Published in May 2016

This publication has been jointly published by the Multiple Sclerosis Association of America (MSAA), the Consortium of Multiple Sclerosis Centers (CMSC), and the International Organization of MS Nurses (IOMSN). This year’s MS Research Update has been published jointly by the Multiple Sclerosis Association of America (MSAA), the Consortium of Multiple Sclerosis Centers (CMSC), and the International Organization of MS Nurses (IOMSN). MSAA greatly appreciates the support from the CMSC and IOMSN to assist with the production of this publication. The MS Research Update provides important new data on approved and experimental treatments for MS, and is a valuable resource to the entire MS community.

Please note that this update gives an overview of the research behind the approved and experimental and therapies for the long-term treatment of multiple sclerosis. It does not include information on any 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 note that due to the timing of the national and international MS conferences, study data from the 2016 conferences could not be included in this writing. Information in this publication includes data presented at the 2015 conferences, as well as any important updates that occurred in early 2016. Please visit MSAA’s website at mymsaa.org for future summaries of 2016 conference highlights.

To learn about the Consortium of Multiple Sclerosis Centers (CMSC), please visit mscare.org . They may also be contacted via phone at (201) 487-1050 or via email at [email protected] . For information about the International Organization of MS Nurses (IOMSN), please visit iomsn.org .

MSAA 1 CONTENTS Introduction ...... 3

FDA-APPROVED MEDICATIONS The Multiple Sclerosis Association of America (MSAA) is a leading New Data resource for the entire MS Tysabri ® () ...... 6 community, improving lives today Gilenya ® (fingolimod) ...... 7 through vital services and support. EXPERIMENTAL MEDICATIONS MSAA publications are intended to inform and educate those with MS Administered Orally and their families. MSAA does not Laquinimod (also known as Nerventra ®)...... 8 endorse or recommend any specific products, services, therapies, or Monoclonal Antibodies activities mentioned in articles or (Zinbryta) ...... 10 ® advertisements that appear in MSAA Rituxan (rituximab) ...... 12 publications. MSAA, its staff, and ...... 13 ® those affiliated with the writing of Ofatumumab (also known as Arzerra )...... 14 this publication cannot be held Vatelizumab ...... 15 responsible for any unintentional errors. New S1P Receptor Modulators Ozanimod (formerly RPC1063) ...... 16 MSAA strives to provide useful, up- Siponimod (BAF312) ...... 17 to-date information on matters of Ponesimod ...... 17 concern to MS patients and their families. This material is intended for Other Therapeutic Strategies ® ® general informational purposes only, Masitinib (also known as Kinavet and Masivet )...... 18 Ibudilast ...... 19 and it does not constitute medical ® advice. You should not use the Tcelna™ (formerly Tovaxin )...... 19 information presented as a means Tetracycline Antibiotics ...... 20 of diagnosis or for determining Statins ...... 20 treatment. For diagnosis and New Therapies under Investigation ...... 22 treatment options, you are urged to consult your physician. NEW DIRECTIONS IN MS RESEARCH Copyright © Multiple Sclerosis New Therapeutic Approaches Association of America, 2016. All Vitamins and Electrolytes ...... 27 rights reserved. No part of this Vitamin D3 ...... 27 publication may be reproduced, Biotin ...... 28 stored in a retrieval system, or Salt ...... 29 transmitted in any form or by any Stem Cells ...... 30 means, electronic, mechanical, Biomarkers ...... 33 photocopying, recording, or Genetic Studies ...... 34 otherwise, without prior written The Microbiome and MS ...... 36 permission from MSAA. Closing Notes ...... 37

Trial Phases for Investigating Drugs and Treatments ...... 38

Approved Long-Term Treatments for MS ...... 40

References ...... 44

RESEARCH UPDATE Written and compiled by Stephen Krieger, MD and Michelle Fabian, MD

Includes additional material by Margaret M. McCormick, RN, BSN, MSCN

Reviewed by Jack Burks, MD Co-authors Michelle Fabian, MD and Stephen Krieger, MD Edited by Susan Courtney

INTRODUCTION

This year’s streamlined MS Research Update and scope of research progress in MS. has been refined to emphasize numerous There is nonetheless far too much ongoing experimental drugs currently under research in MS therapeutics for all of it investigation for the long-term treatment of to be covered here. This is therefore not a multiple sclerosis (MS). Entirely new clinical complete list, and not all study results could trial data on some of the approved disease- be included. modifying therapies (DMTs) has also been This information is based on a wide range of included. Please note that in order to keep this sources, including extensive journal literature on annual Research Update current and up to MS and its management, a review of ongoing date, historical background and completed clinical trials, and papers presented at major trials of approved DMTs are no longer included. national and international conferences. These Background information on approved include the 2015 conferences hosted by the therapies can still be found in our 2015 edition American Academy of Neurology (AAN), the of the MS Research Update . This may be Consortium of Multiple Sclerosis Centers accessed by going to the “Publications” section (CMSC), and the Americas and European of MSAA’s website, under “MS Information,” at Committees for Treatment and Research in mymsaa.org . A chart giving an overview of the Multiple Sclerosis (ACTRIMS and ECTRIMS). approved DMTs may be found on pages 40-43 . More than 20 years have passed since the This 2016 edition of MSAA’s MS Research United States Food and Drug Administration Update is again being printed as a stand-alone (FDA) approved Betaseron ® (interferon beta- issue, reflecting the incredible diversity 1b), the first disease-modifying therapy for MS,

MSAA 3 INTRODUCTION

and the beginning of the MS-treatment era. supports the FDA-approved DMTs for the long- The “watch and wait” approach to MS therapy term treatment of multiple sclerosis. The has become a thing of the past, in favor of a objectives were to provide evidence for the proactive strategy to prevent MS-disease effectiveness of these medications and to activity and disability. provide support for broad access to these Preferably, treatment is now often started approved therapies for people with MS in the when a person is diagnosed as having a United States. Ultimately, the goal is to enable clinically isolated syndrome (CIS). This is individuals with MS and their medical defined as a single attack (or the appearance of professionals to select the most appropriate one or more symptoms characteristic of MS), available. with a very high risk of developing MS, when no This professional paper, titled “The Use of other diseases or causes for symptoms are Disease-Modifying Therapies in Multiple apparent. The use of MRI scans to identify Sclerosis: Principles and Current Evidence,” is lesions characteristic of MS has expedited available on MSAA’s website for anyone to diagnosis. Numerous studies with multiple review. It has been written expressly for types of DMTs have confirmed that early medical professionals, in a highly detailed and treatment at the time of CIS is beneficial in the scientific style. This paper for professionals long term. may be accessed by going to mymsaa.org/msc- The past two years have seen the approval dmt-full . of a new formulation of Copaxone ® (glatiramer Following the release of the professional acetate), dosed three times per week versus paper, member organizations of the MSC have daily, as well as a new type of interferon called collaborated to develop a summary, written in a Plegridy ® (peginterferon beta-1a), which is more reader-friendly style to better serve the dosed once every two weeks. A new agent broader MS community. This paper is available given by a series of infusions once yearly, on MSAA’s website as well and is titled, “The Lemtrada ® (alemtuzumab), was approved by Use of Disease-Modifying Therapies in the FDA at the end of 2014. With the success Multiple Sclerosis: Principles and Current of research initiatives and the expanding Evidence; SUMMARY.” This summary directly number of approved medications, the choice of correlates to the different sections found disease-modifying therapy has grown more within the professional version, but has complex. simplified the information to highlight main In 2014, experts from member points and incorporate more commonly used organizations of the Multiple Sclerosis terminology. In addition, the summary is Coalition (MSC), including the Multiple followed by an extensive glossary to assist with Sclerosis Association of America (MSAA), those terms specific to describing the MS collaborated to develop and write a paper process. This paper on the approved DMTs is a summarizing the current evidence that valuable counterpart to this Research Update,

4 RESEARCH UPDATE which is focused on summarizing new and please visit mymsaa.org and select “Symptoms” emerging data covering available therapies as under “MS Information.” For information on well as emerging treatments still in trial phases, please refer to pages 38 and 39. development. This paper for the MS Readers may also note that studies community may be accessed by going to involving progressive forms of MS are mymsaa.org/msc-dmt-summary . highlighted with the mention of progressive Please note that the authors have MS appearing in bold type. This is because all of reported on the most recent study results the 13 presently approved DMTs are for available at the time of publication. While relapsing forms of MS, and the authors of this every effort has been made to provide publication want to also bring studies for meaningful, timely, and balanced information progressive MS to the readers’ attention. on each medication, keeping the length of information equal for each medication is not EDITOR’S NOTE: Initial study results from possible. Please know that the different lengths therapeutic agents under investigation should of text should in no way be considered as be considered as preliminary, since additional favoritism toward any one product. studies and/or evaluations may be needed to Additionally, references have only been cited prove the safety and efficacy of these agents. for the newer study results. MSAA does not endorse or recommend any As symptom-management drugs do not fall specific products or therapies. Readers are under the scope of this report, for more advised to consult their physician before information on the specific symptoms of MS making any changes to their medication, diet, and treatments for managing these symptoms, exercise, or other treatment regimen.

MSAA 5 FDA-APPROVED MEDICATIONS: NEW DATA

This MS Research Update 2016 , covering information from the year 2015 and early 2016, must begin with a sobering note in regard to the failure of two highly anticipated clinical trials in progressive MS. By testing approved medications for relapsing MS in progressive disease, the possibility of extending the use of these well-known medications for progressive MS may be rigorously explored. Unfortunately, as discussed below, success in relapsing MS does not always predict similar efficacy in those with progressive disease. We begin with some of the unsuccessful studies of 2015 before moving on to the numerous positive avenues of ongoing MS research in both relapsing and progressive forms of MS.

Tysabri ® (natalizumab) study provided encouraging evidence that Tysabri may have beneficial effects in Company: Biogen progressive forms of MS. n Administered via intravenous infusion every To continue this line of investigation, a large, four weeks in TOUCH program-authorized randomized trial of Tysabri in SPMS called infusion centers; dose is 300 mg ASCEND 2 evaluated the effects on the n Approved for individuals with relapsing types accumulation of disability in people with SPMS. of MS There were 889 SPMS patients enrolled, the This laboratory-produced monoclonal majority of whom required assistance for antibody acts against a molecule involved in walking and were no longer experiencing MS the activation and function of lymphocytes relapses. Subjects were randomized to receive (immune-system cells produced to fight either Tysabri 300 mg or placebo intravenously infection and disease) and their migration into every four weeks for 96 weeks. the central nervous system (CNS). The CNS The primary endpoint of the study was the consists of the brain, spinal cord, and optic percentage of patients with confirmed nerves. progression of disability according to several A small Phase II clinical trial, Natalizumab standardized measures. Biogen reported in a Treatment of Progressive Multiple Sclerosis press release in October 2015 that the study (NAPMS), was performed at Copenhagen did not meet its primary or secondary University Hospital to study the safety and endpoints that relate to preventing the efficacy of Tysabri treatment of primary- accumulation of disability. The data have not progressive MS (PPMS) and secondary- yet been presented in detail, but this is progressive MS (SPMS) .1 It enrolled 24 anticipated in 2016. It is hoped that detailed patients and showed a reduction in markers analyses of this trial may yield insight into of inflammation in the spinal fluid, as well as particular groups or types of patients with evidence of protection of brain tissue on progressive MS who may respond favorably to modern MRI measures. This proof-of-concept this available therapy.

6 RESEARCH UPDATE Gilenya ® (fingolimod) Expanded Disability Status Scale (EDSS), the 25-Foot Timed-Walk Test (T25FW), and the Company: Novartis Pharmaceuticals Corp. 9-Hole Peg Test (9-HPT). Other key endpoints n Oral medication; 0.5 mg capsule taken once were the formation of new lesions and daily percentage of brain-volume change (PBVC), n Approved for relapsing forms of MS or brain atrophy (the shrinking or reduction of brain volume). Detailed results of the trial were Gilenya is the first in a class of immuno- presented in spring 2015. Gilenya did not modulatory drugs called “S1P-receptor prevent the accumulation of disability in modulators.” It is similar in structure to a patients with PPMS any greater than placebo. naturally occurring component of cell-surface Furthermore, PBVC did not differ between the receptors on white blood cells. (White blood Gilenya and placebo groups. cells are produced by the to Unsurprisingly, given this agent’s success in fight infection and disease.) Gilenya blocks reducing relapses and new MRI lesions in potentially damaging T cells from leaving RRMS patients, there were fewer new MRI lymph nodes, lowering their number in the lesions seen in the Gilenya-treated patients. blood and tissues. It may reduce damage to the CNS and enhance the repair of damaged The safety results were generally consistent nerves within the brain and spinal cord. with this medication in prior MS trials. It is Although Gilenya was approved for certainly disappointing that Gilenya did not relapsing-remitting MS (RRMS) in 2010, significantly slow disease progression in PPMS. clinical trials have continued to evaluate its role These findings, like those of Tysabri in SPMS, in MS. The 36-month INFORMS trial evaluated have important implications for the the effect of Gilenya relative to placebo on understanding of progressive disease, and will delaying the time to sustained disability no doubt allow researchers to refine how this progression in patients with PPMS . As there is is studied moving forward. presently no FDA-approved medicine for Another ongoing Gilenya clinical trial is a PPMS, this was an important study for the field. Study Evaluating Safety and Efficacy of Two 3 The enrollment of 969 PPMS patients into the Doses of Fingolimod Versus Copaxone. This INFORMS trial was completed in 2011, and the 12-month trial will compare the marketed trial’s data analysis was completed in 2014. dose of Gilenya with one-half this dose, using Novartis announced in December 2014 that Copaxone as a comparison, on annual MS unfortunately, the primary outcome of the relapses and several MRI measures of disease. study was not met. Gilenya did not show a The goal of this study, which was required by significant difference from placebo on a the FDA, is to assess if a lower dose of this combination of disability measures. medication may be equally effective at A novel, primary-composite disability reducing the number of relapses in patients endpoint was used in the trial, based on the with relapsing forms of MS. This study is increase in disability as measured by the expected to report data in 2016.

MSAA 7 EXPERIMENTAL MEDICATIONS: ADMINISTERED ORALLY

Laquinimod (also known as Nerventra ®) tolerability versus placebo. In August 2011, the sponsors announced that the study had Company: Teva Neuroscience, Inc. and failed to achieve its primary goal of reducing Active Biotech the annualized relapse rate, although there n Oral medication taken once daily; dosing is was a trend in that direction if the data are still under investigation adjusted for differences in MRI characteristics n Laquinimod is being studied in RRMS and at the start of the study. PPMS Because the effect of laquinimod on relapses was more modest than has been seen Although its exact mechanisms of action are unknown, laquinimod is an with other disease-modifying therapies for immunomodulator, apparently through its RRMS, the drug was not considered for effects on cytokines (small proteins that may approval in the United States in 2012. In stimulate or inhibit the function of other cells) 2013, the results of two separate analyses of and (immune-system signaling pooled data from the Phase III ALLEGRO and chemicals). It enhances T-regulatory cell BRAVO trials studying laquinimod were 4 activity, which reduces Th1-inflammatory presented. T-cell activity. It also appears to reduce white- The first analysis compared the expected blood-cell penetration of the CNS. In addition risk of disability progression (given a to its immunomodulatory actions, laquinimod particular relapse rate) with that seen in the increases levels of the brain-derived pooled data. In this analysis, the effect of neurotrophic factor (BDNF), possibly laquinimod on reducing the risk of disability contributing to neuroprotection (protecting progression was larger than predicted. The the nerves and myelin from damage) in MS second analysis examined the relationship patients. BDNF is a protein found in the brain between relapses and disability by looking at that helps to support nerves and their disability progression in both relapsing and development. relapse-free patients in the two trials. About The Phase III ALLEGRO study of 1,106 one third of the patients who progressed were individuals with RRMS showed that, relapse-free, suggesting that these two compared to placebo, laquinimod reduced the outcome measures are mediated through annualized relapse rate by 23 percent and the different pathways. progression of disability by 36 percent. It also Since laquinimod may have more of an was effective on several MRI outcomes, effect on disability than on relapses, a new including a reduction in brain atrophy by trial looking primarily at laquinimod’s 33 percent. disability-preventing impact was designed. The BRAVO Phase III trial was another This 24-month trial, The Efficacy and Safety global, 24-month, double-blind study with and Tolerability of Laquinimod in Subjects 1,300 participants. It was designed to With Relapsing Remitting Multiple Sclerosis evaluate laquinimod’s efficacy, safety, and (CONCERTO 5), was designed to compare two

8 RESEARCH UPDATE doses of laquinimod (including a 1.2 mg dose, people and is anticipated to run through the which was higher than that tested in prior end of 2017. Phase III studies) with placebo, looking at Although both the CONCERTO and confirmed disease progression as the primary ARPEGGIO trials were designed to study both outcome. This is the first modern RRMS trial the 0.6 mg dose of laquinimod evaluated in to prioritize prevention of disability over prior trials along with higher doses, in January prevention of relapses. The trial began 2016 Teva announced the decision to enrollment of 1,800 patients in 2013, and discontinue the higher doses of laquinimod in is expected to run into 2018. both ongoing studies. Several cardiovascular Furthermore, based on its effect on side effects had occurred in patients receiving disability in prior trials, laquinimod is also the higher dose, so the decision was made to being studied in a PPMS trial (ARPEGGIO) continue only the lower, 0.6 mg dose in which that began in 2015. 6 This trial will primarily no such events had occurred. The safety of evaluate the effect of laquinimod on brain patients enrolled in these studies will atrophy, and secondarily on clinical outcomes. continue to be monitored closely as the trials It was designed to enroll approximately 375 utilizing the lower dose continue.

New S.E.A.R.C.H. ™ Booklet Now Available

MSAA’s SEARCH booklet has been updated! This new booklet details MSAA’s SEARCH program, which is designed to assist individuals with learning about the approved disease-modifying therapies (DMTs) for the long-term treatment of MS. It provides information on the DMTs, along with important questions to ask your healthcare provider when looking to begin a medication or make a change in your present therapy… questions such as, “What are the side effects?” and “Will I have access through insurance?”

Designed as a memory aid, the Safety Effectiveness SEARCH acronym represents Access the key areas that should be Risk considered when “searching” Convenience for the most appropriate Health Outcomes (overall wellness) MS treatment.

MSAA offers a SEARCH “toolkit,” which includes this detailed booklet, along with a wallet-size reference card, and more. For more information, please visit mymsaa.org or call (800) 532-7667, ext. 154 .

MSAA 9 EXPERIMENTAL MEDICATIONS: MEDICATIONS

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 specifically directed toward a certain part of a system while leaving the other parts of the system untouched. This can be very desirable when trying to impact a structure as complex as the immune system. The name of all monoclonal antibodies ends with “mab,” including natalizumab (Tysabri) and alemtuzumab (Lemtrada), which are already approved for MS. Several other monoclonal antibodies have shown promise in MS, and these are reviewed in this section.

Daclizumab (Zinbryta; known in other approved interferon therapies. The study formulations as Zenapax ®) showed that DAC HYP was well tolerated when added to an interferon. A statistically Companies: Biogen and AbbVie significant 72-percent reduction in the n Administered via intravenous infusion every frequency of gadolinium-enhancing MRI four weeks; also studied when given in lesions was seen in the high-dose group (300 subcutaneous (under the skin) injections mg every four weeks). n Daclizumab is being studied in both RRMS The Phase IIb SELECT trial, with 600 and SPMS participants who have RRMS, was a one-year Daclizumab is a genetically engineered study of treatment with DAC HYP. This study monoclonal antibody that binds to CD25, a was subsequently extended for a second year receptor on T cells that is thought to become as the SELECTION trial. The study included activated in response to MS. Daclizumab is three treatment arms, with two dose levels believed to work by selectively targeting these (at 150 mg and 300 mg) and a placebo group. activated T cells without causing general T-cell Results of the SELECT trial announced in depletion. It is approved by the FDA for use in August 2011 indicated that the annualized rheumatoid arthritis and other autoimmune relapse rate was decreased by 54 percent in diseases. Daclizumab high-yield process the 150-mg-dose group and by 50 percent in (DAC HYP) is administered subcutaneously the 300 mg-dose group. It also met its once every four weeks, rather than via secondary endpoints: in the 150 mg and 300 intravenous infusion. mg groups respectively, the number of new Participants in the Phase II CHOICE study gadolinium-enhancing lesions was reduced by had either RRMS or SPMS, with worsening 69 percent and 78 percent; the number of new disease activity while taking one of the or newly enlarging T2-hyperintense lesions

10 RESEARCH UPDATE was reduced by 70 percent and 79 percent; and was completed in the spring of 2014. Outcome the proportion of patients who relapsed was measures included relapse rate, functional reduced by 50 percent and 51 percent. decline, and disability progression, as well as Sustained disability progression at one year quality of life. was reduced by 57 percent with the lower dose Initial results of the DECIDE trial were and 43 percent with the higher dose. presented in 2014. Treatment 10 with Participants who completed this trial were daclizumab resulted in a 45-percent reduction enrolled in an extended trial called SELECTION in annualized relapse rate (ARR), a 54-percent to evaluate long-term safety and efficacy. One- reduction in new and newly enlarging T2 year results of the SELECTION trial were lesions, and a 65-percent reduction in new presented 7 at the ECTRIMS meeting in the fall gadolinium-enhancing lesions in comparison of 2012. Patients who were on placebo and to Avonex. Risks associated with daclizumab began treatment with DAC HYP in the extension treatment included infections, rash dermatitis, trial had a 59-percent reduction in annualized and liver enzyme abnormalities, some of which relapse rate compared to the year prior, while were serious. More than a third of people on patients who continued on DAC HYP maintained daclizumab reported cutaneous (skin) issues – their low relapse rate from the prior year. twice as many as on Avonex – including some In 2013, further data from this trial was cases severe enough to warrant discontinuing presented; 8 patients who received two years of the drug. One death of a daclizumab-treated treatment with DAC HYP in the SELECT trial patient from the Phase II study was due to and its one-year extension study, SELECTION, complications of a muscle abscess, and a second were evaluated to determine the rate of brain death was due to autoimmune liver inflammation. atrophy (brain-volume loss). During the second The safety profile of this medication including year of treatment, brain-volume loss was 27- the nature of the cutaneous (skin) side effects percent lower in the treated groups compared will be closely evaluated in further analyses of with the placebo group at year one. The the Phase III trial. authors of the study note that this reduction in In abstracts presented at the 2015 the rate of brain atrophy in people with MS ECTRIMS meeting, DAC HYP was shown to may be consistent with neuroprotection. be more effective in patients at risk for high DAC HYP was further studied in the disease activity, as well as for those with less DECIDE trial, 9 a Phase III study of 1,841 active disease, compared to individuals taking participants with relapsing MS, comparing Avonex. Over the course of three years, DAC DAC HYP to Avonex ® (interferon beta-1a). HYP was also associated with less brain- DAC HYP was administered subcutaneously volume loss with RRMS, compared to once every four weeks for 96 to 144 weeks individuals taking interferon beta-1a. The with a dose of 150 mg. This was compared to a safety and tolerability profile has been well weekly 30-mcg intramuscular injection of characterized in clinical studies for periods up Avonex. The study began in March 2010 and to six years. As of spring 2016, this agent is

MSAA 11 EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODY MEDICATIONS

under review by the FDA and a decision on A Phase I/II double-blind study of 80 people approval is anticipated by the middle of the year. with SPMS, sponsored by the National Institute of Neurologic Diseases and Stroke, tested a Rituxan ® (rituximab) combination of intravenous (IV) and intrathecal (IT)(into the spinal fluid) rituximab versus Companies: Genentech and Biogen placebo (the RIVITaLISe 11 study). The study’s n Administered via intravenous infusion authors hypothesized that this combination n Rituxan is being studied in both RRMS and method of Rituxan administration would cause SPMS more complete destruction of B cells both in the blood and the spinal fluid. Theoretically, the Rituxan is a monoclonal antibody (CD20, addition of the IT medication could be more from mouse tissue) that binds to a receptor effective for patients with progressive MS in on the surface of B cells. These cells are then which the immune cells provoking the destroyed and their levels in the circulation continued attack may reside exclusively in the are decreased. It is approved for use in the central nervous system, without circulating treatment of lymphomas, leukemias, and through the blood. autoimmune disorders. A Phase II trial, completed in 2006, The study enrolled 27 patients but analyzed examined the effect of a single course of data in an interim analysis from 22 patients (14 Rituxan treatment in RRMS, with two infusions on active drug and nine on placebo) who had of 1,000 mg each, administered two weeks received at least two doses of the drug. Though apart. At 48 weeks, the number of active the study had originally aimed to measure lesions was reduced by 91 percent and progression of brain atrophy after two years relapses were reduced by 58 percent. of treatment, it was terminated early when the The drug was also tested in a study of study authors did not find that the combination 30 people with RRMS who had experienced of IV and IT Rituxan was adequately decreasing continued clinical activity despite treatment B cells in the spinal fluid. Although there are with one of the approved disease-modifying multiple reasons that might account for this therapies. Participants received two doses of finding (including lower doses of Rituxan used Rituxan, two weeks apart, while continuing to in this study than in previous studies), this take their usual medication. Results showed study raises questions about rituximab’s ability gadolinium-enhancing lesions were reduced to decrease active inflammatory cells in the after treatment with Rituxan: 74 percent of central nervous system. The small size of the post-treatment MRI scans were free of study group did not allow for a true analysis of gadolinium-enhancing activity as compared clinical outcome measures. with 26 percent that were free of gadolinium- Serious adverse events have been enhancing activity at baseline. There was an reported in Rituxan-treated patients with 88-percent reduction in the average number other diseases, including progressive multifocal of these lesions. leukoencephalopathy (PML), the same viral

12 RESEARCH UPDATE infection of the brain that has been seen with a compared to placebo. The annualized relapse small percentage of patients taking Tysabri. rate was significantly lower versus placebo at While no PML has been diagnosed in MS week 24, with a reduction of 73 percent for patients taking Rituxan, the number of ocrelizumab 2,000 mg, and 80 percent for individuals with MS treated with Rituxan is ocrelizumab 600 mg. Ocrelizumab’s relatively small to date. effectiveness was maintained through week Rituxan is not likely to be further developed 72 (roughly one year and five months); the for FDA approval. However, next-generation proportion of relapse-free patients at week 72 anti-CD20 monoclonal antibodies have been was 84 percent for the 600 mg group, and 82 developed to build on the encouraging data from percent for the 2,000 mg ocrelizumab group. Rituxan’s MS studies, including ocrelizumab, as The findings of three important studies of 13 discussed in the following entry. ocrelizumab in MS were announced in 2015. In relapsing MS, ocrelizumab met both the Ocrelizumab primary and major secondary endpoints in the Phase III, OPERA I and OPERA II studies. Companies: Genentech and Roche Pharma AG The OPERA studies had identical designs. n Administered via intravenous infusion The total combined enrollment for both studies was 1,656, which included individuals n Ocrelizumab is being studied in RRMS and in with relapsing forms of MS who either had PPMS relapsing-remitting MS or secondary- Like Rituxan, this drug is an anti-CD20 progressive MS with relapses. monoclonal antibody. It has the potential Taking place at 307 sites in 40 countries, advantage of being a more individuals received either 600 mg of than Rituxan. As noted in the introduction to ocrelizumab via intravenous (IV) infusion every this section, humanized monoclonal antibodies six months, or the approved 44 mcg dose of are antibodies from non-human species whose Rebif ® (interferon beta-1a), given via protein sequences have been modified to subcutaneous injection three-times weekly. increase their similarity to antibodies produced Patients given ocrelizumab had significant naturally in humans. “More humanized” refers reductions in both studies in annualized to a protein sequence that is more similar to relapse rate of 46 and 47 percent over a two- antibodies produced in humans, compared to year period versus the interferon groups. another humanized monoclonal antibody Additionally, in the ocrelizumab groups, new (Rituxan in this instance). MRI lesions were decreased by 94 and 95 In a Phase II study of ocrelizumab 12 in 220 percent, brain atrophy was decreased by 24 individuals with RRMS, reductions in the total and 25 percent, and progression of sustained number of brain lesions detected by MRI scans clinical disability was decreased by 40 percent. (the primary endpoint of the study) were The third ocrelizumab study, ORATORIO, highly significant at 96 percent for 2,000 mg was conducted in patients with PPMS . Prior to ocrelizumab and 89 percent for 600 mg this study, no Phase III studies in PPMS had

MSAA 13 EXPERIMENTAL MEDICATIONS: MONOCLONAL ANTIBODY MEDICATIONS

been successful, despite multiple attempts. had significant rates of serious and ORATORIO was a randomized, double-blind, opportunistic infections, and one patient died and global multi-center trial that studied the of a systemic inflammatory response of effectiveness and safety of ocrelizumab unknown etiology (e.g., the reason why this compared to placebo in 732 people with PPMS. response occurred), no opportunistic infections Every six months, two 300 mg infusions (for a were identified in these trials. Serious adverse total of 600 mgs) were given two weeks apart. events included infusion reactions and the Members of the treatment group were occurrence of several malignancies, which will compared to a placebo group. The primary be carefully reviewed to assess if this endpoint of this study was time to the onset of represents a safety concern with this agent. It confirmed disability progression, defined as an should be noted that in February 2016, the increase in EDSS that is sustained for at least FDA granted “Breakthrough Therapy 12 weeks. Designation” for ocrelizumab for the treatment The ORATORIO study met its primary of PPMS , which will potentially expedite the endpoint, showing that treatment with review process. ocrelizumab significantly reduced the progression of clinical disability (sustained for Ofatumumab (also known as Arzerra ®) at least 12 weeks) by 24 percent compared with placebo. Walking speed, as measured by Company: Novartis the timed 25-foot walk, was improved by 29 n Administered via intravenous infusion and percent. The incidence of adverse events will also be studied via subcutaneous injection associated with ocrelizumab was similar to n Ofatumumab is being studied in RRMS placebo; the most common adverse events were mild-to-moderate infusion-related Like Rituxan and ocrelizumab, this drug is reactions. MRI hyper-intense T2 lesions were an anti-CD20 monoclonal antibody. It has the actually reduced by ocrelizumab, and brain- potential advantage of being a human volume loss as viewed on MRI was reduced by monoclonal antibody (versus antibodies from 17.5 percent. In conclusion, this is the first study non-human species that have been modified). where a disease-modifying therapy has shown Ofatumumab has a unique target on effectiveness in treating PPMS. The incidence the CD20 molecule and is approved for of adverse events associated with ocrelizumab certain forms of leukemia. Genmab, the was similar to placebo; the most common pharmaceutical company developing this adverse events were mild-to-moderate medication prior to Novartis, announced infusion-related reactions. positive interim results for a Phase II safety The number of serious adverse events in the and pharmacokinetics (how the body processes ORATORIO, OPERA I, and OPERA II studies the drug) study of ofatumumab in 2010. This were small and similar among the groups. study had 38 patients with RRMS who were Although Phase III trials in rheumatoid arthritis randomized to ofatumumab or placebo in a

14 RESEARCH UPDATE cross-over design. Statistically, the number Vatelizumab of gadolinium-enhancing lesions and new or Company: Glenmark Pharmaceuticals and enlarging T2 lesions was significantly less in Sanofi Genzyme patients treated with ofatumumab compared to placebo. n Administered via intravenous infusion Results from MIRROR, a 12-week Phase II n Vatelizumab is being studied in RRMS study comparing several doses of ofatumumab Vatelizumab is a humanized monoclonal in RRMS, were reported in 2014. 14 In the antibody that targets VLA-2, a collagen-binding MIRROR study, 231 patients with RRMS were integrin expressed on activated lymphocytes assigned to one of four doses of ofatumumab (immune-system cells produced to fight or placebo. This “dose-ranging study” included infection and disease). This is similar to the doses of 3 mg every 12 weeks, 30 mg every mechanism of action of Tysabri, although with a 12 weeks, 60 mg every 12 weeks, and 60 mg different molecular target. The precise every four weeks. After 12 weeks, the placebo mechanism of action of vatelizumab in MS is group received 3 mg of ofatumumab. The study not known, although it is hypothesized to block treatments were given for 24 weeks. The VLA-2 on activated immune cells, preventing primary endpoint was suppression of MRI- the penetration of inflammatory lymphocytes lesion activity during the first 12 weeks. from crossing into the brain, thus potentially Results suggested a 90-percent or greater reducing inflammatory events in MS. reduction in the active, enhancing lesions for The EMPIRE study, 16 initiated in 2014, is a all cumulative doses of ofatumumab 30 mg or global Phase IIa/IIb double-blind, randomized, greater. placebo-controlled study assessing the efficacy, Five serious adverse events were reported, safety, and dose-response of vatelizumab in all in the highest-dose treatment group. This patients with active RRMS. The study duration study design allows for an “optimal dose” to be is 12 weeks for the MRI portion and two years utilized in future studies of ofatumumab. The for the safety follow-up. It is expected to enroll aim is to achieve suppression of MS-disease 168 patients at 55 sites in 10 countries. activity without completely eliminating B cells, Although no clinical data had been made with the intent of minimizing adverse events. public, Sanofi announced in a press release in The MIRROR trial extension data presented fall 2015 that a pre-planned interim analysis in fall 2015 15 demonstrated continued revealed the primary efficacy endpoint was not suppression of new MRI lesions at week 48 and met. The principal developer of this agent, a dose-responsive effect on B cells. These data Glenmark, planned to continue the EMPIRE will guide future clinical trials of this agent, study, which is expected to be completed in expected to be initiated in 2016. mid-2016.

MSAA 15 EXPERIMENTAL MEDICATIONS: NEW S1P RECEPTOR MODULATORS

New S1P Receptor Modulators Data have been presented on several investigational oral agents, now in ongoing clinical trials, which have a mechanism similar to that of Gilenya, by isolating lymphocytes (that damage myelin) in the lymph nodes. These agents have been well-tolerated and reduced lesions related to RRMS. It is hoped that these agents, ozanimod (RPC1063), siponimod (BAF312), and ponesimod, will maintain or potentially improve on the efficacy and safety of Gilenya. However, researchers continue to remain vigilant with regard to cardiovascular side effects, such as bradycardia (slowed heart rate).

Ozanimod (formerly RPC1063) group. The relapse rates also decreased in the treatment groups compared with placebo, Company: Celgene with a 31-percent decrease in the 0.5-mg n Oral medication being studied at several group and a 53-percent decrease in the doses 1-mg group. n Ozanimod is being studied in RRMS The most common side effects reported were nasopharyngitis, headache, and urinary Ozanimod (RPC1063) is a selective tract infections, as well as mild elevations in modulator of one type of S1P receptor, S1P1. [Correction: Ozanimod is actually a selective liver enzymes in some participants. Notably, modulator of two types of S1P receptors: S1P1 no serious cardiac events were reported in the and S1P5. This note was added after subjects receiving ozanimod. publication.] It is given as a once-daily pill, and In February 2016, the 72-week extension was studied in a Phase II trial called data of the RADIANCE trial were presented. RADIANCE, where the experimental medicine These showed a continued reduction in was compared at two different doses with relapses and gadolinium-enhancing lesions for placebo. A total of 258 RRMS patients were those patients who remained on ozanimod, studied in this trial, which began with a seven- with all efficacy results favoring the 1-mg day gradual titration of ozanimod up to the full dose over the lower 0.5-mg dose. No new dose under investigation. The double-blind safety or tolerability issues were identified study then ran for 24 weeks, followed by a during this blinded extension phase of the yearlong safety-extension period. trial. The drug has moved into a larger, Phase At the end of the initial 24-week treatment III version of the RADIANCE trial, 17 where it period, patients in both groups taking is being compared with Avonex in 1,200 ozanimod showed an 86-percent decrease subjects with RRMS. This trial is expected in the cumulative number of gadolinium- to run through the end of 2017. enhanced lesions compared to the placebo

16 RESEARCH UPDATE

Siponimod (BAF312) Ponesimod Company: Novartis Company: Actelion n Oral medication studied at several doses n Oral medication being studied at a dose of 20 mg per day n Siponimod is being studied in SPMS n Ponesimod is being studied in RRMS Data from a Phase II dose-finding study of siponimod in people with RRMS were also Ponesimod is another selective S1P reported in 2012. Siponimod has a relatively receptor modulator that completed a 19 short half-life compared to Gilenya, which Phase II trial; results were reported in 2012. means that the drug does not stay in the body In this study, 462 people with RRMS were as long. Researchers hope that this will randomized to placebo or 10 mg, 20 mg, or 40 minimize cardiac issues. mg of ponesimod. Reductions in annualized The trial had a complex design, with the relapse rate and reductions in new lesions were primary goal to determine the most seen for all treatment groups versus placebo. appropriate dosing regimen. One group of 188 However, the 40 mg dose generated an patients received placebo or once-daily increase in adverse events, which included swelling of the extremities and difficulty siponimod in doses of 10 mg, 2 mg, or 0.5 mg breathing. With an 83-percent decrease in for six months. A second group of 109 patients gadolinium-enhancing lesions and a favorable were given one of two additional intermediate adverse event profile, the 20 mg dose of doses of 1.25 mg or 0.25 mg for three months. ponesimod may have the best benefit-to-risk At six months, the proportion of relapse- profile in this trial. An extension trial over two free patients as compared to placebo was 84 years (presented in 2013) demonstrated percent for the 10 mg group, 92 percent for the continued efficacy and no new safety issues. 2 mg group, and 77 percent for the 0.5 mg In spring 2015, Actelion decided to group. In the placebo group, 72 percent were advance this agent to a Phase III trial in RRMS: relapse-free. After six months, the ARR (annual OPTIMUM, 20 a multicenter, randomized, relapse rate) was lower for the individuals who double-blind study to compare the efficacy were taking one of the three higher doses. and safety of ponesimod to Aubagio ® (oral Additionally, MRI findings showed a reduction in teriflunomide) in subjects with relapsing forms active lesions. The 2 mg dose reached statistical of multiple sclerosis. The study aims to significance versus placebo, with a reduction in determine whether ponesimod is more active lesions of approximately 80 percent. effective than Aubagio in reducing relapses. A Phase III trial of siponimod in SPMS (the The study is expected to enroll approximately EXPAND trial) 18 began recruitment in 2013 1,100 subjects , randomized in two groups in a and is expected to run through fall 2016. This is 1:1 ratio to receive ponesimod 20 mg per day the first S1P receptor modulator to be studied or Aubagio 14 mg per day, and is expected to in SPMS. last approximately three years.

MSAA 17 EXPERIMENTAL MEDICATIONS: OTHER THERAPEUTIC STRATEGIES

Masitinib mast cells may delay the onset of symptoms (also known as Kinavet ® and Masivet ®) associated with progressive forms of MS. The results showed that for the primary Masitinib is termed a protein kinase endpoint of Multiple Sclerosis Functional inhibitor. It selectively inhibits molecules Composite (MSFC) score, which measures (kinases) that play a major role in the activation upper and lower limb function as well as of mast cells. Although mast cells are best cognition, 32 percent of patients treated with known for their role in allergies, they are also masitinib showed a response to treatment involved in the immune response, in the versus none of those receiving a placebo. recruitment of lymphocytes to the brain and Responses were seen in the third month and also in inflammatory processes associated with were sustained over the 18-month duration of MS. As noted earlier, lymphocytes are immune- the study. system cells produced to fight infection and A Phase IIb/III multicenter, randomized, disease. Additionally, lymphocytes can initiate double-blind, placebo-controlled trial 23 is myelin damage. currently underway. The investigators planned Masitinib has a role in veterinary medicine to recruit 450 people with PPMS or SPMS (it is used to fight mast cell tumors in dogs) and without relapses . The primary endpoint will be is being studied for several human indications, an improvement in the MSFC scale at 96 including cancers and degenerative diseases. weeks. In summer 2015, the trial sponsor A small Phase II trial of masitinib in progressive announced that after one third of patients forms of MS 21 showed a trend toward benefit; enrolled in the trial were treated for a total of however, the results were not statistically 48 weeks (halfway through the trial), they were significant. 22 assessed for an array of disability endpoints. In 2012, results from a Phase II study of 30 The observed changes were significant enough patients taking masitinib were released. These for the masitinib trial to be declared “non futile” indicated what is termed “proof of concept,” by the Independent Data Safety Monitoring showing that this agent may have potential in Committee. This decision indicates that the treating both PPMS and relapse-free SPMS . Phase III clinical trial has the potential to The study investigated the hypothesis that succeed and is thus justified to continue masitinib’s action of targeting and inhibiting forward.

18 RESEARCH UPDATE Ibudilast with the potential to address unmet medical needs for such diseases. According to the FDA, Company: MediciNova Fast Track designation for a drug makes it n Oral medication eligible for things such as more frequent n Ibudilast is being studied in progressive MS communications with the FDA, priority review, and the potential for accelerated approval. Ibudilast (MN-166) is an oral agent with novel immune modulating and potential Tcelna ™ (formerly Tovaxin ®) neuroprotective properties that is being studied in progressive forms of MS. This agent Company: Opexa Therapeutics has also been studied in a range of conditions n Administered as five subcutaneous injections including chronic pain, headache, and in the per year treatment of methamphetamine-dependent n addicts. Based on early MS-trial evidence that Tcelna is being studied in SPMS ibudilast had a primary, neuroprotective role, Tcelna is a T-cell vaccine. In the process of independent from a substantial effect on overt administering this vaccine, myelin-reactive inflammation, the Phase II Secondary and T cells are removed from a small amount of the Primary Progressive MS Ibudilast NeuroNEXT patient’s blood, inactivated, and then injected trial (SPRINT MS) 24 was launched in fall 2013. back into the patient. The body’s immune It includes 28 enrolling clinical sites across the system may then potentially protect the myelin United States. from these cells. The trial is designed to evaluate the safety, The TERMS placebo-controlled, one-year tolerability, and efficacy of ibudilast study in 150 people with clinically isolated administered twice daily to individuals with syndrome (CIS) and RRMS to evaluate Tcelna’s PPMS or SPMS . Primary outcomes of this trial efficacy, safety, and tolerability has been will be MRI findings, including brain atrophy, as completed. The treatment was found to be this is felt to be an important aspect of safe, but did not achieve statistical significance progression in MS. There will also be several in the primary endpoint, which was a reduction other imaging and clinical-disability outcomes in the cumulative number of gadolinium- evaluated. The NIH and National MS Society enhancing lesions. are supporting the study along with a The placebo group did, however, experience commercial partner, MediciNova. The trial is an annualized relapse rate (ARR) of 0.34 per expected to require approximately three years year (or one relapse roughly every three years), for enrollment, treatment, and data analyses, while the Tcelna group had an ARR of 0.21 per and will run through the end of 2016. year (or roughly one relapse every five years), In March 2016, ibudilast received Fast representing a 37-percent decrease. The drug Track designation from the FDA. This was well tolerated with mild skin reactions in designation is intended for drugs under some patients; no serious safety concerns development for treating serious diseases and were raised by this study. In a subgroup of 70

MSAA 19 EXPERIMENTAL MEDICATIONS: OTHER THERAPEUTIC STRATEGIES

patients who had at least one relapse in the on to Rebif in people with RRMS. Patients 12 months prior to enrolling in the study and being treated with Rebif were randomized to who had no previous exposure to MS therapy, oral placebo or minocycline 100 mg twice daily Tcelna reduced their annualized relapse rate by for 96 weeks. Data were presented at 64 percent compared to placebo. Additionally, ECTRIMS in the fall of 2012, 26 and 76 percent of Tcelna-treated patients disappointingly, minocycline did not provide remained relapse-free at one year compared significant improvement to either clinical or with 60 percent of placebo patients. MRI outcomes. After re-branding this agent as Tcelna, a Another Phase III trial looking at new clinical trial initiative was launched in minocycline reported positive data in fall 2015. 2012. Tcelna is being studied in a Phase II trial This Canadian Phase III double-blind study in SPMS in the Abili-T study. 25 This is a placebo- began in 2009, and enrolled 142 individuals controlled two-year trial, evaluating brain with a first clinical demyelinating event, i.e., atrophy on MRI as the primary outcome, and clinically isolated syndrome (CIS). The delay in accumulation of sustained disability participants were randomized to oral as the secondary outcome. The trial has fully minocycline at 100 mg twice daily or to an enrolled 190 patients and data is expected in identical placebo. Treatment was continued for the second half of 2016. Tcelna has been up to two years, or until MS was confirmed. granted Fast Track designation by the FDA in Those receiving minocycline had a 44.6- SPMS. percent lower risk of conversion to MS at six months, and a 37.6-percent lower risk at 12 Tetracycline Antibiotics months, versus individuals taking a placebo. The tetracycline antibiotics, including The authors suggest that with the known minocycline and doxycycline, have safety and low cost of minocycline, this immunomodulatory and neuroprotective medication could be considered for the initial activities. They appear to decrease the treatment of individuals with a first clinical demyelinating event, particularly in geographic passage of lymphocytes across the blood-brain regions without access to approved disease- barrier. In 2009, a small double-blind, placebo modifying therapies. controlled Phase II trial of Copaxone plus minocycline showed favorable magnetic resonance imaging (MRI) data, with Statins minocycline decreasing gadolinium-enhancing Statins are oral medications that are most activity by 50 percent over a period of six commonly prescribed to lower cholesterol. months. A subsequent 24-month trial showed Current interest is based on a non-controlled a significant decrease in lesion activity and observational study (a study without a placebo clinical status. group) suggesting that the risk of developing In a larger study of 305 patients called new brain lesions was reduced by about half in RECYCLINE, minocycline was used as an add- patients with early forms of MS who were

20 RESEARCH UPDATE taking atorvastatin (Lipitor ®). However, a atrophy, and/or disability, in SPMS . three-year Danish study of patients with RRMS In the MS-STAT trial, 140 patients were failed to find any beneficial effect for randomized, and the simvastatin group had a simvastatin as an add-on therapy to Avonex. statistically significant benefit over the placebo The use of statins to lower cholesterol in group on the Expanded Disability Status Scale patients on interferons should be discussed (EDSS) at two years. The rate of brain atrophy with a healthcare professional to consider the was also decreased. This serves as a positive potential benefits versus risks. proof-of-principle project that may allow for a At the ECTRIMS Annual Meeting in fall larger trial, which can look at the clinical 2012, Chataway and colleagues presented the outcomes as the primary outcomes measure. results of the MS-STAT trial. 27 This Phase II As effective treatments for SPMS remain an study evaluated whether high-dose unmet need, and since these are readily simvastatin can slow the rate of whole-brain available drugs, this is an exciting possibility. Ways to Stay Informed Please visit MSAA’s recently redesigned and mobile-friendly website at mymsaa.org to access important and timely information about MS, including treatments and symptom management, as well as MSAA’s programs and services.

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MSAA 21 EXPERIMENTAL MEDICATIONS: NEW THERAPIES UNDER INVESTIGATION

New Therapies under Investigation involving the visual pathways (optic neuritis) to evaluate the drug’s effect on remyelination. The earlier listing of approved and Results were presented in spring 2015. The experimental drugs is only a fraction of the primary outcome of RENEW was an many treatments currently being studied. assessment of recovery of optic-nerve function Some of the following are among the most measured by the speed at which the nerve exciting potential therapies under conducts visual signals. This was studied by investigation. These very brief snapshots of evaluating a test called Full Field Visual Evoked highly technical concepts will warrant more Potential (FF-VEP) in participants treated with in-depth explanations in the future, if pilot anti-LINGO-1, compared with placebo. clinical trials are encouraging. Patients who were treated with at least five of the six doses of anti-LINGO-1 showed Anti-LINGO: LINGO-1 itself is a protein in the a 34-percent improvement in optic-nerve central nervous system whose role is to halt conduction latency (delay in the speed of the myelination and prevent the survival of neurons. visual signal) at week 24, compared with The cells making up all organs in the body placebo. Further recovery in optic-nerve receive such “instructions” regarding when to conduction was observed at the last study grow and when to cease growing. Without visit (week 32), with a statistically significant these sorts of cellular “checks and balances,” tissues could grow without restraint, as seen in 41-percent improvement. Together, the data some malignancies. Anti-LINGO-1 (BIIB033) is demonstrate evidence of treatment effect with an agent with potential remyelinative continuous improvement observed 12 weeks properties, after animal studies showed that it following the last study dose. blocks this protein responsible for stopping the The study showed no effect on secondary growth of myelin. It was shown to promote endpoints, including change in thickness of spinal cord remyelination and axonal integrity the retinal layers (optic nerve neurons and in the animal model of MS (EAE). axons) as measured by optical coherence The first trials of experimental anti-LINGO tomography (OCT), or on visual function, to stimulate myelin repair – human Phase I measured by a test of vision called low- trials, 28 involving 64 healthy adult volunteers contrast letter acuity. Anti-LINGO-1 was and 42 people with relapsing or secondary- generally well-tolerated in this study, noting progressive MS – have been completed. In that two patients had hypersensitivity these trials, intravenous (IV) doses of anti- (allergic) reactions at the time of infusion, LINGO were well tolerated, and there were no and one patient had liver function test serious adverse events; headache was the most abnormalities, which resolved after drug frequent adverse event reported. discontinuation. Taken together, these results The first Phase II trial of anti-LINGO, provide an encouraging indication that anti- called RENEW, launched in 2013. 29 The study LINGO-1 appears safe and may facilitate recruited patients with newly-diagnosed MS remyelination, though meaningful clinical

22 RESEARCH UPDATE outcomes will need to be assessed in larger neurodegeneration (the breakdown of nerves). trials. This hypothesis would suggest that by blocking To that end, a second, larger Phase II trial certain channels in these cells, the buildup of (SYNERGY) 30 is looking at this drug in these molecules can be prevented and combination with Avonex. The study will neurodegeneration can also be prevented. This recruit approximately 400 patients with both strategy was tested and data presented in RRMS and SPMS, and will examine the degree 2013, 33 looking at the use of amiloride – a to which patients have an improvement in potassium-sparing diuretic approved for the disability with anti-LINGO. Since this agent treatment of high blood pressure and does not reduce relapses or prevent new MRI congestive heart failure. This medication may lesions, further studies with anti-LINGO, and have the potential to provide this other potential remyelination therapies, will neuroprotective activity. need to utilize new endpoints to prove The effect of amiloride was studied in efficacy. These include measurements of 14 people with PPMS using MRI markers recovery or improvement on physical, visual, of neurodegeneration as outcome measures cognitive, and other functional assessments of neuroprotection. Patients with PPMS of the effects of MS. underwent MRI scans before and during Results will provide clinical information amiloride treatment, at a standard dose used about this drug’s efficacy for neuroprotection for high blood pressure, for a period of three or repair within the central nervous system years. (CNS). The results will also address two Researchers found a significant reduction in fundamental questions: 1) Are the effects seen the development of brain atrophy, as well as a in the optic neuritis study replicable in other slowing of the development of disability during areas of the nervous system? And 2) Does this the treatment phase. This suggests that translate to improved function in patients with amiloride may exert neuroprotective effects in MS either in the short or long term? patients with PPMS. Because amiloride does Other experimental treatments under not readily cross the blood-brain barrier to gain investigation to potentially foster access to the CNS, the precise mechanism for remyelination or myelin repair include agents these results is not clear. This pilot study was in early stages of development – and still with the first effort in people with MS to focus on experimental names – such as GSK239512 31 neuroprotection using amiloride, and supports and rHIgM22 .32 Proof-of-principle data are further investigation of this drug as a potential expected for both of these agents in 2016. neuroprotective agent in MS. A Phase II trial studying this agent in optic Amiloride, Phenytoin, and Sodium Channel neuritis 34 was initiated in 2013 and data is Blockade: The accumulation of salt and expected in 2016. This study is similar in potassium within the cells of MS lesions may principle to the RENEW study of anti-LINGO-1 possibly contribute to cellular injury and as discussed above, as the attempt is to foster

MSAA 23 EXPERIMENTAL MEDICATIONS: NEW THERAPIES UNDER INVESTIGATION

protection and repair in the optic nerve in the Idebenone (Catena ® Sovrima ®): This acute phase after optic neuritis. experimental drug, similar to coenzyme Q10, It is worth noting that this strategy was was initially developed to treat Alzheimer’s successful in a study of the anti-seizure disease and other cognitive defects. Coenzyme medication phenytoin (brand name Dilantin ®), Q10 is produced within your own body and is which also works by modulating sodium necessary for cells to grow and remain healthy. channels. A Phase II clinical trial assessed This substance also works as an antioxidant, whether phenytoin could be neuroprotective helping to prevent injury from the oxidation in acute optic neuritis 35 (AON). The study process. It is being explored in MS because was comprised of 86 people with AON oxidative stress has been postulated to play randomized within two weeks of symptom a role in the death of myelin-producing cells, onset to receive either phenytoin (4 mg per kg which has been linked to MS progression. daily) or placebo for three months. The Oxidation is the body’s natural metabolism of primary outcome of this AON study was an oxygen. When disturbances occur in this evaluation of the structure of the retinal process, “oxidative stress” can result, causing nerve fiber layer (RNFL) and macular volume damage to the body’s cells and tissues. (MV) at six months. Visual function, optic- Oxidative stress is believed to be a contributing nerve imaging, and visual-evoked potentials factor in many diseases, including those were also measured. affecting the nerves and the immune system. Of the original 86 participants, 81 were A double-blind, placebo-controlled Phase followed to study end. In these patients, the I/II clinical trial of idebenone, 36 sponsored by average adjusted affected eye RNFL thickness the National Institute of Neurological at six months was higher in the active group Disorders and Stroke, recruited participants versus placebo, resulting in a 30-percent with PPMS who had little to moderate protective-treatment effect. Adjusted MV disability. The trial began in July 2009 and is (macular volume) showed a 34-percent scheduled for completion in September 2016, protective-treatment effect. Vision generally with an extension trial continuing through recovered well, with no significant difference 2018. in visual outcomes between the treatment groups. MIS416: This “therapeutic vaccine” is a potent This intriguing study may have broad activator of the innate immune system, which implications, as it found that the administration provides immediate defense against infection of a well-known, relatively safe drug seemed but does not result in long-lasting or protective to be neuro-protective in the period di rectly immunity. As a side note to help explain this following optic neuritis. Both amiloride and type of immune-system defense, the “innate” phenytoin may also represent potential or “natural” immune response is nonspecific. It combination strategies in conjunction with does not have any type of memory, and reacts immune-modulating, disease-modifying therapies. in the same way each time it encounters a

24 RESEARCH UPDATE foreign entity, such as a virus or bacteria. IL-17 Modulators: (AIN457) and MIS416 has been primarily tested in cancer CJM112. IL-17 is one of several cytokines and acquired infections, with the goal of produced by the immune system. Cytokines enhancing the inherent capability of a person’s are small proteins that may stimulate or inhibit immune system to fight disease. the function of other cells. IL-17 appears to be A Phase I/II study to evaluate the safety and a major inflammatory component in MS. tolerability of IV-administered MIS416 in Secukinumab is a humanized monoclonal people with either PPMS or SPMS presented antibody to IL-17. A preliminary study 39 interim results in 2012. This open-label, dose- administered AIN457 by intravenous infusion escalation/confirmation trial showed MIS416 to a very small number of patients with to be well-tolerated and identified a clinical dose psoriasis, rheumatoid arthritis, and uveitis with for further evaluation. Moreover, during the variable results. A proof-of-concept trial in dose-confirmation portion of the study, eight RRMS 40 enrolled 73 patients and showed a of 10 patients with SPMS who were treated reduction in gadolinium-enhancing MRI lesions with MIS416 for 12 weeks showed some compared with placebo. 41 improvement. A further Phase II study 37 in A larger, Phase II trial was planned to enroll SPMS is planned to be completed in late 2016. approximately 380 patients with relapsing MS; the design of the study was presented at Transdermal Administration of Peptides: A ECTRIMS in fall 2013, but was cancelled in small Polish study of 30 individuals 38 with favor of the clinical development of CJM112, RRMS evaluated the efficacy and safety of which also targets IL-17 and is administered transdermal (skin patch) administration of two by subcutaneous injection. The design of the dose levels of three myelin peptides: MBP 85- Phase II trial was presented at ECTRIMS in the 99 , PLP 139-151 and MOG , versus placebo. In fall of 2015. To date, no individuals with MS the lower-dose group, which received 1 mg have received this experimental treatment. each of the three peptides, the annual relapse rate at one year was reduced by 65 percent SB-683699 (firategrast) is an oral agent compared with placebo. Progression, as thought to reduce the number of active white measured by the Expanded Disability Status blood cells entering the brain. It works via a Scale (EDSS), was slightly lower, indicating that similar mechanism to Tysabri. It had positive disability did not worsen, and may have slightly results in a Phase II trial 42 using gadolinium- improved. Additionally, 56 percent were enhancing lesions as the primary outcome. relapse-free versus 10 percent in the placebo group. The treated group also showed a ATL1102 is an oral agent that affects the VLA- decrease in gadolinium-enhancing lesion 4 system, the same molecular mechanism volume and T2-lesion volume. The treatment utilized by Tysabri. It does so via a novel was safe and well-tolerated. This approach of mechanism of action, and falls into a class of using a combination of peptides may be “antisense oligonucleotides” not previously pursued in future studies. used in MS. The results of a Phase II trial were

MSAA 25 published in 2014 43 , noting that ATL1102 and both drugs have similar immuno- decreased the emergence of new active brain suppressive properties in animal studies. lesions as compared with placebo, after only However, the authors state that pixantrone two months of treatment in approximately 70 is less toxic to the heart. RRMS patients. As of 2015, the development path for this agent is still being considered. SR-CRH-01 is a stabilized, neuropeptide, also known as Aimspro ®. In a Phase II Pixantrone (PIX) is under investigation as an double–blind, placebo-controlled study alternative for the effective but cardio-toxic of 20 people with SPMS presented in 2014, 46 drug Novantrone ® (mitoxantrone or MIX) in SR-CRH-01 was well-tolerated when given the treatment of aggressive RRMS or SPMS . by subcutaneous injection twice weekly In a Phase I/II study of 18 patients with for four weeks, resulting in significant aggressive disease, results presented in 2014 44 improvements in several secondary endpoints. showed that pixantrone was as effective as These endpoints included the MS Functional Novantrone, but with less cardiotoxicity. Composite (MSFC), the Timed 25-Foot Walk Although via a different mechanism of action (T25-FW), and the mean 9-Hole Peg Test than rituximab and ocrelizumab, pixantrone (9-HPT). Larger, longer-term studies are was shown in this study to reduce B cells by warranted given these promising results. 95 percent. According to the study abstract, 45 However, no new trials are presently being pixantrone is structurally similar to Novantrone conducted.

26 RESEARCH UPDATE NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

Vitamins and Electrolytes IL-17, stopping its production. This study also demonstrates that Vitamin D increases Vitamin D3 suppressive T cells that combat inflammation. Vitamin D is a type of hormone and a An important longitudinal cohort study powerful mediator of immune function. The presented in 2012 by Mowry and colleagues 49 data documenting an association between low found that in people with MS, each 10 ng/ml Vitamin D and high MS risk, relapses, disability, higher Vitamin D level was associated with a and CNS inflammation now appear to be 15-percent lower risk of a new T2 lesion, and strong, consistent, and reproducible. 47 Data a 32-percent lower risk of a gadolinium- from a number of areas of investigation enhancing lesion. Higher Vitamin D levels were suggest that Vitamin D may be one underlying associated with lower, but not statistically common factor that begins to make sense of significant, relapse rates. While this was not a the large amount of data on the geographic randomized treatment trial, it suggests that distribution of susceptibility to MS. higher levels of Vitamin D may exert a Genetically, a link appears to exist between changes in the genes involved in the synthesis protective role against MS-disease activity. of the Vitamin D hormone and the Vitamin D Similar data were presented in 2013, as hormone receptor, and the risk of developing researchers looked at how Vitamin D may play MS. The strongest genetic risk factor for MS is a role in MS development and disease activity a specific gene (HLA DRB1*1501), whose on a molecular level. The BENEFIT trial studied activity appears to be influenced by Vitamin D. the effects of Betaseron in patients with CIS. A study published in 2015 by Mokry and Blood samples were taken at various intervals, colleagues 48 provided new insights about along with MRIs. genetics and Vitamin D. This study identified This study found that individuals with four genetic variants, each correlated to a higher Vitamin D levels had lower numbers of lower Vitamin D level. Using these variants gadolinium-enhancing lesions. These and data obtained from the largest genetic individuals generally experienced less disease association study to date of MS, conducted by activity, and genes associated with these higher the International Multiple Sclerosis Genetics Vitamin D levels appear to be involved. Studies Consortium, the authors found a direct indicate that roughly 350 genes are relationship between the number of Vitamin “significantly associated” with MS activity, D-lowering variants that an individual had and and of these 350 genes, 155 are associated their risk for developing MS. with Vitamin D regulation. The authors of this In animal models of MS, Vitamin D was study explain that Vitamin D may directly and found to directly terminate the production of indirectly regulate gene expression in a manner disease-causing proteins, which may shed light that reduces MS activity. on the mechanism of Vitamin D in MS. When A number of new clinical trials, mostly using Vitamin D is given to mice with EAE (an animal Vitamin D as an add-on to existing therapies model of MS), it blocks the gene that encodes in Phase IV studies, are ongoing to assess if

MSAA 27 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

supplemental Vitamin D can exert such RRMS treated with Rebif. disease-modifying effects. To follow are The study participants were divided into examples of these types of investigations. two groups: one receiving Vitamin D3 100,000 Mowry and colleagues at Johns Hopkins IU twice monthly along with Rebif treatment, have initiated a multi-center clinical trial in and the other group receiving placebo along which patients with relapsing-remitting MS will with Rebif treatment. Its primary outcome receive high-dose (5,000 IU/day) or low-dose measure is a reduction in relapse rate. (600 IU/day) oral Vitamin D, in addition to Secondary outcome measures include: the Copaxone. 50 Patients will be evaluated for two time to a first documented relapse; the mean years, and the effect of high-dose Vitamin D number of relapses per subject per year; the supplementation on the rate of MS attacks as number of relapse-free patients after two well as on the number of new lesions and years of treatment; MRI measures of changes in brain volume on MRI will be progression and lesion load; and change in determined. This trial is presently enrolling, quality of life. The CHOLINE study began in with a goal of 172 participants, and is expected January 2010 and was completed in 2015, to run through June 2018. but results have not been reported. A Phase II study 51 investigated whether Please note that while no major safety Vigantol ® oil, a form of Vitamin D hormone issues have been reported with these larger supplement (cholecalciferol), provides any daily doses of Vitamin D3 (such as 5,000 to added benefit when given in conjunction with 10,000 IU/day), as with all medications and Rebif. The study had 348 participants and supplements, individuals should always consult began in February 2011. Primary outcome their physician before making any changes to measures are the mean change from baseline their treatment plan. in the total volume of T2 lesions at week 48 and the proportion of relapse-free subjects Biotin (MD1003) at week 96. Secondary outcome measures Biotin is a vitamin involved in key steps of include sustained disability progression, MRI energy metabolism and fatty acid synthesis, measures of disease progression, proportion of though most people think of it as being “good subjects free from disease activity at 96 weeks, for hair and nails.” Among other actions, biotin and changes in cognitive function. Although activates an enzyme in myelin synthesis. Using this study was completed in 2015, results are this hypothesis and building upon data from a not yet available. small, open-label pilot study, MD1003, a high- The French CHOLINE Phase II study 52 dose biotin preparation of 300 mg per day, was recruited 250 individuals with RRMS who were studied in a Phase III trial of patients diagnosed already receiving ongoing treatment with with SPMS or PPMS . (This dose is hundreds Rebif. The aim of this study was to evaluate the of times higher than what can typically be efficacy and safety of supplementary purchased as a supplement of this vitamin.) treatment with Vitamin D3 in people with In a relatively small study, 154 patients were

28 RESEARCH UPDATE randomized to high-dose biotin or placebo. Salt The primary endpoint of the study was An array of recent research ranging from defined as the proportion of patients who molecular studies to animal models and even improved at nine months, with a confirmation some preliminary human data, has implicated of the improvement at 12 months. levels of dietary salt – sodium chloride, or NaCl Improvement was defined as either a decrease – as potentially affecting MS outcomes. In in EDSS (Expanded Disability Status Scale) or research presented in 2013 53 , high dietary an improvement in T25FW (timed 25-foot salt was found to increase autoimmune neuro- walk) of at least 20 percent. inflammation by markedly boosting a Th17 The primary endpoint was met, with 12.6 helper T-cell-driven autoimmune response percent of patients in the MD1003 arm in EAE (an animal model of MS). Th17 is an showing an improvement of EDSS or T25FW immune-system cell (lymphocyte) involved at nine months and confirmed at 12 months, with the inflammation that causes damage compared to none of the patients in the placebo to the myelin and nerves with MS. This Th17- arm. The primary endpoint was supported by boosting property of dietary salt was also secondary analyses showing evidence for a seen in humans. decrease in the risk of disease progression. In a separate study, 54 higher-salt These numbers are encouraging, although it is consumption was associated with increased important to note that the decrease in disability clinical and MRI disease activity in people experienced by the MD1003 group, and the with MS. Seventy patients with RRMS were disease progression seen in the placebo group, followed over two years, tracking sodium were both so small, they would be virtually intake. This was in conjunction with clinical undetectable in clinical practice. MD1003 was and MRI assessment every three-to-six well-tolerated. The overall incidence of adverse months or at the time of relapse. Researchers events was similar across the two groups. found that individuals with high-sodium One patient treated with MD1003 died intake had 3.4-times greater odds of from suicide; however, this event was not developing a new lesion on the MRI, and on considered to be related to the drug. average, had eight more T2 lesions on MRI. These results suggest a possible therapeutic MS relapse rates were higher among those effect of high-dose biotin in progressive MS, with high-sodium intake as well. and merit further study. Noting that the dose of In 2015, many additional studies were biotin studied would require taking hundreds published showing a connection between salt of commercially available vitamin pills, it is not and MS. 55 Krementsov and colleagues fed generally recommended that patients begin high-salt and low-salt diets to three genetically such a regimen at the present time. Studies different groups of mice and compared their also need to determine if any toxic effects EAE disease course. The researchers showed could result from taking such high doses of that in certain strains of mice, high-salt diets this vitamin. led to worsening of EAE. Furthermore, in one

MSAA 29 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES strain of mice, this effect was gender-specific, Stem Cells occurring only in females. Because the Based on encouraging results from a variety investigators did not find an alteration in of studies, clinical trials are now starting to the Th1/Th17 ratio mentioned above, they postulated that the salt caused an increased enroll patients using three different broad permeability of the blood-brain barrier leading classes of stem-cell-based approaches. to attacks by the immune system. The first stem-cell approach is Two other studies were able to show a hematopoietic stem-cell transplantation change in immune cells after exposure to high- (HSCT) . Hematopoietic stem cells from the salt environments. Hafler and colleagues bone marrow are the common precursor cells showed changes in a cell type important for from which both red and white blood cells the regulation of the immune system called originate. The HSCT requires multiple steps. the “Treg” cell. The Treg cell is thought to play First, stem cells, which circulate throughout a key role in suppressing those cells that might the bloodstream, are collected by taking blood initiate autoimmune disease. The researchers from the patient. The stem cells are obtained found the effect of decreased Treg function by filtering the blood, while the other cells – both in individual cells exposed to high salt as especially the white blood cells that are well as in mice fed a high-salt diet. 56 responsible for MS attacks – are removed. Muller and colleagues looked at a different These stem cells are then set aside and type of immune cell that is important in MS: the preserved while a wiping out or “ablation” of macrophage. A macrophage is a type of white the immune system, typically with high-dose blood cell that works to ingest and destroy , occurs. foreign substances. In cells, they found that a This intensive course of chemotherapy certain type of macrophage was less able to destroys most blood cells as well as the bone block the autoimmune activities of damaging T marrow, where the blood cells are formed. cells in a high-salt environment. In mice, they Then, the patient’s own hematopoietic stem found that a high-salt diet led to decreased cells can be transplanted back into the blood, in abilities of macrophages to aid in wound an effort to completely “reset” the immune healing. system with the hopes of abolishing the The theory that salt may increase MS autoimmunity responsible for MS. inflammation remains to be proven, and One trial of this technique is the High-Dose interventional studies will need to be Immunosuppression and Autologous (stem- performed to establish causality. However, this cell) Transplantation for Multiple Sclerosis theory could have far-reaching practical (HALT MS) Study, for poor-prognosis MS. The dietary implications for individuals with MS. HALT Phase II study is being conducted in 25 patients with highly active RRMS who have failed conventional therapy. The two-year follow-up results of the HALT study were

30 RESEARCH UPDATE reported in 2013. 57 The treatment induced EDSS. In addition to the serious though profound immune suppression and a high rate expected side effects, including sepsis and of sustained remissions at two years. fever, a small number of patients experienced Further interim results covering three years other adverse events. These included a of the study were published in early 2015. 58 reactivation of herpes zoster in seven patients The trial found that 78 percent of the study and thyroid disease in four patients; no deaths subjects had no new disease activity. occurred in this trial. Treatment failed in five subjects, and two In 2015, Burt and colleagues published the deaths occurred; one attributed to MS results of a larger study, giving data on 123 progression and one secondary to asthma. patients with RRMS and 28 patients with There have been 130 adverse events that were SPMS who underwent HSCT over a 10-year 60 severe or life-threatening, most relating to low period. The study was open-label, meaning blood counts induced by the treatment that everyone in the study received the approach. There were two suicide attempts, treatment and thus there was no comparison neither completed, both in patients reported to group. The findings included a significant have an unremarkable history before the decrease in relapse rates and new MRI lesions. HSCT, meaning that neither had a history of Four-year data showed that 80 percent were psychological problems that might lead to relapse-free and 87 percent were free of suicide attempts. Study participants will be progression. Importantly, there was also a followed for five years in total to see how long significant improvement in disability scores for the benefits of this treatment may continue, those patients in which long-term data were and if the safety profile proves to be available. manageable. While the data from this study is Another study in Sweden published encouraging, it is important to point out the previously 59 found a high proportion of open-label nature of this study that may have patients with aggressive, relapsing forms of led to biased results. Also, this method of MS, were free from disease activity following treatment is not without risks. The HSCT. A group of 41 patients participated in administration of potent chemotherapy and this study. They had a mean annualized relapse the ablation of the bone marrow put a patient rate of 4.1 in the year preceding treatment, at risk for infections and other complications. which means that on average, these individuals In this trial, the main adverse events were with very active disease were each experiencing related to the development of thyroid disease four relapses in one year. and other autoimmune conditions. Infections With a mean average follow-up time of were not common, and those that did occur nearly four years (47 months) after receiving were not severe. Two cases of cancer occurred the HSCT procedure, 89 percent of participants post-transplant, but it is unknown if there was were relapse-free and 77 percent of participants any causal relationship with the HSCT. The had no disability progression, as measured by group that carried out this study is currently

MSAA 31 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

conducting a randomized trial of HSCT versus the commonsense notions about the potential standard MS therapies. uses of stem cells, is to utilize them for the A second type of stem-cell therapy utilizes purpose of directly regenerating myelin that mesenchymal stem cells. These cells can be has been damaged by MS. This approach derived from tissues other than bone marrow requires multiple, complex steps in order to be and do not require a “wiping out” of the successful. Techniques must be employed to: immune system for their use. In a Phase IIa harvest a patient’s stem cells; grow and study 61 , 10 patients with SPMS with multiply them; administer them to the patient; involvement of the visual system were infused ensure that they get into the central nervous with self-derived (autologous) mesenchymal system; ensure that they are not destroyed by stem cells. the body’s own immune system; ensure that The researchers found an improvement in they grow to become the correct type of cell visual function, as well as an improvement in (for instance, to restore myelin); and to ensure other laboratory and imaging measures of that they do not overgrow or cause damage to optic-nerve function. No serious adverse the nervous system. events or deaths occurred. Although the This approach to stem-cell therapy is being mechanism by which mesenchymal stem cells investigated in an open-label Phase I clinical exert their beneficial effects has not been fully trial 63 announced in fall 2013. This small, understood, these cells do not need to single-center trial of 20 patients with penetrate into the nervous system and grow at progressive MS has fully enrolled. The study the site of lesions, such as the optic nerve. The design involves infusing doses of stem cells results of this study were suggestive of a more harvested from the patients’ own bone marrow generalized neuroprotective effect; this effect directly into the cerebral spinal fluid (CSF), is discussed in the next section. typically done via lumbar puncture, repeatedly Multiple other Phase I or Phase II trials of over six months. mesenchymal stem cell therapies are currently As an open-label study, the primary either in the planning stages or recruiting, endpoint will be to determine the safety of this including a collaborative effort named approach. Potential subsequent investigations MESEMS. 62 MESEMS is an international group may pursue efficacy, determine optimal dose of eight independent study centers that have and route of administration, and identify created a shared study design in order to be patients most likely to benefit from this able to increase the power and significance of therapeutic approach. It is important to their results. The group plans to enroll 160 recognize that as an open-label, uncontrolled, patients in total, with the goal of obtaining the unblinded Phase I study, this project is at the data necessary to plan a more definitive Phase earliest stages of experimental, human III trial. research. It cannot, by its very design, provide A third approach to investigating stem-cell meaningful information about efficacy, despite therapy, and perhaps the one most in-line with what continued to be reported by the media.

32 RESEARCH UPDATE Biomarkers markers that will help determine who should be treated with that drug as well as how In medicine, the term “biomarker” refers to effective the drug is after therapy is begun. We anything that can be used as an indicator of a already utilize one type of blood test to help particular disease state; in effect, a biomarker predict ongoing therapeutic response – is a surrogate for the disease state. It often neutralizing antibodies to the interferons and refers to a protein measured in blood, whose Tysabri. A major goal of biomarker studies is to concentration reflects the severity or presence be able to decide which patient is most likely to of disease and/or that which can be used to respond to which therapy before it is started, measure therapeutic effectiveness. Many types so the decision about which medication to start of biomarkers are being researched in MS, and can be optimized. these are likely to grow in importance in the For example, current studies are showing coming years. that it may soon be possible to determine Although the term itself is relatively new, who might be a suboptimal responder to biomarkers have long been used in medicine. interferons, based on immune system-related For example, body temperature is a well- substances measured in the blood. Another known biomarker for fever, blood pressure study evaluated whether the type of cytokine helps determine the risk of stroke, and cholesterol levels are a biomarker and risk present prior to treatment with Copaxone indicator for coronary and vascular disease. might act as a biomarker to identify those Biomarkers are often seen as the key to the individuals with RRMS who are more likely to future of “personalized medicine.” This refers respond to immunomodulating treatments. to treatments that can be individually tailored It showed that people who responded to to specific patients for highly efficient Copaxone secreted higher levels of specific intervention in disease processes. inflammatory cytokines prior to treatment. The concept of personalizing MS care has A genetic study, with results reported in been implemented in a general way by the use 2012, looking at the response to Copaxone, of disease-modifying therapies based on also suggested that multiple genetic markers someone’s clinical course – CIS, RRMS, SPMS, may predict a favorable response to this PRMS, or PPMS – categories entirely based on medication. A further study of genetic a patient’s clinical history. This approach has predictors of response to Copaxone was been refined as clinicians may recommend presented at ECTRIMS in fall 2014 64 and “more aggressive” therapies based on markers suggested that a particular array of genetic of disease severity (such as MRI lesions), as markers could accurately predict a high well as on demographic factors that may be response to Copaxone. This investigative concerning for a more difficult disease course. procedure is to be evaluated in further studies. The search for biomarkers of MS is referred An additional use of biomarkers will be to to throughout this publication, and studies are predict and minimize the risk of medication- ongoing with all major MS drugs to find related adverse events. This approach has

MSAA 33 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

already proved effective for new infectious involved in interferon regulation and signaling; biomarkers, such as the development of a a subgroup of patients with a higher risk for blood test for JC virus antibodies, to identify relapses showed a different expression of who is at greater or lesser PML risk when specific genes. treated with Tysabri. Based on this blood test, An ongoing clinical trial sponsored by the the option of using Tysabri can be more National Institutes of Health (NIH) is studying precisely personalized to maximize the more than 1,000 people with RRMS who benefit/risk ratio for this medication in participated in the CombiRx study. This study practice. This type of biomarker strategy may includes patients on Avonex only, Copaxone also prove useful in predicting the risk on an only, or a combination of both. Samples of individual basis of non-infectious adverse serum and white blood cells are being obtained events to certain investigational medicines. from each patient prior to the study and at A strong link exists between biomarkers regular intervals thereafter. and genetics, and the line between them may Although Copaxone and Avonex did not sometimes appear blurred. This is because differ greatly in their efficacy in the CombiRx many of the biomarkers that are being trial, certainly both drugs work well for some discovered relate to the activity of specific and less well for others. This study aims to genes that code for proteins involved in identify biomarkers (genes and the proteins inflammation, or are otherwise linked to the they encode) and link them to clinical- and response to disease-modifying therapies. MRI-based outcomes, such as the extent of Studies of the gene expression signature, inflammation and rate of disease progression. through global gene expression analysis, It will examine how biomarkers may be related reveals the pattern of the entire DNA in an to disease development and progression, as individual. This type of study has become well as differences among patients’ symptoms possible due to recent advances in high-speed and response to treatment. Based on these genetic pattern analysis. genetic biomarkers, likely best-responders to For example, genes found to be expressed either form of therapy can be identified. differently in MS effectively become biomarkers for disease progression and may change as the Genetic Studies result of treatment. A recent study identified several candidate genes that could potentially There has been a growing body of evidence serve as biomarkers of interferon treatment or for the genetic component in MS. The studies targets for treatment in MS. on biomarkers have arisen as the result of this Additionally, a study using gene-expression work, and a number of genes that are linked to analysis of whole blood showed significant the development of MS have been identified. differences in expression profiles of patients This field of research saw a major break- with optic neuritis versus healthy controls. through in August 2011, when the journal Another study showed that interferon Nature published the results of the largest MS therapy induces the expression of genes genetics study ever undertaken. 65 A global

34 RESEARCH UPDATE collaboration of scientists identified 29 new presented in spring 2015. Each subject genetic variants associated with MS, and submitted saliva for targeted genotyping and confirmed 23 others that had been previously completed questionnaires online to capture associated with the disease. The study demographics and risk factors. For each subject, confirmed that the immune system plays a a weighted genetic and environmental risk score major role in the development of MS: most of (GERS) was calculated. This score included 64 these genes are related to immune function, genetic variants, as well as gender, whether or and more than one-third of them have not he or she had infectious mononucleosis, previously been confirmed to be associated and if the person has a history of smoking. with other autoimmune diseases, such as By leveraging patient-advocacy groups and Crohn’s disease and type 1 diabetes. social media, the GEMS investigators were able The study involved nearly 10,000 people to recruit more than 2,600 first-degree with MS and more than 17,000 controls relatives of people with MS from across the without MS, taking place in 15 countries. The United States. In an analysis of the initial 1,696 research was carried out by approximately 250 subjects (1,583 without symptoms and 113 investigators. The results are now to be with MS at enrollment), investigators found confirmed and expanded in a second, large- that 27 percent of the individuals with MS and 25 percent of the asymptomatic subjects have scale study. The team found that a large a history of infectious mononucleosis, both number of these genes are related to T-cell doubling that of the general population. This function; they were mainly associated with higher proportion of infectious mononucleosis T-cell activation and proliferation. This was in asymptomatic family members is not particularly important because these are the attributable to known MS-genetic susceptibility. cells believed to be the major mediators of the MS subjects have a significant excess of current early immune attack on the brain and spinal smokers than asymptomatic subjects. Four out cord in MS. Two of the genes are linked to of the initial 1,583 asymptomatic subjects Vitamin D, and low Vitamin D levels have developed MS after enrollment, providing an already been implicated as a risk factor for incidence estimate (123 cases per 100,000 developing MS. As noted earlier, more than first-degree relatives annually), which is one-third of the genes are associated with significantly higher than the incidence of other autoimmune diseases such as Crohn’s sporadic MS in the United States. The average disease and type 1 diabetes; MS is believed to follow-up duration of the study was two years. be an autoimmune disease as well. The GEMS study highlights the role of Investigation of MS prevention requires electronic communication, e.g., using social early identification and understanding of the media and web-based questionnaires, in rapid incidence in a high-risk population. The Genes and large-scale subject recruitment of first- and Environment in Multiple Sclerosis (GEMS) degree relatives. It also provides a first project has a goal of early detection in first- estimate of the incidence of MS among this degree relatives of MS patients. Data were high-risk population, critically informing the

MSAA 35 NEW DIRECTIONS IN MS RESEARCH: NEW THERAPEUTIC APPROACHES

design of a prospective study of high-risk course and phenotype, disease-modifying family members. Identification of patients therapy, and diet. The MSMC has successfully at the highest risk for MS may lead to implemented IRB-approved protocols to opportunities for intervention before the recruit MS patients and controls, as well as to condition becomes clinically apparent. process and analyze their blood and stool These and other genetics studies do not as samples. yet significantly improve our ability to provide Initial results show significant genus-level genetic counseling to individuals concerned differences in the microbiomes of patients about their risk of developing MS. However, treated with Copaxone compared to untreated they should help researchers to better define subjects. Female patients taking Copaxone the biological pathways that lead to the showed significant enrichment of members of development of MS, and may allow us to the Enterobacteriaceae family of bacteria, design better treatments for early MS. compared to gender-matched controls who were not taking Copaxone. Geographical The Microbiome and MS differences were noted as well. Strikingly, when transferred into germ-free The vast collection of organisms that mice, gut microbiota from an MS patient inhabit the human gut, the microbiome, has resulted in more severe EAE (an animal model been demonstrated to influence immune of MS)than microbiota from a healthy control. responses and modulate susceptibility to This may be the most intriguing result from this chronic diseases. Recent studies have related project to date. Observed differences between gut dysbiosis (an imbalance of bacteria) to cases and controls suggest a biological effect Crohn’s disease, type 1 diabetes, obesity, and and warrant further investigation, as do effects autism. Additionally, animal model work of geographic, demographic, and dietary suggests an important role in MS. factors. Study of the human microbiome has The Multiple Sclerosis Microbiome the potential to yield important insights in Consortium (MSMC) is a multi-disciplinary understanding the basic processes underlying collaboration composed of two translational the disorder of MS as well as possible MS Centers (Mount Sinai and UCSF). Together, treatment strategies. they have initiated a microbiome-oriented A separate study of microbiome in MS basic/experimental program and sequencing/ looked at differences in Vitamin D levels bioinformatics program. The MSMC is predicting alterations in gut bacteria. Analysis currently analyzing hundreds of samples by of 43 subjects showed increased abundance of bacterial DNA sequencing aimed at identifying a type of helpful bacteria called group differences at the genus-level (a genus is Ruminococcaceae in untreated MS patients a group of related animals or plants that with a serum Vitamin D level above 40 ng/ml, includes several or many different species 66 ). versus patients with a Vitamin D level below 40. Tracked variables include demographics, body The authors conclude that high levels of mass index (BMI), medical history, MS clinical Vitamin D in untreated MS patients are

36 RESEARCH UPDATE associated with increased amounts of amounts of Ruminococcaceae might be linked Ruminococcaceae in the gut. This has to increased inflammation in MS. Further relevance to MS, as a decreased amount of studies are underway to explain the Ruminococcaceae has previously been mechanism by which Vitamin D regulates the associated with Crohn’s disease. Hence, lower composition of the microbiota in MS.

CLOSING NOTES In summary, the future of disease- Despite the setback of unsuccessful trials modifying therapies (DMTs) for MS continues in progressive MS, ongoing clinical trials to be promising, both in terms of new in both PPMS and SPMS , as well as information about currently approved DMTs investigations into neuroprotection, and exciting results for emerging therapies. remyelination, and repair, offer great promise Advances in genetic and biomarker studies for the treatment of progressive MS and the hold the promise that, in the future, it will be goal of reversing the damage caused by this possible to personalize the decisions about disease. In recent years, our arsenal of MS MS therapy in a precise, biologically-driven therapies has grown considerably, with more manner. on the way. Along with these new therapies More than ever, the field of MS research come a host of new challenges and risks, relies upon the willing participation of patients which will require vigilance and a thoughtful in clinical trials. We now recognize how approach to medication selection and ethnically, racially, genetically and culturally management. diverse the MS community is, but diversity in As clinicians have more numerous and our clinical trial populations is lacking. In 2015, more complex treatment options to offer data from six randomized, placebo-controlled patients, the need for patient education and trials were used to examine the baseline awareness has become more crucial. Now characteristics and clinical outcomes in white, more than ever is the age of empowered, black, Asian, and Hispanic populations. The highly-informed patients, who can be true results were challenging to interpret due to participants in their MS care in collaboration the incredibly low number of non-white with their treatment team. We hope this participants in clinical trials, which in turn update is a valuable part of that process. makes our clinical trial results hard to For more information about clinical trials , interpret in the real world. The field of MS please visit www.clinicaltrials.gov . For more research needs a diverse population recruited information about MS and its treatments, into clinical trials if we are to truly know that please contact MSAA at (800) 532-7667 , our medications are globally effective in MS. or visit mymsaa.org .

MSAA 37 ABOUT TRIAL PHASES

Trial Phases for Investigating Drugs and Treatments

Every approved treatment for MS has better?”) is impossible. undergone extensive study prior to receiving In addition, MS varies over time, even approval by the United States Food and Drug within the same person. He or she may Administration (FDA). The process of testing experience “good days” and “bad days,” as a new drug therapy for MS is time-consuming, well as actual MS relapses that last for days to and all drugs must undergo several phases of weeks and even months. Symptoms may investigation in order to be deemed both safe persist from previous relapses, and other and effective. effects, such as fatigue, stiffness, and pain, Before a pharmaceutical company can are difficult to study. initiate testing in humans, it must conduct Choosing what outcome to study is extensive preclinical or laboratory research. another challenge to MS research design. This research typically involves years of Some of the most commonly studied include: experiments in animal and human cells, to number of relapses; time to next relapse; develop compounds that have the desired number of new lesions seen on MRI; and biological effect. Once such a drug is cumulative disability (as measured by the developed, it is often tested on animals EDSS). “EDSS” refers to the Kurtzke before human studies can even begin. The Expanded Disability Status Scale, which uses clinical testing of experimental drugs is numbers from one to 10 to measure degree normally done in three phases, with each of disability, largely in terms of mobility. successive phase involving a larger number of All of these variables take time to assess. people. Sometimes fourth-phase trials are In general, several years of research are conducted after approval for additional data needed for an MS drug to even begin Phase on effectiveness and adverse events over a III testing. Once begun, Phase III trials longer period of time. require several months to enroll, often two MS poses a specific set of challenges for years to conduct, and another year for the clinical research. It is a highly-variable results to be fully analyzed and published. condition that affects everyone differently. Obtaining FDA approval after studies are Choosing the correct population of MS complete usually takes the better part of a patients to study poses formidable year as well. The standards for proving that a challenges to clinical research, and is a drug is safe for patients and proven effective major reason why accurately comparing against MS are incredibly high, and many the results of different MS drug trials (in years of work are necessary to meet these order to answer the question “which drug is standards.

38 RESEARCH UPDATE PHASE I: Phase I studies are primarily In multiple sclerosis (MS), Phase II concerned with assessing the drug’s safety. trials frequently use disease-activity This initial phase of testing in humans is done measurements determined through MRI in a small number of healthy volunteers, and scans (such as new lesions or gadolinium- is designed to determine what happens to the enhancing lesions) as the primary outcomes. drug in the human body – how it is absorbed, MRI scans are used because this sort of data metabolized, and excreted. can be obtained more quickly and with Phase I trials are referred to as “open fewer patients versus determining clinical label” and “unblinded,” because everyone – outcomes, such as relapse rates or the patient, medical staff, and investigators – permanent disability. Only about one-third knows the drug and dose that each of experimental drugs successfully complete participant is receiving. A Phase I study will both Phase I and Phase II studies. investigate side effects that occur as dosage levels are increased. Phase I trials can take PHASE III: In a Phase III study, a drug is several months to one year to complete. usually tested in several hundred to several thousand patients, usually in multiple medical PHASE II: Once a drug has been shown to be facilities around the world. Phase III studies safe, it must be tested for efficacy. This typically last two or more years. This large- second phase of testing may last from several scale testing provides the pharmaceutical months to two years, and involve up to company and the FDA with a more thorough several hundred patients. Phase II studies understanding of the drug’s effectiveness, are often “double-blinded,” meaning that the benefits, and the range of possible adverse participants, medical staff, and investigators reactions. are not told who is receiving the drug and Most Phase III studies are randomized who is receiving the placebo. and blinded trials. Only after a Phase III These studies are also “randomized,” so study is successfully completed can a that participants are assigned to treatment pharmaceutical company request FDA groups (or “treatment arms”) based on approval for marketing the drug. chance. One group of patients receives the experimental drug, while a second “control” PHASE IV: Phase IV clinical trials are group will receive a standard treatment or conducted after a drug has been approved. placebo. In this manner, the study can provide Participants are enrolled to further monitor information to the pharmaceutical company safety and side effects, while evaluating and the FDA about the relative safety of the long- term efficacy. new drug, and its effectiveness.

MSAA 39 APPROVED LONG-TERM TREATMENTS FOR MS

Self-Injected Medications

NAME AND HOW SIDE EFFECTS ADDITIONAL NOTES TYPE OF DRUG ADMINIS TERED

Avonex ® Flu-like symptoms 30 Side effects may be prevented and/or (Interferon beta-1a) and headache, micrograms managed effectively through various immune system blood count and taken via treatment strategies; side effect problems modulator with liver test weekly are usually temporary. Blood tests may be antiviral properties abnormalities intermuscular given periodically to monitor liver injection enzymes, blood-cell counts, and neutralizing antibodies.

Betaseron ® Flu-like symptoms, 250 Side effects may be prevented and/or (Interferon beta-1b) injection-site skin micrograms managed effectively through various immune system reaction, blood taken via treatment strategies; side effect problems modulator with count and liver test subcutaneous are usually temporary. Blood tests may be antiviral properties abnormalities injection given periodically to monitor liver every o ther enzymes, blood-cell counts, and day neutralizing antibodies .

Copaxone ® Injection-site skin 20 (daily) Systemic reactions occur about five to 15 (glatiramer acetate) reaction as well as or 40 (three minutes following an injection and may Synthetic chain of an occasional times weekly) include anxiety, flushing, chest tightness, four amino acids systemic reaction - milligrams dizziness, palpitations, and/or shortness of found in myelin occurring at least taken via breath. Usually lasting for only a few (immune system once in subcutaneous minutes, these symptoms do not require modulator that approximately 10 injection specific treatment and have no long-term blocks attacks on percent of those negative effects. Copaxone was originally myelin) tested approved at a dose of 20 milligrams daily, but in January 2014, a new dose of 40 milligrams three times weekly was approved by the FDA. The original 20-milligram daily dose remains available, so patients and their doctors may now choose their preferred dosing regimen. Extavia ® Flu-like symptoms, 250 Side effects may be prevented and/or (Interferon beta- injection-site skin micrograms managed effectively through various 1b) immune system reaction, blood taken via treatment strategies; side effect problems modulator with count and liver test subcutaneous are usually temporary. Blood tests may be antiviral properties abnormalities injection given periodically to monitor liver every o ther enzymes, blood-cell counts, and day neutralizing antibodies .

40 RESEARCH UPDATE Self-Injected Medications

NAME AND HOW SIDE EFFECTS ADDITIONAL NOTES TYPE OF DRUG ADMINIS TERED Glatopa™ Using study results 20 milligrams Using study results from trials with (glatiramer acetate) from trials with taken daily via Copaxone, systemic reactions occur about As a generic version Copaxone, side subcutaneous five to 15 minutes following an injection of Copaxone, effects include injection and may include anxiety, flushing, chest Glatopa is a injection-site skin tightness, dizziness, palpitations, and/or synthetic chain of reaction as well as shortness of breath. Usually lasting for only four amino acids an occasional a few minutes, these symptoms do not found in myelin systemic reaction - require specific treatment and have no (immune system occurring long-term negative effects. modulator that at least once in blocks attacks on approximately 10 myelin) percent of those tested with Copaxone

Plegridy ® Flu-like symptoms, 125 Side effects may be prevented and/or (Interferon beta- injection-site skin micrograms managed effectively through various 1a) immune system reaction, blood taken via treatment strategies; side effect problems modulator with count and liver test subcutaneous are usually temporary. Blood tests may be antiviral properties abnormalities injection once given periodically to monitor liver every two enzymes, blood-cell counts, and weeks neutralizing antibodies.

Rebif ® Flu-like symptoms, 44 Side effects may be prevented and/or (Interferon beta- injection-site skin micrograms managed effectively through various 1a) immune system reaction, blood taken via treatment strategies; side effect problems modulator with count and liver test subcutaneous are usually temporary. Blood tests may be antiviral properties abnormalities injection given periodically to monitor liver three times enzymes, blood-cell counts, and weekly neutralizing antibodies.

MSAA 41 APPROVED LONG-TERM TREATMENTS FOR MS

Infused Medications

NAME AND HOW SIDE EFFECTS ADDITIONAL NOTES TYPE OF DRUG ADMINIS TERED

Lemtrada ® Common side effects Lemtrada is Adverse events from Lemtrada can (alemtuzumab) include rash, itching, given for a include infusion reactions to the Humanized headache, pyrexia course of five medication, an increased risk of infection, monoclonal (increase in temper - days via emergent autoimmune diseases, a antibody that ature), nasopharyn - intravenous potentially severe bleeding disorder called rapidly depletes or gitis (inflammation (IV) infusion immune thrombocytopenic purpura (ITP), suppresses immune of the nose and and followed and an increased risk of malignancies system cells (T and throat), nausea, di - one year later including thyroid cancer, melanoma and B cells), which can arrhea and vomit - by a second lymphoproliferative disorders. For early damage the myelin ing, insomnia, three-day detection and management of these risks, and nerves of the numbness/tingling, course. Lemtrada is only available through a central nervous dizziness, pain, restricted distribution program, the system (CNS). flushing, and infec - Lemtrada REMS (Risk Evaluation and tion. Mitigation Strategy).

Novantrone ® Side effects include IV infusion Novantrone carries the risk of cardiotoxic - (mitoxantrone) nausea, thinning once every ity (heart damage) and leukemia; it may not Antineoplastic hair, loss of three months be given beyond two or three years. People agent (immune menstrual periods, (for two to undergoing treatment must have regular system modulator bladder infectio ns, three years testing for cardiotoxicity, white blood cell and suppressor) and mouth sores; maximum) counts, and liver function. Because of the additionally, urine potential risks, Novantrone is seldom pre - and whites of the scribed for individuals with MS. Anyone tak - eyes may turn a ing Novantrone now or given Novantrone bluish color previously needs to have annual evaluations temporarily of his or her heart function, even if no longer receiving this medication.

Tysabri ® Headache, IV infusion Risk of infection (including pneumonia) (natalizumab) fatigue,depression, every four was the most common serious adverse Humanized mono - joint pain, weeks event during the studies (occurring in a clonal antibody (in - abdominal small percentage of patients). The hibits adhesion discomfort, and TOUCH Prescribing Program monitors molecules; thought infection patients for signs of PML, an often-fatal to prevent damag - viral infection of the brain. Risk factors for ing immune cells PML include: the presence of JC virus from crossing the antibodies, previous treatment with blood-brain barrier) immunosuppressive drugs, and taking Tysabri for more than two years.

42 RESEARCH UPDATE Oral Medications

NAME AND HOW SIDE EFFECTS ADDITIONAL NOTES TYPE OF DRUG ADMINIS TERED

Aubagio ® Headache, elevations 7- or 14- More severe adverse events include the (teriflunomide) in liver enzymes, hair milligram risk of severe liver injury and the risk of Immunomodulator thinning, diarrhea, tablet taken birth defects if used during pregnancy. A (affecting the nausea, neutropenia orally, once TB test and blood tests for liver function production of T and (a condition that re - per day must be performed within six months prior B cells; may also duces the number of to starting Aubagio, and liver function inhibit nerve certain white blood must be checked regularly. If liver damage degeneration) cells), and paresthe - is detected, or if someone becomes sia (tingling, burning, pregnant while taking this drug, or numbing sensa - accelerated elimination of the drug is tion) prescribed.

Gilenya ® Headache, flu, 0.5-milligram Adverse events include: a reduction in heart (fingolimod, diarrhea, back pain, capsule taken rate (dose-related and transient); infrequent FTY720) abnormal liver tests orally once transient AV conduction block of the heart; a S1P-receptor and cough per day mild increase in blood pressure; macular modulator (blocks edema (a condition that can affect vision, potentially caused by swelling behind the eye); damaging T cells reversible elevation of liver enzymes; and a from leaving lymph slight increase in lung infections (primarily nodes) bronchitis). Infections, including herpes infection, are also of concern. A six-hour observation period is required immediately after the first dose, to monitor for cardiovascular changes. Tecfidera ® Flushing and 240-milligram Other adverse events include mild or (dimethyl fumarate) gastrointestinal tablet taken moderate upper respiratory infection, Immunomodulator events; reduced twice daily pruritus (chronic itching), and erythema with anti- white-blood cell (skin redness or rash). In studies, the only inflammatory (lymphocyte) serious adverse events to occur in two or properties; may counts; elevated more patients taking Tecfidera was have liver enzymes in gastroenteritis (an inflammation of the neuroprotective small percentage of lining of the intestines) and gastritis (an effects, potentially patients inflammation of the stomach lining). protecting the Reduced white-blood cell (lymphocyte) nerves and myelin counts were seen during the first year of covering from treatment. Liver enzymes were elevated in damage 6 percent of individuals taking Tecfidera, compared to 3 percent on placebo.

MSAA 43 REFERENCES

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56 multiple sclerosis.” Nature . 2011 Aug 10;476(7359):214-9. doi: Hernandez AL, et al. “Sodium chloride inhibits the suppressive 10.1038/nature10251. function of FOXP3+ regulatory T cells.” J Clin Invest. 2015;125(11):4212-4222. doi:10.1172/JCI81151. 66 Definition according to Merriam-Webster.

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