MAY 2019

RESEARCH MS UPDATE Written and compiled by Tom Garry and Pete Kelly

Reviewed by Jack Burks, MD MS and Michelle Fabian, MD RESEARCH UPDATE Edited by Susan Courtney

The Association of America (MSAA) is pleased to present this 2019 edition of its MS Research Update . The Update provides important new data on approved and experimental treatments for MS, and is designed to serve as a comprehensive resource for the entire MS community. Please note that the MS Research Update focuses on research related to approved and experimental and therapies for the long-term treatment of multiple sclerosis. It does not include information on symptom-management medications or therapies.

For additional information about MS, symptoms and symptom management, as well as MSAA’s programs and services, please visit mymsaa.org or call (800) 532-7667 . Questions to MSAA’s Client Services department may also be emailed to [email protected] .

Additionally, please be aware that due to the timing of the national and international MS conferences, study data from 2019 conferences generally could not be included in the Update . Information in this publication includes data presented at the 2018 conferences, as well as any important updates that occurred in early 2019. Please visit MSAA’s website at mymsaa.org for future summaries of 2019 conference highlights.

Multiple Sclerosis Association of America National Headquarters website: mymsaa.org 375 Kings Highway North toll-free phone: (800) 532-7667 Cherry Hill, New Jersey 08034 email: [email protected] CONTENTS

Introduction ...... 2

FDA-ApproveD MeDIcAtIonS recently Approved Mayzent® () ...... 7 Mavenclad® () ...... 8

new Data on previously Approved Medications The Multiple Sclerosis Association Ocrevus® () ...... 10 of America (MSAA) is a leading Tecfidera® () ...... 12 resource for the entire MS Tysabri® () ...... 14 community, improving lives today Gilenya® ()...... 15 through vital services and support. Lemtrada® ()...... 17 Plegridy® (peginterferon beta-1a) ...... 18 MSAA publications are intended Aubagio® () ...... 19 to inform and educate those with Copaxone® () ...... 20 MS and their families. MSAA does Betaseron® (interferon beta-1b) ...... 22 not endorse or recommend any specific products, services, experIMentAl MeDIcAtIonS therapies, or activities mentioned in articles or advertisements that Monoclonal Antibodies Rituxan® (rituximab) ...... 24 appear in MSAA publications. Ofatumumab (also known as Arzerra®) ...... 25 MSAA, its staff, and those affiliated Opicinumab...... 26 with the writing of this publication Ublituximab (also known as TG-1101) ...... 27 cannot be held responsible for Temelimab (formerly GNbAC1) ...... 27 any unintentional errors.

new S1p receptor Modulators MSAA strives to provide useful, (formerly RPC1063) ...... 29 up-to-date information on matters ...... 30 of concern to MS patients and their families. This material is Administered orally intended for general informational Vumerity™ (diroximel fumarate) ...... 32 purposes only, and it does not Evobrutinib (M2951)...... 33 constitute medical advice. You Ibudilast (MN-166) ...... 33 should not use the information Simvastatin (Zocor® and others) ...... 34 presented as a means of diagnosis or for determining new DIrectIonS In MS reSeArch treatment. For diagnosis and treatment options, you are urged Diet and MS ...... 36 to consult your physician. Vitamin D ...... 38 Biotin...... 39 Copyright © Multiple Sclerosis Gut Microbiome ...... 40 Lipoic Acid ...... 41 Association of America, 2019. All Stem-Cell Therapy...... 42 rights reserved. No part of this Genetics ...... 44 publication may be reproduced, Biomarkers ...... 45 stored in a retrieval system, or transmitted in any form or by any closing notes ...... 48 means, electronic, mechanical, photocopying, recording, or chArt: Approved Disease-Modifying therapies for MS ...... 49 otherwise, without prior written permission from MSAA. references ...... 51

1 MS RESEARCH UPDATE

The 2019 MS Research Update highlights a comprehensive overview, rather than an new data and findings on: exhaustive compilation, of relevant research; • Experimental drugs currently under not all study results could be included. investigation for the long-term treatment of The information presented is drawn from a multiple sclerosis (MS) variety of sources, including e-journal literature on MS and its management, a review • FDA-approved disease-modifying therapies of ongoing clinical trials, and papers (DMTs) presented at major national and international • New therapeutic approaches and treatment conferences. targets, such as stem-cell therapy and the Please note that this MS Research Update gut microbiome reports on the most recent study results available at the time of publication. While • Promising areas of inquiry that are every effort has been made to provide enhancing researchers’ and clinicians’ meaningful, timely, and balanced information understanding of MS, such as genetics and on each , keeping the length of biomarkers information equal for each medication is not This 2019 edition of MSAA’s MS Research possible. Please understand that the different Update is once again being printed as a lengths of text should in no way be stand-alone issue, reflecting the great wealth considered as favoritism toward any one and wide scope of research progress in MS. product. Additionally, references have been Nonetheless, there is far too much ongoing cited only for the newer study results. research in MS therapeutics for all of it to be While medications for management of MS covered here. As a result, this update provides symptoms are not within the scope of this

2 Multiple Sclerosis Association of America INTRODUCTION

report, information on the specific symptoms While the DMT Novantrone® of MS and their treatment is available at (), given via IV infusion, has been mymsaa.org . On the website’s homepage, approved since 2000 for reducing the please select “Symptoms” under “MS neurologic disability and/or frequency of Information.” clinical relapses in adults with secondary- Providing these resources is central to progressive MS, its use has been greatly MSAA’s mission of being a leading resource limited due to its side-effect profile. for the entire MS community, improving lives Immediately following the approval of today through vital services and support. Mayzent, Mavenclad® (cladribine) was also Feedback and thoughts on the 2019 MS approved for use in adults with relapsing Research Update , as well as other MSAA forms of MS, including RRMS and active publications, are welcomed. These can be secondary-progressive disease. Mavenclad, directed to the organization at (800) 532- which is a product of EMD Serono, is given in 7667 or [email protected] . a two-course regimen, with the initial course separated from the second course by at least Overview of MS Research Progress 43 weeks (about 10 months). 2, 3, 4 Several other By any measure – the United States Food medications are making their way through and Drug Administration (FDA) approval of late-stage clinical trials and the evaluation new medications, Phase III trials under way, process. These include Vumerity™ (diroximel expanded knowledge of the causes and fumarate), a molecular “relative” of Biogen’s course of MS, emerging treatment strategies, Tecfidera® (dimethyl fumarate) that Biogen and many others – the last 12 months have and Alkermes plc are developing. This agent seen great strides in the effort to better will offer efficacy comparable to that of understand and more effectively manage Tecfidera, but with fewer of the gastrointestinal multiple sclerosis. effects that sometimes are associated with The FDA’s approval of two new disease- Tecfidera use. The companies have filed a modifying therapies (DMTs) – just days apart – New Drug Application (NDA) for Vumerity, gives a sense of the pace of progress. In late and the FDA is expected to issue a decision March 2019, the FDA approved Novartis’ on that application in late 2019. 5 Mayzent® (siponimod) for use in adults Meanwhile, Celgene has filed an NDA with experiencing relapsing forms of MS, including the FDA for its oral S1P receptor inhibitor clinically isolated syndrome (CIS), relapsing- ozanimod, seeking approval for use of the remitting disease, and – notably – active medication in relapsing forms of MS. 6 As the secondary-progressive disease. This FDA MS Research Update was going to press in action made Mayzent, a sphingosine 1- early May, Celgene announced that a post hoc phosphate (S1P) receptor inhibitor, the first analysis of data from its Phase III RADIANCE oral drug to treat secondary-progressive MS Part B trial showed that ozanimod reduced with active disease. 1 brain volume loss across all age groups

MS RESEARCH UPDATE 2019 3 INTRODUCTION

studied in adults with relapsing MS. 7 Other but potentially life-threatening viral disease agents in late stages of clinical development, associated with the use of Tysabri and some including the monoclonal antibodies (mAbs) other DMTs. ofatumumab, ublituximab, opicinumab, and On a related note, a study published in the temelimab, as well as the S1P receptor April 25, 2019 edition of The New England modulator ponesimod and other agents, all Journal of Medicine reported that have reported research findings over the past pembrolizumab, a type of cancer therapy 12 months that are summarized in this called a PD-1 inhibitor, was given to eight publication. individuals diagnosed with PML (all with Important research also is examining the different underlying conditions). Improved optimal use and long-term efficacy and safety laboratory measures of PML were seen in all profiles of medications already approved by eight patients. Five of these eight individuals the FDA. For example, Biogen announced in experienced clinical improvement or January 2019 that it had enrolled the first stabilization of their PML, along with additional patients in its Phase IIIb study evaluating the improvements in laboratory measures, impact of extending the dosing of its DMT including a reduction in JC viral load and an Tysabri® (natalizumab) from every four weeks increase in anti-JC viral activity. 9, 10 to every six weeks. 8 The two-year NOVA study, Two recurring themes mark much of the which ultimately will enroll 480 patients research into current FDA-approved DMTs. worldwide, was initiated after smaller studies The first is that the sooner the therapy is indicated that extending the dosing interval initiated following the diagnosis of MS, the for Tysabri significantly reduced the risk of more effective the medication is likely to be. progressive multifocal leukoencephalopathy This point is highlighted in studies concerning (PML) without diminishing the efficacy of the Ocrevus® (ocrelizumab), Tysabri, and other agent. Caused by the JC virus, PML is a rare agents, as reported in this MS Research Update .11 – 19 The second theme is that long- term studies of various DMTs demonstrate the ongoing effectiveness and consistent safety profiles of the medications, as reported in the pages that follow in summaries of research into Tecfidera, Gilenya® (fingolimod), Lemtrada® (alemtuzumab), Plegridy® (peginterferon beta- 1a), Aubagio® (teriflunomide), glatiramer acetate, Betaseron® (interferon beta-1b), and other agents. 1, 2, 20 – 24 As researchers are able to draw upon data encompassing several years of DMT use by thousands of people with MS, they also are

4 Multiple Sclerosis Association of America INTRODUCTION

able to identify patterns and trends regarding ALS or “Lou Gehrig's disease”), or placebo. the relative impact of various agents. One The primary outcome was the percentage of important study in this regard was published brain volume change as measured on MRI. 3 in the Journal of the American Medical Unfortunately, none of the medications Association , or JAMA , in January 2019. tested slowed the brain atrophy that is a Researchers drew on multi-year data for 1,555 hallmark of SPMS. MS-SMART did, however, patients treated at 68 neurology centers in 21 make many valuable contributions to the countries to examine whether initial use of overall effort to improve outcomes in people particular DMTs was associated with varying with SPMS, which has posed a major degrees of risk of moving from relapsing- challenge to clinicians for many years. The remitting MS to secondary-progressive MS study’s innovative design showed that it is (SPMS). feasible to assess several agents The researchers concluded that initial simultaneously, an important finding as treatment with Gilenya, Tysabri, or Lemtrada neurologists and other physicians seek was associated with a lower risk of conversion treatments for many conditions that historically to SPMS compared with initial use of have lacked effective therapies. The findings interferon beta or glatiramer acetate. 2 also enable researchers to re-focus their “Comparative effectiveness” studies that efforts on other potentially fruitful avenues of examine how various agents perform relative inquiry. to one another represents a growing area of Beyond traditional medications, exciting scientific inquiry. Such studies are likely to help research findings have been reported in clinicians decide which medication is best recent months in promising areas such as suited to the needs of individual patients. stem-cell therapy, dietary strategies, and Of course, not all research yields positive attempts to affect MS by altering the findings. The path to progress can be a composition of the gut microbiome – a key winding one with many a detour and dead component of the immune system. There also end. The results of the MS-SMART trial is important new information on the role of represent a case in point. The study, genetics in MS, the significance of biomarkers sponsored by University College London, such as serum neurofilament light chains and examined whether three established the so-called “central vein sign,” and more. medications used to treat other conditions Highlights from those studies also are would be effective in the treatment of SPMS. included in this 2019 MS Research Update . The Phase II study enrolled 445 patients to Staying current with the latest findings on receive 96 weeks of treatment with either the medications, techniques, and avenues of amiloride (used to treat high blood pressure inquiry in MS is challenging, and can be and congestive heart failure), fluoxetine (an daunting… not only for patients and family antidepressant), riluzole (used to treat members, but for clinicians as well. We hope amyotrophic lateral sclerosis, also known as this MS Research Update will be a helpful

MS RESEARCH UPDATE 2019 5 INTRODUCTION

resource for everyone working to improve the have provided assistance to MS research in lives of people with MS. some other way, you have our deepest Every study reported in this publication gratitude. If you have not participated to date, depended not only on the expertise of we would encourage interested readers to ask physicians, nurses, and other healthcare their providers about possible opportunities professionals, but also on the commitment of to contribute to MS research. The more people with MS who made a decision to diverse populations that enroll in clinical trials, contribute to the effort to better understand, the more meaningful are the results. For more better manage, and one day conquer multiple information about participating in clinical trials sclerosis. If you have been part of that effort for the treatment of MS and its symptoms, and have participated in the clinical trials or readers may visit mymsaa.org/clinicaltrials .

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

TRIAL PHASES FOR INVESTIGATING TREATMENTS

phase I phase II phase III phase Iv

Phase I studies are Once a drug has been In a Phase III study, a Phase IV clinical trials primarily concerned shown to be safe, it must drug is usually tested in are conducted after a with assessing the be tested for efficacy. This several hundred to drug has been drug’s safety. This second phase of testing several thousand approved. initial phase of testing may last from several patients, usually in Participants are in humans is done in a months to two years, and multiple medical enrolled to further small number of involve up to several facilities around the monitor safety and healthy volunteers, hundred patients. Phase II world. Phase III studies side effects, while and is designed to studies are often “double- typically last two or evaluating long-term determine what blinded,” meaning that more years. Only after a efficacy. happens to the drug the participants, medical Phase III study is in the human body – staff, and investigators are successfully completed how it is absorbed, not told who is receiving can a pharmaceutical metabolized, and the drug and who is company request FDA excreted. receiving the placebo. approval for marketing the drug.

6 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: RECENTLY APPROVED

Medications Recently Approved March 2019 saw the United States Food and Drug Administration (FDA) approve two more medications for use in multiple sclerosis (MS) – Mayzent® (siponimod) and Mavenclad® (cladribine). Information on those agents and the clinical trial data that helped secure their approval follow.

Mayzent® (siponimod) reduction of lymphocyte migration into the central nervous system (CNS).25 Further, Company: Novartis Mayzent binds to S1P1 and S1P5 receptors on n Starting dose for most patients: 0.25 mg oligodendrocytes and astrocytes, cells within orally on Day 1, increasing in .25-mg the CNS, which are thought to promote 1 increments over five days to 1.25 mg. remyelination and prevent inflammation. Gilenya is also an S1P-receptor modulator. n For patients with CYP2C9*1/*3 or *2/*3 Mayzent is the first oral drug to treat genotype, 0.25 mg on Days 1 and 2, secondary-progressive MS in adults increasing to 0.5 mg on Day 3 and 0.75 experiencing active disease. This represents on Day 4. an important advance because up to 80% of n Maintenance dose: 2 mg daily orally for patients with relapsing forms of MS will most patients; 1 mg daily orally for patients develop secondary-progressive MS (SPMS) with CYP2C9*1/*3 or *2/*3 genotype at some point. As a side note, just a few days after the FDA approved Mayzent to treat n Approved in 2019 for relapsing forms of MS, SPMS, it approved Mavenclad® (cladribine) including clinically isolated syndrome, for this use, which is discussed in the relapsing-remitting disease, and active following section. Mayzent is also approved secondary-progressive disease, in adults. for use in clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS), giving it Mayzent® (siponimod) is a sphingosine a fairly broad range of indications relative to 1-phosphate (S1P)-receptor modulator, many other disease-modifying therapies meaning that it binds to two receptors, called (DMTs).26 S1P1 and S1P5, on the surface of cells. As a The FDA’s approval of Mayzent followed result of this binding, Mayzent blocks positive findings from the Phase III EXPAND lymphocytes (a type of white blood cell) from study, a randomized, double-blind, placebo- leaving the lymph nodes and entering the controlled study that compared the efficacy peripheral blood. While the mechanism by and safety of Mayzent with placebo in people which Mayzent exerts its therapeutic effects in with SPMS.1, 22 MS is not fully understood, it may involve In EXPAND, 1,645 patients were randomized

MS RESEARCH UPDATE 2019 7 FDA-APPROVED MEDICATIONS: RECENTLY APPROVED

in a 2:1 ratio to receive siponimod (n = 1099) various heart rhythm conditions, or whose or placebo (n = 546). At baseline, the genetic make-up, or phenotype, affects how participants had a mean age of 48 years and their bodies metabolize certain drugs. 23 had been living with MS for approximately 16 In other cases, a person’s phenotype may years; more than half had a median Expanded require that the individual take a lower Disability Status Scale (EDSS) score of 6.0 and ongoing dose of the oral medication. 23 relied on a walking aid. The trial’s primary Phenotype is an individual’s characteristics as endpoint was time to three-month confirmed- determined by a combination of genetic and disability progression (CDP). Mayzent reduced environmental factors. the risk of such progression by 21% compared The phenotype-related recommendations to p lacebo in the overall study population, and reflect a growing understanding of how cut the risk by 33% relative to placebo in those genetics influence a specific person’s who had experienced relapse activity in the response to a medication. Agents approved two years prior to screening. Both reductions several years ago do not carry such were statistically significant. Further, Mayzent requirements, because the science was not delayed the risk of six-month CDP by 26% sufficiently advanced at that time to perform versus placebo and reduced the annualized the in-depth genetic analyses that are possible relapse rate (ARR) by 55%. Treatment with today. Going forward, it is likely that many Mayzent also showed favorable outcomes in more medications will have phenotype- other measures of MS disease activity, specific guidance regarding their use. including cognition, MRI disease activity, and brain volume loss. The most common adverse events were headache, high blood pressure, Mavenclad® (cladribine) and an increase in liver enzyme levels. 1, 22 The FDA-approved prescribing Company: EMD Serono information for Mayzent advises clinicians to n 3.5 mg/kg divided into two yearly treatment assess patients for specific cardiovascular, courses of 1.75 mg/kg ophthalmic, and other conditions before n Approved in 2019 for relapsing forms of MS, starting them on Mayzent. It recommends including relapsing-remitting disease, and obtaining an electrocardiogram (ECG) for all active secondary-progressive disease, in patients, and monitoring those with sinus adults. bradycardia or certain other heart rate and rhythm conditions when they take their first Mavenclad® (cladribine) has followed a dose of Mayzent. The medication is long road to FDA approval for use in MS. contraindicated for individuals who in the past Results from its Phase III CLARITY trial were six months experienced a myocardial announced in 2009. The trial showed that infarction (heart attack) or certain other heart cladribine 3.5 mg/kg cut the annualized and cerebrovascular conditions, who have relapse rate (ARR) by 58% relative to placebo

8 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: RECENTLY APPROVED

over 96 weeks, and that cladribine also had a indicated for treatment of MS.” 3 It should be favorable effect on disability progression, noted that other disease-modifying therapies lesion activity on MRI, and other measures of for MS approved by the FDA include MS activity. 24 Clinical trial data also showed language in their prescribing information that 81% of patients receiving cladribine were concerning a potential increased risk of free of relapses two years after treatment, cancer. Beyond the malignancy concern, compared with 63% of those in the placebo Mavenclad is contraindicated in pregnant group. 2 However, the FDA questioned women, and in men and women of whether use of cladribine in MS might be reproductive potential who do not plan associated with an increased risk for cancer, to use effective contraception. This prompting a long-term effort by EMD Serono contraindication stems from concerns and its parent company, Merck, to assess the about potential birth defects. safety of the medication. Clinicians considering treatment options EMD Serono ultimately collected data for active SPMS or RRMS need to weigh those representing 9,500 patient years of cladribine safety factors against the CLARITY results and use from people who spent up to eight years follow-up data supporting the efficacy of in studies. The clinical program found Mavenclad, as well as the fact that the agent malignancy rates with cladribine use that has a different mechanism of action than other were low overall but higher than those seen MS medications and a short course of with placebo – 0.27 events per 100 patient- treatment. Mavenclad is an antimetabolite that years in patients receiving cladribine versus reduces the number of lymphocytes (white 0.13 events per patient years in the placebo blood cells that are part of the immune group. The studies also found higher rates of system). herpes zoster infection and oral herpes in It long has been used to treat hairy cell people receiving cladribine versus those in leukemia, and regulatory authorities in other the placebo group. 2 In keeping with those countries approved it to treat MS several years findings, the prescribing information for before the FDA granted its approval earlier Mavenclad includes a boxed warning that the this year. Mavenclad, which is given as tablets, medication may increase the risk of has a two-course treatment regimen. Each malignancy, adding that clinicians should course is, in turn, divided into two treatment weigh the benefits and risks of treatment on cycles. In the first course, the drug is an individual basis, considering a patient’s administered on Day 1 and then 23 to 27 days specific history of, or risks for, cancer. The later. The second course involves giving prescribing information also notes that, due tablets at least 43 weeks (approximately 10 to its safety profile, “use of Mavenclad is months) after the last dose from the first generally recommended for patients who course, and then 23 to 27 days later. After have had an inadequate response to, or are completing this two-course regimen, the unable to tolerate, an alternate drug medication is not given again.

MS RESEARCH UPDATE 2019 9 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

Please note that not all of the approved treatments for MS have been included in this section. For a full listing, please see the chart on pages 49 to 51.

Ocrevus® (ocrelizumab) both studies, participants receiving Ocrevus had reductions in annualized relapse rates Company: Genentech and Roche Pharma AG (ARRs) of 46 and 47 percent over a two-year n Starting dose: 300 mg given via IV period versus the interferon groups. infusion, followed two weeks later by a Additionally, in the Ocrevus treatment second 300-mg infusion groups, new MRI lesions were reduced by 94 n Subsequent doses: 600 mg given via IV and 95 percent, brain atrophy was decreased infusion every six months by 24 and 25 percent, and risk of progression of sustained clinical disability was decreased n Approved in 2017 for RMS and PPMS by 40 percent. Recent data from an open-label extension Ocrevus® (ocrelizumab) is an anti-CD20 of OPERA suggest that Ocrevus slows monoclonal antibody. Humanized disease progression among patients with monoclonal antibodies are antibodies from RMS who switched from another disease- non-human species whose protein modifying therapy. Patients who received sequences have been modified to increase Ocrevus or interferon beta-1a during the their similarity to antibodies produced OPERA trial either continued or were naturally in humans. switched to Ocrevus at the start of the trial’s In 2017, the FDA approved Ocrevus for open-label extension phase. The mean ARR use in both relapsing forms of MS (RMS) and in the interferon-to-Ocrevus group fell from primary-progressive MS (PPMS). Approval 0.20 in the year before the patients switched was based largely on the results of three agents to 0.10, 0.08, and 0.07 in years 1, 2, important studies announced in 2015. In and 3 of the open-label phase, respectively. relapsing MS, Ocrevus met both the primary Patients who continued Ocrevus maintained and major secondary endpoints in the Phase low mean ARRs throughout the latter stages III OPERA I and OPERA II studies. The OPERA of the core study and the extension phase. studies had identical designs. The combined Notably, the Ocrevus continuation group enrollment for both studies was 1,656 had a significantly lower proportion of individuals with relapsing forms of MS. patients with 24-week confirmed disability In the OPERA studies, individuals received progression at all points of the open-label either 600 mg of Ocrevus via intravenous (IV) extension, suggesting that the interferon-to- infusion every six months, or the approved 44 Ocrevus group would have benefited from mcg dose of Rebif ® (interferon beta-1a) via earlier Ocrevus initiation. 25 subcutaneous injection three times weekly. In Rates of T1 enhancing lesions and new or

10 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

enlarging T2 lesion development were lower common adverse events were mild-to- among the continuous Ocrevus group, moderate infusion-related reactions. compared with the interferon-to-Ocrevus New data from the ORATORIO open-label group. Rates of brain atrophy likewise were extension suggest that starting Ocrevus significantly lower in the continuous Ocrevus therapy sooner than later in the course of MS group, again suggesting strong benefits of may slow disability progression. Seventy-two early Ocrevus initiation. Whole brain volume, percent of patients who participated in the cortical gray matter volume, and white matter double-blind portion of the ORATORIO trial volume were analyzed. 26 entered the study’s open-label extension Recently released data also provide new phase between 156 and 240 weeks after the details on the ORATORIO study, which core trial started. Depending on which study assessed the effectiveness and safety of arm they had been in during the double- Ocrevus in people with PPMS. Prior to this blind phase, participants were either study, no Phase III studies in PPMS had been switched to Ocrevus from placebo or successful. ORATORIO, which was published continued Ocrevus through the extension in 2015, was a double-blind, global, multi- phase. During the extension period, center trial involving 732 people with PPMS. researchers assessed the prevalence of Participants were randomized to receive disability progression at 24 weeks by means either placebo or Ocrevus, which was of Expanded Disability Status Scale (EDSS) administered every six months in two 300 mg and 9-hole peg test scores. doses given two weeks apart. The primary Throughout the core trial, Ocrevus had endpoint of the study was time to onset of reduced the risk of EDSS-scored disability confirmed disability progression, defined as progression by 25 percent and peg test- an increase in EDSS sustained for at least 12 scored disability progression by 45 percent. weeks. In the open-label extension, overall The ORATORIO study met its primary confirmed disability at 24 weeks was endpoint, showing that treatment with significantly less prevalent in the continuous Ocrevus significantly reduced the Ocrevus group, compared with the placebo- progression of sustained clinical disability by to-Ocrevus group. 9 24 percent compared with placebo. Walking Researchers also recently released pooled speed, as measured by the timed 25-foot safety data from seven Phase III trials and a walk, was improved by 29 percent. Phase II trial that followed a total of 3,811 Hyperintense T2 lesions on MRI actually were Ocrevus-treated individuals with MS. The reduced among patients taking Ocrevus, and researchers reported that per 100 patient brain-volume loss as viewed on MRI was years of use (a measurement of medication reduced by 17.5 percent. The incidence of benefits and risk based on study adverse events associated with Ocrevus in participation) the rates of adverse events ORATORIO was similar to placebo; the most were: any adverse events, 242; serious

MS RESEARCH UPDATE 2019 11 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

adverse events, 7.23; infections, 74.5; serious to obtain a complete blood cell count and to infections, 2.00; malignancies, 0.45. They noted measure liver enzymes and other values that those statistics are consistent with the before initiating the medication. Additionally, adverse event rates reported among patients warnings were added to the prescribing with PPMS and RRMS who have been taking information noting that progressive multifocal Ocrevus outside of clinical trials in the time leukoencephalopathy (PML), a rare but since the medication was approved for use. 27 serious brain infection, and liver injury, have occurred in people taking Tecfidera. 28 Data from the ongoing ENDORSE Tecfidera® (dimethyl fumarate) extension study suggest that Tecfidera helps preserve function over time in RMS. Company: Biogen ENDORSE is a long-term study that follows n Starting dose: 120 mg twice a day, orally people who were newly diagnosed with RMS for seven days; ongoing dose: 240 mg and had participated in a Phase III study of twice a day, orally Tecfidera versus placebo. In the first study, participants received either Tecfidera 240 mg n Approved in 2013 for RMS twice daily or placebo for two years. They The FDA’s 2013 approval of Tecfidera® then had the opportunity to enter ENDORSE. (dimethyl fumarate) for use in RMS followed Those who had received Tecfidera in the completion of two randomized, double-blind, earlier study continued on that medication, placebo-controlled trials in which the while those who had received placebo were medication reduced the annualized relapse switched to Tecfidera. rate (ARR) by 44 percent to 53 percent Adjusted mean ARRs in the placebo-to- relative to placebo. Tecfidera also had a Tecfidera group fell from 0.25 during the favorable impact on disability progression two-year placebo period to 0.09 in seven and MRI measures of MS activity, compared years of Tecfidera treatment, representing a to placebo, in those studies. 28 64-percent decrease. Additionally, between The exact means by which Tecfidera, or 90 and 93 percent of patients in both groups dimethyl fumarate, exerts its therapeutic maintained Expanded Disability Status Scale effects in MS is not known. The agent has (EDSS) scores of 3.5 or less, suggesting that been shown to activate a pathway involved in Tecfidera helps patients maintain function the cellular response to oxidative stress, long-term. 11 which is induced by inflammation. However, it A Swedish MS registry identified two very is unclear whether this pathway activation different paths for its 2,010 participants who plays a role in Tecfidera’s impact on the MS reported taking Tecfidera. One-quarter disease process. 28 discontinued the drug within the first year, In 2017, the prescribing information for and almost half stopped the medicine Tecfidera was amended to include direction eventually. Of those who discontinued

12 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

treatment, 53 percent cited adverse effects as baseline lymphocyte counts and longer their reason for stopping, while 29 percent treatment with Tecfidera might further cited lack of effect. However, the 918 patients increase that risk. 30 who took Tecfidera continuously for two years Tecfidera® (delayed-release dimethyl or longer showed significant improvements fumarate) altered the gut microbiome in in mean scores of several tests used to relapsing-remitting MS (RRMS) patients who measure physical, psychological, and took the oral disease modifying therapy cognitive function in MS. The EDSS, Multiple (DMT) over 12 weeks. 31 The gut microbiome Sclerosis Severity Scale, Symbol Digit is a mix of bacteria and other microbes found Modalities Test, Multiple Sclerosis Impact in the gastrointestinal (GI) tract. In recent Scale, and Visual Analog Scale were among years, the gut microbiome has been the tests used. 29 recognized as a key component of the body’s Another recent study, this one from Italy, immune system. In particular, research looked at risk factors for the development of suggests that the composition of the lymphopenia among people using Tecfidera. microbiome, in terms of the presence and Lymphopenia, a common side effect of number of various microbes, may affect the disease-modifying therapies, is marked by a course of MS. shortage of lymphocytes, a type of white In a study of 36 patients with RMS, 17 blood cell that helps the body fight infection. types of microbes were significantly altered in Data from the Italian researchers suggest that MS patients compared with 165 healthy older age and treatment duration may be risk controls. Notably, people with MS had lower factors for Tecifdera-induced lymphopenia. levels of Faecalibacterium compared to the A total of 147 individuals with RMS were healthy controls. A total of 27 of the study divided into two groups — those with participants received Tecfidera, while nine lymphopenia and those with normal received an injectable DMT. At two weeks, lymphocyte counts — and then were divided subjects receiving Tecfidera reported a again into four groups based on the age at worsening of GI symptoms compared to which they started Tecfidera. Patients aged 50 baseline, but this impact on symptoms was years or older were found to have developed not seen at 12 weeks. Meanwhile, at 12 lymphopenia an average 15.5 months after weeks, the Tecfidera patients had an starting Tecfidera. As patient age decreased, increased abundance of Faecalibacterium . the interval between Tecfidera initiation and Similar changes were not seen in the lymphopenia diagnosis increased, participants receiving an injectable DMT. suggesting an age-related correlation. The Researchers continue to investigate the researchers hypothesized that gradual role of the gut microbiome in MS. As that deterioration of the immune system with effort continues, this study comparing aging might increase an older patient’s risk of patients taking different DMTs adds to the Tecfidera-induced lymphopenia, and that low understanding of the interaction between MS

MS RESEARCH UPDATE 2019 13 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

medications and the composition of the exploring ways to minimize the risk of PML microbiome. As the investigators note, “It associated with Tysabri use. In one could therefore be speculated that direct retrospective study, investigators reviewed effects on the gut microbiome are part of the four years’ of clinical and MRI data from therapeutic actions” of Tecfidera. individuals with RMS at six MS treatment centers in Italy to see if extended-interval dosing of Tysabri reduces PML risk without Tysabri® (natalizumab) diminishing the medication’s efficacy. In the United States, the standard dosing of Tysabri Company: Biogen is 300 mg infused intravenously over the n 300 mg given via IV infusion course of one hour, every four weeks. 33 In this Italian study, patients either received n Approved in 2004 for RMS Tysabri every 35 days (standard-interval This monoclonal antibody acts against a dosing group), received it at longer intervals molecule involved in the activation and stretching up to 56 days (extended-interval function of lymphocytes, which are immune- dosing group), or started with 35-day dosing system cells produced to fight infection and and then were switched to extended-interval disease. It also acts against the passage of dosing. A total of 532 participants were lymphocytes into the central nervous system included in the first-year analysis, and (CNS). The CNS consists of the brain, spinal approximately half of those individuals (270) cord, and optic nerves. were still being followed at four years. None The FDA approved Tysabri in 2004 on the of the participants developed PML. basis of the Phase III AFFIRM trial, in which During the first year of treatment, 84.9 Tysabri reduced the risk of progression of percent of patients (421) in the standard- disability by 42 percent to 54 percent, and dosing group (had no evidence of MS reduced the annual rate of relapse by two- disease activity, compared with 73.6 percent thirds. Tysabri was voluntarily withdrawn from of patients (111) receiving extended-interval the market in 2005, after three cases of dosing. That difference in disease-free progressive multifocal leukoencephalopathy prevalence between groups narrowed at (PML), a rare but potentially fatal brain Years 2 and 3, however, and the prevalence infection caused by the JC virus, were was virtually the same at Year 4. These identified in patients taking the medication. findings suggest that the differences in Tysabri became available again in 2006, Tysabri treatment effectiveness between based on the implementation of a standard and extended-interval dosing comprehensive risk-management program dissipate with treatment duration. 34 that includes testing potential Tysabri users to Meanwhile, data from a retrospective, see if they have anti-JC virus antibodies. 32 multicenter cohort study in France describe a Since then, researchers have been drop in Tysabri-related PML associated with

14 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

the physicians’ ability to identify at-risk who began Tysabri within three years of MS patients. onset, and those who started treatment more The researchers focused on 6,318 people than three years after onset — and then in a French MS patient database who had measured rates of cognitive and physical been treated with Tysabri during a 10-year decline. The patients were also compared period. There were 45 cases of PML among with three sets of similar patients: those who those 6,318 patients. After adjusting for had been diagnosed before 1995, who were patient age and sex, and using statistical treated with interferon beta-1a or glatiramer analysis to estimate yearly incidence rates, acetate injections, or who received no the researchers found a much higher treatment. incidence in PML from 2007 to 2013 During a median six-year follow-up compared with subsequent years. They note period, patients who started Tysabri later that since 2012, physicians have had showed more rapid increases in Expanded information on factors that increase a Disability Status Scale scores (indicating patient’s risk for developing PML. Those risk worsening of disease) and declines in Symbol factors include testing positive for anti-JC Digit Modality Test scores (indicating virus antibodies, having previously used an worsening of cognitive function), compared immunosuppressive medication, and having with patients who started the medication received Tysabri for two years or longer. The sooner. However, disease progression in both investigators surmise that, armed with this Tysabri groups was slower than that seen in knowledge, physicians in recent years have the groups of patients with pre-1995 onset, had a greater ability to determine whether a interferon or glatiramer acetate treatment, or patient is a good candidate for Tysabri or no treatment. 10 would be better suited to receive another DMT. In support of this conclusion, they note that starting in 2013, estimated PML Gilenya® (fingolimod) incidence has decreased by 23 percent each year. 35, 36 Company: Novartis Meanwhile, new data on long-term use of n 0.5 mg capsule given orally once per day Tysabri suggest that the sooner the agent is n Approved in 2010 for RMS started, the longer function can be preserved. In a nationwide, prospective cohort study, Gilenya® (fingolimod) was the first S1P- researchers identified 2,306 individuals with receptor modulator approved for the RMS from neurology clinics across Sweden treatment of MS. Mayzent® (siponimod), who had been diagnosed with MS after which was approved by the FDA earlier this January 1, 1995 and had been receiving year for treatment of RMS, secondary- Tysabri for at least one year. Researchers progressive MS, and clinically isolated divided the patients into two groups — those syndrome, also belongs to this class of

MS RESEARCH UPDATE 2019 15 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

immune-modulatory drugs. Gilenya is most patients citing lack of effect or adverse similar in structure to a naturally occurring effects as reasons. Still, the researchers component of cell-surface receptors on viewed Gilenya as ”a generally well-tolerated white blood cells. (White blood cells are drug that reduces the clinical activity in MS produced by the immune system to fight patients.” 12 infection and disease.) Gilenya blocks Meanwhile, LONGTERMS, an open-label, potentially damaging T cells from leaving single-arm extension study, evaluated the lymph nodes, lowering their number in the long-term effects of Gilenya 0.5 mg in blood and tissues. It may reduce damage people with RMS who had taken the to the CNS and enhance the repair of medication for at least five years and who damaged nerves within the brain and continued to receive it for up to 10 years. spinal cord. The annualized relapse rate (ARR) in this Recent data suggest that Gilenya has a study declined with longer use of Gilenya, positive long-term effect on patients with from 0.26 after one year of use to 0.14 after RMS. The Immunomodulation and Multiple 10 years. Seventy-eight percent of Sclerosis Epidemiology Study 2 in Sweden participants remained free of confirmed six- followed 1,617 patients who had received month disability progression through five Gilenya for MS. Of that group, 91 percent years of treatment. Changes in brain volume had RMS, and 70 percent had been treated remained stable for five years and 10 years with interferons, glatiramer acetate, after Gilenya initiation. 37 natalizumab, dimethyl fumarate, or In a retrospective claims database analysis teriflunomide before switching to Gilenya. in the United States, investigators followed Seventy-six percent (1,230 people) had 1,599 people with MS for three years after taken Gilenya for at least one year at study they started Gilenya. Annualized relapse rates cutoff, and the average treatment duration were calculated over one year before patients was 34 months (two months short of three started the medication, and during each year years). of the three-year follow-up period. Among Relapse rates were expressed in “patient the Gilenya initiators, 1,158 (72 percent) were years,” a method of calculating study still taking the medication at the start of Year participation over a set period to more 2, and 937 (59 percent) were still on Gilenya accurately measure a medication's risks and at Year 3. Median time on Gilenya treatment benefits. Based on this calculation, relapse was 33 months. rates fell significantly among Gilenya-treated The mean baseline ARR of 0.51 recorded patients, from 281 per 1,000 patient years during the pre-initiation period fell more before Gilenya treatment to 87 per 1,000 than 50 percent after Gilenya initiation, and patient years during treatment. However, that reduction was sustained over three nearly half the study group (803 patients) years for the individuals who were still taking discontinued Gilenya at some point, with Gilenya. 38

16 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

Lemtrada® (alemtuzumab) extension study, called TOPAZ. In all, patients were evaluated for eight years after they Company: Genzyme started Lemtrada. During both the initial n Intravenous infusion over four hours for CARE-MS I extension study and TOPAZ, two treatment courses: First course: 12 participants could receive additional courses mg/day on five consecutive days; Second of Lemtrada or another disease-modifying course: 12 mg/day on three consecutive therapy at the investigators' discretion, but days 12 months after the first treatment more than half (56 percent) received no course additional treatment during TOPAZ. At the eight-year evaluation mark, the n Approved for RMS in 2014 annualized relapse rate was 0.14, and 88 Lemtrada® (alemtuzumab) is a monoclonal percent of the participants were relapse-free. antibody. Its exact mechanism of action is Expanded Disability Status Scale (EDSS) unknown, but it is believed to involve binding scores were stable or improved from the core to a cell surface antigen found on key baseline for 78 percent of patients; 71 immune-system cells, including T and B percent were free of six-month confirmed lymphocytes, leading to the depletion of disability worsening; 41 percent achieved six- these cells and other effects on the month confirmed disability improvement; inflammatory process. Because Lemtrada can and 60 percent had no evidence of disease cause serious autoimmune conditions and activity. In addition, 87 percent had no new infusion reactions, and can increase the risk T1-enhancing lesions, and 67 percent had no for some cancers, its use is typically reserved new or enlarging T2-hyperintense lesions. 13 for individuals who have not responded Similarly, people with RMS who received adequately to two or more other disease- interferon beta-1a therapy during the core modifying therapies. CARE-MS II trial and who then were switched Lemtrada was approved for use in RMS on to Lemtrada for the CARE-MS II extension the basis of the Phase III CARE MS I and CARE period and TOPAZ, showed significant MS II trials; both studies compared the improvements six years after switching to medication with subcutaneous interferon Lemtrada. The annualized relapse rate for the beta-1a over two years of treatment. Now, 117 individuals in this group was 0.19, and new data indicate that Lemtrada's effects on EDSS scores were stable or improved from slowing MS disease progression are CARE-MS II baseline in 68 percent of the maintained with long-term use. participants. Similar to the CARE MS I A total of 290 individuals with RMS who findings, reductions in evidence of disease completed two courses of Lemtrada in the activity on MRI, as measured by assessment CARE-MS I trial entered a four-year extension of T1-enhancing lesions, and new or study. They then were evaluated for an enlarging T2-hyperintense lesions, were additional two years as part of a second reported. 39

MS RESEARCH UPDATE 2019 17 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

CARE-MS I researchers also found that Plegridy® (peginterferon beta-1a) Lemtrada reduced levels of serum neurofilament light chain (sNfL), a biomarker Company: Biogen of neuro-axonal damage in MS that can n Dose: 125 mcg every 14 days, self- measure response to a disease-modifying administered subcutaneously (starting therapy. Researchers analyzed more than at 63 mcg at Day 1, then increasing to 1,500 sNfL samples from 329 patients who 94 mcg on Day 15 and to 125 mcg on had active MS at baseline and who then Day 29) were treated with Lemtrada. Median sNfL n Approved for RMS in 2014 levels fell significantly, from 31.6 pg/mL at baseline to 17.2 pg/mL six months after Plegridy® (peginterferon beta-1a) is a Lemtrada treatment, and between 13.0 and synthetic version of the human interferon 13.9 pg/mL two years after therapy. During beta. Interferon beta slows progression of MS the same period, MRI disease activity and by balancing the expression of pro- and anti- brain volume loss also decreased in these inflammatory substances in the brain and patients. The researchers plan to analyze preventing some inflammatory neurons from more than 7,000 sNfL samples across seven crossing into the brain. This reduces neuron years to obtain a more-detailed picture of inflammation and is believed to increase how sNfL reduction may slow MS disease production of nerve growth factor. progression. 40 Plegridy gained FDA approval in 2014 for In another trial, researchers in the United relapsing forms of MS (RMS). The pivotal Kingdom and Ireland found positive results in double-blind study followed 1,012 individuals with RMS who switched from individuals with RMS who had a baseline Tysabri® (natalizumab) to Lemtrada. Of the 79 Expanded Disability Status Scale (EDSS) score participants in the trial, 51 were followed for of 5.0 or less and who had experienced at more than two years after initial Lemtrada least two relapses within the previous three infusions, and independent blinded MRI years and at least one relapse in the previous analysis was performed in 20 patients. Data year. The participants were randomized to were analyzed in five phases: pre-Tysabri Plegridy 125 mcg or placebo once every 14 treatment, Tysabri treatment, the medication days. Neurological evaluations were switch period, Lemtrada treatment, and post- performed at baseline, every 12 weeks, and Lemtrada treatment. during a suspected relapse. Brain MRI Mean annualized relapse rates fell from evaluations were done at baseline, week 24, 2.3 before Tysabri treatment to: 0.8 during and week 48. Tysabri treatment; 0.4 during Lemtrada At 48 weeks, the mean number of T1- treatment; and 0.5 after the last Lemtrada enhancing lesions was significantly lower in treatment. 41 the Plegridy group than among placebo- treated patients (0.2 versus 1.4), as was the

18 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

mean number of T2 new or enlarging- anti-inflammatory properties and has been hyperintense lesions (3.6 versus 10.9). shown to inhibit the synthesis of pyrimidine, Relapse rates also were significantly reduced an organic compound involved with various among individuals receiving Plegridy, cells and processes throughout the body. 43 compared with placebo. 42 Aubagio secured FDA approval for use in New Phase IV (post-approval) data RMS following positive results from four suggest Plegridy slows MS-related disability randomized, controlled, double-blind clinical with long-term use. Researchers studied 963 trials. In the first study, 1,088 patients were patients who received at least one dose of randomized in a 1:1:1 ratio to receive the medication. The individuals were split into Aubagio 7 mg, Aubagio 14 mg, or placebo, two groups: newly diagnosed (242) and non- and were followed for up to 26 months. newly diagnosed (721). More than 80 percent Individuals receiving Aubagio had a of the participants with either newly statistically significant reduction in the annual diagnosed or long-standing RMS remained relapse rate (ARR) – the study’s primary relapse-free for up to two years. endpoint – compared to those receiving Nearly one-third of the individuals in both placebo. The second study followed 1,165 groups discontinued Plegridy at some point patients for up to 40 months, also after initiation. Adverse events and lack of randomizing them in a 1:1:1 ratio to receive effect were the most commonly cited reasons Aubagio 7 mg, Aubagio 14 mg, or placebo, for discontinuation, and influenza-like illness and specifying ARR as the primary endpoint. and injection-site irritation were the most Both doses of Aubagio again showed commonly reported adverse effects. 14 statistically significant advantages over placebo in terms of a lower relapse rate and Aubagio® (teriflunomide) on other measures of efficacy. 43 The third study followed a similar design Company: Genzyme in terms of randomization and endpoint but n Oral; 7 mg or 14 mg once daily focused on people who had experienced a first clinical event consistent with acute n Approved for RMS in 2012 demyelination (damage to protective nerve As with many other disease-modifying fibers in the brain) occurring within 90 days of therapies (DMTs) for MS, the exact randomization. After following these mechanism by which Aubagio® individuals for up to 108 weeks (two years (teriflunomide) exerts its therapeutic effect and four weeks), the study found that has not yet been fully determined. In the case significantly higher proportions of Aubagio- of Aubagio, the mechanism may involve treated patients remained free of relapse, reducing the number of activated compared with those receiving placebo. The lymphocytes – immune-system cells – in the fourth study examined MRI characteristics of central nervous system. The medication has 179 individuals with RMS. The mean number

MS RESEARCH UPDATE 2019 19 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

of active lesions per MRI scan of the brain percentage of brain-volume loss was during the 36-week treatment period was significantly lower in the Aubagio-treatment lower in people treated with Aubagio 7 mg group compared with the placebo group. (1.06) and Aubagio 14 mg (0.98) than with Median reductions in whole-brain-volume placebo (2.69). The difference was statistically loss at six, 12, and 18 months were 87 significant for both. 43 percent, 29 percent, and 36 percent, New data show low ARRs in patients who respectively, in the Aubagio-treatment previously received no DMT or who switched group. 15 to Aubagio from another DMT. A post-hoc analysis of data from a Phase II study and Copaxone® (glatiramer acetate) from the Phase III TEMSO, TOWER, and TENERE studies identified 2,643 patients who Company: Teva Pharmaceuticals received Aubagio 14 mg/d or placebo and n Dose: 20 mg/mL daily or 40 mg/mL three had received another DMT or no therapy times weekly, self-administered before switching to Aubagio or placebo. The subcutaneously participants were divided into three groups: n Approved for RMS in 1996 those who discontinued another DMT six months before randomization (348), those Copaxone® (glatiramer acetate) is a who stopped another therapy six months to synthetic protein that simulates myelin basic two years before randomization (412), and protein, a component of the myelin that those who received no prior DMT (1,883). insulates nerve fibers in the brain and spinal ARRs ranged from 0.33 to 0.53 for the three cord. Though its mechanism of action is not groups, and the mean rates were all completely understood, this medication significantly lower than those for placebo. 44 appears to work by blocking myelin- Meanwhile, a separate post-hoc analysis damaging T cells. The Copaxone brand of showed that long-term Aubagio use reduced glatiramer acetate was approved in 1996, and brain-volume loss. Researchers identified generic formulations have since become individuals who had received Aubagio 14 available. mg/d (214) or placebo (197) during the Copaxone gained FDA approval for the Phase III TOPIC study, which measured the treatment of RRMS based on five placebo- efficacy of Aubagio in people with a first controlled studies. In the first two studies, a clinical episode suggestive of MS. The total of 301 individuals with RRMS with at investigators used an automated brain- least two exacerbations in the two years measurement system to calculate preceding the study were randomized 1:1 to brain-volume loss at six-month intervals over Copaxone 20 mg/mL daily or placebo. In two years. At endpoint, an overall 43-percent both studies, relapse rates and frequency reduction in whole-brain-volume loss was were reduced in the Copaxone groups, but reported with Aubagio use, and the median the sample sizes in both studies were small. In

20 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

the third study, 481 individuals who had after baseline. After a mean follow-up period experienced demyelination (damage to of 7.12 years, individuals who had received protective fibers around nerves in the brain) glatiramer acetate showed a 16.5-percent within the previous 90 days and who showed reduction in disability progression and 25- lesions on MRI received Copaxone 20 mg/mL percent reduction in loss of function, daily or placebo. After a maximum three-year compared with the untreated group. 16 follow-up period, time to a second Meanwhile, findings on the effects of exacerbation was significantly delayed in the DMTs on pregnancy and breast feeding Copaxone group compared with placebo. 45 suggest that neither glatiramer acetate nor In the fourth study, 239 individuals who interferon beta cause significant had suffered at least two exacerbations in two developmental delays in children who may years and showed at least one enhancing have been exposed to either medication via lesion on MRI at screening were randomized breast milk. The researchers note that both to double-blind administration of Copaxone interferon and glatiramer acetate are large or placebo for nine months. During that molecules that are unlikely to enter breast period, all study participants underwent milk, but that the specific effects on child monthly MRI scans. At study's end, the median development from using these disease- cumulative number of T1-enhancing lesions modifying therapies during breast feeding was significantly lower in the Copaxone group have not been studied. compared with placebo (11 versus 17). In the Drawing on information in a German fifth study, 1,404 people with RMS received pregnancy database, researchers reviewed Copaxone 40 mg/mL (943) or placebo (461) data on 76 pregnancies in 72 women who three times weekly for one year. At study's had received either glatiramer acetate or end, the Copaxone group had experienced interferon beta for MS. The mothers provided fewer confirmed relapses and showed information on both their disease activity and significantly fewer cumulative new or their children’s development by completing a enlarging T2 lesions and cumulative T1- questionnaire after delivery. Forty-seven enhancing lesions, compared with placebo. 45 women stopped treatment during pregnancy New data from an analysis of disease- and resumed treatment after delivery, and 18 modifying therapies point to the long-term women continued treatment through the effectiveness of glatiramer acetate in delaying entire pregnancy. At ages 1 and 2 years, the disability and preserving function in MS. children's body lengths were within normal Researchers in the United Kingdom ranges for their ages. Four percent of compared 755 individuals with RRMS who mothers reported that their children were had received glatiramer acetate with 898 experiencing developmental delays in motor similar patients who received no treatment. skills, but the percentage was similar to the Participants were evaluated at least once with prevalence of early motor skill delays in the the Expanded Disability Status Scale (EDSS) general population. 46

MS RESEARCH UPDATE 2019 21 FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

Finally, an extended-release formulation of expression of pro- and anti-inflammatory glatiramer acetate is under development. The agents in the brain and restricts the flow of experimental long-acting formulation, called inflammatory neurons through the blood- “GA Depot,” consists of extended-release brain barrier. This slows MS disease microspheres of glatiramer acetate released progression by reducing neuron over approximately one month. GA Depot inflammation, and is believed to increase would be dosed once every 28 days, which production of nerve growth factor. researches hypothesize may improve patient Betaseron secured FDA approval for adherence to the treatment regimen, and relapsing forms of MS (RMS) after a double- thus, may also improve outcomes. blind, placebo-controlled study. The 372 Recently released Phase IIa data suggest patients with RMS in the study had a baseline that GA Depot is well tolerated and efficacious. mean Expanded Disability Status Scale (EDSS) Eleven individuals with RRMS who participated of 5.5, indicative of severe disability that in a one-year core efficacy study of GA Depot impedes daily activities. Participants also also completed a 48-week extension study. The were required to have had at least two patients received GA Depot 40 mg once every exacerbations in the two years before the trial, 28 days during the extension. No adverse but with no exacerbations in the preceding effects other than mild injection-site reactions month. The patients were randomized at a were reported. Mean EDSS scores did not nearly 1:1:1 ratio to Betaseron 0.25 or 0.05 mg change significantly from the core-study or placebo, self-administered subcutaneously baseline, and 81.8 percent of participants every other day for two years. showed no evidence of disease activity (NEDA) At endpoint, the mean annual when the extension study ended. 47 exacerbation rate was 0.9 among patients who received Betaseron 0.25 mg, compared Betaseron® (interferon beta-1b) with 1.14 in the Betaseron 0.05 mg group and 1.31 with placebo. An exacerbation was Company: Bayer defined as the appearance of a new clinical n Dose: 25 mg (1 mL) self-administered sign/symptom or the clinical worsening of a subcutaneously (starting at 0.0625 mg previous sign/symptom that had been stable (0.25 mL), then increasing over six weeks for at least 30 days. The exacerbation had to to 25 mg) persist for at least 24 hours to be considered as a true relapse. 48 n Approved in 1993 for RMS New data support early initiation and Betaseron® (interferon beta-1b) is the first long-term use of Betaseron in individuals disease-modifying therapy (DMT) to receive who develop a clinically isolated syndrome FDA approval for the long-term treatment of (CIS). A CIS is a preliminary episode of nerve MS. It is a synthetic version of the human inflammation or damage that may develop interferon beta. Interferon beta balances the into clinically definite MS (CDMS) sometime

22 Multiple Sclerosis Association of America FDA-APPROVED MEDICATIONS: NEW DATA ON PREVIOUSLY APPROVED MEDICATIONS

in the future. A recently reported study sought to determine whether extended beta followed 468 individuals who received interferon therapy, such as with Betaseron, Betaseron or placebo, either immediately increases survival in MS. Researchers after or within two years of a CIS episode. followed 5,989 patients registered at two MS Participants in the placebo group were clinics in British Columbia and France who switched to Betaseron after two years, or were diagnosed with RMS and treated with were switched immediately after they beta interferon. The patients had never developed CDMS. received an immunosuppressant or DMT Fifteen years after initial randomization, before the study period. A maximum of 18 261 of the initially enrolled patients years of data were reviewed for each person, completed a comprehensive clinical and MRI and most of the 742 individuals who died examination, and information was available during the study were matched with controls on six additional study enrollees who had from the two databases. died. Risk of relapse in the early-treatment After a series of mathematical analyses, group (individuals who received Betaseron the researchers found that treatment with from the start) was 18.9 percent lower than beta interferon for three years or more was that of the placebo/delayed-treatment group. associated with increased survival in patients Also, the risk of conversion to CDMS was 30.5 with RMS. However, the investigators did not percent lower in the immediate-treatment find an association with extended survival for group versus the delayed-treatment group. 17 beta interferon treatment that lasted between Meanwhile, another team of researchers six months and three years. 18

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MS RESEARCH UPDATE 2019 23 EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODIES

About Monoclonal Antibodies Monoclonal antibodies are derived from cells that are identical (cloned from a single cell and then replicated). They are produced from animal tissue, most commonly laboratory mice. Humanized monoclonal antibodies are antibodies from non-human species, again commonly a mouse, whose protein sequences have been modified to increase their similarity to antibodies produced naturally in humans. Monoclonal antibodies can be extremely powerful and effective, as they can be directed specifically toward a certain segment of one of the body’s systems – such as the immune system – while leaving the other parts of the system unaffected. This can be very desirable when trying to impact 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 already are approved for MS. Several other monoclonal antibodies have shown promise in MS, and five of these are reviewed in this section.

Rituxan® (rituximab) MS treated with Rituxan is relatively small to date. Company: Genentech/Roche New data from the University of Colorado n Given via IV infusion assessed the safety profile and effectiveness of Rituxan in patients with MS. Researchers at n Being studied in RMS the university’s Rocky Mountain MS Center Rituxan is a monoclonal antibody that followed 125 individuals with either relapsing- binds to a receptor on the surface of B cells. remitting, primary-progressive, or secondary- These cells are then destroyed, and their progressive MS. The mean follow-up period levels in the circulation are decreased. It is was 40.6 months, and participants received approved for use in the treatment of an average of six infusions or 4,954 mg of lymphomas, leukemias, and autoimmune Rituxan. disorders. Rituxan was found to be effective overall, Serious adverse events have been with just 32 of the 125 participants reported in Rituxan-treated patients with experiencing a clinical relapse, enhancing other diseases, including rare cases of lesion, or T2 lesion during the follow-up progressive multifocal leukoencephalopathy period. Infections occurred in 34 of the (PML), the same viral infection of the brain participants and resulted in either emergency that has been seen with a small percentage of room or hospital treatment. Sixty people patients taking some approved DMTs. While suffered a mild-to moderate infusion reaction no PML has been diagnosed in MS patients during the first or second infusion; 57 taking Rituxan, the number of individuals with individuals had abnormally low counts of the

24 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODIES

infection-fighting IgM or IgG antibodies, and 22 years. These teens and young adults had nine of the participants had a deficit of certain been diagnosed with MS nine months to nine white blood cells. Two people were years before the MRI, and had been treated diagnosed with malignant cancer after they with Rituxan for a duration of between nine started Rituxan, but it is unclear whether the and 46 months. Sixteen patients were drug was a factor. 49 relapse-free while receiving Rituxan, while Meanwhile, a review of Kaiser Permanente one developed . and Swedish data found that all-cause death Based on the MRI results, 14 of the 17 rates among people with MS receiving patients had no T2 or contrast-enhancing Rituxan are lower compared with those of MS lesions and showed no evidence of disease patients receiving other disease-modifying activity. Expanded Disability Status Scale therapies. The researchers analyzed data on scores also remained stable, with a mean 1,246 individuals with MS from a Kaiser score of 0.5, suggesting near-normal Permanente Southern California database, function. 51 and 1,252 patients from a chart-validated subset of a Swedish MS registry. Most of Ofatumumab (also known as these individuals had received initial Rituxan Arzerra®) infusions of 1,000 mg and subsequent infusions of 500 mg. Company: Novartis Seventeen deaths were reported from the n Given via IV infusion and also studied via two databases, but none occurred within two subcutaneous injection weeks of the last Rituxan infusion. Causes of n Being studied in RMS death included suicide, cardiovascular disease, and complications from an MS- Like Rituxan and Ocrevus, ofatumumab is related disability (such as a fall or an anti-CD20 monoclonal antibody. It has the pneumonia). No deaths from infusion, potential advantage of being a human systemic inflammatory response syndrome, monoclonal antibody (versus antibodies from or drug-induced acute coronary syndrome non-human species that have been were reported. Similar complications have modified). Ofatumumab has a unique target been reported among patients with cancer on the CD20 molecule and is approved for who received doses of Rituxan higher than certain forms of leukemia. 1,000 mg. The findings suggest that Rituxan Two simultaneous Phase III clinical trials – at 500 mg or 1,000 mg is a safe option for ASCLEPIOS I and ASCLEPIOS II – are individuals with MS. 50 comparing ofatumumab to teriflunomide in Meanwhile, retrospective data suggest patients with RMS. Investigators in both trials Rituxan is also effective in pediatric-onset MS. are following patients aged 18 to 55 years Researchers at Texas Children’s Hospital with a baseline Expanded Disability Status reviewed MRI scans of 17 patients aged13 to Scale (EDSS) score of 0 to 5.5 at screening.

MS RESEARCH UPDATE 2019 25 EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODIES

An EDSS score of less than 4.0 represents of physical and cognitive function. By moderate disability, while a score between 4 blocking LINGO-1, opicinumab is formulated and 5.5 indicates more severe MS-related to promote regeneration of axons and disability that could interfere with daily myelin. 55 activities. The Phase II, double-blind AFFINITY study Participants in both trials will receive either is assessing the effectiveness of opicinumab subcutaneous ofatumumab at three weekly as an add-on therapy in people with 20-mg doses for two weeks followed by one relapsing or secondary-progressive forms of 20-mg injection every four weeks, or oral MS (RMS or SPMS). Approximately 240 teriflunomide 14 mg daily. The primary individuals treated with an interferon beta endpoint for both trials is the annual rate medication, dimethyl fumarate (Tecfidera), or relapse. Secondary endpoints include MRI- natalizumab (Tysabri) will receive IV related outcomes and confirmed disability opicinumab 750 mg or placebo every four worsening at three and six months. The 1,884 weeks for 72 weeks. people enrolled in the two studies represent Researchers will measure overall disability a typical RMS population (more than 65 improvement or worsening, as well as specific percent female and 90 percent Caucasian). measures of physical and cognitive function. Sixty percent of the participants had received Participants entering the study have had MS another disease-modifying therapy prior to for 20 years or less, and have moderate to entering the studies, and 40 percent showed severe disability, preserved brain function, enhancing lesions on MRI at screening. The stable disease status, and at least one relapse trials are scheduled for completion around between four months and two years before May 2019. 52 – 54 the study. 55 The estimated completion date for the study is May 2022. 56 Opicinumab A previous Phase II trial evaluated four doses of opicinumab as an adjunct to Company: Biogen interferon beta therapy in an MS patient n 750 mg given via intravenous (IV) infusion group with similar characteristics. Patients who received 10 mg of opicinumab per n Being studied in RMS and SPMS kilogram of body weight each month saw a Opicinumab is a human monoclonal 65.6 percent improvement in MS disability, antibody that targets LINGO-1, a protein that while those who received 30 mg/kg every suppresses the redevelopment of axons four weeks improved by 68.8 percent. (brain cells that send functional information However, individuals who received lower and throughout the body) and re-formation of higher doses (3 mg/kg or 100 mg/kg) did not myelin sheaths (fibers that protect the axons). see significant improvement compared with Axons and myelin sheaths are lost or those in the placebo group. In all, 334 damaged in patients with MS, leading to loss participants completed the study. 57

26 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODIES

incidence did not increase with faster Ublituximab 58, 59 (also known as TG-1101) infusion. Two parallel, placebo-controlled, Phase III Company: TG Therapeutics trials of ublituximab are also in progress. The n Given via IV infusion global, multicenter ULTIMATE I and ULTIMATE 2 studies are comparing n Being studied in RMS ublituximab with teriflunomide in people with Like Ocrevus, Rituxan, and ofatumumab, RMS. The primary endpoint for both studies is ublituximab targets the CD20 molecule to annualized relapse rate after 96 weeks of deplete B cells. Its developer, TG treatment. 60 Therapeutics, is evaluating the monoclonal antibody for use in treating both Temelimab (formerly GNbAC1) hematological malignancies and relapsing forms of MS (RMS). One area of inquiry in MS Company: GeNeuro SA is whether the activity of ublituximab will n Intravenous (IV) medication in monthly enable it to be administered in lower doses 6-mg, 12-mg, or 18-mg/kg doses and shorter infusion times than currently n Being studied in RMS available anti-CD20 agents. 58 Findings from a Phase II multi-center, Temelimab (GNbAC1) targets a human placebo-controlled study suggest that endogenous retrovirus (HERV) believed to ublituximab reduces MS disease activity, play a role in the development of MS. This suppresses relapses, and can be safely treatment approach, or mechanism of action, infused in approximately one hour. Forty- differs from those of currently approved eight individuals with RMS received an initial medications. HERVs are genetic elements that infusion of ublituximab, subsequent infusions are either hereditary, replicated from a host 15 days and 24 weeks later, and then were cell, or result from a germ. The viral envelope followed for 48 weeks. Infusion times ranged protein encoded by one HERV has been between one and four hours. found in active MS lesions. Temelimab, a Median depletion of B cells exceeded 99 monoclonal antibody, is formulated to percent at Week 4, and that level of depletion neutralize this protein and, thus, it is hoped, was maintained at Weeks 24 and 48. No block harmful inflammation and facilitate enhancing lesions were seen at Weeks 24 restoration of the myelin sheath that coats and 48, and T2-lesion volume was decreased nerve fibers and that is damaged in MS. The by 10.6 percent at Week 48, compared with agent is also being studied in Type 1 diabetes baseline. Also, none of the patients who and other autoimmune disease. 61 could be evaluated showed sustained In the Phase IIb CHANGE-MS trial, MRI disability progression. Mild to moderate findings were used to assess the impact of infusion reactions were reported, but the temelimab on MS lesions in the central

MS RESEARCH UPDATE 2019 27 EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODIES

nervous system. A total of 270 people with ANGEL-MS study was designed to examine relapsing forms of MS were randomized in a the safety and efficacy of the medication over near 1:1:1:1 ratio to receive monthly IV roughly two years of treatment. Individuals infusions of temelimab in doses of 6, 12, or who had participated in the CHANGE-MS trial 18 mg per kilogram of body weight or were offered the opportunity to continue placebo for 24 weeks. After week 24, receiving treatment in ANGEL-MS. Ninety- participants in the placebo group were four percent of eligible patients (219) opted randomized to receive one of the three to enter the trial; each received the same temelimab doses for a second 24-week dose of temelimab that he or she had been period. Individuals who had been receiving receiving at the conclusion of CHANGE-MS. temelimab during the first 24-week period Although the study was ended early when kept receiving their original doses for the one of the companies involved in developing second period. temelimab ended its partnership with the After 48 weeks, temelimab use was other company involved, 154 patients associated with significant reductions in received temelimab for at least 96 weeks. both central nervous system deterioration Data from this study found that the and development of T1-enhancing hyper- medication had a positive effect of reducing intense lesions measuring at least 3 brain atrophy, maintaining the integrity of millimeters in diameter. These improvements myelin, and measures of impact on slowing were more substantial among those who had MS progression, with the 18 mg/kg dose received temelimab for 48 weeks, compared having the greatest benefit. GeNeuro, the with those who started with placebo, Swiss company developing temelimab, notes underscoring the potential effectiveness of that because the protein temelimab targets temelimab as a long-term treatment. In most “has no known physiological function,” measures, benefits were dose-dependent: temelimab was anticipated to have a good The higher the dose, the more substantial the safety profile, with no effect on the patient’s benefit. 62 Temelimab has also shown immune system, which has been shown in ongoing benefit over the longer term. The clinical trials conducted thus far. 63

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28 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: NEW S1P RECEPTOR MODULATORS

About S1P Receptor Modulators Several investigational oral agents currently under study work in a manner similar to Gilenya® and Mayzent® in that they also trap immune cells in the lymph nodes so that they cannot get into the CNS to create lesions. Researchers recently reported new data on two of these S1P receptor modulators, ozanimod and ponesimod.

Ozanimod (formerly RPC1063) 0.5-mg group and a 53-percent decrease in the 1-mg group. Company: Celgene The most common side effects reported n Oral medication studied at several doses were nasopharyngitis (the common cold) and headache. However, both of these events n Being studied in RMS were reported more commonly by placebo- Ozanimod (RPC1063) is a selective treated individuals than by ozanimod-treated modulator of two types of S1P receptors: participants. Notably, none of the subjects S1P1 and S1P5. The once-daily pill was receiving ozanimod experienced serious studied in a trial called RADIANCE, where the cardiac events, infections, or episodes of experimental medicine was compared at two macular edema (a buildup of fluid in the different doses with placebo. A total of 258 retina that can cause vision loss. It can occur individuals with relapsing forms of MS (RMS) in rare cases with use of Gilenya). 64 were studied in this trial, which began with a In 2016, the 72-week extension data of seven-day gradual titration of ozanimod up the RADIANCE trial were released. These to the full investigational dose. (Titration data showed a continued reduction in refers to starting with a lower dose and relapses and gadolinium-enhancing lesions gradually increasing until the full dose is for those individuals who remained on reached. This helps reduce the risk of side ozanimod, with efficacy results favoring the 1- effects when starting a new medication.) The mg dose over the lower 0.5-mg dose. No double-blind study ran for 24 weeks, new safety or tolerability issues were followed by a year-long safety-extension identified during this blinded extension period. phase of the trial. At the end of the initial 24-week treatment Celgene, the company that is developing period, individuals in both groups taking ozanimod, has submitted a New Drug ozanimod showed an 86-percent decrease in Application asking the United States Food the cumulative number of gadolinium- and Drug Administration to approve enhanced lesions compared to the placebo ozanimod for the treatment of RMS. Celgene group. The relapse rates also decreased in has also submitted a Marketing Authorization the treatment groups compared with Application to the European Medicines placebo, with a 31-percent decrease in the Agency for the same indication. Pivotal data

MS RESEARCH UPDATE 2019 29 EXPERIMENTAL MEDICATIONS: NEW S1P RECEPTOR MODULATORS

from RADIANCE and from another Phase III deficits. MS can slow "processing speed" (the study, SUNBEAM, were included in both time needed to perform a mental task). applications. 5, 65 Slowed processing speed can make executive More recently, SUNBEAM and RADIANCE functions such as paying attention and making data showed dose-dependent improvements decisions more difficult, and can impair the in relapse frequency and MRI-measured quality of life for individuals with MS. disease activity in individuals with early or More than 1,300 people who received advanced RMS. A total of 2,659 patients, ozanimod 1 mg or 0.5 mg or intramuscular including 1,267 with advanced RMS, received interferon beta-1a were studied in an analysis either daily ozanimod 0.5 mg or 1 mg or in which researchers administered the weekly interferon beta-1a injections (30 mcg) Symbol Digit Modalities Test (SDMT), which for one to two years. The median time since measures cognitive impairment, at baseline, MS diagnosis was 0.5 years for the early RMS six months, and one year. Improvements in group and 5.7 years for the advanced RMS SDMT scores of 4 points or greater were group. more common among the participants in After one year, the mean number of T1- both ozanimod-treatment groups than enhancing lesions and T2 new and enlarging among those treated with interferon. A 4- lesions were lower among participants who point SDMT increase signifies clinically received the higher ozanimod dose versus meaningful improvement in processing the lower dose, but both groups had speed, and these improvements were seen significantly fewer lesions than the six months and one year after baseline participants who were treated with interferon. testing among individuals receiving Ozanimod improved all measures of disease ozanimod. 68 activity among both the early and advanced RMS groups. 66 Ponesimod Overall relapse rates were 42 percent and 26 percent lower among the ozanimod 1 mg Company: Actelion and 0.5 mg groups, respectively, compared n Oral medication being studied at 20 mg with interferon-treated group. Relapses that per day required hospitalization or treatment with n Being studied in RMS steroids decreased by 43 percent and 26 percent in the ozanimod 1 mg and 0.5 mg Ponesimod is another selective S1P1 groups, respectively. The incidence of acute receptor modulator that completed a Phase II relapses was 20 percent to 35 percent lower trial; results were reported in 2012. In this among ozanimod-treated patients compared study, 462 people with RMS were with interferon. 67 randomized to placebo or 10 mg, 20 mg, or Ozanimod also was shown in the 40 mg of ponesimod. Reductions in SUNBEAM trial to prevent or delay cognitive annualized relapse rate and reductions in

30 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: NEW S1P RECEPTOR MODULATORS

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new lesions were seen for all treatment activity, and measures of the safety and groups versus placebo. However, the 40-mg tolerability of ponesimod. Study completion dose was associated with an increase in is scheduled for March 2020. 69, 70 adverse events. Two randomized, double- Meanwhile, the ongoing OPTIMUM blind, phase III trials involving the 20-mg (Oral Ponesimod Versus Teriflunomide in dose are now under way. Relapsing MUltiple Sclerosis) trial is The POINT study is examining ponesimod comparing ponesimod and teriflunomide as adjunctive therapy to Tecfidera® (dimethyl (Aubagio®) in patients with RMS. A total of fumarate). Investigators are following 1,133 participants have been randomized to approximately 600 individuals with RRMS ponesimod 20 mg/d or teriflunomide 14 who had been taking Tecfidera for at least six mg/d over 108 weeks. Investigators are months at screening. The participants, all of measuring annualized relapse rate, changes whom are being randomized at a 1:1 ratio to in symptoms, cumulative number of add-on ponesimod 20 mg/d or placebo for T1 enhancing or T2 lesions on MRI, and 60 weeks, showed clinical or MRI evidence of prevalence of patients who report disease activity within 12 to 15 months of confirmed disability at 12 and 24 weeks. screening. Major endpoints will include The trial is scheduled for completion in annual relapse rate, clinical and MRI disease May 2019. 71

MS RESEARCH UPDATE 2019 31 EXPERIMENTAL MEDICATIONS: ADMINISTERED ORALLY

Vumerity™ (diroximel fumarate) patients (people who were diagnosed with MS less than one year before study entry and who Company: Alkermes plc and Biogen Inc. have not had a prior disease-modifying therapy n Oral medication being studied at 462 mg [DMT]) and those with more long-standing twice daily RMS. All participants in the Phase III trial receive diroximel fumarate 462 mg twice daily. n Being studied in RMS Interim results from the Phase III study Diroxime l fumarate is in the same class of were reported at the American Academy of MS therapy as Biogen’s Tecfidera® (dimethyl Neurology’s 2019 Annual Meeting, held in fumarate), but is believed to cause fewer Philadelphia in May. Data covering 48 weeks gastrointestinal (GI) side effects – such as of treatment showed that relapse rates fell diarrhea, nausea, vomiting, and abdominal approximately 80 percent among the entire pain – than Tecfidera. The exact mechanism of study group relative to baseline. In addition, action by which diroximel fumarate exerts the number of gadolinium-enhancing lesions therapeutic effect in MS is not completely seen on MRI was reduced by 77% from understood. However, upon entering the baseline for the entire group and by 96% body, the medication is rapidly converted from baseline for the individuals who were into the molecule monomethyl fumarate. The newly diagnosed. 72 converted molecule is thought to activate an Meanwhile, the five-week EVOLVE-MS-2 antioxidant protein that reduces oxidative study, which is comparing the GI tolerability stress, which in turn slows damage to of diroximel fumarate with that of its kindred protective nerve fibers in the brain. 4 medication, dimethyl fumarate (Tecfidera), The FDA in February accepted a New Drug was scheduled for completion in June Application (NDA) from Biogen and Ireland- 2019. 73 During this Phase III, double-blind based Alkermes plc, seeking approval of trial, approximately 420 patients with RMS are diroximel fumarate for treatment of relapsing being randomized in a 1:1 ratio to receive forms of MS (RMS). The FDA, which under twice-daily doses of diroximel fumarate 462 federal law has six to 10 months to rule on an mg or dimethyl fumarate 240 mg. NDA, is expected to decide in late 2019 Investigators are measuring the incidence, whether to approve the agent for RMS. 4 intensity, onset, duration, and functional The ongoing open-label EVOLVE-MS-1 impact of medication-rela ted nausea, trial is assessing the safety/tolerability and vomiting, upper or lower abdominal pain, and efficacy of diroximel fumarate over 96 weeks diarrhea. Their goal is to show that diroximel in 503 individuals with RMS. Those study fumarate is better tolerated than dimethyl subjects include both newly diagnosed fumarate while offering comparable efficacy. 74

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32 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: ADMINISTERED ORALLY

Evobrutinib (M2951) 75 mg once or twice daily compared with placebo, but the difference was not statistically Company: Merck significant. Asymptomatic liver enzyme n Oral medication being studied at 25 mg elevations were reported with evobrutinib 75 daily, 75 mg daily, and 75 mg twice daily mg twice daily, but were considerably less common in other groups. 76 n Being studied in RMS and SPMS Upon completing the trial’s first 24-week B cells, which help the body fight infection, period, participants then entered the second have become an increasingly prominent focus 24-week phase, during which patients in the of MS research. That’s because when B cells placebo group were switched to evobrutinib become overabundant, they activate the T 25 mg once daily. In all, 227 subjects lymphocytes (T cells) known to cause the completed both 24-week phases of the 48- central nervous system inflammation that week trial. damages brain cells and their protective fiber During the second study phase, T1- (myelin) in MS. Bruton's tyrosine kinase (BTK) enhancing lesions still were significantly less inhibitors, currently approved to treat certain common among both the evobrutinib 75 mg B-cell cancers, impede B-cell proliferation by daily and 75 mg twice daily treatment groups blocking an enzyme that contributes to B-cell at weeks 12, 16, 20, and 24, compared with development. 75 the original placebo group now receiving 25 Evobrutinib is a BTK inhibitor under mg of evobrutinib daily. Researchers said that development for relapsing and secondary- these findings suggest that evobrutinib may progressive forms of MS (RMS and SPMS). This be effective as a long-term disease-modifying investigational medication demonstrated therapy. 76 efficacy in a recent 48-week, Phase II, double- blind trial. A total of 243 participants with RMS Ibudilast (MN-166) or SPMS were assigned to one of five arms for the first 24 weeks of the study: evobrutinib 25 Company: Medicinova mg daily, 75 mg daily, or 75 mg twice daily; n Oral medication being studied at up to open-label dimethyl fumarate (Tecfidera®) 240 100 mg/day (50 mg twice daily) mg twice daily; or placebo. n Being studied in PPMS and SPMS At 24 weeks, the average total number of T1-enhancing lesions on MRI was significantly Ibudilast is a small-molecule targeted lower among patients in the groups receiving treatment that works on several sites in the 75 mg of evobrutinib daily or twice daily (1.69 brain to prevent macrophages, a type of with daily dosing and 1.39 with twice-daily immune cell, from migrating. This action dosing) than among participants receiving suppresses production of cytokines, which are placebo (4.07). Relapse rates were also lower inflammatory molecules, and promotes among individuals who received evobrutinib regeneration of brain cells and the protective

MS RESEARCH UPDATE 2019 33 EXPERIMENTAL MEDICATIONS: ADMINISTERED ORALLY

fiber that surrounds them. This treatment among those with SPMS who had suffered a approach, or mechanism of action, differs relapse. 79 These findings underscore the from those of currently approved MS value of looking at the impact of medications medications. 77 in very specific patient populations in order to The efficacy and safety of ibudilast in tailor treatments as closely as possible to a people with progressive forms of MS was patient’s situation. assessed in the randomized, placebo- controlled Phase IIb SPRINT-MS trial. That Simvastatin (Zocor® and others) 96-week study included 134 people with primary-progressive MS (PPMS) and 121 Company: Medicinova individuals with secondary-progressive MS n Oral medication being studied at 80 mg (SPMS). Participants were randomized in a 1:1 daily ratio to receive ibudilast 100 mg daily or n Being studied in SPMS placebo. Based on MRI analyses, the study found that ibudilast reduced the rate of HMG-CoA reductase inhibitors, commonly progression of whole brain atrophy (or known as statins, long have been a mainstay shrinkage) by 48 percent compared to of lipid control in the United States. One of placebo, while being well tolerated and these agents has shown promise in early showing other benefits. 77 clinical trials as a potential disease-modifying Further analyses of the SPRINT-MS data therapy for secondary-progressive MS sought to determine whether response to (SPMS). ibudilast differed among people with primary- Results from the Phase II MS-STAT study in progressive MS, secondary-progressive MS the United Kingdom suggest that simvastatin, without relapse, and secondary-progressive which is available in the United States MS with relapse. After assessing the data, generically and under brand names such as investigators reported that the overall effect of Zocor and FloLipid, may slow disease and ibudilast on progression of brain atrophy in disability progression in SPMS. A total of 140 patients with progressive forms of MS individuals with SPMS were randomized to appeared to result mainly from its impact on receive simvastatin 80 mg daily (twice the people with primary – rather than secondary – recommended high-end dosage for lipid progressive MS. 78 control) or placebo for two years. MRI scans Subgroup analysis also found that – relative performed at each patient visit showed slower to placebo – the risk of confirmed disability rates of brain deterioration among individuals progression was 46 percent lower among who received simvastatin compared with the individuals with SPMS without relapse who placebo-treated group. 80 received ibudilast, and 29 percent lower Expanded Disability Status Scale (EDSS) among treatment-group individuals with scores, a common measurement of disability PPMS. That benefit, however, was not seen progression in MS, also increased more slowly

34 Multiple Sclerosis Association of America EXPERIMENTAL MEDICATIONS: ADMINISTERED ORALLY

among simvastatin-treated participants, potential role of simvastatin in treating SPMS compared with placebo. For anyone not from the upcoming Phase III MS-STAT2 clinical familiar, the higher the EDSS score, the greater trial. An estimated 1,180 individuals with SPMS the severity of MS-related disability. 80 from throughout the United Kingdom and The mechanism by which simvastatin Ireland will be randomized to receive exerts a therapeutic effect on MS is unclear. simvastatin 40 mg daily for one month Researchers, however, believe that the followed by 80 mg for 35 months, or placebo. medication’s actions in reducing “bad” Participants’ physical and cognitive function cholesterol and preserving brain function in will be tested every six months during the MS are independent of each other. 80 three-year study. Results are expected late Researchers hope to learn more about the summer 2023. 81, 82

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MS RESEARCH UPDATE 2019 35 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

Diet and MS researchers drew on the MSPT results to see how performance in various aspects of People with multiple sclerosis long have neurologic function differed from group to sought to improve their health and stabilize group. 83 the course of their MS through diet. While the The analysis found that people in the impact of specific eating plans and foods on highest quartile of dietary quality had MS itself continues to be investigated (as significantly faster cognitive processing discussed below), clinicians emphasize the speeds and 25-foot walking speeds than importance of following sound nutritional those in the lowest quartile, and marginally approaches generally to improve overall faster manual dexterity speeds. They also were health, reduce risk for common comorbid at significantly lower risk of moderate conditions such as high blood pressure and disability. The study’s authors concluded, diabetes, and to support energy levels and “High dietary quality was associated with immune function. lesser disease severity using measures of Turning to studies looking at specific issues disability, mobility, and cognitive function.” related to MS and diet, one recent analysis They added that ongoing studies would be involving 277 people with MS found that the important to determine if high-quality diets better you eat, the better you think – and are associated with slower rates of disease move. In this study, the participants had an and disability progression. 83 average age of 48.2 years and an average Ketogenic diets (KD), which are high-fat, body mass index (BMI) of 28.2, which is in the low-carbohydrate eating plans, have attracted overweight range. More than three-quarters significant interest from people with MS. were women. Proponents of these diets point to indications All participants completed the MS that this approach to food intake reduces Performance Test (MSPT) assessment of inflammation and oxidative stress. A recent neurologic function and a questionnaire on study examined the ability of people with MS how often they ate 153 different food items. to follow a ketogenic diet over time, as well as Investigators used the Healthy Eating Index- how that diet affected conditions that 2010, a measure of dietary quality, to assign commonly accompany MS. 84 each participant a score from 0 (poorest The study involved 20 individuals with quality diet) to 100 (highest quality diet). stable relapsing multiple sclerosis (RMS). A Based on those scores, researchers placed dietitian provided study participants with in- people into four quartiles, or groups, with one person education on how to adhere to a group composed of people with the highest- modified ketogenic diet, such as the Atkins quality diets, one made up of people with the diet. Daily urine testing then was employed to worst-quality diets, and the other two groups check levels of ketone – markers of adherence for people with intermediate degrees of to the diet. Researchers also collected data on lower- or higher-quality diets. Next, the patient-reported fatigue and depression, while

36 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

laboratory testing at the start of the study participants into three groups based on (before people began their ketogenic diets) whether the people had reported low, and at six months assessed insulin resistance, medium, or high intake of fatty acids when liver function, electrolytes, and other markers completing a food-frequency questionnaire. of health. Brain magnetic resonance imaging The researchers then used MRI to measure was also performed at baseline and at six participants’ cortical thickness (CT) and months. normalized grey matter (nGM) in the brain. None of the study participants showed Reduced cortical thickness reflects atrophy, clinical or imaging signs of disease worsening which is a shrinking or loss of brain cells. while on the diet. Meanwhile, improvements The study found that cortical thickness was were seen in fatigue and depression scores lower among patients with low MUFA intake (p=0.03), as were reductions in body mass than in patients with medium or high intake. index (BMI). Insulin resistance was significantly Results were similar for normalized grey reduced at three months. matter. By contrast, the researchers did not While data were still being collected when find significant links between saturated or these initial results were released, the findings polyunsaturated FA intake and cortical to date prompted researchers to conclude thickness or amount of normalized gray that for people with RMS, a ketogenic diet matter. “appears to be safe, feasible, and well- The researchers concluded that their tolerated,” while offering a number of health findings suggest that “MUFA intake may serve benefits. 84 a protective role in MS patients, limiting the Another recent study showed that high impact of MS-related lesions on cerebral gray consumption of monounsaturated fatty acids matter, which may have important implications (MUFAs) – which are found in olive oil, later in the disease.” 85 avocados, nuts, and other foods – may limit Turning to another question regarding the negative impact of MS on gray matter in nutrition and multiple sclerosis, a recent study the brain. 85 of 479 people recently diagnosed with MS Researchers used baseline data from the found no indication that mineral intake was an NYC RESERVE cohort, an ongoing study important factor in their developing the evaluating risk factors and protective factors condition. 86 Researchers drew on more than for disability in people who have been 170,000 food-frequency questionnaires diagnosed with MS in the past five years. They completed by participants in the Nurses’ analyzed information on 140 people with MS. Health Study (which ran from 1984 to 2002) Ninety of those study subjects were women. and the Nurses’ Health Study II (1991 to 2007), The average age of the overall group was 34.7 focusing especially on the information years, and the average time from diagnosis of provided by 479 participants who were MS was 2.2 years. diagnosed with MS during follow-up. They The investigators divided the study found no association between MS risk and the

MS RESEARCH UPDATE 2019 37 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

amount of potassium, magnesium, calcium, adults. The researchers noted, “This study phosphorus, iron, zinc, manganese, or copper lends further support to the hypothesis that in participants’ diets. 86 While negative studies vitamin D may be protective against MS.” 87 such as this one do not yield guidance on Further support for the protective benefits whether patients should increase or decrease of Vitamin D comes from extended follow-up their intake of certain foods, they nonetheless of 278 people with clinically isolated are valuable in helping investigators set syndrome (CIS), a common precursor to research priorities. MS. 88 A recently reported study examined long-term cognitive status in CIS patients who had participated in the BENEFIT Vitamin D (Betaferon/ Betaseron in Newly Emerging Perhaps no nutrient has been the subject Multiple Sclerosis for Initial Treatment) clinical of more MS-related research than Vitamin D. trial, and who had undergone 11 years of This focus arose in part from the observation follow-up. After assessing a number of that the prevalence of MS is higher in northern potential factors, researchers found that latitudes, where exposure to the sun – which higher levels of 25-OH Vitamin D, a facilitates the body’s production of vitamin D – biomarker for Vitamin D concentrations, is limited. As more and more research predicted better cognitive function. Smoking, demonstrated the immune-related benefits of meanwhile, predicted worse cognitive Vitamin D, efforts to determine whether the function over the long te rm. 88 nutrient protects against MS intensified. Another study examined whether adding a One of the latest studies pursuing these high-dose Vitamin D supplement to interferon questions comes from Sweden, where beta-1b therapy would affect the number of investigators analyzed blood samples from central nervous system (CNS) lesions found 666 people who later developed relapsing on MRI in people with relapsing multiple MS and from 666 healthy controls matched to sclerosis (RMS). 89 The randomized, double- the people with MS in terms of age, sex, and blind trial involved 53 people. Twenty-eight other factors. All of the blood samples from of those patients received 20,400 IU of MS patients were collected before the people cholecalciferol, a Vitamin D supplement, ev ery developed symptoms and before they other day for 18 months, while 25 participants reached 40 years of age. 87 received of 400 IU cholecalciferol, also given An analysis of Vitamin D levels in every other day for 18 months. The primary participants’ blood samples found that those endpoint of the study was the cumulative with the highest concentrations of Vitamin D number of new hyper-intense T2 lesions after had a significantly lower risk of developing MS 18 months compared to baseline. Secondary compared with people with lower endpoints were safety, T2-lesion volume, concentrations. This effect was more disability progression, and annualized relapse pronounced in younger adults than in older rate, or ARR.

38 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

At the study’s completion, researchers add significantly to investigators’ knowledge analyzed data on 38 patients who fulfilled the base. protocol for the trial. Twenty-one of those people were in the high-dose arm; 17 were in the low-dose arm. Serum levels of 25-OH- Biotin Vitamin D increased in both groups over 18 Biotin is another vitamin being studied in months, more than tripling from 18 ng/ml to MS, particularly in progressive forms of the 65 ng/ml in the high-dose group and rising condition. In particular, recent and ongoing from 16 ng/ml to 24 ng/ml in the low-dose studies have focused on MD1003, which is a group. However, the change in cumulative pharmaceutical-grade version of the B- number of new lesions over 18 months was complex vitamin. not significantly different between the study In MS-SPI, the first trial of MD1003 in arms. The median T2-lesion count in the high- progressive MS, study participants taking the dose arm rose from 42 at baseline to 46 in the vitamin had a significant sustained high-dose arm, while that number rose from improvement in disability. Based on those 64 to 70 in the low-dose arm. Meanwhile, 44 results, researchers now are conducting a adverse events were recorded in the high- Phase III trial called SP12. 90 A total of 660 dose arm versus 34 in the low-dose arm. individuals with either primary- and Importantly, however, no serious adverse secondary-progressive MS have been events related to Vitamin D were recorded. enrolled in the trial, which is fully recruited and In examining the study findings, underway now. researchers concluded, “High-dose The study participants have been supplementation increased serum 25-OH- randomized on a 1:1 basis to receive either Vitamin D to sufficient levels with no positive MD1003 at 300 mg/day or placebo. The effect on the cumulative number of new T2 study’s primary endpoint is a composite of a lesions. Supplementation with high dose decrease in Expanded Disability Status Scale Vitamin D (20.400 IU) as an add-on therapy (EDSS) score and/or improved timed 25-foot to IFN β is safe and tolerable in RRMS walk of 20 percent or more from baseline to patients.” 89 Month 12, confirmed at Month 15. The study The study and its results examined an will also assess changes in brain volume, important question – whether the protective cognitive measures, quality of life scores, and benefit against developing MS seen with other metrics. Final results are expected by higher blood levels of Vitamin D could be late 2019. 90 translated into an effective strategy for While the SP12 study moves toward reducing the number of CNS lesions in completion, researchers from a French MS people who already have MS. While the Center recently reported their experience in results were disappointing, they underscore treating people with progressive MS with 300 the complexity of the MS disease process and mg a day of MD1003. 91 From January 2016 to

MS RESEARCH UPDATE 2019 39 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

May 2018, the investigators had treated 220 sophisticated tests, those investigators patients with MD1003, and had acquired 12 determined that at the onset of MS, the gut months’ worth of data on 91 of those microbiomes of patients were markedly individuals. different from those of healthy volunteers. After one year of treatment with MD1003, People with MS had fewer different types of 23 percent of patients for whom data were microbes than healthy volunteers, and a available had experienced improvement in reduced presence of butyrate-producing their EDSS score, and a separate 23 percent bacteria that are believed to have an impact on experienced a 20 percent or greater various immune system cells. They concluded, improvement in the time it took them to walk “Our data indicate that gut microbial dysbiosis 25 feet. Eleven percent had experienced a [an imbalance of the bacteria in the gut] exist clinically defined relapse or had a gadolinium- at the onset of MS and could be associated enhancing T1 lesion on MRI. The investigators, with the autoimmune response in the who reported that MD1003 was well- periphery, highlighting the importance of gut tolerated, concluded that, “This real-world microbiome in the etiology of MS.” 92 study supports the growing body of evidence Another study found that a toxin potentially that MD1003 is an effective and safe treatment associated with the formation of central for PMS.” 91 nervous system (CNS) lesions was present in the gut microbiome of 21% of people with MS studied, but in none of the healthy volunteers Gut Microbiome studied. Researchers used sophisticated tests The gut microbiome is the milieu of to identify the presence and genetic bacteria and other microbes found in the characteristics of Clostridium perfringens gastrointestinal (GI) tract. It is a major epsilon toxin in fecal samples from people component of the body’s immune system, and with MS and matched healthy volunteers. They a growing body of evidence suggests that the noted that the toxin is an attractive candidate presence and number of various microbes in for new lesion formation because it targets the microbiome may affect the course of MS. both CNS endothelial cells and In one recent study, Italian investigators oligodendrocytes/myelin. 93 explored whether changes in the mix of Based on the fact that one in five people microbes that make up the microbiome were with MS had a specific type of the toxin in their associated with the onset of MS as indicated gut microbiome, while it was absent from all of by an initial episode of demyelination. The the healthy volunteers participating in the researchers examined stool and blood study, the researchers concluded, samples from 18 recently diagnosed MS “Colonization of the gut by C. perfringens type patients and 18 healthy volunteers who were B is statistically associated with MS. While two matched for age, sex, diet, and lifestyle. epsilon toxin-producing C. perfringens strains Using DNA analysis and other (type B and type D) exist in nature, thus far we

40 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

have identified only type B strains from MS be obtained as a means of assessing safety. subjects.” 93 At the time that investigators presented an Meanwhile, another group of investigators update on their research, 16 patients had is exploring whether borrowing an unusual been enrolled in the study. The participants technique from their infectious disease had experienced MS symptoms for an colleagues may help change the gut average of 18 years, and 11 of the 16 were microbiome of people with MS. Positive using a disease-modifying therapy. Six of the results in terms of altering the microbiome’s participants had begun receiving fecal composition would set the stage for pursuing microbial transplants, with a total of 24 the larger questions of whether those changes interventions performed in those patients. No affect the course of MS. 94 serious adverse events had been reported. The technique is called fecal microbial The investigators stated, “This proof of transplantation, or FMT. It involves using a concept, first in humans, independent pilot rectal enema to transfer fecal material from a study will shed light on the relationships healthy person into the GI system of someone between gut bacteria and MS. We aim to with MS to see if this intervention changes the explore FMT feasibility in MS and its possible mix of microbes present in the gut of the MS impact on disease inflammation. Moreover, we patient. Infectious disease specialists have hope that these study results can guide future employed FMT to treat people suffering from large-scale researches.” 94 colitis due to infection with Clostridium difficile , a bacterium that can cause severe diarrhea and other complications. Lipoic Acid The single-site, randomized, open-label Lipoic acid is a naturally occurring study will randomize 40 people with MS into compound that has antioxidant properties two groups of 20 subjects each. Participants in and also has an impact on the function of the the early-intervention group will receive FMT mitochondria, the so-call “energy plants” of by rectal enema, while the other group will cells. A Phase II trial involving 118 participants receive standard MS treatment for the first six is examining whether daily oral intake of lipoic months of the study. Thereafter, the early- acid can reduce the impact that progressive intervention group no longer will receive FMT, MS has on brain atrophy and patients’ while the second group will begin a six-month mobility. 95 course of FMT. The study’s primary outcome Fifty-nine study participants will take 1,200 will be the level of cytokines – inflammatory mg of lipoic acid by mouth every day for two molecules – in the peripheral blood. Ten years. The other 59 participants will take a healthy volunteers will serve as a reference placebo. The primary outcome measure will control group for cytokine levels. Secondary be the change from baseline to Year 2 in the outcomes are blood DNA bacteria and gut time it takes subjects to walk 25 feet. Other permeability. MRI scans of the head also will endpoints include change in brain volume

MS RESEARCH UPDATE 2019 41 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

from baseline to Year 2 as measured by MRI, administer high-dose chemotherapy, and change from baseline to Year 2 in number radiation, or both to kill cells in the bone of falls and in distance covered in a two- marrow so that the transplanted stem cells can minute timed walk. Safety measures will also then “re-set” the body’s immune system. This be assessed. The estimated completion date “myeloablative conditioning” can cause for the study is April 2021. 95 severe side effects. In an attempt to enable The Phase II study under way now follows a patients to benefit from stem-cell transplants smaller, single-center randomized trial of while facing fewer side effects, researchers lipoic acid that yielded favorable results in have experimented with myeloablative- people with secondary-progressive MS. In that conditioning approaches that use less-toxic double-blind study, 27 people took 1,200 mg chemotherapy regimens. These approaches of lipoic acid daily for two years, while 24 usually are referred to as “mini-transplant” participants took placebo on the same strategies. schedule. After two years, people in the lipoic An international team of researchers acid group had a 68% reduction in the recently pursued such a strategy in a study annualized percent change in brain volume – that involved 110 individuals with RRMS who a measure of brain atrophy, or shrinkage – had experienced at least two relapses while compared to the placebo group. More receiving a DMT in the prior year. These gastrointestinal upset but fewer falls occurred participants were randomized to either switch among the people taking lipoic acid relative to another DMT believed to be more effective to those receiving placebo, and there was one than their initial therapy or to undergo case of unexpected renal failure and a hematopoietic stem-cell transplantation separate case of serious kidney injury in the (HSCT). Hematopoietic stem cells are lipoic acid group. 96 immature blood cells that can grow into white Other studies are assessing the impact of blood cells, which fight infection; red blood lipoic acid on blood glucose, diabetes, and cells, which carry oxygen; or platelets, which complications of diabetes. aid in the clotting process. The 55 patients in the HSCT group received 200 mg/kg of cyclophosphamide, a chemotherapy that Stem-Cell Therapy suppresses the immune system; and anti- In a preliminary study, researchers found thymocyte globulin, which is used to prevent that a stem-cell transplant process using a the body from rejecting transplanted cells. relatively mild version of chemotherapy was This regimen is milder than the chemotherapy more effective than disease-modifying that traditionally has been used in HSCT therapies (DMTs) in slowing the progression of patients. relapsing-remitting multiple sclerosis (RRMS). While some participants left the trial, 98 In preparing participants for stem-cell were evaluated at one year and 23 were transplantation, physicians generally evaluated each year for five years. The average

42 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

follow-up period was 2.8 years. As measured RRMS in individuals experiencing “aggressive” by Expanded Disability Status Scale (EDSS) disease. The study involved 20 patients from scores, three patients in the HSCT group had five centers in Europe and North America. The disease progression, as compared with 34 individuals’ median age at diagnosis was 33 patients in the DMT group. The median time years, and their median pre-treatment EDSS to progression could not be measured in the score was 6.5, indicating significant disability. HSCT group because there were too few None had received any standard DMTs for events to allow for a calculation. In the DMT more than three months before undergoing a group, the median time to progression was 24 chemotherapy conditioning regimen and months. During the first year, the average autologous HSCT (AHSCT). “Autologous” EDSS score in the HSCT group improved from refers to using each patient’s own stem cells, 3.38 to 2.26 (a lower score reflects less which had been removed prior to the disability), and worsened from 3.31 to 3.89 in conditioning regimen and then transplanted the DMT group. back into each of the patients. No deaths occurred among the After a median follow-up period of 30 participants in the study, and no individuals months, median EDSS score was 2.0 (as who received HSCT developed serious compared with 6.5 prior to treatment). No (Grade 4) adverse events in other organ participants experienced a clinical relapse systems or tissues. 97 The researchers following AHSCT. Three of the study subjects conducting the trial noted that it was a had new T2 lesions at their first follow-up MRI, preliminary study, and that further research is but no new or enhancing lesions were seen needed to replicate its favorable findings and on subsequent scans. Researchers reported assess long-term outcomes and safety. that participants had routine side effects As researchers have explored the viability associated with AHSCT, but no treatment- of stem-cell transplantation as a therapy in MS related deaths. and other conditions, the side effects The investigators concluded, “AHSCT was associated with traditional myeloablative safe and highly effective in inducing rapid and conditioning have been a significant concern. sustained remission in this cohort and was If subsequent trials confirm this preliminary associated with a significant improvement in study’s findings that patients can receive a patients’ level of disability. This demonstrates milder form of chemotherapy while enjoying the potential role of AHSCT as first line therapy significant reduction in disease progression in ‘aggressive’ MS.” 98 with HSCT, it will constitute a major step Meanwhile, another study is examining the forward in the effort to make stem-cell effectiveness and safety of a therapy that transplantation a mainstream treatment for would use patients’ own stem cells to treat RRMS. progressive MS. In December 2018, the FDA Another study examined the effectiveness approved an application from BrainStorm Cell and safety of HSCT as initial treatment for Therapeutics to conduct a Phase II clinical trial

MS RESEARCH UPDATE 2019 43 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES of NurOwn® mesenchymal stem cell- Genetics neurotrophic factors (MSC-NTF) cells. 99 The trial has an estimated primary completion date The last decade has seen an increased of February 2020 and full completion date of focus on the role of genetics in multiple September 2020. 100 sclerosis (MS). The process by which genetics The trial will involve 20 people with interact with other health factors and progressive MS, and will be conducted at environmental influences in driving the multiple locations. 100 Participants’ development and course of MS is not fully mesenchymal stem cells will be removed from understood. However, researchers have their bone marrow via insertion of a hollow identified more than 230 common genetic 101 needle. Those cells then will be converted into variants tied to increased risk for MS. New MSC-NTF cells by growing them under insights are emerging on a regular basis, as patented conditions that cause the cells to reflected in the three studies summarized secrete high levels of neurotrophic factors, below. molecules that support the development and The International Multiple Sclerosis differentiation of neurons. 99 The MSC-NTF Genetics Consortium brings together cells will be re-introduced into the patients’ investigators from around the world to bodies through three intrathecal cell conduct large-scale research projects drawing transplantations over 16 weeks. 100 on information from tens of thousands of Autologous (meaning from the patient’s own people. One such initiative recently analyzed body) MSC-NTF cells can deliver neurotrophic data from more than 68,000 people with MS factors and other immune-modulating and healthy subjects; the analysis found that molecules “directly to the site of damage to up to 5% of the risk for MS heritability can be elicit a desired biological effect and ultimately explained by low-frequency (or seldom slow or stabilize disease,” BrainStorm Cell occurring) variations in gene coding Therapeutics explained in outlining the sequence. rationale for the treatment. 99 The research identified four novel genes – Participants will be followed for 28 weeks PRF1, HDAC7, PRKRA, and NLRP8 – that drive after the start of treatment. Researchers will the risk for MS, independent of more common monitor these individuals for adverse events variants. The investigators noted that their and will assess change from baseline to 28 research was important because it weeks post-treatment in patients’ 25-foot demonstrates the value of looking beyond walking speed. Sixteen weeks after treatment, common variants in seeking the genetic basis researchers will analyze participants’ of MS risk, because identification of these cerebrospinal fluid (CSF) to determine how novel genes will help scientists better explore many patients had changes in neurotrophic the mechanisms by which MS develops. factors in their CSF. 100 Additionally, all four novel genes that they identified serve immunologic purposes,

44 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

reinforcing the central role of immunologic examines how different genetic loci – fixed dysfunction in the origination of MS. 101 positions on chromosomes, such as the Clinicians long have noted that people location of a gene – associated with increased with MS who are overweight often have risk for MS affect particular populations. A greater disease activity and more disability group of researchers recently performed a than individuals with MS who maintain a genomic association study involving almost healthy weight. To explore the reasons for this 4,000 Italians – 1,727 with MS and 2,258 difference, a team of researchers evaluated 54 healthy controls. To increase the statistical people with relapsing-remitting MS who were power of their analysis, they examined their not receiving disease-modifying therapy findings in the context of data on roughly (DMT). Twenty-seven of the subjects had a 40,000 Americans of European ancestry – half high BMI, meaning that they were overweight of whom had MS and half of whom did not. or obese, while the other 27 had a normal After further genetic analyses, they BMI. People in the two groups had a similar identified 203 loci on chromosome 17 degree of disability at baseline. associated with increased risk for MS among At the two-year follow-up, however, the Italian people with MS. They now plan to look high-BMI group had an increased lesion load more closely at the impact of those loci and at on MRI, increased disease activity, and how they may play a causative role in worsened disability relative to those with a development of MS. 103 With gene therapy normal BMI. Genetic analyses performed on making promising strides in the treatment of people in both groups found that a process cancer and other life-threatening diseases, the called ceramide-induced DNA methylation hope is that this enhanced understanding of contributed to the worse outcomes in the the specific genetic contributors to MS risk high-BMI group by increasing the number of may one day translate into effective monocytes, a type of white blood cell, in their interventions. blood. Ceramides are waxy lipid molecules, while DNA methylation is the process by which methyl groups are added to the DNA Biomarkers molecule. Methylation can interfere with the A biomarker is a finding on an imaging way DNA conveys its genetic “instructions.” 102 study or from an analysis of blood or other While the researchers continue to pursue substances or tissues from a patient’s body this avenue of inquiry in animal models and that can help clinicians assess the patient’s with sophisticated genetic analyses, their health. Biomarkers are used to make findings are a reminder that while our genes diagnoses, assess any changes in the status of influence our health, our health – in terms of a condition, and evaluate how an individual is body weight, physical activity, and the like – responding to a treatment, among other can also influence genetic processes. purposes. Two biomarkers – one involving MRI Another important area of research studies and the other involving a blood test –

MS RESEARCH UPDATE 2019 45 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

have emerged in recent years as having concerns about the correct diagnosis; and considerable potential value in guiding the one had imaging findings that created management of MS. uncertainty. The first is called the central vein sign, or Each patient underwent a single- CVS. This term refers to the identification of a standardized 3T MRI protocol, with two central vein in brain lesions on MRI. A recent independent raters evaluating the images multi-center study examined how useful the obtained to look for a CVS. Meanwhile, expert finding of a central vein sign on high-powered clinicians who did not know the results of the 3 Tesla (3T) MRI was in distinguishing MS from CVS assessment conducted a thorough other conditions. The study involved 606 evaluation of the patients and then made a subjects, including 236 with relapsing- diagnosis. Twelve of the 17 participants were remitting MS, 142 with various types of diagnosed with MS, while the remaining five cerebral small-vessel disease, 117 with received alternative diagnoses. More than half clinically isolated syndromes (CIS) suggestive of the lesions in those diagnosed with MS had of MS, 25 with systemic lupus erythematosus, the CVS, while less than 50% of the lesions in 29 with migraine, 20 with diabetes, and 37 those who received other diagnoses had the with other conditions. sign. The investigators said this finding was Clinicians examined the images of 4,447 “preliminary evidence that the CVS detected lesions without knowing the associated on 3T FLAIR images can accurately predict MS diagnosis. The median proportion of lesions diagnosis in patients suspected to have MS, with a positive CVS identified was 50% among but with atypical clinical, laboratory, and patients with CIS or RRMS, and was 0% among imaging features.” 105 patients who did not have MS. The researchers The CVS also has shown promise in the also found that the ability to identify RRMS or diagnosis of MS in children and adolescents. CIS was greater with the use of specific Investigators analyzed 232 lesions found on imaging techniques and when the individual the imaging of 26 individuals with pediatric- had at least three lesions with a central vein onset multiple sclerosis (POMS). All of the evident on imaging. 104 participants had at least one lesion containing Another, smaller study found that the CVS a central vein, while 21 of the 26 patients had can help improve the diagnosis of MS in two lesions with CVS, and 17 (65%) had three people who have some signs of MS but who or more lesions with a central vein. The also have atypical findings, or “red flags,” that researchers said that their findings suggest “a cast doubt on whether they actually have MS high potential of the CVS to improve POMS or some other condition. The prospective diagnosis.” 105 study was conducted at three centers in Other investigators are focusing on how Europe, and included 17 people. Eight had blood levels of a protein called neurofilament clinical signs that were “red flags”; another light chain (NfL) can predict brain atrophy and eight had laboratory findings that raised response to treatment in MS. NfL is a

46 Multiple Sclerosis Association of America NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

“scaffolding protein” that helps give form to NfL levels were higher in those with neurons. When axons, or nerve fibers, are gadolinium-enhancing lesions on MRI at damaged, NfL is released and can be found in baseline relative to those without such lesions. the cerebrospinal fluid (CSF) and peripheral Similarly, in both PPMS and SPMS, high serum blood. However, since obtaining CSF requires NfL at baseline was associated with a greater a lumbar puncture procedure, investigators percentage of brain-volume loss at Month 12 have focused on understanding the and Month 24. The researchers concluded, “In significance of NfL levels, which are more both SPMS and PPMS patients, NfL may serve easily obtained from blood samples. as a prognostic marker of brain atrophy.” 107 One study involving 85 people with Serum NfL levels may also be useful in relapsing forms of MS, 42 with progressive measuring response to therapy, according to MS, and 20 with CIS, examined how serum NfL researchers who drew on data from the Swiss levels correlated with MRI measures of brain MS Cohort Study. These investigators atrophy and disability progression. The examined baseline and annual follow-up NfL researchers found the baseline serum NfL levels on more than 230 patients who were predicted brain-volume change, atrophied taking disease-modifying therapies (DMTs). lesion volume as measured by T2 MRI They found that serum NfL levels increased imaging, and absolute change in lesion with age, with worsening disability as volume as measured by T1 MRI. After five measured by the Expanded Disability Status years of follow-up, participants who had Scale (EDSS) score, and by history of relapse in baseline serum NfL of 30 pg/ml or more had the past 120 days. Conversely, blood levels of significantly higher atrophied lesion volume NfL decreased with time on DMT at a rate of on T2 MRI imaging as well as a higher 3.2 percent per year, with the rate of decrease percentage of brain-volume change, varying among different DMTs. The compared to study participants with serum investigators concluded that by following the NfL levels of less than 30 pg/ml. 106 change in serum NfL levels over time, this Another study drew on data from Phase III provides another means of monitoring how a trials of two DMTs to analyze the impact of patient is responding to treatment. 108 serum NfL in secondary-progressive MS (SPMS) versus primary-progressive MS (PPMS). The retrospective analysis involved 1,452 people with SPMS and 378 with PPMS. Baseline serum NfL levels were categorized as low (<30 pg/ml), medium (30 pg/ml to 60/pg/ml), or high (>60 pg/ml). Researchers found that baseline serum NfL levels were higher in people with SPMS than in those with PPMS. In both forms of progressive MS, serum

MS RESEARCH UPDATE 2019 47 CLOSING NOTES

The 2019 edition of the MS Research Update is a powerful testament to the progress that has been made in understanding the potential causes of multiple sclerosis and in developing therapies to effectively treat the condition. The studies reported in this update examine everything from intricate biochemical processes occurring at the molecular level to long-term treatment outcomes in international registries with records on tens of thousands of patients. Squarely in between hopefully, control multiple sclerosis – which what can be seen with an electron brings us back to the individual patient. microscope and what patterns can be People with MS are the unsung heroes of the discerned from Big Data analytics stands the advances reported in this MS Research ultimate focus all of this research – the Update . Without their participation in clinical individual patient. trials, without their willingness to act on the Regardless of which questions clinical findings of those trials, and without their researchers and basic-science investigators commitment to being proactive partners in set their sights on, their shared vision is to their care, all of the efforts documented here develop treatments and apply knowledge so would be for naught. that people with MS can live healthier, fuller, Because knowledge truly is power, staying and richer lives. Recent months have seen informed of recent developments in MS is a several important advances toward that goal, prerequisite to taking a proactive approach. as evidenced by this publication’s reports on That is why MSAA is proud to provide this newly approved therapies, other agents 2019 edition of its annual MS Research under consideration by the FDA, and still Update . We hope that you will find it of more in late stages of clinical development. interest and value. We also hope that you will Other research is better defining the role of turn to MSAA throughout the year for the diet and nutrition in enhancing the health of latest information in this exciting time of people with multiple sclerosis, while scientists frequent, significant advances in the also are steadily mapping the complex treatment of MS. For information about interactions that give rise to MS and opportunities to participate in clinical trials, identifying biomarkers that can speed its please visit mymsaa.org/clinicaltrials or diagnosis and predicts its course. www.clinicaltrials.gov . For more information In short, while MS remains a formidable about MS, its treatments, and MSAA’s foe, there never has been more cause for programs and services, please contact MSAA hope, nor more opportunity to confront and, at (800) 532-7667 , or visit mymsaa.org .

48 Multiple Sclerosis Association of America APPROVED DISEASE-MODIFYING THERAPIES FOR MS

SELF-INJECTED MEDICATIONS

nAMe type oF MeDIcAtIon how ADMInIS tereD AnD SIDe eFFectS

Avonex ® immune system modulator 30 micrograms taken via weekly intramuscular injection; (interferon beta-1a) with antiviral properties side effects include flu-like symptoms and headache, as well as blood count and liver test abnormalities; side effects are manageable and usually temporary

Betaseron ® immune system modulator 250 micrograms taken via subcutaneous injection every (interferon beta-1b) with antiviral properties other day; side effects include flu-like symptoms, headache, and injection-site reactions, as well as blood count and liver test abnormalities; side effects are manageable and usually temporary

copaxone ® synthetic chain of four 20 (daily) or 40 (three times weekly) milligrams taken via (glatiramer acetate) amino acids found in subcutaneous injection; side effects include injection-site myelin; it is an immune reaction as well as an occasional systemic reaction, usually system modulator that lasting only a few minutes with no long-term effects blocks attacks on myelin

extavia ® immune system modulator 250 micrograms taken via subcutaneous injection every (interferon beta-1b) with antiviral properties other day; side effects include flu-like symptoms, headache, and injection-site reactions, as well as blood count and liver test abnormalities; side effects are manageable and usually temporary

Generic Glatiramer synthetic chain of four 20 (daily) or 40 (three times weekly) milligrams taken via Acetate Injection amino acids found in subcutaneous injection; side effects include injection-site (glatiramer acetate) myelin; it is an immune reaction as well as an occasional systemic reaction, usually system modulator that lasting only a few minutes with no long-term effects blocks attacks on myelin

Glatopa® synthetic chain of four 20 (daily) or 40 (three times weekly) milligrams taken via (glatiramer acetate) amino acids found in subcutaneous injection; side effects include injection-site myelin; it is an immune reaction as well as an occasional systemic reaction, usually system modulator that lasting only a few minutes with no long-term effects blocks attacks on myelin

plegridy® immune system modulator 125 micrograms taken via subcutaneous injection once (interferon beta-1a) with antiviral properties every two weeks; side effects include flu-like symptoms, headache, and injection-site reactions, as well as blood count and liver test abnormalities; side effects are manageable and usually temporary

rebif® immune system modulator 44 micrograms taken via subcutaneous injection three (interferon beta-1a) with antiviral properties times weekly; side effects include flu-like symptoms, headache, and injection-site reactions, as well as blood count and liver test abnormalities; side effects are manageable and usually temporary

MS RESEARCH UPDATE 2019 49 APPROVED DISEASE-MODIFYING THERAPIES FOR MS

ORAL MEDICATIONS

nAMe type oF MeDIcAtIon how ADMInIS tereD AnD SIDe eFFectS Aubagio® immunomodulator affecting 7 or 14 milligram tablet taken orally, once per day; side (teriflunomide) the production of T and B effects include headache, elevated liver enzymes, thinning cells; may also inhibit nerve hair, diarrhea, nausea, neutropenia (a condition causing a degeneration reduction of certain white blood cells), and paresthesia (tingling, burning, and numbness); adverse events include severe liver injury and birth defects if pregnant

Gilenya® S1P-receptor modulator, 0.5 milligram capsule taken orally once per day; side effects (fingolimod) which blocks potentially include headache, flu, cough, diarrhea, back pain, and abnormal damaging T cells from leaving liver tests; adverse events include transient heart-rate reduction lymph nodes and AV block, swelling behind the eye, and possibly PML*, a viral brain infection

Mavenclad® Selectively targets and Two annual courses are given orally for a maximum of 20 days (cladribine) depletes the immune system’s over two years; no treatment is needed for Years 3 and 4. B cells and T cells, followed by The most common adverse reactions include upper a ‘reconstitution, ’ as new B respiratory tract infections, headache, and decreased cells and T cells are produced lymphocyte counts. Potential adverse events include lymphopenia, a condition that causes abnormally low counts of white blood cells, and herpes zoster infection. Mavenclad has an increased risk of malignancy (cancer) and fetal harm.

Mayzent® Its primary actions are at the After starting at a low dose, the recommended maintenance (siponimod) S1P1 and the S1P5 receptors, dosage is 2 mg taken orally once daily starting on Day 6. blocking the movement of Headache, high blood pressure, and changes in liver function lymph cells from lymph nodes; tests were the most common adverse reactions. Serious it has a relatively short half-life adverse events include a decrease in white blood cells, heart compared to similar rate, and rhythm abnormalities, as wel --- l as hypertension, medications, meaning that it swelling of the macula of the eye, varicella zoster reactivation, does not stay in the body as and convulsions. Women who could become pregnant should long use contraception to avoid potential risk of fetal harm.

tecfidera® immunomodulator with anti- 240-milligram tablet taken twice daily; side effects include (dimethyl in flamma tory properties; may flushing, gastrointestinal events, reduced white fumarate) have neuroprotective effects, blood cell count, and elevated liver enzymes; adverse events potentially protecting the include respiratory infection, chronic itching, rash, gastric-lining nerves and myelin covering inflammation, and possibly PML*, a viral brain infection

*Progressive multifocal leukoencephalopathy (PML), a potentially fatal, viral infection of the brain, can develop in some individuals taking Tysabri. Risk factors include the presence of anti-JCV antibodies, taking Tysabri for two years or more, and prior immunosuppressant treatment. Currently, PML has occurred in a few patients taking Gilenya, Tecfidera, or Ocrevus; some of these cases are still under investigation.

50 Multiple Sclerosis Association of America APPROVED DISEASE-MODIFYING THERAPIES FOR MS

INFUSED MEDICATIONS

nAMe type oF MeDIcAtIon how ADMInIS tereD AnD SIDe eFFectS lemtrada® humanized monoclonal anti - Five-day course of 12 mgs daily via intravenous (IV) infusion (alemtuzumab) body that rapidly depletes or and followed one year later by a second three-day course; suppresses immune system side effects include rash, itching, headache, fever, cells (T and B cells), which nasopharyngitis, nausea, diarrhea and vomiting, insomnia, can damage the myelin and numbness, dizziness, pain, and flushing; adverse events nerves of the CNS include infusion reactions, infection, autoimmune diseases, potentially severe bleeding disorder (ITP), and malignancies

novantrone® antineoplastic agent; IV infusion once every three months (for two to three years); (mitoxantrone) immune system modulator side effects include nausea, thinning hair, loss of menstrual and suppressor periods, bladder infections, and mouth sores; seldom prescribed for MS due to the potential for heart damage and leukemia

ocrevus™ humanized monoclonal anti - 600-milligram dose given via IV every six months; initial dose (ocrelizumab) body designed to selectively given in two 300-milligram doses; side effects include target CD20-positive B cells, a potentially serious infusion reactions, infections (respiratory type of immune cell important and skin infections most common); adverse events include to the MS-disease process. cancer and possibly PML*, a viral brain infection tysabri® humanized monoclonal 300 mg dose given via IV infusion every four weeks; side (natalizumab) antibody; inhibits adhesion effects include headache, fatigue, depression, joint pain, molecules; thought to prevent abdominal discomfort, and infection; serious adverse damaging immune cells from events include infection (including pneumonia), and the crossing the blood-brain barrier potential for PML*, a viral brain infection

*Progressive multifocal leukoencephalopathy (PML), a potentially fatal, viral infection of the brain, can develop in some individuals taking Tysabri. Risk factors include the presence of anti-JCV antibodies, taking Tysabri for two years or more, and prior immunosuppressant treatment. Currently, PML has occurred in a few patients taking Gilenya, Tecfidera, or Ocrevus; some of these cases are still under investigation.

REFERENCES

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52 Multiple Sclerosis Association of America REFERENCES

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