NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Emerging Therapies for Relapsing Multiple Sclerosis

Jeffrey A. Cohen, MD

ix agents are currently approved by regulatory agencies to treat relapsing multiple sclerosis. Although these agents are effective and generally safe, some patients have continued disease activity or adverse effects. A sizable number of new agents are under investigation currently. This article reviews emerging agents that have shown promiseS in phase 2 trials. Arch Neurol. 2009;66(7):821-828

Six agents are approved by regulatory agen- phase 2 study results (Table 2 and cies to treat relapsing multiple sclerosis Table 3). (MS). First-line agents include beta-1b, intramuscular or subcutaneous in- MS TREATMENT AGENTS terferon beta-1a, and glatiramer acetate. Piv- otal trials and postmarketing experience support the efficacy, tolerability, and safety of these agents. However, all have modest Alemtuzumab is a humanized monoclo- efficacy for patients as a group and are ad- nal (mAb) directed against the sur- ministered by injection. Two agents, mi- face CD52, which is expressed by toxantrone and , are more po- T cells, B cells, monocytes, natural killer tent and generally well tolerated but cells, macrophages, eosinophils, and sper- typically are second line because of poten- matozoa. Intravenous administration pro- tial safety concerns. In addition, some pa- duces rapid, profound, and prolonged lym- tients treated with interferon beta or na- phopenia via complement-mediated lysis talizumab develop neutralizing and antibody-dependent cellular cytotox- that abrogate efficacy. icity. T cells recover for 16 months, while Multiple sclerosis treatment priorities B cells recover for 3 to 6 months. Alemtu- include (1) better understanding of MS zumab is approved to treat B-cell chronic pathogenesis and heterogeneity to guide lymphocytic leukemia. development of better therapies and moni- Single-center pilot studies at the neurol- toring methods; (2) additional treatment ogy unit of the University of Cambridge options for relapsing-remitting MS (RRMS) demonstrated potent suppression of MS re- that are more effective, convenient, and/or lapses and lesion activity on magnetic reso- tolerable; (3) effective therapies for purely nance imaging (MRI) by alemtuzumab but progressive MS; (4) neuroprotective and no benefit on disability accrual in progres- repair strategies; and (5) more effective sive MS.1-3 A multicenter, randomized, treatments for common symptoms such evaluator-blind, active-comparator, phase as fatigue, pain, tremor, and cognitive 2 study enrolled 334 treatment-naïve par- impairment. Potential approaches to im- ticipants with early (onset within 36 months prove therapy in relapsing MS are sum- of screening and Expanded Disability Sta- marized in Table 1. This review summa- tus Scale [EDSS] score Յ3.0), active (Ն2 rizes emerging therapies for relapsing MS, relapses in the previous 2 years) RRMS.4 with a focus on agents with promising Participants were randomized 1:1:1 to re- ceive 44 µg of subcutaneous interferon Author Affiliation: Mellen Center for Multiple Sclerosis Treatment and Research, beta-1a thrice weekly or high-dose (24 mg Cleveland Clinic, Cleveland, Ohio. per day) or low-dose (12 mg per day) in-

(REPRINTED) ARCH NEUROL / VOL 66 (NO. 7), JULY 2009 WWW.ARCHNEUROL.COM 821

©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Potential Strategies to Improve Therapy Table 2. Parenteral Multiple Sclerosis Therapies of Relapsing Multiple Sclerosis With Positive Phase 2 Results

Address comorbidities Postulated Mechanism Potential Better use of existing agents Agent of Action Adverse Effects Initiate treatment early Alemtuzumab Anti-CD52 mAb, T- and Antibody-mediated Optimize dose B-cell depletion autoimmunity (Graves Reduce the incidence or titer of neutralizing antibodies disease and ITP), infection Distinguish responders/nonresponders Anti-CD25 mAb, IL-2R Cutaneous reactions, Customize therapy antagonist infection, autoimmunity Combination therapy Anti-CD20 mAb, B-cell Infusion reactions, cytokine Develop new therapies depletion release syndrome, infection (including PML) Dirucotide Soluble MBP-derived Infusion reaction, peptide, immune autoimmunity travenous alemtuzumab for 5 days at month 0, 3 days at tolerance month 12, and for some participants, 3 days at month 24. BHT-3008 DNA vaccine encoding Autoimmunity Coprimary outcome measures were EDSS progression sus- human MBP, immune tolerance tained for 6 months and relapse rate. There were no sig- nificant differences between results of the 2 alem- Abbreviations: ITP, immune thrombocytopenia purpura; mAb, monoclonal tuzumab doses. Alemtuzumab significantly reduced the antibody; MBP, myelin basic protein; PML, progressive multifocal rate of sustained disability progression vs interferon beta-1a leukoencephalopathy. (9.0% vs 26.2%; hazard ratio, 0.29; PϽ.001). Mean EDSS scores improved 0.39 points vs baseline scores in alem- Daclizumab tuzumab-treated participants compared with mean wors- ening of 0.38 points with interferon beta-1a (PϽ.001). The Daclizumab is a humanized mAb directed against IL- relapse rate was significantly reduced (0.10 vs 0.36; haz- 2R␣ (CD25) that is approved to treat acute renal allo- ard ratio, 0.26; PϽ.001). A significant benefit was dem- graft rejection. It was the third therapeutic mAb to be ap- onstrated for proportion of relapse-free participants, T2- proved, the first humanized mAb, and the first directed hyperintense MRI lesion volume change, and brain volume. against a cytokine receptor. Infusion reactions and cytokine release syndrome -2 is postulated to play a central role in MS (fever, headache, hypotension, malaise, and urticaria) oc- pathogenesis. The IL-2R␣–encoding gene was recently cur with alemtuzumab treatment initiation but can be at- identified in a whole-genome screen as an MS risk al- tenuated with concomitant administration of antipyretic, lele.7 Interleukin-2R blockade is effective in experimen- antihistamine, and corticosteroid drugs. Serious infusion tal autoimmune encephalomyelitis (EAE). Daclizumab reactions occurred in 1.4% of subjects treated with alem- blocks the binding of IL-2 to the high-affinity IL-2R and tuzumab in the phase 2 study.4 With prolonged lympho- subsequent IL-2–dependent T-cell and B-cell prolifera- penia, infection is a potential concern. In the phase 2 study, tion, a critical step in the generation and amplification infections were more common with alemtuzumab treat- of antigen-specific immune responses. It also leads to ment,4 but to date increased serious infection-related ad- down-modulation of IL-2R from the cell surface. Inter- verse effects have not been seen in the MS population. The estingly, studies in MS suggested that daclizumab’s clini- most significant adverse effect is antibody-mediated au- cal benefit was mediated through generation of CD56ϩ toimmunity. Thyroid disorders, particularly Graves dis- natural killer cells with regulatory effects.8 ease, occurred in up to 30% of alemtuzumab-treated pa- Two pilot studies in MS supported safety, tolerability, tients with MS in earlier studies5 and in 23% in a phase 2 and efficacy of intravenous daclizumab.9,10 A multicenter, study.4 In addition, immune thrombocytopenia purpura randomized, double-blind, placebo-controlled phase 2 study developed in 6 alemtuzumab-treated participants (2.8%) enrolled 230 participants with relapsing MS and contin- in a phase 2 study vs 1 participant treated with interferon ued activity despite treatment with interferon beta.11 Par- beta-1a (0.9%) and was fatal in 1 participant who did not ticipants continued to take interferon beta and were ran- seek medical attention. The other 5 participants recov- domized to receive 2-mg/kg subcutaneous daclizumab every ered with medical treatment. 2 weeks (n=75), 1-mg/kg daclizumab alternating with pla- Two randomized, evaluator-blind, 3-arm phase 3 trials cebo, or placebo for 24 weeks, with 48 weeks of subse- of alemtuzumab in early RRMS currently are enrolling quent follow-up. There was a 72% reduction (P=.004) in subjects.6 Both trials compare 12 mg of intravenous alem- the cumulative number of new gadolinium-enhancing tuzumab per day for 5 consecutive days at month 0 and (GdE) lesions on MRI scans during 6 months, the pri- 3 days at month 12 with 44 µg of subcutaneous inter- mary outcome measure, in the high-dose daclizumab group feron beta-1a thrice weekly; time to sustained disability and a nonsignificant trend in the low-dose group. There accumulation is the primary outcome measure. One phase was also a nonsignificant reduction of annualized relapse 3 study will enroll approximately 525 treatment-naïve rate, a secondary outcome measure. There was rapid on- participants, and another phase 3 study will enroll ap- set of action, rapid loss of efficacy with treatment discon- proximately 1200 participants with continued disease ac- tinuation, and no apparent rebound. The magnitude of ben- tivity while undergoing interferon beta or glatiramer efit on MRI was roughly comparable with that seen in acetate therapy. previous studies of monthly intravenous daclizumab.

(REPRINTED) ARCH NEUROL / VOL 66 (NO. 7), JULY 2009 WWW.ARCHNEUROL.COM 822

©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 Daclizumab was generally safe and well tolerated in the relatively short studies to date; long-term safety with chronic Table 3. Oral Multiple Sclerosis Therapies use needs to be determined. In the phase 2 study, the main With Positive Phase 2 Results adverse effects were cutaneous reactions and possibly in- Postulated Mechanism Potential creased severity of common infections. The overall inci- Agent of Action Adverse Effects dence of infection was similar in the daclizumab and pla- cebo groups, and there were no opportunistic infections. Purine analogue, Myelosuppression and lymphocytotoxic infection There were no malignancies or increase in interferon beta agent toxicity or incidence of anti–interferon beta–neutralizing Dimethyl fumaric Nuclear factor Hepatotoxicity antibodies. Although IL-2 plays a role in eliminating au- acid E2–related factor-2 toreactive T cells through activation-induced cell death and transcriptional ϩ pathway activator, maintenance of FoxP3 regulatory T cells, no autoim- immunomodulation mune phenomena were observed. The frequency and sig- Estriol Immunomodulation Vascular events nificance of anti-daclizumab antibodies need further study. Myriocin derivative, Lymphopenia, infection, In an ongoing multicenter, randomized, double-blind, S1P receptor bradycardia, placebo-controlled phase 2 study evaluating subcutaneous agonist/antagonist, increased airway altered lymphocyte resistance, macular daclizumabasmonotherapy,approximately297participants recirculation edema, with RRMS will receive 1 of 2 doses of subcutaneous da- hepatotoxicity clizumab or placebo every 4 weeks for 48 weeks.6 Roquinimex derivative, Hepatotoxicity, immunomodulation proinflammation Rituximab Minocycline Matrix None metalloproteinase inhibition Rituximab is a chimeric murine/human mAb directed Statins 3-Hydroxyl-3-methyl- Rhabdomyolysis, against CD20, a surface antigen expressed on pre–B cells glutaryl coenzyme A hepatotoxicity and mature B cells. Intravenous rituximab leads to rapid reductase inhibitor, depletion of circulating B cells by complement- immunomodulation Rapamycin analogue, Leukopenia, mediated lysis, cell-mediated cytotoxicity, and apopto- cell cycle inhibition thrombocytopenia, sis. Rituximab currently is approved to treat non- mucous membrane Hodgkin lymphoma and, combined with , ulcers to treat rheumatoid arthritis with an inadequate re- Dihydroorotate Pancytopenia, sponse to anti–tumor necrosis factor agents. dehydrogenase hepatotoxicity inhibitor (pyrimidine Although MS is traditionally postulated to be a – synthesis), inhibition mediated autoimmune disorder, several lines of evi- of T- and B-cell dence support involvement of B cells and humoral im- proliferation mune mechanisms, including intrathecal antibody production, autoreactive antibody in cerebrospinal fluid, Abbreviation: S1P, sphingosine-1-phosphate. complement deposition associated with vesicular my- elin disruption in MS lesions, and the presence of B cells probably due to B-cell lysis and cytokine release. The in perivascular cuffs and meningeal lymphoid follicles. infusion reactions rarely are severe with acute respira- However, the lack of CD20 expression by plasma cells tory distress syndrome, myocardial infarction, or ana- (the principal source of antibodies) and the rapidity of phylaxis. Concomitant corticosteroid administration the clinical and MRI response in MS (circulating anti- reduces these symptoms. In the phase 2 trial, rituximab bodies have a relatively long half-life) suggest that ritux- was associated with rapid circulating B-cell depletion imab benefit is not mediated by decreasing antibody ti- that remained nearly complete (Ͼ95%) until week 24, ters.12,13 Rather, these observations suggest that the initial with gradual partial return thereafter. Therefore, in- benefit results from loss of antigen presentation or pro- creased risk of infection is a potential concern. Most in- duction of proinflammatory mediators by B cells. fections were mild and occurred equally in treatment In a multicenter, randomized, double-blind, placebo- groups. No opportunistic infections were seen. How- controlled phase 2 trial, 104 participants with RRMS re- ever, progressive multifocal leukoencephalopathy was ceived 1000 mg of intravenous rituximab (n=69) or pla- reported in patients treated for malignancy, hemato- cebo (n=35) on days 1 and 5 and were followed up for 48 logic disorders, systemic lupus erythematosus, and weeks.14 Benefit favoring rituximab was demonstrated on rheumatoid arthritis, typically in the setting of con- the primary outcome measure, total GdE lesions at weeks comitant chemotherapy, , or stem 12, 16, 20, and 24 (mean, 5.5 vs 0.5 lesions, PϽ.001). Ben- cell transplantation.15 efit was also shown for total new GdE lesions at weeks 12 In the phase 2 trial, 16 of 65 participants (24.6%) who to 24 (mean 4.5 vs 0.2 lesions, PϽ.001), GdE lesions at received rituximab had human antichimeric antibodies 48 weeks (PϽ.001), and proportion of relapsing partici- at week 48 or early termination. Although there was no pants at weeks 24 (14.5% vs 34.3%, P=.02) and 48 (20.3% relationship to adverse effects or efficacy, these antibod- vs 40.0%, P=.04). Gadolinium-enhancing lesion inhibi- ies may be an issue with repeated administration. There- tion on MRI was apparent as early as week 12. fore, future development in MS will use , a Initial rituximab infusions produce fever, rigors, humanized anti-CD20 mAb. A 6-month phase 2 study tachycardia, dyspnea, headache, pruritus, and rashes, comparing 2 doses of intravenous ocrelizumab, pla-

(REPRINTED) ARCH NEUROL / VOL 66 (NO. 7), JULY 2009 WWW.ARCHNEUROL.COM 823

©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 cebo, and intramuscular interferon beta-1a in RRMS is 3009 intramuscularly or placebo (n=96) at weeks 0, 2, in progress.6 and 4, then every 4 weeks until week 44.18 In the analy- sis population of 267 participants, GdE lesions seen on Dirucotide monthly MRI from weeks 28 to 48, the primary out- come measure, were reduced 50% by the 0.5-mg dose Dirucotide is a synthetic peptide corresponding to amino relative to placebo (P=.07), which was associated with acids 82 through 98 of human myelin basic protein, an dramatic reduction in 23 myelin-specific antibodies mea- immunodominant T- and B-cell epitope in MS patients sured by protein microarray. Interestingly, the higher dose with the HLA-DR2 haplotype. Intravenous administra- was ineffective on GdE lesions and antibody titers. The tion is postulated to induce high-dose tolerance. DNA vaccine was well tolerated, with no evidence of Dirucotide is of interest, as it is being tested in sec- disease activation by clinical or MRI parameters. Plans ondary progressive MS (SPMS). In a single-center, 24- for future studies of BHT-3009 in MS have not been month, placebo-controlled, double-blind phase 2 trial, announced. 32 participants with progressive MS received 500 mg of intravenous dirucotide or placebo every 6 months.16 By Cladribine contingency analysis of EDSS score progression, there was a nonsignificant trend favoring dirucotide on relative rate Cladribine is an adenosine deaminase-resistant purine of progression for the overall study population (relative nucleoside analogue. The phosphorylated triphosphate rate of progression=0.56; n=32; P=.29). There was sig- deoxynucleotide accumulates in lymphocytes, leading to nificant benefit favoring dirucotide in HLA-DR2– apoptosis of resting and dividing lymphocytes and long- positive and/or DR4-positive participants (relative rate lasting lymphocyte depletion preferentially affecting CD4ϩ of progression=0.23, n=20, P=.01). All but 3 dirucotide- T cells.19 Cladribine is approved to treat hairy cell leu- treated participants had reduced cerebrospinal fluid anti– kemia. Several trials supported some aspects of efficacy myelin basic protein antibody levels, but antibody changes of parenteral cladribine in RRMS20 and progressive did not predict clinical outcome. MS.19,21,22 In general, parenteral cladribine is well toler- In general, dirucotide was well tolerated with no se- ated. Infectious complications are the principal concern rious treatment-related adverse effects in this study or with prolonged lymphocyte depletion. This issue has been previous pilot studies. The most common drug-related less prominent in MS than in the oncology experience. adverse effects were injection-site reactions with inter- Recent development of cladribine has examined an oral stitial injection, facial flushing, and mild blood pressure formulation. A randomized, double-blind, 3-arm, placebo- decrease. There were no clinical or MRI findings sug- controlled phase 3 study assessed oral cladribine for 96 gesting disease activation. weeks in approximately 1300 participants with RRMS.6 Par- Subject recruitment is complete in 2 ongoing 2-year ticipants were randomized to high-dose (1.4 mg/kg in year phase 3 studies comparing dirucotide and placebo in HLA- 1 and 0.7 mg/kg in year 2) or low-dose (0.7 mg/kg in years DR2–positive and/or DR4-positive participants with SPMS.6 1 and 2) oral cladribine or placebo. The primary outcome A 15-month, double-blind, placebo-controlled phase 2 study measure was relapse rate throughout 96 weeks. The re- in RRMS will enroll approximately 215 participants.6 sults of this completed trial have not yet been reported. One ongoing 2-year phase 2 study is evaluating the BHT-3009 safety, tolerability, and efficacy of oral cladribine com- bined with interferon beta.6 There were approximately BHT-3009 is a DNA vaccine, a plasmid encoding the 18.5- 200 participants with relapsing MS and at least 1 relapse kDa isoform of full-length human myelin basic protein that within 48 weeks of screening during treatment with in- is intended to generate immune tolerance, both antigen- terferon beta. Participants continue taking interferon beta specific and generalized to other myelin , by by- and are randomized 2:1 to undergo up to 4 cycles of clad- stander suppression. In a multicenter, randomized, double- ribine treatment (0.875 mg/kg per cycle) or placebo at blind, placebo-controlled, dose-escalation phase 1/2 trial, weeks 0, 5, 48, and 52. There is also a randomized, double- 30 participants with RRMS or SPMS were treated with BHT- blind, placebo-controlled phase 3 trial of oral cladribine 3009, BHT-3009 plus 80 mg of oral atorvastatin daily, or in approximately 642 participants with a clinically iso- placebo.17 BHT-3009 was administered in 0.5-, 1.5-, or 3-mg lated syndrome at high risk of converting to MS.6 Par- doses intramuscularly at weeks 1, 3, 5, and 9 after ran- ticipants are randomized to low-dose (1.75 mg/kg per domization. The vaccine was safe and well tolerated, with year) or high-dose (3.5 mg/kg/year) cladribine or pla- no indication of disease activation clinically or radio- cebo once a week for 4 weeks each year. The primary out- graphically. There were favorable trends of GdE lesion come measure is time to conversion to MS by revised number and volume. Immunologic changes included a McDonald criteria.23 marked decrease in proliferation of interferon ␥–produc- ing myelin-reactive CD4ϩ T cells in peripheral blood and decreased titers of myelin-specific cerebrospinal fluid an- tibodies measured by protein microarray. There was no Oral fumaric acid esters have a long history of use in treat- additional benefit from combination with atorvastatin. ing psoriasis. Dimethyl fumarate is a second-generation In a randomized, double-blind, placebo-controlled fumarate derivative with improved tolerability. The pri- phase 2 trial, 289 participants with RRMS were random- mary metabolite, monomethyl fumarate, activates the ized to receive 0.5 mg (n=104) or 1.5 mg (n=89) of BHT- nuclear factor E2–related factor-2 transcriptional path-

(REPRINTED) ARCH NEUROL / VOL 66 (NO. 7), JULY 2009 WWW.ARCHNEUROL.COM 824

©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 way, which is involved in regulating both immune func- Fingolimod tion and the response to oxidative stress.24 Immuno- logic actions include inhibition of T-cell activity by Glycerol- and sphingosine-based phospholipids are abun- inducing apoptosis in activated T cells and stimulating dant structural components of cellular membranes plus a Th1 to Th2 shift in cytokine profile. Methyl hydrogen pleiotropic-soluble mediators of a variety of biologic func- fumarate and dimethyl fumarate inhibit clinical and his- tions. Sphingosine is generated by deacylation of ce- topathologic features of EAE through both anti- ramide by ceramidase then phosphorylated by sphingo- inflammatory25 and neuroprotective24 actions. sine kinase, forming sphingosine-1-phosphate (S1P). In a randomized, double-blind, placebo-controlled, Actions of S1P are mediated by 5 G protein–coupled re- dose-ranging phase 2b study, 257 participants with RRMS ceptors with 7 membrane-spanning domains. The S1P were randomized to receive oral placebo (n=65) or 120 receptor subtype 1 predominates in lymphoid tissue and mg (n=64), 360 mg (n=64), or 720 mg (n=64) of di- is highly expressed by resting T cells and B cells. Lym- methyl fumarate per day.26 Seven hundred twenty mil- phocyte egress from secondary lymphoid organs is de- ligrams of dimethyl fumarate per day reduced the mean pendent on detection of a chemoattractant S1P gradient cumulative new GdE lesion number on monthly scans mediated by S1P receptor subtype 1. from week 12 to 24 compared with placebo (1.4 vs 4.5 Fingolimod, an orally active myriocin derivative, is lesions, 69% reduction, PϽ.001). The 720-mg dose also phosphorylated in vivo by sphingosine kinase, forming produced a 48% reduction in new or enlarging T2 le- fingolimod phosphate, a structural analogue of S1P. Fin- sions at 24 weeks (P =.006), 53% reduction in T1- golimod-phosphate binding leads to aberrant internal- hypointense lesion number (P=.01), and a nonsignifi- ization of S1P receptor subtype 1, rendering lympho- cant 32% reduction in relapses. There were nonsignificant cytes insensitive to the S1P gradient and blocking egress trends favoring the 120-mg and 360-mg doses vs pla- from secondary lymphoid organs.30 Fingolimod admin- cebo on some outcome measures. istration produces a rapid, reversible decrease in circu- Dimethyl fumarate was generally well tolerated. The lating lymphocytes (approximately 70%). Interruption most common adverse effects were flushing, feeling hot, of lymphocyte recirculation between central nervous sys- gastrointestinal symptoms (abdominal pain, nausea, vom- tem and secondary lymphoid organs is probably respon- iting, and diarrhea), headache, and fatigue. There was rare sible for clinical benefit in MS. Fingolimod does not affect elevation of liver enzymes that resolved with drug dis- lymphocyte activation or memory T-cell and B-cell re- continuation. There was no increase in infections and no sponses, so general immunosuppression is not pro- opportunistic infections. During the double-blind ex- duced. In addition, fingolimod is lipophilic, allowing cen- tension, participants who continued active treatment had tral nervous system penetration. The S1P receptors are decreased adverse effects. widely expressed by central nervous system cells and me- There are 2 ongoing 2-year phase 3 trials of dimethyl diate a variety of actions that potentially lead to neuro- fumarate.6 One phase 3 study will randomize approxi- protective or reparative effects.31 Interaction of fingoli- mately 1011 participants with RRMS to receive 720 or mod with widely expressed S1P receptors in other tissues 480 mg of dimethyl fumarate per day or placebo. The pri- probably accounts for its adverse effects. mary outcome measure is the proportion of relapsing par- In a randomized, double-blind, placebo-controlled ticipants. The other phase 3 study will randomize ap- phase 2 trial, 281 participants with RRMS were random- proximately 1232 participants to treatment with 720 or ized to 1.25 or 5 mg of oral fingolimod daily or placebo 480 mg of dimethyl fumarate per day, oral placebo, or for 6 months.32 Median total number of GdE lesions on 20 mg of subcutaneous glatiramer acetate daily. The pri- monthly MRI was reduced with 1.25 mg (1 lesion, mary outcome measure is relapse rate. PϽ.001) and 5 mg (3 lesions, P=.006) of fingolimod vs placebo (5 lesions). The annualized relapse rate was also Estriol reduced (1.25 mg of fingolimod, 0.35; P=.009; and 5 mg of fingolimod, 0.36; P=.01; vs placebo, 0.77). In the ex- Multiple sclerosis disease activity decreases during preg- tension study, benefits were maintained in participants nancy.27 A variety of pregnancy-related factors are prob- who continued to take fingolimod and were reproduced ably involved, including estrogens, which have immuno- in participants who switched from placebo. modulatory effects in vitro28 and ameliorate EAE.29 In an Adverse effects included nasopharyngitis, dyspnea, head- open-label pilot study of 12 women with RRMS or SPMS, ache, diarrhea, nausea, and asymptomatic elevations of liver the number and volume of GdE lesions on monthly MRI enzymes. There was 1 case of posterior reversible encepha- were reduced in months 7 through 12 and 19 through lopathy in the 5-mg group. Fingolimod treatment pro- 22 during treatment with 8 mg of oral estriol per day com- duced bradycardia with the first dose and a mild decrease pared with months 1 through 6 and 13 through 18 with- in forced expiratory volume in 1 second. As with any im- out treatment. This dose of estriol produced blood lev- munomodulatory treatment, infections are a potential con- els comparable with those at pregnancy month 6. In cern with fingolimod, though no opportunistic infections general, estriol was well tolerated aside from increased were seen in the phase 2 study. Possible increased inci- risk of vascular adverse effects. Also, its use is restricted dence and severity of herpes infections have occurred in to female patients. A 2-year, multicenter, randomized, ongoing phase 3 studies. Macular edema was seen in the double-blind trial of glatiramer acetate combined with 8 studies of fingolimod in renal transplant. mg of oral estriol per day or placebo in RRMS is ongo- Ongoing phase 3 studies will evaluate a 1.25-mg and ing.6 The primary outcome measure is relapse rate. a 0.5-mg dose. A double-blind, double-dummy, random-

(REPRINTED) ARCH NEUROL / VOL 66 (NO. 7), JULY 2009 WWW.ARCHNEUROL.COM 825

©2009 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/29/2021 ized, 3-arm trial compares 1.25- and 0.5-mg daily doses Two phase 3 trials of 0.6-mg doses of laquinimod per of oral fingolimod and 30 µg of weekly intramuscular in- day in RRMS are under way.6 One study compares la- terferon beta-1a in 1292 participants with RRMS.6 The quinimod with placebo in 1000 participants. A second primary outcome measure is annualized relapse rate dur- study compares laquinimod with placebo with an inter- ing 12 months. The core study is complete, but the re- nal comparator (weekly intramuscular interferon beta- sults have not yet been reported. A randomized, double- 1a) in 1200 participants. blind, placebo-controlled phase 3 trial of fingolimod in RRMS randomized 1272 participants with RRMS to 1.25 Minocycline or 0.5 mg of daily oral fingolimod or placebo.6 The pri- mary outcome measure is annualized relapse rate dur- Minocycline is a semisynthetic tetracycline antibiotic with ing 24 months. A parallel placebo-controlled phase 3 study extensive clinical experience supporting safety and tol- is being conducted in the United States with a 1080- erability. Minocycline crosses the blood-brain barrier, and participant target.6 biologic actions of minocycline potentially of benefit in MS include inhibition of microglial activation, apopto- Laquinimod sis, inducible nitrous oxide and free radicals, mitogen- activated kinases, proinflammatory cytokine produc- Laquinimod is a once-daily oral immunomodulatory agent tion by T cells, and matrix metalloproteinase activity.37 derived from linomide. Promising results with linomide In a pilot study of 10 participants with active RRMS, 100 were demonstrated in EAE and preliminary clinical trials.33 mg of oral minocycline twice daily reduced GdE lesions However, a phase 3 trial of linomide was terminated during 6 months compared with 3 months before shortly after enrollment completion owing to unantici- therapy.38 This result was driven by activity in 5 partici- pated toxicity, including pericarditis, pleural effusion, pants. A small, randomized, placebo-controlled phase 2 myocardial infarction, possible pulmonary embolism, pan- study assessed minocycline combined with glatiramer creatitis, and death.34 Other common adverse effects in- acetate in 44 participants with RRMS.39 At months 8 and cluded arthralgia, myalgia, bursitis, and edema. Laquini- 9, GdE lesions were reduced by 63% in the glatiramer mod was identified by extensive screening of linomide acetate plus minocycline group compared with the glat- derivatives for efficacy in EAE and lack of proinflamma- iramer acetate group (mean 1.47 vs 2.95 lesions, P=.08) tory effects in beagles. and the number of new T2 lesions were reduced by 65% A multicenter, randomized, double-blind, placebo- (mean, 1.84 vs 5.14 lesions, P=.06). Future studies will controlled phase 2 study in RRMS and SPMS demon- assess the efficacy of minocycline monotherapy follow- strated that daily doses of 0.3 mg of laquinimod re- ing a clinically isolated demyelinating syndrome and mi- duced cumulative active MRI lesion number during 24 nocycline combined with subcutaneous interferon beta-1a weeks, the primary outcome measure, in the per- in RRMS. protocol cohort (n=187; mean, 5.2 vs 9.4 lesions; 44% reduction; P=.0498), with a nonsignificant trend in the Statins intention-to-treat cohort (n=