Multiple sclerosis (MS) is a

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1 THERAPY UPDATE ar Layar Oral disease-modifying therapies for relapsing-remitting multiple sclerosis Rachel Hutchins Thomas and Richard A. Wakefield Purpose. The efficacy and safety of the three oral agents approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS) are reviewed. Summary. Limitations to parenteral disease-modifying therapies (DMTs) (interferon beta-1a, interferon beta-1b, and glatiramer acetate) for the treatment of RRMS have been addressed by the approval of three oral DMTs: fingolimod, teriflunomide, and dimethyl fumarate. In clinical trials, each of the oral DMTs was superior to placebo in annualized relapse rate, a key indicator of clinical efficacy, and in neuroradiological efficacy. A reduction in disability progression was evident with higher doses of teriflunomide but was not consistently demonstrated with fingolimod or dimethyl fumarate. Each of the oral DMTs demonstrated acceptable safety in clinical trials, with adverse-effect profiles that differ from injectable agents. The safety of both teriflunomide and dimethyl fumarate is supported by long-term use of related agents for other diseases; however, postmarketing surveillance studies are needed to determine the safety of each of the oral DMTs in patients with RRMS. Dimethyl fumarate seems to have the most innocuous safety profile of the three agents. Fingolimod requires first-dose inpatient monitoring due to cardiac safety concerns and multiple laboratory tests prior to initiation of therapy, while teriflunomide has been associated with hepatotoxicity and teratogenicity. Conclusion. With the approval of three oral drugs for RRMS fingolimod, teriflunomide, and dimethyl fumarate the therapeutic strategy for RRMS has evolved to include options that are efficacious and appear to have administration advantages over established parenteral treatments. Am J Health-Syst Pharm. 2015; 72:25-38 Multiple sclerosis (MS) is a chronic, progressive, immunemediated disease of the central nervous system (CNS) and is characterized by multifocal demyelination, inflammation, and axon degeneration. The resulting formation of sclerotic plaques and neurodegeneration within the CNS lead to the clinical manifestations of MS, which vary depending on the location of the damage but may include sensory and motor deficits, visual disturbances, autonomic dysfunction, cognitive impairment, and pain. 1,2 MS is characterized as relapsingremitting MS (RRMS), secondaryprogressive MS (SPMS), primaryprogressive MS (PPMS), or progressiverelapsing MS (PRMS), depending on disease presentation. Approximately 80% of patients with MS are initially diagnosed with RRMS, characterized by acute, disabling attacks followed by periods in which symptoms completely or partially subside. 2 These symptoms may persist, leading to a diagnosis of SPMS. 1,2 The progression of RRMS to SPMS occurs in approximately 80% of patients. 3 PPMS is characterized by continuous progression of neurologic symptoms from onset, while PRMS has a progressive course that is also accompanied by periodic attacks. 1,2 The diagnosis of MS is based on the McDonald criteria, which uses a combination of clinical examination of episodes of neurologic impairment and magnetic resonance imaging (MRI). 4 The presence of lesions in the CNS disseminated in time and space (i.e., more than one clinical episode involving lesions in more than one area of the CNS) are Rachel Hutchins Thomas, Pharm.D., M.S., is Clinical Pharmacist, Shelby Baptist Medical Center, Alabaster, AL; at the time of writing she was Assistant Professor of Pharmacy Practice, McWhorter School of Pharmacy, Sanford University, Birmingham, AL. Richard A. Wakefield, Pharm.D., is Clinical Pharmacist, St. Dominic-Jackson Memorial Hospital, Jackson, MS; at the time of writing he was Resident, Drug Information Practice, McWhorter School of Pharmacy, Samford University. Address correspondence to Dr. Thomas (rahutchi@samford.edu). The authors have declared no potential conflicts of interest. Copyright 2015, American Society of Health-System Pharmacists, Inc. All rights reserved /15/ DOI /ajhp Am J Health-Syst Pharm Vol 72 Jan 1,

2 required for the differential diagnosis of MS. T 2 -weighted scans identify both new lesions and older, inactive lesions and give an indication of the overall disease burden; as such, T 2 - weighted scans are useful for tracking long-term progression of MS. Gadolinium-enhancing lesions on T 1 -weighted images indicate active inflammation and new disease activity and are commonly used as surrogate markers of treatment efficacy. 5 The migration of peripherally activated autoreactive T-lymphocytes across the blood-brain barrier is thought to initiate the inflammation in MS that culminates in neuronal damage. 1 Current therapy for RRMS is aimed at reducing inflammation and axonal damage with the goals of limiting relapses and preventing disease progression. Immunomodulators are the cornerstone of treatment for RRMS. Early immunomodulatory therapy with a disease-modifying therapy (DMT), either recombinant interferon beta or glatiramer acetate, is recommended. 6,7 Long-term treatment with a DMT may be accompanied by pharmacologic and nonpharmacologic therapies for direct symptom management and short-term corticosteroid regimens for acute exacerbations. 2,6 Limitations of injectable DMTs include variable efficacy in preventing MS relapses and slowing disease progression, adverse effects, development of neutralizing antibodies that contribute to loss of drug efficacy, and patient inconvenience and noncompliance associated with parenteral administration. 8 These shortcomings have stimulated the development of oral DMTs for the treatment of RRMS. Three oral agents for the treatment of RRMS have been approved by the Food and Drug Administration (FDA) in the past four years: fingolimod, teriflunomide, and dimethyl fumarate (Table 1). This article reviews the efficacy, safety, and place in therapy of fingolimod, teriflunomide, and dimethyl fumarate for the treatment of RRMS. Fingolimod The FDA approval of fingolimod in 2010 marked the advent of oral DMTs for the treatment of RRMS. Fingolimod is derived from the fungus Isaria sinclairii and displays unique immunomodulatory effects. Fingolimod is a prodrug that is phosphorylated in vivo by sphingosine kinase-2 to the biologically active compound fingolimod phosphate, a structural analog of sphingosine- 1-phosphate (S1P). As a signaling Table 1. Oral Disease-Modifying Therapies Approved for Treatment of Relapsing-Remitting Multiple Sclerosis 14,33,48,a Drug Mechanism of Action Dosage Adverse Effects Required Monitoring Fingolimod Teriflunomide Dimethyl fumarate Sequesters autoreactive lymphocytes via functional antagonism of S1P1 receptors Prevents T-cell proliferation by inhibiting dihydroorotate dehydrogenasemediated de novo pyrimidine production Shifts T-cell differentiation to an antiinflammatory pattern; induces the nuclear factorlike 2 antioxidant response pathway a ALT = alanine transaminase, CBC = complete blood count. 0.5 mg once daily 7 or 14 mg once daily 120 mg twice daily for 7 days, followed by 240 mg twice daily; take with food to reduce flushing; capsules must be discarded 90 days after bottle is opened Bradycardia, hypertension, infection, elevated ALT levels, dyspnea, rare macular edema Elevated ALT levels, alopecia, diarrhea, nausea, paresthesia, teratogenicity Flushing, gastrointestinal effects, renal effects First-dose 6-hr cardiovascular monitoring, baseline CBC, baseline hepatic transaminases, ophthalmic examination at baseline and 3 4 mo after therapy initiation, blood pressure Baseline CBC; baseline hepatic transaminases and bilirubin, then monthly for 6 mo; pregnancy test Baseline CBC, then annually 26 Am J Health-Syst Pharm Vol 72 Jan 1, 2015

3 lysophospholipid, S1P plays key roles in multiple biological processes, including neuroinflammation and migration of lymphocytes from lymphoid tissues into the peripheral circulation. Fingolimod phosphate initially acts as an agonist at four of the five known S1P G proteincoupled receptors (S1P 1, S1P 3, S1P 4, and S1P 5 ); its immunomodulatory effects are attributed to interaction with S1P 1 on lymphocytes within lymph nodes. Despite the initial agonist activity of fingolimod phosphate on the S1P 1 receptor, fingolimod acts as a functional antagonist with repeated exposure. The activated receptor is internalized, leading to downregulation of S1P 1 receptors on lymphocytes and inhibition of the cell s natural response to endogenous S1P. The ultimate effect is sequestration of potentially autoreactive T cells within the secondary lymphoid organs, thereby preventing their infiltration into the CNS A decrease in the number of circulating naive and central memory T cells occurs, including interleukin 17-producing T cells, which are thought to play an important role in the pathogenesis of MS. 9,11,12 Effector memory T cells, which are involved in immune surveillance and provide defense against recall infection on restimulation by an antigen, are not affected by fingolimod. 12 Fingolimod is lipophilic and enters the CNS, where it exerts additional mechanisms that are unclear but are thought to involve suppression of neurotoxic effects and enhancement of the neuroprotective effects of microglia. 9,11,13 The pharmacokinetics of fingolimod are summarized in Table 2. 14,15 Efficacy. The FDA approval of fingolimod was based on two Phase III, randomized, double-blind clinical trials: one placebo controlled (FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis, or FREEDOMS) 16 and one active controlled (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing-Remitting Multiple Sclerosis, known as TRANSFORMS). 17 Eligible participants were age years, were diagnosed with RRMS Table 2. Pharmacokinetics of Oral Disease-Modifying Therapies Approved for the Treatment of Relapsing-Remitting Multiple Sclerosis 14,15,33,48,a and had recent inflammatory activity (at least 1 relapse during the previous year or at least 2 relapses during the previous 2 years), and had a score of on the Expanded Disability Status Scale (EDSS), an instrument that measures disability on a scale of 0 10, with higher scores corresponding to greater disability. The primary endpoint of both trials was the annualized relapse rate (ARR), defined as the number of confirmed relapses per year. Secondary endpoints included time to disability progression (defined as an increase of at least 1 point in EDSS score or 0.5 point in patients with a baseline score of 5.5, confirmed after three months in the absence of relapse), MRI measures, and safety. In both FREEDOMS and TRANSFORMS, the study population had a median baseline EDSS score of 2.0 (range, 0 5.5), indicative of minimal MS disability, and a median of 1 relapse (range, 0 20) within the year before enrollment. 16,17 FREEDOMS was a 24-month placebo-controlled trial in which patients (n = 1272) were randomized Parameter Fingolimod Teriflunomide Dimethyl Fumarate b Absorption Distribution Metabolism Elimination Oral bioavailability, 93%; unaffected by food Highly protein bound (>99%); V d, 1200 ± 260 L Phosphorylation by sphingosine kinase-2 to active metabolite; hydroxylation and oxidation via cytochrome P-450 isoenzyme 4F2 t ½, 6 9 days for both fingolimod and fingolimod phosphate; inactive metabolites excreted in urine (81% of total dose); intact drug excreted in feces (<2.5%) Oral bioavailability, 100%; unaffected by food Highly protein bound (>99%); V d, 11 L after a single i.v. administration Hydrolysis (primary); oxidation, N-acetylation, and sulfate conjugation (secondary) t ½, days; excreted via feces (37.5%) and urine (22.6%); elimination may be accelerated with cholestyramine Not quantifiable in plasma. Food decreases C max of monomethyl fumarate by 40% and delays t max from 2 to 5.5 hr; AUC unaffected Minimal protein binding (27 45%); V d, L Hydrolysis by esterases to active metabolite, monomethyl fumarate; further metabolism via tricarboxylic acid cycle t ½, 1 hr; excreted via exhalation of carbon dioxide (60%), urine (16%), and feces (1%) a V d = volume of distribution, t ½ = half-life, C max = maximum concentration, t max = time to maximum concentration, AUC = area under the concentration time curve. b Data based on plasma monomethyl fumarate. Am J Health-Syst Pharm Vol 72 Jan 1,

4 to receive either fingolimod 0.5 mg, fingolimod 1.25 mg, or matching placebo once daily. 16 In the intentionto-treat analysis, the ARR was significantly lower with fingolimod 0.5 mg (0.18; 95% confidence interval [CI], ) and fingolimod 1.25 mg (0.16; 95% CI, ) than with placebo (0.40; 95% CI, ; p < for each fingolimod dose versus placebo), representing relative reductions (RRs) in the ARR of 54% and 60%, respectively. No significant difference in efficacy between the two fingolimod doses was evident. The risk of disability progression was reduced with fingolimod, with a hazard ratio (HR) for time to disability progression of 0.70 (95% CI, ) and 0.68 (95% CI, ) in the fingolimod 0.5- and 1.25-mg groups, respectively, versus placebo (p = 0.02 for both comparisons). MRI measurements corroborated clinical efficacy, with patients in both fingolimod groups having 82% fewer gadolinium-enhancing T 1 -weighted lesions and 74% fewer new or enlarged T 2 -weighted lesions at 24 months compared with patients receiving placebo (p < for each comparison). In a 24-month extension of FREEDOMS (n = 773), clinical efficacy was sustained in patients receiving continuous fingolimod, as demonstrated by ARRs of 0.19 and 0.16 in the fingolimod 0.5- and 1.25-mg groups, respectively. The number of new or enlarged T 2 lesions remained consistently low in patients receiving continuous fingolimod. Study results have not yet been published in full. 18 Preliminary reports of the primary endpoint results of FREEDOMS II, a 24-month placebo-controlled Phase III trial in patients with RRMS (n = 1083), were consistent with FREEDOMS, with ARRs of 0.21 and 0.20 with fingolimod 0.5 and 1.25 mg, respectively, compared with an ARR of 0.40 with placebo (p < 0.001). However, unlike FREEDOMS, there was no statistically significant difference between fingolimod and placebo in the time to disability progression. 19 TRANSFORMS was a 12-month active-controlled, double-dummy trial comparing the efficacy and safety of fingolimod versus interferon beta-1a. 17 Patients (n = 1292) were randomized to receive either fingolimod 0.5 or 1.25 mg once daily or intramuscular interferon beta-1a 30 mg once weekly for 12 months. For the primary endpoint of the ARR, fingolimod 0.5 mg (0.16; 95% CI, ) and fingolimod 1.25 mg (0.20; 95% CI, ) were each superior to interferon beta-1a (0.33; 95% CI, ; p < for each comparison). No dose response relationship with regard to efficacy was evident (p = 0.16 for fingolimod 0.5 mg versus fingolimod 1.25 mg). There was no significant difference between fingolimod and interferon beta-1a in the time to disability progression or in the proportion of patients with confirmed disability progression. MRI metrics favored fingolimod over interferon beta-1a, with fingolimod treatment resulting in fewer gadolinium-enhancing lesions (RRs, 55% and 72% in the fingolimod 0.5- and 1.25-mg groups, respectively; p < for each comparison) and fewer new or enlarged lesions on T 2 -weighted images at 12 months (RRs, 35% and 42% in the fingolimod 0.5- and 1.25-mg groups, respectively; p < 0.05 for each comparison). 17 In a dose-masked one-year extension study of TRANSFORMS (n = 882), patients who received fingolimod continuously for 24 months displayed sustained reductions in the ARR (0.11; 95% CI, in the fingolimod 0.5- and 1.25-mg groups) and sustained or improved MRI measures. 20 Safety. Adverse effects associated with fingolimod are diffuse and reflect the presence of S1P receptors on a variety of tissues. The most frequently reported adverse effects in Phase III trials were headache, diarrhea, back pain, elevated alanine transaminase (ALT) levels, cough, infection, and fatigue. 16,17 Discontinuation due to adverse effects was dose dependent in clinical trials, with discontinuation rates nearly twofold greater with the 1.25-mg dose ( %) versus the 0.5-mg dose ( %). 16,17 Given the apparent lack of a dose response relationship with regard to the ARR in Phase III trials and the greater frequency of adverse effects associated with the 1.25-mg dose, fingolimod 0.5 mg was approved by FDA. 21 During fingolimod therapy, immunologic effector functions are preserved through selective sequestration of naive and central memory T cells and sparing of effector memory T cells 12 ; however, Phase III trials suggested that fingolimod may be associated with increased susceptibility of infection, particularly viral infection, and malignancy. The overall rates of infection were similar across study groups with the exception of herpes infections, which occurred with greater frequency in fingolimod groups ( % with fingolimod 0.5 mg compared with 7.9% with placebo and 2.8% with interferon beta-1a). 16,17 Two fatal herpetic infections (1 case of herpes simplex encephalitis and 1 case of disseminated primary varicella zoster infection) occurred in TRANSFORMS in patients receiving fingolimod 1.25 mg, a dose higher than the FDA-approved dose of 0.5 mg. 17 Circulating peripheral lymphocyte counts decreased from baseline by an average of 73% in patients receiving fingolimod 0.5 mg in Phase III trials and stabilized after one month. 16,17 Reduced lymphocyte counts may persist for three months after fingolimod discontinuation. 21 While decreased peripheral lymphocyte counts in patients receiving fingolimod reflect redistribution and not depletion and have not been shown to correlate with infection risk, 21,22 the manufacturer recommends temporary discontinuation of fingolimod during serious 28 Am J Health-Syst Pharm Vol 72 Jan 1, 2015

5 infections. 14 Malignant neoplasms, particularly skin cancers, appeared to be associated with fingolimod therapy in TRANSFORMS, with 0.5% and 1.4% of patients experiencing localized skin cancers in the fingolimod 0.5- and 1.25-mg groups, respectively, compared with 0.2% of patients in the interferon beta-1a group; however, in FREEDOMS, the frequency of skin cancers associated with fingolimod (0.5 mg, 0.9%; 1.25 mg, 0.5%) was similar to that seen with placebo (0.9%). 16,17 In a sevenyear uncontrolled extension of a Phase II study, 12 cases of skin malignancies were reported in patients receiving fingolimod, most within the first three years of therapy. 23 Given the potential effects of fingolimod on immunosurveillance, additional long-term data are needed to determine the risks of infection and malignancy associated with long-term fingolimod therapy. Progressive multifocal leukoencephalopathy (PML) is a lifethreatening, opportunistic, demyelinating viral infection associated with impaired cell-mediated immunity and has been linked to natalizumab, an immunomodulator used in the treatment of RRMS. 24 PML is a concern with fingolimod due to the drug s immunomodulatory effects on T-cell migration, which are similar to those of natalizumab. Of the approximately 71,000 patients who were treated with fingolimod as of July 2013, PML has been reported in 2 patients, both of whom had other risk factors, including prior use of natalizumab, other immunosuppressants, or i.v. corticosteroids. 25,26 Continuing surveillance is warranted to quantify the risk of PML associated with fingolimod and to determine if a risk assessment is needed before initiating fingolimod therapy. Posterior reversible encephalopathy syndrome (PRES) has been reported rarely with fingolimod. Symptoms include severe headache, altered mental status, seizure, and visual disturbances and are usually reversible but may progress into ischemic stroke or cerebral hemorrhage. The labeling of fingolimod was updated in April 2014 to include a warning concerning PRES. 14 Dose-dependent adverse cardiovascular effects have been observed with fingolimod. First-dose bradycardia, bradyarrhythmia, or sinus bradycardia occurred in % of patients receiving fingolimod 0.5 mg in Phase III trials. 16,17,19,20 All episodes of bradycardia occurred within 2 hours after administration of the first dose of fingolimod, reached the nadir (maximal reduction in mean resting pulse rate, 8 beats/min) 5 hours after the first dose, and began to subside at 6 hours, with all cases resolving within 24 hours. First- and second-degree atrioventricular block occurred in less than 1% of patients receiving fingolimod. Continued alterations in heart rate or atrioventricular conduction were not noted with continued fingolimod therapy. 16,17 Hypertension was also reported as an adverse effect in % of patients receiving fingolimod 0.5 mg compared with % of patients receiving placebo. 16,19 Fingolimod has been associated with adverse pulmonary events that, though mild, may limit its use in patients with baseline pulmonary impairment. In Phase III trials, a progressive but reversible decline in pulmonary function test results occurred, with reductions of 2.3% and 3.1% in mean forced expiratory volume in one second (FEV 1 ) at 12 and 24 months, respectively, in patients receiving fingolimod 0.5 mg compared with 1.5% and 2% with placebo at 12 and 24 months, respectively. These declines in FEV 1 in the fingolimod 0.5-mg group correspond with decreases in FEV 1 that are considered clinically significant ( 0.1 L at 12 months and 0.15 L at 24 months). Pulmonary function returned to baseline after discontinuation of fingolimod. 27 Dyspnea was reported in % of patients receiving fingolimod compared with 4.5% of those receiving placebo. 16,17 Despite these data, results from a small clinical trial in otherwise healthy patients with asthma (n = 36) showed no statistically significant differences in pulmonary function or exacerbations in patients receiving fingolimod 0.5 mg compared with placebo. 28 Macular edema occurred in 1% of the 2431 total patients who received fingolimod in FREEDOMS, FREEDOMS II, and TRANSFORMS and appeared to be dose dependent. Most cases occurred within 3 months of initiation of fingolimod therapy and typically resolved within 1 6 months after discontinuation. 16,17,20 Diabetes or uveitis may increase the risk of fingolimod-associated macular edema. 14,29 Elevated ALT levels to three or more times the upper limit of normal occurred in 8 8.5% of patients receiving fingolimod 0.5 mg compared with 1.7% of patients receiving placebo and 2% receiving interferon beta-1a. The elevations occurred predominantly in men, were not accompanied by increases in bilirubin concentration, and were reversible on drug discontinuation. 16,17 Preliminary results from a multinational fingolimod pregnancy registry have not shown an increased risk of teratogenicity or spontaneous abortion 30 ; however, rat studies have demonstrated teratogenicity and embryolethality. 14 Fingolimod is a pregnancy category C drug and should be avoided during pregnancy and at least two months before conception unless the benefits outweigh the risks to the fetus. 14 Limited long-term data support the extended safety of fingolimod, with no unexpected adverse effects reported during a seven-year extension of a Phase II trial (n = 122). 23 Continued postmarketing surveillance is warranted to identify any additional risks associated with chronic use of fingolimod and to quantify the Am J Health-Syst Pharm Vol 72 Jan 1,

6 risk of rare adverse effects such as macular edema and PML. Dosage and administration. The FDA-approved dosage of fingolimod for the first-line treatment of RRMS is 0.5 mg orally once daily without regard to meals. The labeling for fingolimod was revised in April 2012, and a risk evaluation and mitigation strategy (REMS) was initiated to reflect cardiac safety concerns after 11 deaths that were potentially associated with fingolimod. 31 The current REMS also addresses infections, macular edema, respiratory effects, hepatic effects, and fetal risk associated with fingolimod therapy. 32 Fingolimod is contraindicated in patients with second- or third-degree atrioventricular block or sick sinus syndrome in the absence of a pacemaker, patients with a baseline Q-T interval of 500 milliseconds, and patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, or Class III/IV heart failure within the six months before initiating fingolimod therapy. Caution must be used in patients with preexisting conditions that prolong the Q-T interval; overnight first-dose continuous electrocardiogram monitoring is required in these patients. In-clinic monitoring for six hours after administration of the first fingolimod dose is required for all patients initiating therapy or reinitiating therapy after an interruption in treatment of 14 or more days, with hourly heart rate and blood pressure measurements and electrocardiogram results measured at baseline and after the six-hour observation period. 14 In addition to first-dose cardiac monitoring, a complete blood count (CBC), an assessment of liver enzymes, and an ophthalmic examination are recommended before initiating fingolimod therapy. Blood pressure should also be monitored during treatment. 14 Fingolimod and fingolimod phosphate are metabolized by pathways shared by structurally related endogenous compounds, including sphingosine and fatty acids. The elimination of fingolimod primarily involves hydroxylation by cytochrome P-450 (CYP) isoenzyme 4F2. 14 Fingolimod has a low potential for pharmacokinetic drug interactions, as CYP4F2 is rarely involved in drug metabolism. Ketoconazole, a CYP4F2 inhibitor, is one of the few drugs that may increase fingolimod exposure. 14 Fingolimod should be used cautiously with drugs that have negative chronotropic effects (e.g., b-blockers, digoxin, nondihydropyridine calcium-channel blockers) or drugs that prolong the Q-T interval; concomitant use of class Ia or III antiarrhythmic drugs is contraindicated. The terminal halflife of fingolimod is six to nine days, and blood levels of fingolimod phosphate decline at the same rate as with fingolimod. 14 The pharmacodynamic effects (e.g., immunosuppression) and safety concerns (e.g., teratogenicity) of fingolimod phosphate can persist for up to two months after drug discontinuation. 14 The use of other DMTs during this time may cause additive immunosuppression. The total exposure (i.e., area under the concentration time curve) and half-life of fingolimod are increased in patients with severe hepatic impairment; thus, fingolimod should be used cautiously in these patients. Dosage adjustment for renal impairment is not required. 14,15 Teriflunomide Teriflunomide received FDA approval in September 2012, becoming the second oral agent available for the treatment of RRMS. 33 Teriflunomide is the active metabolite of the antirheumatic drug leflunomide and is a selective, reversible inhibitor of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme necessary for de novo pyrimidine synthesis in proliferating T and B cells. 34 Compared with resting lymphocytes, activated lymphocytes require an eightfold expansion of their pyrimidine pools; this demand must be met using de novo mechanisms, as salvage pathways are inadequate. Inhibition of DHODH-mediated de novo pyrimidine synthesis by teriflunomide arrests cells in the G 1 phase of cell growth, resulting in a decrease in activated peripheral T and B cells. 34 Teriflunomide s specificity for DHODH spares the salvage pathways for pyrimidine synthesis, which are utilized by the majority of resting lymphocytes; consequently, teriflunomide has a low potential for cytotoxicity. 35 The reduction in pyrimidine synthesis may also affect phospholipid metabolism in immune cells and alter the expression of surface proteins needed for cell-tocell signaling. Teriflunomide appears to have immunomodulatory properties that are independent of DHODH inhibition. In experimental models, teriflunomide has been shown to inhibit cyclooxygenase-2 isoenzyme and various tyrosine, serine, and threonine kinases; however, the in vivo relevance of these off-target effects is unknown. 34,35 A summary of the pharmacokinetic profile of teriflunomide is provided in Table Efficacy. The pivotal trial considered in the FDA approval of teriflunomide was a Phase III, randomized, double-blind, placebo-controlled, 108-week clinical trial (Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis, or TEMSO) in which patients (n = 1088) were randomized to receive either teriflunomide 7 mg, teriflunomide 14 mg, or placebo daily. 36 Eligible patients were age years, were diagnosed with relapsing MS with or without progression, had baseline EDSS scores of 0 5.5, and experienced at least one relapse in the previous year or at least two relapses in the previous 2 years. The ARR was the primary endpoint; secondary 30 Am J Health-Syst Pharm Vol 72 Jan 1, 2015

7 endpoints included time to disease progression (defined as an increase in EDSS score from baseline of at least 1 point or at least 0.5 point if baseline EDSS score exceeded 5.5, sustained for at least three months) and change in total lesion volume. The study population had minimal MS disability at baseline (median baseline EDSS score, 2.5) and a median of one relapse within the year before enrollment. Over 90% of patients had RRMS, 4.7% had SPMS, and 3.9% had PRMS. In the intention-to-treat analysis, teriflunomide significantly reduced ARRs compared with placebo (ARR with teriflunomide 7 mg, 0.37; 95% CI, ; ARR with teriflunomide 14 mg, 0.37; 95% CI, ; ARR with placebo, 0.54; 95% CI, ; p < for each group versus placebo). Although efficacy with regard to relapse prevention was similar between the two teriflunomide doses, only the 14-mg dose had a significant effect on the time to disease progression compared with placebo (HR, 0.70; 95% CI, ; p = 0.03). Teriflunomide also improved MRI measures in a dose-dependent manner, with RRs of 39% and 67% in total lesion volume and 57% and 80% in gadolinium-enhancing T 1 lesions with 7- and 14-mg doses, respectively, compared with placebo (p < 0.05 for each comparison). Interim results from a 6-year open-label extension of TEMSO revealed sustained efficacy of teriflunomide, with ARRs of 0.22 and 0.19 in 742 patients receiving 8 years of continuous therapy with teriflunomide 7 and 14 mg daily, respectively. 37 Interim results of a second Phase III, randomized, double-blind, placebo-controlled clinical trial (Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis, or TOWER) were also considered by FDA in its approval of teriflunomide. 38 Patients with relapsing MS (n = 1169) were randomized to receive teriflunomide 7 mg, teriflunomide 14 mg, or placebo daily for 48 weeks. The mean baseline EDSS score in each group was 2.7. Approximately 97% of patients had RRMS, 0.8% had SPMS, and 1.7% had PRMS. Both doses of teriflunomide were superior to placebo in the primary outcome of relapse prevention, with ARRs of 0.39 (95% CI, ) and 0.32 (95% CI, ) in the teriflunomide 7- and 14-mg groups, respectively, compared with 0.50 (95% CI, ) in the placebo group (p < 0.05). These results correspond to RRs in ARR of 22.3% and 36.3% in the teriflunomide 7- and 14-mg groups, respectively, compared with placebo. Similar to the findings of TEMSO, time to disability progression was significantly reduced with teriflunomide 14 mg compared with placebo (HR, 0.68; p = 0.044) but not with teriflunomide 7 mg (HR, 0.95; p = 0.76). The efficacy of teriflunomide versus interferon beta-1a was investigated in a 48-week, Phase III, randomized, rater-blinded clinical trial (Teriflunomide and Rebif, or TENERE) in patients with relapsing MS (n = 324)with an EDSS score of at baseline. 39 Patients were randomized to receive teriflunomide 7 or 14 mg once daily (double-blind groups) or subcutaneous interferon beta-1a 44 mg three times per week (open-label group). The primary composite endpoint was time to treatment failure, defined as the first occurrence of confirmed relapse or all-cause permanent treatment discontinuation. The key secondary endpoint was ARR. Baseline mean EDSS scores ranged from 2.0 to 2.3. Nearly all patients (99%) had RRMS; 1 patient with SPMS, and 2 patients with PRMS were also enrolled. The time to treatment failure was comparable among both teriflunomide groups and the interferon beta-1a group, with Kaplan-Meier estimates for probability of treatment failure at 48 weeks of 0.36 (95% CI, ), 0.33 (95% CI, ), and 0.37 (95% CI, ) in the teriflunomide 7-mg, teriflunomide 14-mg, and interferon beta-1a groups, respectively (p not significant for each teriflunomide group versus interferon beta-1a). More patients receiving teriflunomide did not respond to treatment due to relapse (42.2% and 23.4% of patients in the 7- and 14- mg groups, respectively) than those receiving interferon beta-1a (15.4%). In contrast, fewer treatment discontinuations occurred in the teriflunomide groups (6.4% and 13.5% for 7 and 14 mg, respectively) than the interferon beta-1a group (24.0%), with adverse effects being the most common reason for discontinuation. More relapses occurred per year with teriflunomide 7 mg (ARR, 0.41; 95% CI, ) than with interferon beta-1a (ARR, 0.22; 95% CI, ; p = 0.03); relapse rates did not significantly differ between interferon beta-1a and teriflunomide 14-mg groups (ARR, 0.26; 95% CI, ; p = 0.59). Safety. The most common adverse effects observed in clinical trials with teriflunomide were headache, elevated ALT levels, nausea, diarrhea, paresthesia, and alopecia Many of the warnings related to teriflunomide therapy are derived from experience with its precursor, leflunomide, which has over 1.5 million personyears of exposure in the treatment of rheumatoid arthritis. 35 Based on adverse effects seen with leflunomide, the labeling of teriflunomide has boxed warnings for hepatotoxicity and teratogenicity. Additional rare but serious concerns associated with teriflunomide therapy are peripheral neuropathy, Stevens-Johnson syndrome, toxic epidermal necrolysis, hypertension, hyperkalemia, acute renal failure, and interstitial lung disease. 33 Teriflunomide has been associated with transient, reversible elevations of liver enzymes. In TEMSO, the rates of ALT elevation of one or more times the upper limit of nor- Am J Health-Syst Pharm Vol 72 Jan 1,

8 mal were 54% and 57% in patients treated with teriflunomide 7 and 14 mg, respectively, compared with 36% for patients who received placebo. 36 However, the rates of ALT elevations of three or more times the upper limit of normal with teriflunomide were comparable to those with placebo (6.3%, 6.7%, and 6.7% with teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively) and were lower than those of interferon beta-1a (6.4%, 10%, and 15.8% with teriflunomide 7 mg, teriflunomide 14 mg, and interferon beta-1a, respectively). 36,39 The use of teriflunomide should be limited in patients receiving concomitant hepatotoxic drugs and is contraindicated in patients with severe hepatic impairment. 33 Bone marrow suppression occurred in patients receiving teriflunomide in clinical trials, with a decrease of approximately 15% in mean white blood cell count occurring during the first six weeks of therapy and persisting throughout treatment and a decrease of 10% in platelet count. 33,36 The overall frequencies of infections in TEMSO were similar among teriflunomide and placebo groups 36 ; however, in TENERE, infections occurred with comparable frequency with teriflunomide 14 mg and interferon beta-1a (49.1% and 46.5%, respectively) but occurred more frequently with teriflunomide 7 mg (64.5%). 39 The rate of serious infections associated with teriflunomide was similar to that seen with placebo (1.6%, 2.5%, and 2.2%, with teriflunomide 7 mg, teriflunomide 14 mg, and placebo, respectively) and with interferon beta-1a (1.8%, 1.8%, and 1% with teriflunomide 7 mg, teriflunomide 14 mg, and interferon beta-1a, respectively). 36,39 Opportunistic infections occurred in five patients receiving teriflunomide in TOWER and have been reported with leflunomide in the postmarketing setting. 33,38 To date, no documented cases of PML have been associated with teriflunomide; however, two cases of PML with leflunomide therapy have been reported, both of which involved the prior use of immunosuppressants Currently, there is no evidence of increased rates of lymphoproliferative disorders or other malignancies associated with leflunomide or teriflunomide. 33 Alopecia was the most common adverse effect of teriflunomide that led to treatment discontinuation in clinical trials. 33 Hair loss or thinning hair was reported in 11.4% and 15.2% of patients receiving teriflunomide 7 and 14 mg, respectively, compared with 4.2% receiving placebo in combined Phase II and III clinical trial data. 43 The hair loss was typically mild to moderate, occurred early in the course of therapy, and reached a plateau after six to nine months of treatment. Most patients recovered spontaneously without the need for corrective therapy. 43 Teriflunomide is a pregnancy category X drug, so the risk of pregnancy and fetal harm should be evaluated in women of childbearing age before drug initiation. Both male and female patients should adhere to adequate contraceptive measures throughout therapy. If pregnancy is suspected during treatment with teriflunomide, therapy should be discontinued. Due to its long half-life (18 19 days), teriflunomide requires up to two years to be fully eliminated from the body; in pregnant patients, an 11-day, rapid-elimination procedure using cholestyramine or activated charcoal should be used. 33 Extensive long-term safety data regarding leflunomide in patients with rheumatoid arthritis may be extrapolated to teriflunomide; however, postmarketing surveillance is needed to substantiate the safety of chronic teriflunomide therapy in RRMS. Dosage and administration. The FDA-approved dosage of teriflunomide for the treatment of RRMS is 7 or 14 mg orally once daily without regard to meals. Drug interactions of concern with teriflunomide include other immunomodulators, which may contribute to an additive infection risk. The concurrent use of teriflunomide and leflunomide is contraindicated. Teriflunomide is metabolized independently of the CYP isoenzymes; however, it may interact with some drugs that are metabolized by CYP2C8, CYP2C9, and CYP1A2. Teriflunomide inhibits CYP2C8 and may contribute to elevated concentrations of drugs such as repaglinide, paclitaxel, and pioglitazone. Teriflunomide is a weak inducer of CYP1A2 and may increase the clearance of drugs such as duloxetine, theophylline, lidocaine, and tamoxifen. Careful monitoring is required when teriflunomide is administered concomitantly with warfarin, as teriflunomide induces CYP2C9 and can decrease the International Normalized Ratio by up to 25%. In vitro, teriflunomide is a substrate and inhibitor of the efflux transporter breast cancer-resistant protein and an inhibitor of hepatic uptake transporter (organic aniontransporting peptide 1B1) and renal uptake transporter (organic anion transporter 3). Renal impairment or mild-to-moderate hepatic impairment is not expected to affect levels of exposure to teriflunomide. 33 Baseline CBC measurement, tuberculin skin testing, pregnancy testing in women, and measurement of ALT and bilirubin levels are recommended before initiation of teriflunomide therapy. In addition, monthly liver function tests are needed for at least six months after initiation of therapy with teriflunomide. Discontinuation is recommended if ALT levels increase to over three times the upper limit of normal. 33 Dimethyl fumarate The labeling for dimethyl fumarate, an ester derivative of fumarate, was approved by FDA in March 2013 for the treatment of RRMS. Dimethyl fumarate exerts a dual mechanism 32 Am J Health-Syst Pharm Vol 72 Jan 1, 2015

9 of action, with both immunomodulatory and antioxidant effects. 44,45 Dimethyl fumarate and its active metabolite, monomethyl fumarate, modulate antiinflammatory activity by shifting the differentiation pattern of naive CD4+ T-helper cells from Th1 (proinflammatory) to Th2 (antiinflammatory), suppressing production of proinflammatory mediators, and inhibiting adhesion of leukocytes. 44,45 Dimethyl fumarate and monomethyl fumarate may also possess neuroprotective effects that are poorly understood but are thought to involve the activation of transcription factors including nuclear factor (erythroid-derived 2)-like 2 that play a role in the antioxidant response. 46,47 The pharmacokinetics of dimethyl fumarate are summarized in Table 2. Pharmacokinetic analyses were performed using monomethyl fumarate, as dimethyl fumarate is rapidly hydrolyzed to monomethyl fumarate and is not quantifiable in plasma. 48 Efficacy. The FDA s approval of dimethyl fumarate was based on two 24-month, randomized, doubleblind, placebo-controlled Phase III clinical trials that evaluated the efficacy and safety of two doses of dimethyl fumarate (240 mg twice daily and 240 mg three times daily) in patients with stable RRMS. 49,50 Eligible participants were years of age diagnosed with RRMS with a baseline EDSS score of 0 5 and at least one relapse during the previous year or at least one recent gadolinium-enhancing lesion. Patients in both studies had minimal MS disability at baseline (mean baseline EDSS score, ) and a mean of relapses within the year before enrollment. Dosing was initiated at half the target dose for seven days before escalating to the full dose. In both studies, disability progression was defined as an increase of at least 1 point in EDSS score (or at least 1.5 points in patients with a baseline score of 0) confirmed after 3 months. In the Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS (DEFINE) study, the primary endpoint was the percentage of patients experiencing relapse; secondary endpoints included the ARR, time to disability progression, and MRI findings. 49 Analysis of the intention-to-treat population (n = 1234) revealed the superiority of dimethyl fumarate over placebo in the percentage of patients relapsing over the 24-month study period (27% and 26% in the twice-daily and thrice-daily dimethyl fumarate groups, respectively, versus 46% with placebo; p < for each comparison). Relapse rates were significantly reduced with twice-daily dimethyl fumarate (ARR, 0.17; 95% CI, ) and thrice-daily dimethyl fumarate (ARR, 0.19; 95% CI, ) compared with placebo (ARR, 0.36; 95% CI, ; p < for each comparison). Dimethyl fumarate also reduced the risk of disability progression by 38% in the twice-daily group (HR, 0.62; 95% CI, ; p = 0.005) and by 34% in the thrice-daily group (HR, 0.66; 95% CI, ; p = 0.01). MRI assessments in a subgroup of 469 patients were consistent with clinical efficacy, with dimethyl fumarate-treated patients having significantly fewer gadolinium-enhancing T 1 -weighted lesions (RR, 94% and 56% in the twice-daily and thrice-daily dimethyl fumarate groups, respectively) and fewer new or newly enlarging T 2 - weighted lesions (RR, 85% and 74% in the twice-daily and thrice-daily dimethyl fumarate groups, respectively) compared with placebo (p < for each comparison). 49 In the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study, participants were randomized to receive twice-daily dimethyl fumarate, thrice-daily dimethyl fumarate, an active comparator (glatiramer acetate 20 mg daily given by subcutaneous injection), or placebo. 50 The primary endpoint of the CONFIRM study was the ARR over 24 months; secondary endpoints included the percentage of patients with relapse, time to disability progression, and MRI measures. This study was not designed to test the noninferiority or superiority of glatiramer acetate compared with dimethyl fumarate. In the intention-to-treat population (n = 1417), the ARR was significantly reduced in patients receiving twice-daily dimethyl fumarate (0.22; 95% CI, ) or thrice-daily dimethyl fumarate (0.20; 95% CI, ) compared with placebo (0.40; 95% CI, ), corresponding to RRs of 44% and 51% (p < versus placebo). In comparison, the ARR in patients receiving glatiramer acetate was 0.29 (95% CI, ), representing a 29% reduction versus placebo. The rates of relapse were 29% and 24% in the twice-daily and thricedaily dimethyl fumarate groups, respectively, compared with 41% in the placebo group and 32% in the glatiramer acetate group. In contrast to the DEFINE trial, the time to disability progression compared with placebo was not significantly reduced in the CONFIRM study with twice-daily dimethyl fumarate (HR, 0.79; 95% CI, ; p = 0.25), thrice-daily dimethyl fumarate (HR, 0.76; 95% CI, ; p = 0.20), or glatiramer acetate (HR, 0.93; 95% CI, ; p = 0.70). 50 The apparent lack of benefit in disability progression in the CONFIRM trial may be attributed to the randomization of fewer patients per group compared with the DEFINE study, resulting in inadequate power to detect an effect. Compared with placebo, dimethyl fumarate demonstrated significant improvements in MRI measures in a subgroup of 681 patients, including fewer gadolinium-enhancing T 1 - weighted lesions (RRs, 75% and 80% in the twice-daily and thrice-daily dimethyl fumarate groups, respectively) and fewer new or enlarging Am J Health-Syst Pharm Vol 72 Jan 1,

10 T 2 -weighted lesions (RR, 71% and 73% in the twice-daily and thricedaily dimethyl fumarate groups) at 24 months (p < for each comparison). 50 Interim results of an ongoing integrated, dose-masked, five-year extension study of the DEFINE and CONFIRM trials, revealed sustained efficacy in patients (n = 1736) receiving up to four years of continuous treatment with twicedaily dimethyl fumarate (ARR, 0.13; 95% CI, ) or thrice-daily dimethyl fumarate (ARR, 0.16; 95% CI, ). 51 Safety. Clinical trials showed no additional efficacy with dimethyl fumarate 240 mg three times daily compared with twice-daily regimens. 49,50 Therefore, the recommended dosage is 240 mg twice daily for the treatment of RRMS. 48 The overall adverse-effect profile of dimethyl fumarate was similar to that of placebo in clinical trials; flushing (31 38%) and gastrointestinal (i.e., nausea, vomiting, diarrhea, abdominal pain) effects (10 15%) occurred more frequently in patients receiving twice-daily dimethyl fumarate than in those receiving placebo. Severity was greatest during the first month of dimethyl fumarate therapy. 49,50 In the five-year extension study of the CONFIRM and DEFINE trials, patients continuing on longterm twice-daily dimethyl fumarate therapy reported substantially lower rates of flushing (9%) and gastrointestinal effects (8%) compared with short term use. 52 Mean white blood cell and lymphocyte counts were reduced approximately 10 12% and 28 32%, respectively, from baseline in patients receiving dimethyl fumarate in Phase III trials, with decreases noted during the first 12 months of therapy and no evidence of progression with continued use. 49,50,52 Four weeks after discontinuation of dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. 48 The frequency of infections was similar in patients receiving twice-daily dimethyl fumarate (56 64%) and those receiving placebo (50 65%); the frequency of serious infections was also comparable in both groups (2%). Opportunistic infections, including PML, have not been reported with dimethyl fumarate. Four cases of PML in patients receiving fumaric acid esters for psoriasis have been reported over 180,000 person-years of use in Germany; in all but one case, other risk factors for PML were present. 53 Malignant neoplasms occurred in less than 1% of patients receiving dimethyl fumarate in Phase III trials 49,50,52 ; however, the limited duration of follow-up (less than five years) precludes any assessment of potential long-term risk. Prolonged exposure to dimethyl fumarate has been associated with irreversible renal toxicity in animal studies at clinically relevant doses. 54 Clinical trial results do not suggest that dimethyl fumarate is associated with an increased risk of renal toxicity, with similar rates of proteinuria reported in patients receiving dimethyl fumarate (8 9%) and placebo (7 8%) 49,50 ; however, the duration of the studies may have been insufficient to detect renal toxicity in humans. 54 Preliminary safety results of the five-year extension of the DEFINE and CONFIRM trials reported adverse renal or urinary events in 18% of patients receiving twice-daily dimethyl fumarate, including proteinuria, microalbuminuria, and hematuria, with no evidence of worsening with continued use. 52 ALT levels were elevated to three or more times the upper limit of normal in twice as many patients receiving dimethyl fumarate compared with placebo (6% versus 3%, respectively) in the DEFINE trial but were similar across groups in the CONFIRM study. There were no differences in frequency of elevated bilirubin concentrations between dimethyl fumarate- and placebotreated patients. 49,50 In the five-year extension of the DEFINE and CONFIRM trials, ALT levels were similar to baseline values observed in the parent studies. 52 Collectively, these findings suggest that minimal adverse hepatic effects occur with dimethyl fumarate. Dimethyl fumarate is a pregnancy category C drug. While there have been no studies in pregnant women, clinically relevant doses in pregnant or lactating rats resulted in adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function. 48 A dimethyl fumarate pregnancy registry has been established to collect data to identify the risk of teratogenicity associated with dimethyl fumarate. No fetal anomalies were present in the 22 live births that were reported for patients with RRMS treated with dimethyl fumarate. 55 No newly emergent or worsening adverse effects with prolonged dimethyl fumarate exposure were detected in the 5-year extension study, representing 6133 person-years. 52 Although safety data associated with the long-term use of dimethyl fumarate itself are limited, no increased risk of renal toxicity and other adverse effects such as severe infection and malignancy have been found in the 20 years experience with fumaric acid esters in the treatment of psoriasis. 56 Postmarketing surveillance studies are warranted to further quantify the potential risks of longterm exposure to dimethyl fumarate in patients with RRMS. Dosage and administration. To reduce adverse gastrointestinal effects and flushing, dimethyl fumarate should be initiated at a dosage of 120 mg twice daily and increased to the maintenance dose of 240 mg twice daily after seven days. 48 Administration with food has been shown to decrease these adverse effects by approximately 25%. While not included in the product labeling, data from preliminary studies have shown that pretreatment with a 325-mg aspirin may reduce flushing. 54 Given the risk 34 Am J Health-Syst Pharm Vol 72 Jan 1, 2015