the Lemtrada group,while relapse activity in the two years prior totreatment initiation was lower.

The study’s primary outcome measurewas no evidence of disease activity (NEDA),meaning no clinical relapse, no MRI activity,and no Expanded Disability Status Scale(EDSS) progression. Average follow-up timewas just under five years for the stem celltransplant group and just over two years forthe individuals receiving Lemtrada. Theresearchers reported that significantly morepatients receiving stem cell transplantsachieved the goal of NEDA compared topeople treated with Lemtrada, although nodifference was seen in confirmed diseaseprogression, as measured by EDSS scores,between the two groups. 78

Diet and MSA diet consisting primarily of vegetables,

whole grains, berries, poultry, fish, and olive oilwas associated with larger thalamic volume – ameasure of brain health and function – in a



study examining how eating habits correlatedwith MRI findings in 185 people with MS.

Study participants were an average ageof 34 years, and on average, had beendiagnosed with MS a little more than twoyears before study entry. Two-thirds werefemale, and the participants’ medianExpanded Disability Status Scale (EDSS) was1.0, indicating that most study subjects had nodisability and only minimal symptoms in onefunctional area.

The participants underwent MRIassessment and completed a detailedquestionnaire about their eating habits. Theywere then divided into four groups based ontheir reported dietary practices. Investigatorsexamined how various MRI parametersdiffered across groups once adjustments hadbeen made for patient demographics andmarkers of fitness.

The researchers found that people whofollowed the Mediterranean-DASHIntervention for Neurodegenerative Delay, orMIND, diet, which emphasizes the fooddescribed at the start of this section, tended tohave larger thalamic volume than people inother groups. The thalamus is a grey-matterarea of the brain that processes and relayssensory information, while also helping toregulate sleep and wakefulness.

Study findings showed that dairy intakewas associated with smaller T2-weightedlesions and greater cortical thickness, whilehigher intake of polyunsaturated fatty acids,such as omega-3, was associated withincreased microstructural integrity in normal-appearing white matter.

The researchers concluded that theirfindings showing an association betweendietary factors and MRI metrics in people inthe early stages of MS warranted similarstudies in MS patients with longer diseaseduration.79

People in Italy embraced the so-called“Mediterranean diet” long before that heart-healthy style of eating gained popularity, andits name, in America. So what better placethan Italy to assess the impact that the diet –which emphasizes vegetables, fruits, wholegrains, fish and poultry, with moderate use ofdairy and limited red meat – has on MS?

Italian researchers recently enrolled 301people with MS in a study to look at how diet,smoking, body mass index (BMI), waist-hipratio (WHR), and other factors affect the courseof MS. Two-thirds of the patients were women.Study participants’ average age was 43 years.Their median Expanded Disability Status Scale(EDSS) score was 2, indicating that most hadminimal disability.

Based on their responses to extensive dietquestionnaires, the participants were dividedinto two groups. The first group (64.8% of allsubjects) was composed of people who weretotally adherent to a Mediterranean diet. Thesecond group consisted of people deemed tobe “sufficiently” adherent to the diet, meaningthat they followed it less often than people inthe other group.

Perhaps surprisingly, the investigatorsdid not find an association between greateradherence to the Mediterranean diet andmeasures of MS disease severity, such asEDSS score or Fatigue Severity Scale (FFS)



score. Rather, they found that people withhigher BMI had worse EDSS and FFS scores.Similarly, they found a direct and statisticallysignificant relationship between waist-hip ratioand higher (meaning worse) EDSS and FFSvalues. Not surprisingly, higher smokingintensity was associated with higher EDSSscores, while people who were morephysically active had less impairment asmeasured on the EDSS and reported lessfatigue.80

Gut MicrobiomeThe gut microbiome – the milieu of

bacteria found in the digestive tract – is amajor component of the immune system, andhas emerged in recent years as a focus of MSresearch. Investigators are exploring how theoverall mix of bacteria and different levels ofspecific types of bacteria may affect the riskfor MS and the course of disease. otherresearchers are examining whether alteringthe composition of the microbiome can helpreduce relapses, slow MS progression, orotherwise improve outcomes.

one recent study suggests that increasinglevels of a fatty acid that typically is reduced inpeople with MS can affect immune function. Italso suggests that in conjunction with disease-modifying therapies (DMTs), it may reducerelapses.81

Propionic acid (PA) is a short-chain fattyacid (SFCA). PA and other fatty acids areproduced when bacteria in the gutmicrobiome process indigestible dietaryfibers. Reduced levels of PA, as is seen in MS,are associated with alterations in the

composition of the gut microbiome.Investigators in Germany, Denmark, and

Israel recently assessed blood and stoolsamples from people with MS and healthycontrols. They found that the MS patientshad reduced amounts of PA and of SCFA-producing bacteria compared to the controls.The people with MS also had reducedamounts of regulatory T (Treg) cells, whichplay an important role in maintainingimmune system function. In MS, Treg cellsoften are decreased, while two types of pro-inflammatory, autoreactive cells – T helper(Th) 1 and 17 – are increased. Researchersbelieve that this imbalance contributes to theinflammation and neurodegeneration seen inMS.

The investigators then had 91 people withMS and 24 healthy controls take 1,000 mg perday of PA. After 14 days of taking PA, peoplewith MS saw their Treg cell amounts increaseby 30%, while the controls had a 25% increasein their Treg cells. Several people in the initialphase of the study continued on PA for 90days, as did a separate group of newlydiagnosed people with MS who had notinitiated any disease-modifying therapy(DMT). Both groups of people with MS sawtheir Th1 and Th17 cell counts decrease after14 days and 90 days of PA supplementation.The researchers noted that along withincreases in Treg cell amounts, this helpedto improve the balance between immune-system modulating Treg cells andinflammatory, reactive Th cells.

To assess the clinical implications of theseimmune system changes, the investigators



studied annual relapse rates in 97 studyparticipants with MS. All of the patients hadtaken PA continuously for at least one year,and had data on prior relapse rates, with thedata in some cases going back six years. Theparticipants were stratified, or categorized,based on their baseline annualized relapserate (ARR), Expanded Disability Status Scale(EDSS) score, and current MS therapy.

The researchers found that 41.2% ofpatients improved on PA, 47.4% remainedstable, and 11.3% had an increase in theirARR. overall, the annualized relapse ratedecreased from 0.24 at baseline to 0.008after one year or more of PA supplementation,and that difference was statistically significant.Additionally, EDSS scores generally werestable in the patients taking PA. While nosevere adverse events were reported, <5% ofparticipants in the long-term group reportedmild adverse events, including nausea,flatulence, and abdominal swelling.

The investigators concluded, “PAsupplementation had a beneficial effect onimmunological, neurodegenerative, andclinical parameters in MS patients, includingrelapse rate and disability progression. Theresults of our proof-of-concept study revealnot only that purified PA supplementation is asafe add-on to existing immune-modulatingdrugs but also confirm that one mode ofaction of this supplemental treatment isbecause of stimulation of Treg cells.” 81 Theseintriguing results are, as the authors note,generated by a proof-of-concept study, whichby its nature calls for validation through alarger trial. With their findings, the

investigators have identified several importantareas for further research.

Meanwhile, a study from Spain suggeststhat elevated levels of one family of bacteria,Lactobacillaceae, in the gut microbiome areassociated with a greater number of relapsesin people with MS. Investigators drew thatconclusion after studying 16 people withrelapsing-remitting MS and 15 healthycontrols. The researchers used sophisticatedgenetic sequencing to identify the types andlevels of bacteria found in each person’smicrobiome. They also followed the studyparticipants over a period of 24 months,tracking how often the people with MShad relapses and new or newly enlargedgadolinium-enhancing lesions seen on MRIduring that follow-up period.

Investigators found that the healthycontrols had more types of bacteria in theirmicrobiome than did the people with MS.Further, in the study subjects with MS, anassociation was found between increasedlevels of Lactobacillaceae – particularly thegenus Lactobacillus and the genusLachnoclostridium – and new relapses, newlesions on MRI, or both. Eighty-one percent ofstudy participants with MS were on a disease-modifying therapy (DMT) when they enteredthe study.82

Another recent study found that onealteration in the gut microbiome seen in earlyMS appears to be consistent across differentethnic groups. Researchers performed geneticanalysis and sequencing on the bacteria infecal samples from 15 Caucasian, 16 Hispanic,and 14 African-American people with MS, as



well as 44 healthy controls matched byethnicity. They also conducted genomicsequencing involving 24 people with MS –all of whom were newly diagnosed, not on aDMT, and not taking steroids – plus 24controls.

The researchers found that individuals withMS in all three ethnic groups had an increasedabundance of the genus Clostridium in theirmicrobiome relative to controls from the sameethnic groups. The genomic analysis identifiedspecific species within the Clostridium genusthat were significantly enriched in the peoplewith MS. Identifying a type of bacteria that hasan increased abundance in MS patients acrossethnic groups, provides investigators with avaluable target for further research, potentiallybenefiting a wide range of people.83

Vitamin DLower-than-normal blood levels of 25-

hydroxyvitamin D (25(oH)D) are associatedwith elevated risk for MS and greater diseaseactivity. However, research has yieldedconflicting results on how vitamin D3supplementation affects disease activity in MS.Additionally, no consensus has been reachedon the optimal supplemental dose to give orthe blood level of Vitamin D3 to target.

Against that backdrop of uncertainty,researchers in Slovenia investigated the safetyand efficacy of administering relatively highdoses of vitamin D3 to people with relapsingforms of MS. In particular, they focused on theimpact of vitamin D3 supplementation in thewinter months, when sunlight exposure isreduced. This timing is significant because the

body’s production of vitamin D depends inpart on the skin’s absorption of sunlight.

The researchers randomized 78 peoplewith relapsing-remitting MS to receive either1,000 international units (IU) per day or 4,000IU/day of Vitamin D3 supplementation. A doseof 1,000 IU/day is considered a standard dose,and 4,000 IU/day is designated as the higherdose. Neither the study participants nor theirclinicians knew who was receiving which dose.

At the outset of the study, patients in thetwo groups had similar average blood levelsof 25(oH)D: 59.53 nmol/l in the standardgroup and 55.19 nmol/l in the higher-dosegroup. The two groups were also similar inother ways. After four months of daily VitaminD3 supplementation, average blood levels of25(oH)D were 74.97 nmol/l in the standard-dose group and 104.92 nmol/l in thehigher-dose group.

At the end of the four-month treatmentperiod, people in both groups had betteraverage walking time as measured by theTimed 25-Foot Walk. No side effects oftherapy were reported in either group.Similarly, measures of kidney function andcalcium levels were normal, and notsignificantly changed, in both groups.However, when asked to use a visual scale toassess their health, people in the higher-dosegroup gave themselves higher scores than didthe people in the standard-dose group.

Those findings prompted the researchersto conclude that higher-dose vitamin D3supplementation is safe and effective, andshould be employed, particularly in wintertime.84



Meanwhile, a study by Dutch researchersfound that longer treatment with an evenhigher dose of vitamin D3 did not have ameaningful impact on one key biomarker ofMS disease activity.

The investigators examined whether14,000 IU/day of vitamin D3 taken for 48weeks would lower blood levels ofneurofilament light chain (NfL) in people withMS who already were taking an interferon-based disease-modifying therapy (DMT).Elevated levels of NfL in the blood areassociated with MS disease activity.

The study involved 40 people withrelapsing-remitting MS. All received interferontherapy, while 24 also received Vitamin D3and the remaining 16 instead received aplacebo. After 48 weeks, blood levels of 25-hydroxyvitamin D were roughly four timeshigher in the treatment group than in theplacebo group, as would be expected, butserum NfL levels were almost exactly thesame – at a median level of 25.4 pg/mL inthe treatment group and 25.3 pg/mL in theplacebo group. While this does not mean thatVitamin D3 supplementation may not have arole to play in the overall management of MS,the study findings failed to show a connectionbetween increased Vitamin D levels and a keybiomarker of disease activity.85

BiomarkersResearchers and clinicians continue to

look for ways to speed the diagnosis of MS inpatients with suspicious symptoms, monitorthe course of the disease, and assessresponse to treatment. Biomarkers play a

major role in those efforts. While findings onMRI studies are the biomarkers mostfrequently employed and best known topatients, recent research has examined howsubstances in the blood and cerebrospinalfluid (CSF) may also yield importantinformation. To follow are two studies thatexamine such findings.

Neurofilament light chain (NfL) is a proteinthat serves as a biomarker of damage toaxons, the parts of a nerve cell that carrymessages from the brain to other parts of thebody. Recent research has shown that bloodlevels of NfL are elevated in people with MS.Based on this finding, researchers areinvestigating additional ways in which NfLlevels may reveal evidence of disease courseand severity, response to treatment, and otheraspects of MS.

one team of investigators recently decidedto explore whether serum (blood) levels of NfLare elevated well before a person experiencessymptoms of MS. They noted thatunrecognized demyelinating events, in whichthe myelin sheath that covers and protectsnerve is damaged, can occur prior to theclinical onset of MS. They added,“Identification of these events at the time ofoccurrence would have implications for earlydiagnosis and treatment, as well as the searchof causal factors for the disease.”

To see if serum NfL could aid in identifyingthose events, the researchers conducted acase-controlled study involving active-dutyUnited States military personnel who hadserum samples stored in the Department ofDefense Serum Repository. They selected 60



people with MS, each of whom either had twoserum samples collected before MS onset orwith one sample collected before and oneafter onset of MS. They then matched each ofthose people with a “control” – a person of thesame age, sex, race, ethnicity, and dates ofsample collection.

Their analysis found that people who wenton to develop MS symptoms had higherserum NfL than their matched controls amedian of six years before the clinical onset ofthe disease. Further, the differences in NfLlevels became greater as time to symptomonset became shorter. Meanwhile, for peoplewith MS, the arrival of MS symptoms wasmarked by a significant increase in serum NfLlevels.

The researchers said their findings showthat MS has a “prodromal” phase, meaning abuild-up to obvious symptoms, which lastsseveral years. They also noted that theelevated blood NfL levels identified duringthis period indicate that damage to thenervous system is occurring long beforesymptoms are apparent.86

While NfL is a topic of intense interest toMS researchers, other potential biomarkersare also being evaluated. For example, agroup of Canadian investigators recentlyreported that plasma levels of a protein knownas interleukin-1 receptor antagonist (IL-1RA)can help identify the transition from relapsing-remitting MS (RRMS) to secondary-progressiveMS (SPMS).

The researchers analyzed plasma levels ofthe protein in 110 people with RRMS, 17people with SPMS, and another 17 people

who – based on neurological assessment andExpanded Disability Status Scale (EDSS)scores – were transitioning from RRMS toSPMS. They found that the average level of IL-1RA was markedly higher in patientstransitioning to secondary-progressive MS.The mean level was 857.4 pg/ml in thetransitioning group, as compared to 299.8pg/ml in the RRMS group and 156.2 ng/ml inpeople with SPMS.

Further, plasma levels of IL-1RA werecorrelated with EDSS scores in people withRRMS and those transitioning to SPMS. Plasmalevels of the protein did not, however,correlate with patient age, disease duration, oruse of disease-modifying therapy (DMT). Alack of correlation with those patientcharacteristics actually may enhance the utilityof using IL-1RA to identify or confirm transitionto SPMS by eliminating “background noise,”or confounding factors that would need to betaken into consideration.

While further research into the protein’spotential role in monitoring disease course isneeded, the investigators noted that, “ourresults demonstrate that IL-1RA is a novelexploratory biomarker that both correlateswith EDSS and may suggest when a patient iseither in a transitional clinical phase or has fullyconverted to SPMS.” 87

GeneticsResearchers continue to unravel the

genetic basis of MS, identifying geneticvariants associated with increased risk formultiple sclerosis and exploring how complexinteractions between genetics and



environmental factors affect disease onset andcourse. The summarized studies to followhighlight representative findings from theseinvestigations.

A team of Spanish investigators concludedthat environmental factors play a larger rolethan genetic predisposition in developmentof MS. They reached this conclusion afterexamining the relative contributions of the twotypes of risk factors in a study that involved150 people with MS and 150 healthy controls.

In terms of environmental factors, theresearchers focused on latitude, smokingstatus, and Vitamin D deficiency. Theyincluded study subjects from three differentlatitudes within Spain and surveyed thoseparticipants on their smoking history.Interestingly, they used skin tone as a markerfor Vitamin D status, employing a medicalclassification system that relates skin tone tolevels of Vitamin D, which influences skin tone.In examining genetic factors, they focused onthe HLA-DRB1*15:01 allele, a genetic variationlinked to elevated risk for MS.

The researchers then used sophisticatedstatistical processes to identify the significanceof various risk factors and combinations of riskfactors. Looking at individual factors, theyfound that having light brown skin rather thanclear skin and being a smoker versus a non-smoker were associated with greater risk fordeveloping MS than was having the HLA-DRB1*15:01 allele versus not having thatgenetic variation.

However, the genetic factor had moreinfluence on MS risk than whether a personwas female or male (nonetheless, compared

to men, women had roughly twice the risk forMS). In looking at combinations of risk factors,they found that smokers with light brown skinwere 1.5 times more likely than those withlight brown skin and the HLA-DRB1*15:01 allele to develop MS. However,both groups were at far greater risk for MSthan people without any of the risk factorsstudied. The investigators concluded, “ourstudy suggests that the confluence of severalenvironmental factors contributes to MSdevelopments to a greater extent than thegreatest genetic risk factor known today.” 88

Why do relapses tend to peak in spring (atleast in the northern hemisphere), and occurleast often in autumn? Similarly, why are newfocal lesions more frequently identified in thespring and summer than in autumn or winter?While those questions remain unanswered,researchers and clinicians have proposedcauses including seasonal fluctuations inVitamin D levels related to sun exposure andthe waxing and waning of viral infections overthe course of the year. More recently, a teamof international investigators exploredwhether genetics play a role in these patterns.

The researchers analyzed data on 731people with MS who participate in a long-term study at the Brigham and Women’sHospital in Boston. They looked for thepresence or absence of 9 single nucleotidepolymorphisms (SNPs), or types of geneticvariations. Seven of those SNPs previouslyhave been linked to increased risk for MS andare positionally or functionally linked to so-called “seasonal genes,” meaning geneswhose expression varies by season. The two



other SNPs that were assessed are linked toVitamin D metabolism or function.

The investigators then used a statisticalmethod called a Wald test to see whetherthere were significant differences in whenrelapse peak occurred among patients withdifferent genotypes for the various SNPsbeing studied. They found that participantswho carried an MS-risk allele (an alternativeform of a gene resulting from mutation) forthe SNP known as rs2248137 had asignificant shift in time of relapse peakcompared to other patients who did not havethat allele. Interestingly, this SNP affects anenzyme involved in Vitamin D metabolism,further focusing attention on that vitamin –and the genetic factors influencing Vitamin Dlevels – in seasonal patterns of diseaseactivity.89

Certain genetic variations long have beenassociated with increased susceptibility toMS, but do specific genes or geneticmutations also influence disease severity?Researchers sought to answer that questionby drawing on data from three large,randomized controlled trials sponsored bythe biopharmaceutical company Biogen.

The investigators focused on two measuresof disease severity – levels of serumneurofilament light (sNfL), a protein found inthe blood that is elevated in people with MSand other neurologic diseases – and percentbrain volume change (PBVC). For sNfL, theyexamined data on 500 patients with secondary-progressive MS and 474 study participantswith relapsing MS. Their assessment of percentbrain volume change (PBVC) involved data on

1,796 people with MS. The researchers performed genome-wide

association studies (GWAS) to identify loci, orareas, on different chromosomes associatedwith increased sNfL levels and decreasingbrain volume over time. The investigatorsfound loci on chromosomes 17 and 18 thatwere associated with elevated sNfL. Theoverall analysis found no genome-widesignificant “hits” for brain atrophy, but did identify three significant hits, onchromosomes 2 and 5, in the secondary-progressive MS group. “Thus far,” they wrote,“we have not found overlap in signalbetween MS susceptibility, sNfL, and brainatrophy.”

Having identified genetic regionspotentially associated with those two measuresof MS progression, the researchers now areworking to validate their results by examiningdata on 1,056 patients, for sNfL, and 1,555people with MS, for PBVC, who participated inlarge clinical trials sponsored by anotherbiopharmaceutical company, Roche.90



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This 2020 edition of the MS ResearchUpdate highlights a representative selectionof some of the most important studiesshaping the care of people with MS. Thedozens of clinical trials showcased here arebut the proverbial “tip of the iceberg.”Thousands of researchers in hundreds ofclinics and laboratories around the world areexploring questions and possibilities thatoffer considerable hope for progress.

of course, this global research effort istaking place against the backdrop of theCoVID-19 pandemic. The coronavirusoutbreak poses particular challenges andconcerns for people with MS in terms ofuncertainty regarding disease susceptibilityand severity, among other issues. While someMS-related research initiatives have beenhalted due to the CoVID-19 crisis, otherinvestigators are exploring whether MStherapies may help speed recovery fromthe viral infection. Above all else, the terribletoll of CoVID-19 has underscored theimportance of research into the causes andtreatment of both acute and chronicconditions.

As people with MS continue to beproactive partners in their care, theirparticipation in clinical trials has enabled thedevelopment of several new DMTs, includingthree approved by the FDA in the past severalmonths and others now being assessed bythe FDA or in late stages of investigation.

The challenges and complexities that 2020has presented thus far are, in the end, nomatch for the resilience of people with MSand the dedication of their clinicians. That iswhy MSAA is proud to provide patients andclinicians alike with this edition of itsannual MS Research Update. We hope that itwill be a valuable resource for all who arecommitted to enhancing the lives and healthof people with MS. We also hope that you willturn to MSAA throughout the year for thelatest information in this exciting time offrequent, significant advances in the treatmentof MS. For information about opportunities toparticipate in clinical trials, please visitmymsaa.org/clinicaltrials. For moreinformation about MS, its treatments, andMSAA’s programs and services, please contactMSAA at (800) 532-7667, or visitmymsaa.org.

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1 GeNeuro. GeNeuro Phase 2 multiple sclerosis trial update. March 19, 2020.Available athttp://www.geneuro.com/data/news/GeNeuro-PR-TemelimabCoVID19-EN.pdf. Accessed April 19, 2020.

2 MediciNova. MediciNova announces plans to initiate a clinical trial of MN-166 (ibudilast) for CoVID-19 acute respiratory distresssyndrome (ARDS). April 8, 2020. Available at https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-plans-initiate-clinical-trial-mn-166. Accessed May 1, 2020.

3 Banner Life Sciences. Banner Life Sciences announces final FDA approval of Bafiertam for multiple sclerosis, April 30, 2020. Availableat https://www.businesswire.com/news/home/20200430005256/en/Banner-Life-Sciences-Announces-Final-FDA-Approval. AccessedMay 5, 2020.

4 Tecfidera® (dimethyl fumarate) delayed-release capsules, for oral use [prescribing information]. Cambridge, MA: Biogen Inc. February2020.

5 Bafiertam™ (monomethyl fumarate) delayed-release capsules, for oral use [prescribing information]. High Point, NC: Banner LifeSciences. 2020.

6 Biogen, Inc. and Alkermes, plc. Biogen and Alkermes announce FDA approval of Vumerity™ (diroximel fumarate) for multiplesclerosis. october 30, 2019. Available at https://investors.biogen.com/news-releases/news-release-details/biogen-and-alkermes-announce-fda-approval-vumeritytm-diroximel. Accessed April 20, 2020.

7 Zeposia (ozanimod) capsules for oral use [prescribing information]. Summit, NJ: Bristol-Myers Squibb Company. March 2020.8 Janssen. Janssen submits ponesimod New Drug Application to the U.S. FDA for treatment of adults with relapsing multiple sclerosis.

March 18, 2020. https://www.janssen.com/janssen-submits-ponesimod-new-drug-application-us-fda-treatment-adults-relapsing-multiple-sclerosis. Accessed April 14, 2020.

9 Kappos L, et al. ECTRIMS 2019. [Abstract 93]10 Johnson & Johnson. New head-to-head Phase 3 study data show ponesimod superiority versus Aubagio® (teriflunomide) 14 mg in

adults with relapsing multiple sclerosis (MS). September 11, 2019. Available at https://www.jnj.com/new-head-to-head-phase-3-study-data-show-ponesimod-superiority-versus-aubagio-teriflunomide-14-mg-in-adults-with-relapsing-multiple-sclerosis-ms.Accessed April 7, 2020.

11 Genmab. U.S. FDA filing acceptance and priority review for sBLA, submitted by Novartis, for ofatumumab in relapsing multiplesclerosis. February 24, 2020. Available at https://ir.genmab.com/news-releases/news-release-details/us-fda-filing-acceptance-and-priority-review-sbla-submitted. Accessed May 1, 2020.

12 Arzerra® (ofatumumab) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation. August 2016.13 Hauser SL, et al. ECTRIMS 2019. [Abstract 336]14 Genmab. Detailed results from the Phase III ASCLEPIoS I & II studies of ofatumumab in patients with relapsing multiple sclerosis

presented at ECTRIMS. September 13, 2019. Available at https://ir.genmab.com/news-releases/news-release-details/detailed-results-phase-iii-asclepios-i-ii-studies-ofatumumab. Accessed May 1, 2020.

15TG Therapeutics. TG Therapeutics presents data for ublituximab at the 35th Annual Congress of the European Committee forTreatment and Research in Multiple Sclerosis (ECTRIMS). September 12, 2019. Available at http://ir.tgtherapeutics.com/news-releases/news-release-details/tg-therapeutics-presents-data-ublituximab-35th-annual-congress. Accessed April 15, 2020.

16 EMD Serono. EMD Serono initiates pivotal phase III program for investigational evobrutinib in relapsing multiple sclerosis. September10, 2019. Available at http://media.emdserono.com/2019-09-10-EMD-Serono-Initiates-Pivotal-Phase-III-Program-for-Investigational-Evobrutinib-in-Relapsing-Multiple-Sclerosis. Accessed April 23, 2020.

17 MediciNova. MediciNova announces Phase 3 clinical trial plan for MN-166 (ibudilast) in progressive MS." July 11, 2019. Availableat https://investors.medicinova.com/news-releases/news-release-details/medicinova-announces-phase-3-clinical-trial-plan-mn-166.Accessed May 1, 2020.

18 Bristol-Myers Squibb Company. U.S. Food and Drug Administration approves Bristol Myers Squibb’s Zeposia® (ozanimod), a new oraltreatment for relapsing forms of multiple sclerosis. March 26, 2020. Available at https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-bristol-myers-squibbs. Accessed April 20, 2020.

19 Cohen, JA, Comi, G, Selmaj, KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis(RADIANCE): a multicenter, randomized, 24-month, phase 3 trial. The Lancet: Neurology. 2019 Nov;18(11):1021-1033.

20 Comi, G, Kappos, L, Selmaj, KW, et at. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis(SUNBEAM): a multicenter, randomized, minimum 12-month, phase 3 trial. The Lancet: Neurology. 2019 Nov;18(11):1009-1020.

21 Steinman L, et al. ECTRIMS 2019. Abstract: P1031.22 Banner Life Sciences. Banner Life Sciences announces first subject enrolled in randomized, double-blind, head-to-head study of

Bafiertam and Tecfidera for comparative assessment of GI tolerability. July 23, 2019. Available at https://bannerls.com/en/news-events/. Accessed May 9, 2020.

23 ClinicalTrials.gov, Identifier: NCT04022473


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39 Mayzent® (siponimod) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation. March 2019. 40 Vermersch P, et al. ECTRIMS 2019. [Abstract 158] 41 Gold R, et al. ECTRIMS 2019. [Abstract P750] 42 Kappos L, et al. ECTRIMS 2018. [Abstract P911] 43 Aubagio® (teriflunomide) prescribing information. Cambridge, MA: Genzyme Corporation. February 2020.44 Mavenclad® (cladribine) prescribing information. Rockland, MA: EMD Serono, Inc. April 2019.45 De Trane S, et al. ECTRIMS 2019. [Abstract P985]46 Signoriello E, et al. ECTRIMS 2019. [Abstract P994] 47 Briner M, et al. ECTRIMS 2019. [Abstract P1368] 48 Hellwig K, et al. ECTRIMS 2019. [Abstract 1147] 49 de Seze J, et al. ECTRIMS 2019. [Abstract P1157] 50 Hestvik AL, et al. ECTRIMS 2019. [Abstract P452] 51 Gilenya® (fingolimod) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation. December 2019. 52 Arnold DL, et al. "Effect of fingolimod on MRI outcomes in patients with paediatric-onset multiple sclerosis: results from the phase 3

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