New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis.

Clinical Therapeutics/Volume ], Number ], 2015

New FDA-Approved Disease-Modifying Therapies for Multiple Sclerosis Clayton English, PharmD, BCPP1,2; and Joseph J. Aloi, PharmD, BCPS2 1

Albany College of Pharmacy & Health Sciences, Colchester, Vermont; and 2University of Vermont Medical Center, Burlington, Vermont

ABSTRACT Purpose: Interferon injectables and glatiramer acetate have served as the primary disease-modifying treatments for multiple sclerosis (MS) since their introduction in the 1990s and are first-line treatments for relapsing-remitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state that once had a limited treatment portfolio. The purpose of this review is to critically evaluate the safety profile and efficacy data of diseasemodifying agents for MS approved by the US Food and Drug Administration (FDA) from 2010 to the present and provide cost and available pharmacoeconomic data about each new treatment. Methods: Peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies were identified from MEDLINE (January 2000–December 2014) by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics. Citations from available articles were also reviewed for additional references. The databases publically available at www. clinicaltrials.gov and www.fda.gov were searched for unpublished studies or studies currently in progress. Findings: A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010. Peginterferon beta-1a and high-dose glatiramer acetate represent 2 new effective injectable options for MS that reduce burden of administration seen with traditional interferon and low-dose glatiramer acetate. Fingolimod, teriflunomide, and dimethyl fumarate represent new oral agents available for MS, and their efficacy in reducing annualized relapse rates is 48% to 55%, 22% to 36.3%, and 44% to 53%, respectively, compared with placebo. Alemtuzumab is a biologic given over a

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2-year span that reduced annualized relapse rates by 55% in treatment-naive patients and by 49% in patients relapsing on prior disease-modifying agents. Treatment emergent adverse effects were common with all new drug treatments. The cost of treating MS remains high, because MS therapies accounted for the highest spending growth of any specialty drug class in 2013. Most therapies cost, on average, US $6000/mo based on wholesale acquisition cost, and few cost–benefit studies are available for new treatments. Implications: With expansion of new treatments, patients and providers now have multiple options and improved flexibility in managing MS. The relative place in therapy of new treatments is unknown, and treatment decisions are largely based on patient preference, efficacy, and risk potential. The cost of treating MS continues to be high, even with more treatment options available. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: cost, disease-modifying treatments, multiple sclerosis, new drugs, pharmacotherapy.

INTRODUCTION Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system that often presents in persons between their second and fourth decade of life. The primary pathophysiologic feature of MS is demyelination and axonal destruction, leading to incomplete and poor nerve conduction and signaling. Symptoms of MS often depend on the severity, extension, and location of areas of inflammation and the course of the disease.1 Although there Accepted for publication March 3, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.03.001 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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Clinical Therapeutics is large variability in symptom manifestation and disease progression, MS is still the most common cause of non-traumatic disability in young adults and is associated with an average reduction in life span of 5 to 10 years.2,3 Because of the timing of onset and the disease burden on patients, MS can greatly affect patients financially. Annual direct medical costs per patient are approximately $47,000, with direct costs reaching 4$10 billion per year in the United States.4,5 Indirect costs such as disability, loss of employment, loss of productivity, and reduced quality of life can further increase the financial affliction of the disease. Before 1993, the treatment of MS had limited options for reducing relapses and hospitalizations. Therapy primarily consisted of treating acute exacerbations with corticosteroids, and no treatments altered the course of the illness. Interferon injectables and glatiramer acetate (GA), which were both released in the mid-1990s, offered new treatment options to decrease disease activity which were not previously available. These medications have served as the mainstay treatments for MS for the past 20 years and are still considered first-line treatments for relapsingremitting forms of MS (RRMS). Many new drug therapies were launched since early 2010, expanding the drug treatment options considerably in a disease state with once a limited treatment portfolio. Since this time new oral agents, modified release systems of older therapeutics, and new biologics have come to the forefront in treating MS. Many of these new agents offer better routes of administration, improvements in dosing flexibility, and improvements in decreasing relapses. A list of all disease-modifying agents approved by the Food and Drug Administration (FDA) is provided in Table I.6–17 Although many of the new treatments offer substantial advantages, disease-modifying agents make up most of the direct costs for patients with MS, with many of these new disease-modifying agents costing upward of $6000 per month.18 In addition, treatment emergent adverse effects are common with many of these therapies which can further complicate their use. This review summarizes the principle safety profile and efficacy data of FDA-approved disease-modifying agents for the treatment of MS incorporated into clinical practice within the past 5 years and provides available pharmacoeconomic and cost data about each new treatment.

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METHODS A literature search was performed with the MEDLINE search engine (January 2000–December 2014) for peer-reviewed clinical trials, pharmacoeconomic studies, and relevant pharmacokinetic/pharmacologic studies by using the search terms multiple sclerosis, fingolimod, teriflunomide, alemtuzumab, dimethyl fumarate, pegylated interferon, peginterferon beta-1a, glatiramer 3 times weekly, and pharmacoeconomics, Citations from available articles were also reviewed for additional references. The databases publically available at www.clinicaltrials.gov and www.fda.gov were searched for unpublished studies, studies currently in progress and approval history.

RESULTS A total of 5 new agents and 1 new dosage formulation were approved by the FDA for the treatment of RRMS since 2010.

Fingolimod Fingolimod* was the first, once-daily oral medication approved by the FDA in September 2010 for the treatment of RRMS. Fingolimod acts on the sphingosine-1-phospate receptor and blocks the capacity of lymphocytes to egress from lymph nodes, thus reducing the number of lymphocytes into the peripheral circulation to start the inflammatory cascade associated with myelin destruction.12,19 Relevant pharmacokinetic parameters for fingolimod and other oral disease-modifying agents are included in Table II.6,12,15 Fingolimod gained FDA approval on the basis of 2 randomized, double-blind, controlled trials titled FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) and TRANSFORMS (Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis).20,21 For both trials patients had to be 18 to 55 years of age, have a diagnosis of RRMS, and have Z1 documented relapses in the past year or two or more relapses in the past 2 years. Patients also had to have an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. The EDSS assesses disability, with higher scores indicating more severe disability. The primary outcome was to assess the annualized relapse rate (ARR), which is the number of confirmed relapses, or periods of symptom exacerbation, during a 12-month Trademark: Gilenyas (Novartis AG, Basel, Switzerland).

*

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C. English and J.J. Aloi Table I. FDA-approved disease-modifying treatments for multiple sclerosis.6–17 FDA approval

Year of approval

Usual treatment dose and route of administration

Interferon beta-1b*

RRMS

1993, 2009

Interferon beta-1a† Interferon beta-1a‡

RRMS RRMS

1996 2002

Glatiramer acetate§ Fingolimod║ Mitoxantrone¶

RRMS RRMS RRMS PRMS SPMS RRMS RRMS RRMS

1996, 2014 2010 2000

Starting dose: 0.0625 mg SC every other day Titration: increase over a 6-week period to 0.25 mg every other day Recommended dose: 0.25 mg SC every other day 30 mg IM once weekly Starting dose: 8.8 mg SC TIW Titration: After 2 weeks of initial dose increase to 22 mg SC TIW for 2 weeks, then titrate if needed Recommended dose: 22 or 44 ug SC TIW 20 mg SC daily or 40 mg SC TIW 0.5 mg PO once daily 12 mg/m2 IV infusion every 3 months

RRMS

2014

RRMS

2014

Treatment

Natalizumab# Teriflunomide** Dimethyl fumarate†† Peginterferon beta-1a‡‡ Alemtuzumab§§

2004 2012 2013

300 mg IV infusion every 4 weeks 7 mg or 14 mg PO once daily 120 mg PO twice a day for 7 days After 7 days: 240 mg PO twice a day 125 mg SC every 2 weeks First course: 12 mg/d infusion on 5 consecutive days Second course: 12 mg/d infusion on 3 consecutive days given 1 year after first treatment course

PRMS ¼ progressive-relapsing multiple sclerosis; RRMS ¼ relapsing-remitting multiple sclerosis; SPMS ¼ secondary progressive multiple sclerosis; TIW ¼ 3-times weekly. * Trademark: Betaserons (Bayer, Barmen, Germany); Extavias (Novartis Pharmaceuticals Corp, Basel, Switzerland). † Trademark: Avonexs (Biogen Idec, Cambridge, Massachusetts). ‡ Trademark: Rebifs (EMD Serono Inc, Rockland, Massachusetts). § Trademark: Copaxones (Teva Pharmaceutical Industries, Petah Tikva, Israel). ║ Trademark: Gilenyas (Novartis AG, Basel, Switzerland). ¶ Trademark: Novantrones (EMD Serono, Inc, Rockland, Massachusetts). # Trademark: Tysabris (Biogen Idec, Cambridge, Massachusetts). ** Trademark: Aubagios (Sanofi Aventis, Paris, France). †† Trademark: Tecfideras (Biogen Idec, Cambridge, Massachusetts). ‡‡ Trademark: PlegridyTM (Biogen Idec, Cambridge, Massachusetts). §§ Trademark: LemtradaTM (Genzyme Corporation, Cambridge, Massachusetts).

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Clinical Therapeutics Table II. Pharmacokinetics of oral disease-modifying agents for multiple sclerosis.6,12,15 Fingolimod

Teriflunomide

Bioavailability, %

93

100

Tmax, h Effects of food

12–16 None

1–4 None

Volume of distribution, L Protein binding, % Metabolism pathway

1200

11

499.7 CYP4F2 and to a minor degree by CYP2D6, CYP2E1, CYP3A4, and CYP4F12

99.5 Hydrolysis at to a minor degree through oxidation, N-acetylation, and sulfate conjugation Inhibitor of CYP2C8, BCRP, OAT3, OAT polypeptide 1B1 and OAT polypeptide 1B3 Inducer of CYP1A2 Rosuvastatin should be dosed reduced by 50% when given concurrently with teriflunomide Bile acid sequestrants increase clearance of teriflunomide

Drug interactions

Half-life Elimination

Dose adjustments in hepatic insufficiency

Dose adjustments in renal insufficiency

Few pharmacokinetic drug interactions based on metabolism with exception of ketoconazole. QT-prolonging drugs, vaccines, drugs that slow heart rate or AV conduction; antineoplastic, immunosuppressive, or immunomodulating therapies may have additional pharmacodynamic effects 6–9 days 81% excreted in urine as inactive metabolites None with mild-to-moderate hepatic impairment, monitor and consider adjustments with severe hepatic impairment None with severe renal impairment

Dimethyl fumarate Absolute is unknown; presumably high and well absorbed 2–2.5 Decrease in Cmax, but no change in AUC 53–73 27–45 Esterases for DMF, TCA for active metabolite MMF

None identified

20 days 37.5% in the feces and 22.6% in the urine (22.6%) over a 21-day period None with mild-to-moderate hepatic impairment; not studied in severe hepatic impairment

1 hour Exhalation of CO2 (60%), renal (16%), fecal (1%)

None with severe renal impairment

No studies, however, would not expect change in exposure

No studies, however, would not expect change in exposure

AV = atrioventricular; BCRP = breast cancer resistant protein transporter; DMF = dimethyl fumarate; MMF = monomethyl fumarate; OAT3 = organic anion transporter 3; TCA = tricarboyxlic acid cycle.

time frame. In the FREEDOM trial, fingolimod 0.5 mg/d had a lower ARR than placebo (ARR = 0.18; 95% CI, 0.15–0.22; P o 0.001).20 In the TRANSFORMS trial, fingolimod again decreased the annual relapses rates (ARR ¼ 0.16; 95% CI, 0.12–0.21; P o 0.001) at 12 months in

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patients with RRMS compared with intramuscular interferon beta-1a (ARR ¼ 0.33; 95% CI, 0.26–0.42; P o 0.001).21 Only the FREEDOMS study reported improvements with fingolimod treatment at reducing risk of disability progression (hazard ratio [HR] ¼ 0.70; 95% CI, 0.52–0.96; P ¼ 0.02).20 Both trials

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C. English and J.J. Aloi found statistically significant improvement compared with placebo on magnetic resonance imaging (MRI) outcomes, including changes in brain volume, enlarged T2 lesions, and gadolinium-enhancing lesions.20,21 A post hoc analysis of both trials analyzed the efficacy of fingolimod in early MS, which was defined as patients with symptoms for o3 years. ARR was reduced by 73.4% (P = 0.0002) compared with intramuscular interferon beta-1a and by 67.4% (P o 0.0001) compared with placebo.22 A large, double-blind, randomized, placebocontrolled trial, titled FREEDOMS II, was completed after the original approval date. The trial mimicked the first FREEDOM trial, but the patient population was older, had a longer duration of illness, and more patients had received previous treatment with a disease-modifying agent. The findings in the trial were largely similar to the FREEDOMS trial. Fingolimod decreased ARR (ARR ¼ 0.21; 95% CI, 0.17–0.25; P o 0.0001) compared with placebo (ARR ¼ 0.40; 95% CI, 0.34–0.48). In addition, the trial found statistical improvement in MRI outcomes similar to those achieved in the FREEDOMS study; however, no difference was found in confirmed disability progression with fingolimod compared with placebo (HR ¼ 0.83; 95% CI, 0.61 to 1.12; P ¼ 0.227).23 Several extension studies of previous trials were conducted for fingolimod, and their results, along with the pivotal phase 3 trials, are provided in Table III.20,21,23–27 The safety profile of fingolimod was also evaluated in the aforementioned studies.20,21 Notable adverse effects include bradycardia, atrioventricular conduction disturbances, decreased peripheral lymphocyte count, increased transaminases, macular edema, and infection (herpes zoster). Because of the bradycardia and atrioventricular blockade, pulse and blood pressure must be monitored for 6 hours after the initial dose, in addition to an electrocardiogram at baseline and 6 hours after dose. The package insert gives further guidance and recommendations about this monitoring and management if there are interruptions in therapy. Because of the risk of herpes infections (including herpes simplex encephalitis), patients without a clear history of chicken pox or without vaccination against varicella zoster virus should be tested for antibodies to varicella zoster virus. Vaccination of antibody-negative patients should be considered before initiating fingolimod, and therapy should be postponed for 1 month to allow the full effect of

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vaccination. Other monitoring includes baseline complete blood count and liver function tests within 6 months of the initiation of therapy and ophthalmologic examination at baseline and again at 3 to 4 months after initiation.12 In 2013, an FDA Drug Safety Communication was issued because of the development of progressive multifocal leukoencephalopathy (PML) in a patient on fingolimod. At the time of the report, Novartis reported that approximately 71,000 patients were treated with fingolimod. No final conclusions or recommendations were published by the FDA or the manufacturer. Providers should be aware of the risk of infectious complications, including PML, and review it with patients.28

Teriflunomide

Teriflunomide† is an oral disease-modifying agent for the treatment of RRMS approved by the FDA in September 2012.6 Teriflunomide is the active metabolite of leflunomide,‡ a disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis. The proposed mechanism of action of teriflunomide is that it inhibits dihydro-orotate dehydrogenase, an enzyme responsible for pyrimidine synthesis of nucleic acids. Through inhibition of this enzyme, teriflunomide halts the production of nucleic acids needed in the proliferation of activated lymphocytes and B cells involved in the inflammatory cascade responsible for myelin destruction.29 Pertinent pharmacokinetic parameters and drug interaction information for teriflunomide are reported in Table II.6 The approval of teriflunomide by the FDA was largely based on the results of a single phase 3, randomized, double-blind trial, titled TEMSO (Teriflunomide Multiple Sclerosis Oral Trial).30 In addition, 1 randomized, double-blind, placebo-controlled phase 2 study and 2 small randomized, double-blind, placebo add-on trials were used in the approval.31–33 The efficacy and safety profile data of the phase 2 and phase 3 studies are reviewed in Table IV.30–38 In the TEMSO study, 1088 patients with MS were randomly assigned to receive placebo, teriflunomide 7 mg/d, or teriflunomide 14 mg/d for 108 weeks. The primary efficacy end point was ARR. Patients enrolled in the trial were aged 18 to 55 years, had an EDSS †

Trademark: Aubagios (Sanofi Aventis, Paris, France). Trademark: Aravas (Sanofi Aventis, Paris, France).

‡

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Name of clinical trial (year); study type

Treatment (n)

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Kappos et al24 (2006); doubleblind, placebo-controlled, proof-of-concept study

Fingolimod 1.25 mg (83) Fingolimod 5 mg (77) Placebo (81) 6-month extension study, with placebo group randomly assigned to fingolimod Fingolimod 1.25 mg/placebo (40) Fingolimod 5mg / placebo (43) Fingolimod 1.25 mg (87) Fingolimod 5 mg (80)

O’Connor et al25 (2009); phase 2, double-blind, controlled, extension trial

Fingolimod Fingolimod Fingolimod Fingolimod

FTY720 D220126; phase 2 open-label, active drug extension

All patients were switched to 1.25 mg because of benefit–risk assessment by data safety monitoring board, indicating no efficacy advantage and possibly a less-favorable safety profile with the higher dose Fingolimod 1.25 mg (94) Fingolimod 5 mg to 1.25 mg (94) Fingolimod/placebo (93)

1.25 mg (87) 5 mg (80) 1.25 mg/placebo (40) 5 mg/placebo (43)

Treatment duration, mo 6 12 with extension

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36

Primary efficacy end point

Adverse events

Nasopharyngitis (17%–28%), Headache Gdþ-enhancing lesions on T1-weighted MRI at (19%–23%), ALT increased (10%–12%), 6 months, mean (SD) diarrhea (10%–12%), nausea (9%–11%), Fingolimod 1.25 mg: 1.29 (5.8); P o 0.001 vs placebo bradycardia Fingolimod 5 mg: 0.27 (0.7); P ¼ 0.006 vs placebo (0%–3%) Placebo: 2.21 (4.3) ARR at 6 months Fingolimod 1.25 mg: 0.35; P ¼ 0.009 vs placebo (relative reduction vs placebo ¼ 55% [95% CI, 18%–75%]) Fingolimod 5 mg: 0.36; P ¼ 0.01 vs placebo (relative reduction vs placebo ¼ 53% [95% CI, 14%–74%]) Placebo: 0.77 Gdþ-enhancing lesions on T1-weighted MRI at 12 months, mean (SD) Fingolimod 1.25 mg/placebo: 0.2 (0.6); P o 0.001 vs 6 months Fingolimod 5mg/placebo: 0.4 (0.7); P ¼ 0.004 vs 6 months Fingolimod 1.25 mg: 1 (6.4); P ¼ 0.34 vs 6 months Fingolimod 5 mg: 0.2 (0.5); P ¼ 0.24 vs 6 months ARR at 12 months Fingolimod 1.25 mg/placebo ¼ 0.21 Fingolimod 5 mg/placebo: 0.10 Fingolimod 1.25 mg: 0.29 Fingolimod 5 mg: 0.23 Nasopharyngitis (13%–26%), headache (11%– Gdþ-enhancing lesions on T1-weighted MRI at 24 19%), lymphopenia (9%–15%), ALT months, mean (SD) increased (5%–14%), depression (4%–12%) Fingolimod 1.25 mg/placebo: 0.2 (0.4) Fingolimod 5 mg/placebo: 0.2 (0.6) Fingolimod 1.25 mg: 0.7 (3.0) Fingolimod 5 mg: 0.2 (0.5) ARR months 7–24 Fingolimod 1.25 mg/placebo: 0.26 Fingolimod 5 mg/placebo: 0.12 Fingolimod 1.25 mg: 0.14 Fingolimod 5 mg: 0.17 Infection (70.5%), headache (30%), fatigue Gdþ-enhancing lesions on T1-weighted MRI at (19%), increased ALT (15%), lymphopenia 36 months, mean (SD) (14%), back pain (14%), nausea (10%), Mean number of Gd-enhanced lesions across all groups hypertension (10%), extremity pain (11%), was 0.2 serious infection (1.4%) ARR months 7–24 Fingolimod 1.25 mg/placebo: 0.31 Fingolimod 1.25 mg: 0.2 Fingolimod 5 mg/1.25 mg: 0.21

(continued)

Clinical Therapeutics

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Table III. Pivotal clinical studies on the use of fingolimod in multiple sclerosis.20,21,23–27

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Table III. (continued). Name of clinical trial (year); study type

Treatment (n)

Treatment duration, mo

Fingolimod 0.5 mg (425) Fingolimod 1.25 mg (429) Placebo (418)

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TRANSFORMS21; phase 3 randomized, controlled trial

Fingolimod 0.5 mg (431) Fingolimod 1.25 mg (426) Interferon beta-1a 30 mg (435)

12

TRANSFORMS Extension trial27

Fingolimod 0.5 mg continuous (356) Fingolimod 1.25 mg continuous (330) Patients on interferon in TRANSFORMS trial were reassigned to either fingolimod 0.5 mg or 1.25 mg Interferon to fingolimod 0.5 mg (167) Interferon to fingolimod 1.25 mg (174)

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Adverse events

Headache (25%), abnormal liver function tests ARR, n (95% CI) (15.8%–18.6%), bradycardia (2.1%–3.3%), Fingolimod 1.25 mg: 0.16 (0.13–0.19) AV block (0.5%–1.2%), diarrhea (9.3%– Fingolimod 0.5 mg: 0.18 (0.15–0.22) 11.8%), infection (69%–72%), serious Placebo: 0.40 (0.34–0.47) infection (1.6%–2.6%) P o 0.001 for both fingolimod groups vs placebo Change in EDSS score, mean (SD) Fingolimod 1.25 mg: 0.03 (0.288) Fingolimod 0.5 mg: 0.00 (0.88) Placebo: 0.13 (0.94) P o 0.002 for both fingolimod groups vs placebo Infection, headache (23%), fatigue (10.3%– Primary end point: ARR 14%), nausea (6.7%–9.3%), herpes virus Secondary end points: number of new/enlarged infection (0.2%–0.7%), bradycardia, (0.5%– lesions on MRI; progression of disability sustained 2.4%, AV block (0.2%–0.7%), macular for 3 months edema (0.5%–1%) ARR, n (95% CI) Fingolimod 1.25 mg: 0.20 (0.16–0.26) Fingolimod 0.5 mg: 0.16 (0.12–0.23) Interferon: 0.33 (0.26–0.42) P o 0.001 for both fingolimod groups vs interferon New/enlarged lesions on T2-weighted MRI images, mean (SD) Fingolimod 1.25 mg: 1.5 (2.7) Fingolimod 0.5 mg: 1.7 (3.9) Interferon: 2.6 (5.8) P o 0.001 for both fingolimod groups vs interferon Patients with no confirmed disability progression, % (95% CI) Fingolimod 1.25 mg: 93.3 (90.9–95.8), P ¼ 0.5 vs interferon Fingolimod 0.5 mg: 94.1 (91.8–96.3); P 0.25 vs interferon Interferon: 92.1 (89.4–94.7) Infection (50%–58%), lymphopenia (12%– ARR, n (95% CI) 18%), headache (14%–20%), bradycardia Fingolimod 0.5 mg continuous: 0.18 (0.14–0.22) (1%), macular edema (1%), neoplasms Fingolimod 1.25 mg continuous: 0.2 (0.16–0.25) Interferon to fingolimod: 0.33 (0.27 to 0.39); P o 0.0001 (1%) for both comparisons 30% and 36% relative reductions in ARR during months 13– 24 in patients switched from IFN to fingolimod 0.5 mg (ARR ¼ 0.7; 95% CI, 0.49–1.00; P ¼ 0.049) and 1.25 mg (ARR ¼ 0.64; 95% CI, 0.43–0.94; P ¼ 0.024), respectively Number of new/enlarged T2 lesions, mean (SD) Fingolimod 0.5 mg continuous: 2.5 (4.51) Fingolimod 1.25 mg continuous: 2.4 (4.00)

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(continued)

C. English and J.J. Aloi

FREEDOMS20 ; phase 3 placebo-controlled, randomized trial



FREEDOMS II23; phase 3 randomized, placebocontrolled trial

Treatment (n)

Fingolimod 0.5 mg (358) Fingolimod 1.25mg (370) Placebo (355)


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Primary efficacy end point Interferon to fingolimod: 3.3 (5.25) P ¼ 0.035 fingolimod 0.5 vs interferon/fingolimod P o 0.068 fingolimod 1.25 vs interferon/ fingolimod groups Changes in EDSS, mean (SD) Interferon to fingolimod 0.5 mg: 0.02 (1.352) Interferon to fingolimod 1.25 mg: 0 (1.276) P ¼ NS Primary end point: ARR Secondary end point: PBVC; time-to-disability progression at 3 months ARR, n (95% CI) Fingolimod 1.25 mg: 0.20 (0.17–0.25) Fingolimod 0.5 mg: 0.21 (0.17–0.25) Placebo: 0.4 (0.34–0.48) P o 0.001 for both fingolimod group vs placebo PBVC, mean (SD) Fingolimod 1.25 mg: 0.595% (1.390%) Fingolimod 0.5 mg: 0.858% (1.222%) Placebo: 1.279% (1.503%) P o 0.001 for both fingolimod groups vs placebo Patients without disability progression at 3 months, % (95% CI) Fingolimod 1.25 mg: 78.3 (73.7–82.9); P ¼ 0.056 vs placebo Fingolimod 0.5 mg: 74.7 (69.9–79.5); P ¼ 0.320 vs placebo Placebo: 71 (65.9–76.1)

Adverse events

Infection (73%), headache (23%), nausea (15%–18%), lymphopenia (8%–-10%), bradycardia (1%–2%), abnormal liver function tests (3%–-10%), AV block (1%– 2%), macular edema (1%)

ALT ¼ alanine transaminase; ARR ¼ annualized relapse rate; AV ¼ atrioventricular; EDSS ¼ Expanded Disability Status Scale; FREEDOMS ¼ FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis; Gdþ ¼ gadolinium; IFN ¼ interferon; MRI ¼ magnetic resonance imaging; NS ¼ not significant; PBVC ¼ percentage of brain volume change; TRANSFORMS ¼ Trial Assessing Injectable Interferon versus FTY720 Oral in Relapsing–Remitting Multiple Sclerosis.


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Table III. (continued).

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C. English and J.J. Aloi score of 0 to 5.5, and had at least 1 relapse in the previous year or at least 2 relapses in the previous 2 years. Patients were prevented from entering the trial if they were pregnant, had intentions to become pregnant, or had other systemic diseases. Both dosages of teriflunomide were superior to placebo in reducing relapse rate, 31.2% relative reduction in the 7-mg/d group and 31.5% reduction in the 14-mg/d group (P o 0.001 for both teriflunomide treatment arms). The ARR was 0.54 and 0.37 for placebo and both teriflunomide groups, respectively. Both teriflunomide groups found superiority to placebo in preventing disability progression and had improvements on multiple MRI outcomes, including total lesion volume, unique active lesions per scan, and gadoliniumenhancing lesions.30 A post hoc analysis of TEMSO was conducted to assess health care use and neurologic sequelae. Both doses of teriflunomide significantly reduced annualized rates of relapses with neurologic complications on the basis of the EDSS/Functional System (P ¼ 0.0019 for 7 mg/d, P ¼ 0.0011 for 14 mg/d), relapses with neurologic complications on the basis of investigator determination (P ¼ 0.071 for 7 mg/d, P o 0.0001 for 14 mg/d), relapses that required hospitalization (P ¼ 0.015 for 7 mg/d, P o 0.0001 for 14 mg/d), fewer nights spent in the hospital for relapses (P o 0.001 for both groups), and relapses that required intravenous corticosteroids (P ¼ 0.001 for 7 mg/d and P ¼ 0.0003 for 14 mg/d). In addition, the 14-mg/d treatment group decreased emergency department visits (P ¼ 0.004) and annualized rates of all hospitalizations (P ¼ 0.01).39 The results of TEMSO were confirmed in the TOWER (Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis) study, which had a similar design to TEMSO. TOWER was the second large, double-blind, randomized, placebocontrolled trial that evaluated the efficacy of teriflunomide at reducing annualized relapse. A total of 1169 patients aged 18 to 55 years with RRMS were randomly assigned to teriflunomide 7 mg/d, teriflunomide 14 mg/d, and placebo. For eligibility patients had to have an EDSS score of r5.5, had 1 relapse in the past year, or 2 relapses in the past 2 years. In addition patients could not have had a relapse 30 days before being randomly assigned to treatment, or received disease-modifying agents 3 months before being randomly assigned to treatment. Furthermore, patients

] 2015

who were pregnant, breastfeeding, or planning to conceive were excluded along with patients with other serious medical conditions. Patients who had received natalizumab were not allowed entry into the trial. The ARR was 0.5 (95% CI, 0.43–0.58), 0.39 (95% CI, 0.33–0.46), and 0.32 (95% CI, 0.7–0.38) for placebo, teriflunomide 7 mg/d, and teriflunomide 14 mg/d, respectively. A 22.3% reduction (95% CI, 4.2%– 37.0%; P ¼ 0.0183) in ARR was seen in the teriflunomide 7-mg/d treatment arm and a 36.3% reduction in ARR was seen in the teriflunomide 14-mg/d group (95% CI, 20.7%–48.8%; P ¼ 0.0001). Only the 14-mg/d dose of teriflunomide showed significant improvement in time to sustained accumulation of disability (HR ¼ 0.68; 95% CI, 0.47–1.00; P ¼ 0.0442).35 A post hoc analysis of TOWER was conducted similar to one used in the TEMSO study. Both doses of teriflunomide significantly reduced annualized rates of relapses with neurologic complications that were based on EDSS/Functional System (P ¼ 0.0104 for 7 mg/d, P ¼ 0.0021 for 14 mg/d) and relapses that required intravenous corticosteroids (P ¼ 0.0337 for 7 mg/d, P ¼ 0.0002 for 14 mg/d). In addition, the 14-mg/d treatment group decreased relapses with neurologic complications according to investigator determination (P ¼ 0.0004), relapses that required hospitalizations (P ¼ 0.0155), intense relapses (P ¼ 0.0015), nights spent in the hospital for a relapse (P ¼ 0.009), and annualized rates of all hospitalizations (P ¼ 0.030).40 In addition to the TOWER trial, 2 additional phase 3 trials were published and 1 phase 2 study was published since the approval of teriflunomide. The one phase 2 study, TERIVA (Teriflunomide Effect on Immune Response to Influenza Vaccine in Patients with Multiple Sclerosis), investigated the effect on teriflunomide on immune response to the influenza vaccine. Patients treated with teriflunomide generated effective immune responses to the seasonal influenza vaccination.34 One of the phase 3, randomized, double-blind, placebo-controlled trials, titled TOPIC (Teriflunomide versus Placebo in Patients with First Clinical Symptom of Multiple Sclerosis), assessed the time to relapse in patients with clinically isolated syndrome treated with teriflunomide. A total of 608 patients aged 18 to 55 years with clinically isolated syndrome (defined as a neurologic event consistent with demyelination with Z2 T2-weighted MRI lesions at least 3 mm in

9


Volume ] Number ]

Treatment (n)

Treatment duration


Safety end points

O’Connor et al31 (2006); phase 2, randomized, placebo-controlled, double-blind clinical trial

Placebo (61), teriflunomide 7 mg (61), teriflunomide 14 mg (57)

36 weeks

Alopecia, nausea, ALT increase, paresthesia, nasopharyngitis, back pain, diarrhea, limb pain, and arthralgia were more common in teriflunomide treatment groups than with placebo.

Confavreux et al38 (2012); phase 2 open-label extension trial

Teriflunomide 7 mg (81), teriflunomide 14 mg (66)

528 weeks

Number of combined unique active lesions on MRI in patients with RRMS, (mean ⫾ SE) Placebo: 0.5 (2.68 ⫾ 0.39) Teriflunomide 7 mg/d: 0.2 (1.04 ⫾ 0.37); P o 0.03 Teriflunomide 14 mg/d: 0.3 (1.06 ⫾ 0.38); P o 0.01 Primary end point was safety

Freedman et al32 (2012); phase 2 randomized, placebo-controlled, double-blind adjunctive therapy trial to interferonbeta

Placebo þ interferon-beta (41), teriflunomide 7 mg þ interferonbeta (37), teriflunomide 14 mg þ interferon-beta (38)

24 weeks with 24-week extension

Primary assessment was safety and adverse effects

Study 604633; phase 2 randomized, placebocontrolled, double-blind adjunctive therapy trial to glatiramer acetate TERIVA34; phase 2 study to assess immune response to influenza vaccine

Placebo þ glatiramer acetate (41), teriflunomide 7 mg þ glatiramer acetate (42), teriflunomide þ glatiramer acetate (40)

24 weeks

Primary assessment was safety and adverse effects

Teriflunomide 7 mg þ influenza vaccine (41), teriflunomide 14 mg þ influenza vaccine (41), interferon beta-1 (46)

28 days

Primary end point was safety

Fatigue, sensory disturbances, diarrhea, and mild infections were the most common reported adverse effects. Discontinuation of treatment occurred in 18.5% of patients who received teriflunomide 7 mg/d and 19.7% of patients who received teriflunomide 14 mg/d secondary to adverse effects. Increased ALT, increased AST, diarrhea, urinary tract infection, fatigue, nasopharyngitis, decreased lymphocyte count, headache, and decreased white blood cell count were the most common reported adverse effects. Discontinuation of treatment secondary to adverse effects occurred in 8.1% of patients who received teriflunomide 7 mg/d and 7.9% of patients who received teriflunomide 14 mg/d at the end of 48 weeks. Discontinuation of treatment secondary to adverse effects occurred in 7.1% of patients who received 7 mg/d and 12.2% of patients who received 14 mg/d at the end of 24 weeks. All treatment groups mounted an effective immune response to the seasonal influenza vaccine on the basis of antibody titers 440 at day 28.

(continued)


10

Table IV. Pivotal clinical studies on the use of teriflunomide in multiple sclerosis.30–37

] 2015

Table IV. (continued). Name of clinical trial (year); study type

Treatment duration


Safety end points

TEMSO30; phase 3, randomized, doubleblind, placebo-controlled trial


108 weeks

ARR, n (95% CI) Placebo: 0.54 (0.47–0.62) Teriflunomide 7 mg: 0.37 (0.32–0.43); P o 0.001 vs placebo Teriflunomide 14 mg: 0.37 (0.31–0.44); P o 0.001 vs placebo

TOWER35; phase 3 randomized, doubleblind, placebo-controlled trial35


Variable; ended 48 weeks after last patient was randomly assigned to treatment

ARR, n (95% CI) Placebo: 0.50 (0.43–0.58) Teriflunomide 7 mg: 0.39 (0.33–0.46) Teriflunomide 14 mg: 0.32 (0.27–0.38)

TOPIC36; phase 3, randomized, doubleblind, placebo-controlled trial


108 weeks

Time to relapse in patients with clinically isolated syndrome Placebo: 28% relapsed Teriflunomide 7 mg/d: 19% relapsed (HR ¼ 0.628; 95% CI, 0.416–0.949); P ¼ 0.0271 vs placebo Teriflunomide 14 mg/d: 18% relapsed (HR ¼ 0.574; 95% CI, 0.379–0.869); P ¼ 0.0087 vs placebo

TENERE37; phase 3, randomized, rater-blinded clinical trial

Interferon beta-1a 44 mg SC (104), teriflunomide 7 mg (109), teriflunomide 14 mg (111)

Variable; ended 48 weeks after last patient randomly assigned to treatment

Time to failure (confirmed relapse or any-cause treatment discontinuation) Interferon beta-1a 44 mg: 42.3% treatment failure Teriflunomide 7 mg/d: 48.6% treatment failure

Nasopharyngitis, headache, diarrhea, fatigue, increased ALT, nausea, alopecia, influenza, back pain, and urinary tract infection were the most common reported adverse effects. Discontinuation of treatment secondary to adverse effects occurred in 9.8% of patients who received teriflunomide 7 mg/d and 10.9% of patients who received teriflunomide 14 mg/d. Increased ALT, alopecia, headache, nasopharyngitis, diarrhea, fatigue, and nausea were the most common reported adverse effects. Discontinuation of treatment secondary to adverse effects occurred in 13% of patients who received teriflunomide 7 mg/d and 16% of patients who received teriflunomide 14 mg/d. Increased ALT, alopecia, headache, nasopharyngitis, diarrhea, paraesthesia, and upper respiratory tract infection were the most common reported adverse effects. Discontinuation of treatment secondary to adverse effects occurred in 12% of patients who received teriflunomide 7 mg/d and 10% of patients who received teriflunomide 14 mg/d. Diarrhea, nasopharyngitis, alopecia, paresthesia, and back pain were more frequently reported with teriflunomide than with interferon beta-1a. Discontinuation of treatment secondary to adverse effects occurred in 8.2% of patients who received teriflunomide 7

11

(continued)


Treatment (n)

12

mg/d and 10.9% of patients who received teriflunomide 14 mg/d. Teriflunomide 14 mg/d: 37.8% treatment failure No statistical difference between probability of treatment failure between teriflunomide and interferon beta-1a.

ALT ¼ alanine aminotransferase; ARR ¼ annualized relapse rate; AST ¼ aspartate aminotransferase; HR ¼ hazard ratio; TEMSO ¼ Teriflunomide Multiple Sclerosis Oral Trial; TENERE ¼ The Teriflunomide and Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis trial; TERIVA ¼ Teriflunomide Effect on Immune Response to Influenza Vaccine in Patients with Multiple Sclerosis; TOPIC ¼ Teriflunomide versus Placebo in Patients with First Clinical Symptom of Multiple Sclerosis; TOWER ¼ Teriflunomide Oral in People with Relapsing-Remitting Multiple Sclerosis.


Table IV. (continued).

Treatment (n)

Treatment duration


Safety end points

Clinical Therapeutics diameter present on scan, and occurring within 90 days of randomization) were randomly assigned to receive placebo, teriflunomide 7 mg/d, or teriflunomide 14 mg/d for up to 108 weeks. Patients were not allowed entry into the trial if they were pregnant, planning to conceive, breastfeeding, had serious medical conditions, received steroids 2 weeks before being randomly assigned to treatment, or had ever received disease-modifying treatment for MS. Patients had a 42.6% and 37.2% reduction in time to relapse (confirming true MS) with teriflunomide 14mg/d (P ¼ 0.0087) and 7 mg/d (P ¼ 0.0271), respectively. Patients who received placebo had a higher incidence of relapse (28%) than patients who received teriflunomide 7 mg/d (19%) and teriflunomide 14 mg/d (18%). TOPIC represents the first study to confirm an oral disease-modifying agent of having efficacy in early MS. Teriflunomide may have a role in treatment of patients with early clinical features of MS.36 One head-to-head comparative efficacy study exists for teriflunomide, titled TENERE (The Teriflunomide and Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis trial). TENERE was designed as a randomized, controlled, raterblinded study to evaluate the time to failure between teriflunomide and subcutaneous interferon beta-1a 44 mg given 3 times a week. Failure was defined as any-cause treatment discontinuation or confirmed relapse. A total of 324 patients aged Z18 years with RRMS and an EDSS score o5.5 at baseline were randomly assigned to receive teriflunomide 7 mg/d, teriflunomide 14 mg/d, or subcutaneous interferon beta-1a 44 mg 3 times a week. Patients were excluded from the study if they were not relapse free 30 days before being randomly assigned to treatment or if they had used any disease-modifying agents within 3 months of treatment. In addition, patients could not be in the trial if they were pregnant, planning on conceiving, or had serious medical illnesses that could affect the trial. No difference was found in time to failure between the teriflunomide groups and the interferon beta-1a group. The cumulative percentage of estimated failures that were based on Kaplan-Meier analysis was 59% in the teriflunomide 7-mg/d treatment arm, 41% in the teriflunomide 14-mg/d treatment arm, and 44% in the subcutaneous interferon beta-1a treatment arm. ARR, a secondary end point, was significantly lower in the interferon beta-1a group (ARR ¼ 0.22; 95% CI, Volume ] Number ]

C. English and J.J. Aloi 0.11–0.42) than in the teriflunomide 7-mg/d group (ARR ¼ 0.41; 95% CI, 0.27–0.64; P ¼ 0.03). No statistical difference was found in ARR between interferon beta-1a and teriflunomide 14 mg/d (ARR ¼ 0.26; 95% CI, 0.15–0.44).37 The safety profile and tolerability of oral teriflunomide was assessed in all clinical trials, and adverse effects were pooled in a combined safety profile analysis that was updated in the package insert in 2014.6,41 Safety profile data were pooled from 4 double-blind studies: TEMSO, TOWER, TOPIC, and the proof-of-concept phase 2 trial. A total of 2047 patients received teriflunomide, both 7-mg and 14-mg dosages. Adverse effects reported in 410% of the study population were headache (18%), increase in alanine aminotransferase (13%), diarrhea (13%), and alopecia (10%) for the 7-mg/d treatment group. Headache (16%), increase in alanine aminotransferase (15%), diarrhea (14%), alopecia (13%), and nausea (11%) represented the adverse effects reported in 410% in the 14-mg treatment arm. The most common cause of discontinuation was an increase in alanine aminotransferase, which occurred in 3.3% and 2.6% of patients receiving teriflunomide 7 mg/d and 14 mg/d, respectively. Elevations in alanine aminotransferase 43 times the upper limit of normal occurred in 5.8% and 6.2% of patients who received teriflunomide 7 mg and 14 mg/d, respectively. Elevations in liver enzymes occurred more frequently in the first year of treatment. Monitoring of liver function tests should be completed at baseline, then monthly for the first 6 months, then every 6 months while patients receive teriflunomide. Within the pooled analysis, 1 patient was hospitalized for liver injury. Teriflunomide could not be excluded as a cause of the injury. Discontinuations due to adverse effects were higher in both the teriflunomide 14-mg/d treatment arm (12.5%) and 7-mg/d treatment arm (11.2%) than placebo (7.5%). No malignancies or lymphoproliferative disorders were noted in the pooled analysis, although the trials were not long enough to determine this risk. Risk of serious infection was no different between teriflunomide 7 mg (2.2%), teriflunomide 14 mg (2.7%), or placebo (2.2%). One death related to Klebsiella pneumonia sepsis occurred in a patient who received the 14-mg/d dose. Two other deaths occurred in the teriflunomide treatment arms, but they were unrelated to teriflunomide treatment. Other notable but less common adverse effects associated with

] 2015

teriflunomide include peripheral neuropathy (1.1%– 1.9%), hypertension (3.1%–4.3%), and rash.6,41 Teriflunomide possesses teratogenic potential because of its ability to inhibit nucleic acid synthesis, and it has a pregnancy category X rating by the FDA. Contraception is recommended both for women and men, because teriflunomide was detected in human semen. Patients who become pregnant on teriflunomide should undergo rapid elimination with cholestyramine to reduce the risk of fetal complications and abnormalities.6

Dimethyl Fumarate Dimethyl fumarate,§ previously known as BG-12 or DMF, is a newer oral agent for the management of RRMS that was approved by the FDA in March 2013. The mechanism of action is not completely understood, but DMF and its metabolite, monomethyl fumarate (MMF), were reported to activate the nuclear factor (erythroid-derived 2)-like 2 pathway that is involved in the cellular response to oxidative stress. MMF was identified as a nicotinic acid receptor agonist.15 On the basis of this mechanism, DMF may have protective properties for neurons and could further modulate immune response. MMF primarily is responsible for the mechanism of action, because DMF is rapidly hydrolyzed presystemically by esterases into MMF. Pharmacokinetic data for DMF are based only on MMF, because no quantifiable level of DMF is reached in the body. Pharmacokinetic information for DMF and MMF is provided in Table II.15 The approval of DMF was based on 1 small phase 2 study and 2 large, placebo-controlled, phase 3 studies titled CONFIRM (Comparator and an Oral Fumarate in RRMS) and DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS).42–44 To enter the phase 3 studies, patients had to be 18 to 55 years of age, have a diagnosis of RRMS, have a score of 0 to 5 on the EDSS, and have evidence of 1 clinical documented relapse within the past 12 months. In the DEFINE and CONFIRM trials, DMF significantly reduced annual relapse rates over a period of 2 years with a 47% reduction seen in the DEFINE trial for twice-daily DMF (95% CI, 37%– 61%; P = 0.01) and a 44% reduction seen in the Trademark: Tecfideras Massachusetts).

§

(Biogen

Idec,

Cambridge,

13

Clinical Therapeutics CONFIRM trial for twice-daily DMF (95% CI, 26%– 57.7%; P r 0.01). In addition both studies found significant improvements on secondary MRI outcomes compared with placebo.42,43 In the DEFINE study, the rate of disability progression, as measured by the EDSS, was significantly improved with twice-daily DMF (HR = 0.62; 95% CI, 0.44–0.87; P = 0.005).43 This result was not seen in the CONFIRM trial. In addition, 4 post hoc analyses were conducted on the basis of data from the DEFINE and CONFIRM studies to assess health-related quality of life and to investigate efficacy in subgroup populations. Patients treated with dimethyl fumarate showed improvements in health-related quality of life, and dimethyl fumarate was effective across the range of subgroups analyzed, regardless of treatment history, demographic characteristics, and disease characteristics at baseline.45–48 Efficacy and safety profile results of the phase 2 and phase 3 studies for DMF are shown in Table V.42–44 The safety profile of DMF was also evaluated in the DEFINE and CONFIRM studies which were pooled together for the safety profile analysis that consisted of 769 patients.42,43 The most common side effects include flushing (40%), nausea (12%), abdominal pain (18%), and diarrhea (14%). The flushing is generally self-limiting, lasting about a week and can be prevented by taking DMF with food or premedication with aspirin. The gastrointestinal side effects are also commonly self-limiting, lasting 2 to 4 weeks after initiating DMF. Other adverse reactions include lymphopenia and elevations in hepatic transaminases. Because of the risk of lymphopenia, it is recommended that a complete blood count be available before initiating therapy, yearly, and as clinically indicated. In studies, the increase in aspartate aminotransferase was seen in 4% of the treatment population, occurring primarily during the first 6 months of therapy.15 Although the US package insert does not require hepatic transaminases, many clinicians obtain them at baseline and after 6 months of therapy. In November 2014, the FDA released a Drug Safety Communication because of a case of PML in a patient on DMF.49 The patient was not taking any other drugs known to affect the immune system or that were associated with PML. The patient ultimately died. In addition, 4 cases of PML treated with other forms of fumaric acid derivatives were reported.50 To date, the FDA or Biogen Idec, the manufacturer of DMF, has provided no changes to

14

the product labeling or final recommendations. Longterm safety profile analysis is currently being investigated with DMF.51

High-Dose GA

GA,║ which was approved as a 20-mg once-daily injectable treatment of RRMS since 1996, is now available in a new dosage form that offers a higher dose that is administered three times weekly. The new dosage form was approved by the FDA in January 2014. The new formulation is similar to the traditional dosage form, which functions as a synthetic amino acid sequence (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine) that resembles myelin-based protein.52 GA can serve as a decoy to the pathogenic attack of myelin sheath and functions multifactorially as an immunomodulator in transitioning T-helper activation from a type 1 T helper proinflammatory immune-mediated response to type 2 T helper cell response.53 Previous trials investigated high-dose (40 mg) oncedaily GA for treatment of RRMS. In these trials, highdose GA found a similar adverse effect profile to low-dose GA; however, no significant difference was found in primary outcomes for the high-dose versus standard-dose treatment.54,55 Dosages of GA are largely hydrolyzed at the injection site. The AUC for GA administration has a large variation, with singleand multiple-dose administrations appearing similar.56 On the basis of similar efficacy and no substantial differences in pharmacokinetics, less-frequent dosing could potentially be used. On the basis of this information, investigators assessed the efficacy and safety profile of highdose–low-frequency GA in 1 double-blind, randomized, placebo-controlled trial with 943 patients randomly assigned to receive GA 40 mg 3 times a week and 461 patients to receive placebo. The primary outcome measure for the trial was number of confirmed relapses during a 12-month period in an intention-to-treat population. Patients who received 3 times weekly GA had a 34% reduction in confirmed relapses compared with placebo (relative risk ¼ 0.656; 95% CI, 0.539–0.799; P o 0.0001). On secondary MRI imaging outcomes, patients 2 who received 3 times a week GA reported a 45% and ║

Trademark: Copaxones (Teva Pharmaceutical Industries, Petah Tikva, Israel).

Volume ] Number ]

] 2015

Table V. Pivotal clinical studies on the use of dimethyl fumarate in multiple sclerosis.42–44 Name of clinical trial (year); study type

Treatment (n)

Treatment duration

Kappos et al44 (2008); randomized, placebo-controlled trial

DMF 120 mg/d (64) DMF 240 mg/d (64) DMF 720 mg/d (63) Placebo (65)

24 weeks

CONFIRM42; phase 3 randomized, placebo-controlled trial

DMF 480 mg/d (359) DMF 720 mg/d (345) Glatiramer acetate 20 mg/d (350) Placebo (363)

24 months

DMF 480 mg/d (410)

24 months

DEFINE43; phase 3 randomized, placebo-controlled trial43

DMF 720 mg/d (416) Placebo (408)

Primary efficacy end point Gdþ-enhancing lesions on MRI, mean (SD) DMF 120 mg/d: 3.3 (5.1) DMF 240 mg/d: 3.1 (5.9) DMF 720 mg/d: 1.4 (3.8) Placebo: 4.5 (7.4) ARR, n (95% CI) DMF 120 mg/d: 0.42 (0.24–0.71); P ¼ 0.196 vs placebo DMF 240 mg/d: 0.78 (0.52–1.16); P ¼ 0.572 vs placebo DMF 720 mg/d: 0.44 (0.26–0.76); P ¼ 0.272 vs placebo Placebo: 0.65 (0.43–1.01) ARR, n (95% CI); relative reduction vs placebo DMF 480 mg/d: 0.22 (0.18–0.28); 44%; P o 0.001 DMF 720 mg/d: 0.20 (0.16–0.25); 50.5%; P o 0.001

Flushing (47%), headache (15%), nausea (10%), diarrhea (10%), abdominal pain (5%–9%)

Flushing (24%–31%), headache (13%–14%), diarrhea (13%–15%), nausea (11%–15%)

Flushing (32%–38%), diarrhea (15%–19%), nausea (13%), abdominal pain (9%–12%)

15

ARR ¼ annualized relapse rate; CONFIRM ¼ Comparator and an Oral Fumarate in RRMS; DEFINE ¼ Determination of the Efficacy and Safety of Oral Fumarate in RRMS; DMF ¼ dimethyl fumarate; Gdþ ¼ gadolinium; MRI ¼ magnetic resonance imaging; RRMS ¼ relapsing remitting forms of multiple sclerosis.


Glatiramer acetate 20 mg/d: 0.29 (0.23–0.35); 28.6%; P o 0.05 Placebo: 0.40 (0.33–0.49) Proportion of patients who had a relapse at 24 months, %; hazard ratio vs placebo (95% CI) DMF 480 mg/d: 27; 0.51 (0.40–0.66); P o 0.001 DMF 720 mg/d: 26; 0.5 (0.39–0.65); P o 0.001 Placebo: 46 ARR, n (95% CI) DMF 480 mg/d: 0.17 (0.14–0.21) DMF 720 mg/d: 0.19 (0.15–0.23) Placebo: 0.36 (0.3–0.44) Time to confirmed progression of disability Gdþ-enhancing lesions on MRI, mean (SD) DMF 480 mg/d: 0.1 (0.6) DMF 720 mg/d: 0.5 (1.7) Placebo: 1.8 (4.2)

Adverse events

Clinical Therapeutics 35% reduction in cumulative number of T1 lesions and T2 lesions, respectively (P o 0.0001). Percentage of change in normalized brain volume was not significantly different between the treatment groups. In addition to imaging outcomes, time to first relapse was lower in patients who received 3 times a week GA than in patients who received placebo, 393 days versus 377 days, respectively (HR ¼ 0.606; 95% CI 0.439–0.744; P o 0.001). The overall reduction of annualized rate of severe relapse with GA 3 times a week was 35%. No direct efficacy and safety profile studies were conducted to date versus traditional disease-modifying agents. Injection-site reactions that consist of erythema, itching, and injection site pain remain the most common adverse effect with highdose GA (35.2% versus 5% with placebo).57

PEGylated Interferon Beta-1a Pegylated interferon beta-1a or peginterferon beta1a¶ was approved by the FDA for the treatment of RRMS in August 2014 as a 125-mg subcutaneous injection administered every 2 weeks. Peginterferon beta-1a retains similar pharmacodynamic activity to interferon beta-1a, but because of pegylation it possesses different pharmacokinetic properties. Peginterferon beta-1a consists of interferon beta-1a covalently attached at the α-amino group of the N terminus to polyethyelene glycol. The addition of polyethylene glycol to medications often causes a decrease in clearance of the medication, increases half-life, and reduces degradation of the compound.58 Currently available formulations of interferon beta-1a are either limited by their frequent administration schedule, as seen with 3 times weekly subcutaneous interferon beta-1a#, or a reduction in efficacy as seen with intramuscular interferon beta-1a**.59–61 The addition of polyethylene glycol improves the pharmacokinetic properties of interferon beta-1a. Subcutaneous peginterferon beta-1a given at the dose of 125 mg demonstrated a 9-fold increase in AUC in healthy persons compared with 30 mg of interferon beta-1a administered intramuscularly, allowing less-frequent administration and improved plasma concentration.62 Pharmacokinetic studies are currently under way to ¶

Trademark: PlegridyTM (Biogen Idec, Cambridge, Massachusetts). Trademark: Rebifs (EMD Serono Inc, Rockland, Massachusetts). ** Trademark: Avonexs (Biogen Idec, Cambridge, Massachusetts). #

16

assess pharmacokinetic differences between peginterferon beta-1a and 3 times weekly subcutaneous interferon beta-1a.63 The efficacy and safety profile of peginterferon beta-1a was established in the ADVANCE study (Pegylated Interferon β-1a for Relapsing-Remitting Multiple Sclerosis). The ADVANCE study was a 2-year, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial designed to assess the efficacy and safety profile of peginterferon in the treatment of relapsing forms of MS. Patients were randomly assigned into 3 treatment arms. The first treatment arm received placebo for 48 weeks, followed by 125 mg of peginterferon beta-1a subcutaneously every 2 or 4 weeks for 48 weeks. The second treatment arm received 125 mg of peginterferon beta1a subcutaneously every 2 weeks for 96 weeks, and the third arm received 125 mg of peginterferon beta-1a subcutaneously every 4 weeks for 96 weeks. A total of 1512 patients were randomly assigned in a 1:1:1 ratio in the 3 treatment groups with 500 patients assigned to placebo, 512 assigned to peginterferon beta-1a every 2 weeks, and 500 patients assigned to peginterferon beta-1a every 4 weeks. At the end of year 1, ARR was reduced significantly with every 2-week dosing of peginterferon beta-1a (ARR ¼ 0.256; 95% CI, 0.206–0.318) and every 4-week dosing of peginterferon beta-1a (ARR ¼ 0.288; 95% CI, 0.234–0.355) compared with placebo (ARR ¼ 0.397; 95% CI, 0.328–0.481). Secondary outcomes, including the proportion of patients with a relapse at 1 year, disability progression at 1 year, and new or enlarging T2 lesions at 1 year, were all significantly better with both peginterferon treatments than with placebo.64 At the end of year 2, ARR continued to be reduced with every 2-week dosing of peginterferon beta-1a (ARR ¼ 0.221; 95% CI, 0.183–0.267) and every 4-week dosing of peginterferon beta-1a (ARR ¼ 0.291; 95% CI, 0.244–0.388) compared with patients who started delayed treatment at the end of year 1 (ARR ¼ 0.351, 95% CI, 0.295–0.418). Secondary outcomes, including the proportion of patients with a relapse at 2 years, disability progression (12-week confirmed) at 2 years, and new or enlarging T2 lesions at 2 years, were all significantly better with both peginterferon treatments than with placebo. Disability progression at 2 years (24-week confirmed) and gadolinium lesions at 2 years were only significantly

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C. English and J.J. Aloi better with every 2-week dosing and were not significantly improved with every 4-week dosing. In addition, greater reductions were seen with every 2-week dosing compared with every 4-week dosing on all efficacy end points evaluated.65 Patients who reported adverse effects with peginterferon treatment were similar between both groups at the end of year 2. Injection site erythema (59%–64%), flulike symptoms (50%–51%), fever (41%–43%), headache (41%–42%), myalgias (19%), chills (17%), and injection site pain (14%–17%) were the most commonly reported adverse effects from patients who received peginterferon at the end of year 2.65 The most common adverse effects with placebo treatment during phase 1 of the study were injection site reactions (7%), fever (15%), myalgias (6%), chills (5%), and flu-like symptoms (13%). These adverse effects occurred less frequently with placebo than with peginterferon.64 Because of the exclusion of an active comparator, tolerability and efficacy comparison data do not exist between traditional dosage forms of interferon beta1a or other disease-modifying agents used for MS. Currently, a long-term study of peginterferon beta-1a titled the ATTAIN study (Long-Term Safety and Efficacy Study of Pegylated Interferon Beta-1a) is under way to assess the long-term efficacy and safety profile results in patients originally treated in the ADVANCE trial.66

Alemtuzumab

Alemtuzumab†† was the latest medication approved by the FDA in November 2014. Alemtuzumab is a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes. It readily depletes monocytes and B and T lymphocytes, leading to longlasting changes in adaptive immunity, and reduces the pathogenesis of inflammatory response in MS. When administered, alemtuzumab remains within the blood and interstitial space and has a volume of distribution of 14.1 L. Alemtuzumab is generally fully eliminated from the body within 30 days of a treatment course and has an average half-life of 2 weeks. The standard dosing is 12 mg daily for 5 consecutive days, followed 12 months later by 12 mg daily for 3 consecutive days.17 The approval of alemtuzumab was primarily based on 1 phase 2 study and 2 randomized-controlled trials ††

Trademark: Lemtradas (Genzyme Corporation, Cambridge, Massachusetts).

] 2015

titled CARE-MS I and CARE-MS II (Comparison of Alemtuzumab and Rebifs Efficacy in Multiple Sclerosis).67–69 Both phase 3 studies were randomized, rater-blinded, controlled trials that evaluated alemtuzumab versus subcutaneous interferon beta-1a 44 mg given every 3 days. Patients enrolled in CARE-MS I had active RRMS, were naive to treatment, had an EDSS r 3, and had symptom onset o5 years. Patients who received alemtuzumab had a 55% reduction in ARR (ARR 0.18; 95% CI, 0.08–0.16; P o 0.0001) compared with interferon beta-1a (ARR = 0.36; 95% CI, 0.29–0.44) in CARE-MS I.68 CARE-MS II was similar in design to CARE-MS I, but patients enrolled had an EDSS r 5, had onset of symptoms o10 years, and had a relapse on prior disease-modifying treatment. Patients had a 49.4% relative reduction in annualized relapsed rates with alemtuzumab treatment (ARR ¼ 0.26; 95% CI, 0.21– 0.33; P o 0.0001) compared with interferon beta-1a (ARR ¼ 0.52; 95% CI, 0.41–0.66).69 Efficacy and safety profile of alemtuzumab in controlled trials for MS used in its approval is reported in Table VI.67–70 The safety profile of alemtuzumab led to the delayed approval in the United States. Reported adverse events include idiopathic thrombocytopenia, autoimmune thyroid disease, neoplasm, and opportunistic infections.17,68,69 Infusion-associated reactions were also reported in patients who received alemtuzumab. It is recommended that patients are pretreated with corticosteroids before the first 3 days of each treatment course; in addition, antihistamines and antipyretics may be considered. Antiviral prophylaxis with acyclovir 200 mg twice daily should be provided during treatment and for at least 2 months after completion of alemtuzumab and until the CD4þ lymphocyte count is Z200/mL.17

PHARMACOECONOMIC CONSIDERATIONS FOR NEW TREATMENTS In 2013, treatments for MS represented the tenth most costly treatment class and were the fourth most costly specialty treatment class behind oncology, other autoimmune therapeutics, and HIV antivirals. In addition, MS therapies accounted for the highest spending growth of any therapeutic class, with a 20.7% increase in total spending. The total cost for MS treatments have substantially grown, with nondiscounted US spending doubling from $5 billion in 2009 to $10.6 billion in 2013.71 Disease-modifying agents used for MS are typically grouped into a class

17


Treatment (n)


Coles et al67 (2008); phase 22, randomized, blinded trial

Interferon beta-1a 44 mg (111), alemtuzumab 12 mg (112), alemtuzumab 24 mg (110)

36

Coles et al70 (2012); 5-year follow-up of phase 2 randomized, blinded trial

Interferon beta-1a 44 mg (111), alemtuzumab 12 mg (112), alemtuzumab 24 mg (110)

60

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Adverse events

ARR, n (95% CI) Alemtuzumab 12 mg: 0.11 (0.08–0.16) Alemtuzumab 24 mg: 0.08 (0.05–0.12) Interferon: 0.36 (0.29–0.44) p o 0.001 vs interferon Mean change in EDSS from baseline, (95% CI) Alemtuzumab 12 mg: 0.32 (0.55 to 0.10); P ¼ 0.006 Alemtuzumab 24 mg: 0.45 (0.68 to 0.22); P o 0.001 Interferon: 0.38 (0.13–0.63); P ¼ 0.003 Mean change in EDSS to month 60, mean (SD); odds ratio for improved disability (95% CI) Alemtuzumab 12 mg: 0.15 (0.15), P ¼ 0.0056; 2.65 (1.22–5.76); P ¼ 0.014 Alemtuzumab 24 mg: 0.44 (0.14), P ¼ 0.0001; 2.64 (1.22–5.71); P ¼ 0.014 Alemtuzumab pooled: 0.30 (0.10), P ¼ 0.0002; 2.64 (1.32–5.31); P ¼ 0.0063 Placebo: 0.46 (0.18) ARR to month 60, n (95% CI) Alemtuzumab 12 mg: 0.12 (0.09–0.16) Alemtuzumab 24 mg: 0.15 (0.10–0.23) Alemtuzumab pooled: 0.11 (0.09–0.14) Interferon: 0.35 (0.29–0.42) P o 0.001 vs interferon

Infusion-associated reactions (headache, rash, nausea, pyrexia, pruritus) (98.6%), infection (65.7%), thyroid-associated event (22.7%), ITP (2.8%), fatigue (31%), headache (31%), menstrual disorder (16.5%)

Infusion-related reactions (99%), infection (72%), thyroid-associated events (30%), ITP (2.8%)

(continued)


18

Table VI. Pivotal clinical studies on the use of alemtuzumab in multiple sclerosis.67–70

] 2015

Table VI. (continued). Name of clinical trial (year); study type

Treatment (n)


CARE-MS 168; phase 3 randomized, controlled trial

Alemtuzumab 12 mg (376), Interferon beta-1a 44 mg (187)

24

CARE-MS 269; phase 3 randomized, controlled trial

Alemtuzumab 12 mg (426) Alemtuzumab 24 mg (170) Interferon beta-1a 44 mg (202) Enrolled adults between 18 and 55 years with RRMS and at least 1 relapse on interferon beta-1a or glatiramer acetate

24


Adverse events

ARR, n (95% CI) Alemtuzumab: 0.18 (0.13–0.23) Interferon: 0.39 (0.29–0.53) P o 0.0001 Disability at 6 months Alemtuzumab: 30 patients (8%) Interferon: 10 patients (11%) P ¼ 0.22 Change in EDSS score from baseline, (95% CI) Alemtuzumab: 0.14 (0.25 to 0.02) Interferon: 0.14 (0.29 to 0.01) P ¼ 0.97 ARR, n (95% CI) Alemtuzumab 12 mg: 0.26 (0.21–0.33) Interferon: 0.52 (0.41–0.66) P o 0.0001 Sustained accumulation of disability Alemtuzumab 12 mg: 54 patients (13%) Interferon: 40 patients (20%) Risk reduction: 42%; P ¼ 0.0084 Change in EDSS from baseline (95% CI) Alemtuzumab 12 mg: 0.17 (0.29 to 0.05) Interferon: 0.24 (0.07–0.41) P o 0.0001

Infusion-associated reactions (90%), infections (67%), thyroid disorders (18%), ITP (1%), agranulocytosis (1%), fatigue (13%), headache (23%), rash (12%)

Infusion-associated reactions (97%), infection (83%), thyroid disorders (19%), autoimmune thrombocytopenia (1%), basal cell carcinoma (1%), vulvar cancer (1%), colon cancer (1%), fatigue (22%), headache (63%), rash (60%)

19


ARR ¼ annualized relapse rate; CARE-MS ¼ Comparison of Alemtuzumab and Rebifs Efficacy in Multiple Sclerosis; EDSS ¼ Expanded Disability Status Scale; ITP ¼ immune thrombocytopenia purpura; RRMS ¼ relapsing remitting forms of multiple sclerosis.

Clinical Therapeutics of medications titled specialty medications. Specialty medications are often more difficult to administer, require special handling and patient education, and require ongoing clinical evaluation. Specialty medications are generally not used in large treatment populations and are more expensive treatments than traditional therapeutic entities, representing o1% of total prescriptions but accounting for 20% of all drug costs.72 The price of specialty medications is expected to continually rise and may represent 50% of pharmacy spending by 2018.72 On the basis of the substantial increase in price and drug spending of MS therapeutics, cost and cost effectiveness of treatments will play a role in treatment decision making. Few cost-effectiveness studies based in the United States are available for recently approved disease-modifying agents. Cost-effectiveness results for fingolimod are mixed. The cost effectiveness of fingolimod was compared with first-line disease-modifying agents, including interferons and GA, by using cost data from published sources and efficacy data from controlled trials. The cost per relapse avoided was the lowest with fingolimod, $74,843, compared with other first-line treatments which ranged from $94,423 (subcutaneous interferon beta1b) to $197,073 (intramuscular interferon beta-1a) in cost per relapse prevented.73 The analysis was primarily derived from placebo-controlled studies and not based on direct comparisons with treatment. Incremental cost-effectiveness ratios or willingnessto-pay thresholds, the maximum amount of money an entity would potentially pay to have the treatment, were not provided. The cost effectiveness of using fingolimod treatment early versus late was evaluated with an Excel-based model (Microsoft Corp, Redman, Washington). The cost in preventing a relapse was $83,125 versus $103,624 in patients delaying fingolimod treatment by 1 year, showing no cost saving in delaying treatment.74 Cost-effectiveness analysis that compared fingolimod with intramuscular interferon beta-1a was conducted from the TRANSFORMS trial. An incremental cost-effectiveness ratio of $73,975 per quality-adjusted life-years was seen with fingolimod; however, this value was higher than the $50,000 willingness-to-pay threshold set by the investigators, thus concluding it not likely to be cost effective. If set at $150,000, fingolimod would be considered cost effective.75 Cost effectiveness of fingolimod versus natalizumab was conducted with data from the

20

AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) and FREEDOMS trials. This dataset was not from headto-head comparisons, and the analysis did not capture cost related to adverse effects. Natalizumab reported superior cost effectiveness, because the cost in preventing a relapse was less with natalizumab therapy ($79,977 compared with fingolimod treatment, $95,902).76 One cost-effectiveness study was published about other oral therapies. A cost-effectiveness analysis that compared the 3 new oral therapies with intramuscular interferon beta-1a was conducted on the basis of a Markov model to calculate the net monetary benefit to the payee of each therapy. Price calculations were based on 2012 whole acquisition costs. The net monetary benefit was higher with the 3 oral agents than with interferon beta-1a, with fingolimod, teriflunomide, and dimethyl fumarate having net benefits of $36,567, $49,780, and $80,611, respectively. Fingolimod was only cost effective if the price remained below $5,132.77 The willingness to pay was set at $150,000 in this study, which is higher compared with other pharmacoeconomic studies and may overinflate the net monetary benefits. Regardless, dimethyl fumarate reported the most cost effectiveness compared with the 4 other treatments over a wide range of willingness-to-pay amounts ($0–$180,000) and was dominant versus other treatments.77 Cost-benefit analyses of traditional therapies were reviewed in the literature78,79; however, the cost of previous traditional MS therapies, such as interferon injectables and GA, have increased in price over the past 5 years, each doubling in wholesale acquisition cost.18,80 This will make the current utility of these former analyses difficult to interpret because of large shifts in price and lack of a large price differential that was once seen with new treatments. In addition, cost of the new treatments, teriflunomide and dimethyl fumarate, are marketed substantially higher than their respective parent molecule and compounded formulation. Leflunomide is priced at $492 for a 1-month supply, and bulk dimethyl fumarate for compounding is priced at $4.59 per gram.18 These substantial price differences may influence prescribing practices to avoid high prescription costs even though these nonapproved agents do not have the same efficacy data backing their use. New long-acting injectable

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C. English and J.J. Aloi Table VII. Average wholesale price of disease-modifying agents for multiple sclerosis in 2010 and 2014.18,80 All prices listed in US dollars. Medication Interferon beta-1b* Interferon beta-1b† Interferon beta-1a‡ 30 mg Interferon beta-1a§ 44 mg Glatiramer acetate║ 20 mg Glatiramer acetate║ 40 mg Natalizumab 300 mg IV Infusion Fingolimod¶ 0.5 mg Teriflunomide# 7 mg or 14 mg daily Dimethyl fumarate** 240 mg Peginterferon beta-1a†† 125 mg Alemtuzumab‡‡ 12 mg

Month Supply (AWP) Month supply (AWP) Annual yearly cost (AWP) 201080 201418 201418 2951.46 2951.42 2964.00 2973.46 3303.05 NA 3109.72 NA NA NA NA NA

6043.28 5249.64 5726.40 6209.94 6672.00 5569.49 5614.80 6132.36 6093.88 6210.00 5726.40 23,700.00 per dose

72,519.36 62,995.68 68,716.80 74,519.28 80,064.00 66,833.88 67,377.60 73,588.32 73,126.56 74,520.00 68,716.80 118,500.00

AWP ¼ average wholesale price; NA ¼ not available. * Trademark: Betaserons (Bayer, Barmen, Germany). † Trademark: Extavias (Novartis Pharmaceuticals Corp, Basel, Switzerland). ‡ Trademark: Avonexs (Biogen Idec, Cambridge, Massachusetts). § Trademark: Rebifs (EMD Serono Inc, Rockland, Massachusetts). ║ Trademark: Copaxones (Teva Pharmaceutical Industries, Petah Tikva, Israel). ¶ Trademark: Gilyenas (Novartis AG, Basel, Switzerland). # Trademark: Aubagios (Sanofi Aventis, Paris, France). ** Trademark: Tecfideras (Biogen Idec, Cambridge, Massachusetts). †† Trademark: PlegridyTM (Biogen Idec, Cambridge, Massachusetts). ‡‡ Trademark: LemtradaTM (Genzyme Corporation, Cambridge, Massachusetts).

agents are also being priced less than their traditional counterparts, which may entice providers to switch patients to reduce cost and improve compliance. Additional cost-effectiveness studies that used directcomparative trials between older and newer therapies on the basis of their current pricing is needed to better determine whether treatment with new diseasemodifying agents outweigh the cost of treatment. The pricing of all disease-modifying treatments is provided in Table VII.18,80

CONCLUSION The clinical armamentarium for treating MS has substantially increased over the past 5 years. Additional drugs are expected to be approved by the FDA in the future, including several biologics, which will further increase treatment options for patients and providers. All new drug treatments approved are efficacious at reducing ARRs associated with MS.

] 2015

Numbers needed to treat (NNTs) for reducing ARR over a 2-year period are 5, 6, and 5 for fingolimod, teriflunomide, and dimethyl fumarate, respectively.20,30,42 The NNTs for reducing annualized relapse were 5.5 and 4 for naive patients and previously treated patients, respectively, receiving alemtuzumab.68,69 Peginterferon and high-dose GA had NNTs of 7 and 6, respectively, for decreasing ARR.57,64 These NNTs are based on separate clinical trials for each drug and cannot be directly compared with each other or former treatments. For relative position of treatments in therapy, the place of new agents is still fairly unknown. US guidelines have yet to be updated to reflect the new diseasemodifying agents, and recent guidelines released by the National Institute for Health and Care Excellence do not provide recommendations about disease-modifying agents.81,82 Many experts speculate that teriflunomide and dimethyl fumarate will replace the older injectables

21

Clinical Therapeutics because of their ease of administration and tolerability profiles.83 Fingolimod and alemtuzumab might be reserved for patients with high disease activity and for patients who have failed traditional therapies.84 Regardless of respective place, all of the new treatments are FDA approved for RRMS and have shown proven efficacy compared with placebo in preventing relapses associated with RRMS. Treatment decisions will largely continue to be based on provider and patient preference by weighing the cost, risks, and potential therapeutic gain of treatment.

CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.

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Volume ] Number ]

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Address correspondence to: Clayton English, PharmD, BCPP, Department of Pharmacy Practice, Albany College of Pharmacy and Health SciencesVermont Campus, 261 Mountainview Drive, Office 202D, Colchester, VT 05446. E-mail: [email protected]

] 2015

25

Current and future therapies for multiple sclerosis.

Oral disease-modifying therapies for multiple sclerosis.

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis.

It's Time For Combination Therapies: in Multiple Sclerosis.

[New and emerging treatments for multiple sclerosis].

[Two new oral disease modifying therapies in relapsing remitting multiple sclerosis].

[Do new oral therapies show advantages in the basal therapy of multiple sclerosis? Pro].

New multiple sclerosis phenotypic classification.

Multiple sclerosis: Five new things.

Multiple sclerosis: Switching sides--fingolimod versus injectable MS therapies.

Multiple sclerosis research: diagnostics, disease-modifying treatments, and emerging therapies.

Disease-modifying therapies in multiple sclerosis in Latin America.

Effectiveness of glatiramer acetate compared to other multiple sclerosis therapies.

Dimethyl fumarate (Tecfidera): a new oral agent for multiple sclerosis.

Alemtuzumab: a new therapy for active relapsing-remitting multiple sclerosis.

A new dawn for genetic association studies in multiple sclerosis.

MSer - A new, neutral descriptor for someone with multiple sclerosis.

The meninges: new therapeutic targets for multiple sclerosis.

Teriflunomide - a new oral agent for multiple sclerosis treatment.

New management algorithms in multiple sclerosis.

[Multiple sclerosis and retroviruses: new findings].

[New therapeutic options in multiple sclerosis].

Multiple sclerosis in New Zealand Māori.

Considerations in the development of generic disease therapies for multiple sclerosis.