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Supplements Cost-Effectiveness of Disease- Modifying Therapies in Multiple Sclerosis: A Managed Care Perspective

Current and Emerging Treatment of Multiple Sclerosis

Felecia M. Hart, PharmD, and Jacquelyn Bainbridge, BSPharm, PharmD
The treatment of multiple sclerosis (MS) falls into 3 categories: treatment of exacerbations, slowing disease progression with disease-modifying therapies (DMTs), and symptomatic therapies. The management of MS is becoming increasingly complex with the development of additional DMTs that, like the older DMTs, reduce the frequency and severity of relapses, and the accumulation of lesions detected by magnetic resonance imaging. Initiating treatment to slow or reverse inflammatory lesion formation early in the course of the disease is advocated as a way to prevent accumulation of disability. Nevertheless, there is a lack of comparative efficacy data and few clinical guidelines to aid healthcare providers in the optimal selection of DMTs. Given that some of the newer agents are associated with potentially serious, but rare, adverse events, careful consideration of the risk-benefit profile is necessary to minimize the risk to patients. This article provides an overview of the existing treatments for MS with an emphasis on DMTs and emerging therapies.
Am J Manag Care. 2016;22:S159-S170
     Although there is no cure for multiple sclerosis (MS), appropriate management strategies can slow disease progression, improve symptoms, and help maintain quality of life. MS is a complex and unpredictable disease with similarly complex management that calls for a coordinated, multidisciplinary approach to care.1 Comprehensive care requires a team of professionals with experience in treating MS, including consulting neurologists, MS nurses, MS pharmacists, physical and occupational therapists, speech-language pathologists, psychologists/neuro-psychologists, dieticians, other medical subspecialists (eg, urologists), and social workers. Treatment of MS is an ongoing process that begins with the management of the first symptoms and subsequent relapses, and it continues
over the course of the disease. Also, interventions exist to address acute and chronic symptoms, and modify the disease course. Depending on the clinical situation, different interventions may be prescribed. Comprehensive treatment encompasses 3 areas: relapse management, disease modification, and symptom management.
Relapse Management
One component of comprehensive MS treatment is the management of relapses, which are defined as spontaneous episodes of new or recurrent neurologic dysfunction; they must be differentiated from unrelated neurologic symptoms due to infection, fever, or other stresses (which are termed pseudo-relapses). By definition, true relapses usually last at least 24 hours (although the average total duration is approximately 3 months) and are associated with the emergence of new symptoms not previously experienced by the patient; however, in some cases, old symptoms may reemerge.2 In contrast, pseudo-relapse symptoms, which may fluctuate in severity with a rise or drop in a person’s body temperature, or as a consequence of physical or emotional stress, are not considered to be relapses; instead, they are referred to as a pseudo-relapse or pseudo-exacerbation, unless the symptoms are more severe and of a greater duration than usual.2
Determining whether a person is having a true relapse or a pseudo-relapse or pseudo-exacerbation can be challenging. Fatigue, overexertion, and exposure to heat and humidity can cause fluctuations or worsening of symptoms in the absence of a true relapse (Uhthoff’s phenomenon).2 Treatment of acute relapses aims to: (1) speed functional recovery from the neurologic deficits
sustained as a result of inflammatory demyelination, (2) alleviate the severity of the attack, and (3) lessen or eliminate potentially persistent residual deficits.2

The treatment of MS exacerbations with short-term courses of anti-inflammatory agents, such as high-dose intravenous or oral corticosteroids, represents an established practice among neurologists.2,3 Although steroids do not affect the course of MS, over time, they have been shown to reduce symptoms, improve motor function, and shorten time to recovery from acute attacks.2

Corticosteroids may be administered orally or parenterally,2 and their effect on the immune system is presumed to be dependent on dose and duration. Although longterm use of low corticosteroid doses has been found to be effective and relatively safe, shorter courses of high-dose corticosteroids are generally preferred to treat acute exacerbations of inflammatory disorders. With regard to MS,
high-dose, short-term intravenous corticosteroids provide symptomatic relief, improve motor function, and shorten the recovery phase of acute disease-related attacks.2
The Optic Neuritis Trial established the efficacy of intravenous corticosteroids for the management of MS relapses.4 In this trial, intravenous methylprednisolone 1g/day for 3 days, followed by oral prednisone for 11 days, accelerated the recovery of visual loss due to optic neuritis and resulted in slightly better vision at 6 months compared with placebo.
     For pregnant women who experience relapses, intravenous immunoglobulin, which can be used safely during pregnancy,5 should be considered; however, relapses during pregnancy are very uncommon. Through an unknown mechanism, MS disease activity generally subsides during pregnancy and breast-feeding.
     Infrequently, adrenocorticotropic hormone may be prescribed for individuals with poor venous access, those who prefer self-injection, or those who respond poorly to corticosteroids.5 Additionally, plasmapheresis should be reserved for patients who have not responded to corticosteroids and are still experiencing severe attacks.6

Disease-Modifying Therapies
The mechanism of action of disease-modifying therapies (DMTs) is linked to the pathophysiology of MS, which is a central nervous system (CNS) disease that consists of damage to the myelin sheath and axonial destruction. The damage is associated with inflammation caused by a perivenular infiltrate consisting of T and B lymphocytes, macrophages, antibodies, and complement.7 Until
recently, it was largely thought that the autoimmune disease was primarily mediated by T cells; however, it is now understood that B cells within the immune system also play a pivotal role in MS disease pathology. It is this new understanding that has led to the advent of new DMTs targeting B-cell involvement within the disease.

       DMTs are a component of the long-term management of patients with MS. The goal of disease modification is to reduce the early clinical and subclinical disease activity that is thought to contribute to long-term disability.8 Treatment is highly variable and differs based on disease severity, cost, adverse effect (AE) profiles, and patient and prescriber preference.

      All of the approved DMTs for MS reduce the frequency and severity of relapses, and the accumulation of lesions detected by magnetic resonance imaging (MRI) in relapsing-remitting MS (RRMS). DMTs also appear to impede the accumulation of disability.8 Unfortunately, they have little, if any, demonstrated benefit in progressive forms of MS.9 Moreover, it is important to recognize
that efficacy, tolerability, and safety profiles vary greatly among agents. Newer DMTs are more efficacious than their counterparts, but many have uncommon, but serious potential AEs, and some carry significant risks that result in somewhat restricted distribution utilizing a Risk Evaluation and Mitigation Strategy (REMS) program, such as the TOUCH Prescribing Program associated with
natalizumab use.9,10 In addition, some DMTs require frequent monitoring of a patient’s John Cunningham (JC) virus infection status, which has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare viral brain infection that is often severely disabling or fatal.

       Because few head-to-head trials have been conducted with DMTs, there is a paucity of data on the comparative efficacy of these treatments. Likewise, few clinical guidelines exist to guide healthcare providers in the use of these agents. The most recent treatment guidelines come from a consensus paper released by the Multiple Sclerosis Coalition in March 2015, and clinical guidelines
from the Association of British Neurologists published in May 2015.9,10 Thus, DMTs often are prescribed on a trialand-error and case-by-case basis, attempting to achieve a balance between efficacy, patient tolerability, and safety. For eligible patients, treatment should begin as early as possible after diagnosis and continue indefinitely. The initial and/or subsequent treatments may be modified
if the individual has a suboptimal treatment response, develops intolerable AEs, or does not adhere to the treatment regimen. All patients with MS should avoid live attenuated virus vaccinations, if possible, no matter which DMT they are on; pharmacists should review the National Multiple Sclerosis Society recommendations for more information on vaccinations.8

Table 111-25 identifies the DMTs approved by the FDA that have been found to slow or reverse inflammatory lesion formation in patients with MS.11-25 In addition, oral dalfampridine (Amprya) is a potassium channel blocker that, while not a DMT, is indicated to improve walking in patients with MS (see symptomatic therapy in Ampyra prescribing information).26 The generic (compounded) version, 4-aminopyridine, has also shown benefit in treating other MS symptoms, such as fatigue, poor coordination, and strength.

Self-Injected DMTs: Interferon Beta-1a, Interferon Beta-1b, Peginterferon Beta-1a, and Glatiramer Acetate
      The interferons (IFNs) and glatiramer acetate (GA) were the first-approved DMTs for MS.27 For both IFN and GA, the reduction in relapse frequency and severity is about 30%; however, this may be slightly lower in patients treated with low-potency IFNs.1 To date, 5 forms of IFN beta (Avonex, Betaseron [or Extavia], Rebif, and Plegridy) have been approved by the FDA for RRMS.11-15 IFN beta has been shown to reduce the number of exacerbations and may slow the progression of physical disability. The mechanism behind the efficacy of IFNs in MS is poorly understood; however, it is believed that the efficacy is mediated by the immunomodulating properties of IFNs.The safety of IFNs has been established over 2 decades of use; most AEs are minor or benign. These include flu-like symptoms for up to 24 hours post injection, reversible decreases in white blood cell count, and elevated liver enzymes. IFNs are also associated with rare allergic reactions such as anaphylaxis, seizures, and a decrease in peripheral blood counts. Because of the risk of uncommon hepatic injury, periodic liver function testing is required during treatment. The efficacy and AE profiles of IFN
products vary based on dose and frequency of administration. IFN products that contain higher dosages, and are administered more frequently, are more effective; however, patients are more likely to develop antibodies that render the IFN less effective.28,29 Betaseron, Extavia, and Rebif are considered high-potency IFNs, whereas Avonex is considered a low-potency IFN.
      Two forms of GA have been approved by the FDA for RRMS. Copaxone is a synthetic form of myelin basic protein called copolymer 1; it is available in 2 dosage forms: 20 mg/mL daily or 40 mg/mL 3 times weekly.21 Glatopa is a generic version of the Copaxone 20-mg dose.23 Evidence supporting the effectiveness of GA comes from 5 placebocontrolled trials; 4 used a 20-mg/mL daily dose, and 1 examined the 40-mg/mL 3 times weekly dose. Both GA doses had a beneficial effect on relapse rate, delaying the time to second exacerbation and reducing the number of new or enlarging MRI lesions compared with placebo. GA has few AEs, and does not require any monitoring of liver function. An immediate postinjection reaction exists that consists of various symptoms, including flushing, chest pain, palpitations, anxiety, dyspnea, constriction of the throat, and urticaria.21,23 These symptoms are transient and self-limiting, not requiring any specific treatment. The more recent advent of the 40-mg/mL 3-times–weekly dose may improve tolerability and adherence because it requires less frequent administration.30
Although none of the DMTs eliminate all risk of relapse, the IFNs and GA were studied in combination to evaluate whether there is an increased benefit. The 3-year, randomized CombiRx trial investigated whether the combined use of IFN beta-1a intramuscular once weekly and GA weekly was more efficacious than either agent alone in 1008 patients with RRMS.31 The primary end point was annualized relapse rate; secondary end points were disability progression and MRI outcomes. At 36 months, combination therapy was not superior to GA monotherapy, and GA monotherapy was significantly better than IFN monotherapy, reducing the risk of exacerbation by 31% (P = .027). The combination IFN and GA was significantly betterthan IFN alone, reducing the risk of exacerbation by 25% (P = .022). There were no significant differences with regard to disability progression between the combined treatment group and either agent alone. At 7 years, annualized relapse rates were similar to the 3-year data. The combination was not better at reducing disability than GA monotherapy.32

Oral DMTs: Dimethyl Fumarate, Fingolimod, and Teriflunomide
Dimethyl fumarate is a second-generation fumaric acid ester.24 Although its exact mechanism of action in MS is not known, dimethyl fumarate and its metabolite, monomethyl fumarate, have been shown to activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is associated with the cellular response to oxidative
stress. In 2 placebo-controlled trials that used doses of 240 mg twice daily or 3 times daily, dimethyl fumarate significantly reduced relapse rate (P <.0001) and the number of new or enlarging MRI lesions (P <.0001) in patients with RRMS. The relative risk reduction in the proportion of patients relapsing was 49% in the first study, and 44% in the second study for the 240-mg twice-daily dose
compared with with placebo. Safety issues with dimethyl fumarate include angioedema and anaphylaxis, lymphopenia, and the very rare PML.
      Fingolimod, a sphingosine-1-phosphate (S1P) agonist, binds and activates S1P receptors.22 As a functional antagonist, fingolimod prevents lymphocytes from exiting lymph nodes, thereby reducing the number of lymphocytes in peripheral blood. This results in lymphopenia within hours of administration, reducing the number of naïve T cells and memory T cells available to enter the CNS, and mediates the MS disease process.33 Fingolimod may also independently act on CNS sphingosine receptors with potential neuroprotective and remyelinating effects, although to what effect is unclear.34 Fingolimod is the first DMT on the market where drugdrug interactions have become a concern. It is highly protein-bound, and utilizes the hepatic cytochrome P450 (CYP450) 4F2 enzyme as a primary route of metabolism. It is also a substrate of CYP2D6, CYP2E1, and CYP3A4, so medications that induce or inhibit CYP450 enzymes have the potential to substantially affect fingolimod
serum concentrations. Fingolimod causes bradycardia and can cause atrioventricular conduction block, so special consideration and additional monitoring should occur when used in combination with other drugs known to cause the same cardiac effects (eg, beta-blockers, diltiazem, verapamil, digoxin). Concurrent use with drugs that cause an increased risk of torsades de pointes via QT prolongation (eg, citalopram, chlorpromazine, haloperidol, methadone, erythromycin) should warrant extra caution, with continuous electrocardiogram (ECG) monitoring overnight after administration of the first dose of fingolimod. Additionally, the concomitant use of class Ia and class III antiarrhythmics is contraindicated with fingolimod therapy.22
      Treatment with fingolimod is associated with an increased risk for bradyarrhythmia and atrioventricular blocks during treatment initiation, elevated liver function tests, and an increased risk of infections, including herpes simplex, cryptococcal, and varicella zoster viral infections.22 Prior to initiating therapy with fingolimod, documentation of a confirmed history of chickenpox or a full course of vaccinations against varicella zoster virus by a healthcare professional is required. If this information is unavailable, patients should be tested for antibodies to varicella zoster virus, and an antibody-positive status is required to be eligible for treatment with fingolimod. When initiating treatment with fingolimod, patients should have hourly pulse and blood pressure measurements
for the first 6 hours after the first dose to monitor for bradycardia. They should also obtain an ECG prior to the first dose and at the end of the 6-hour monitoring period. First-dose monitoring should be repeated in anyone who has discontinued fingolimod for longer than 14 days. Individuals taking fingolimod should also be monitored for signs and symptoms associated with PML, along with periodic JC virus blood titers.
      Fingolimod was compared in a head-to-head trial with intramuscular IFN beta-1a weekly and showed superior efficacy with respect to relapse rates and MRI outcomes.34 The adjusted annualized relapse rate was 16% with fingolimod 0.5 mg, 20% with fingolimod 1.25 mg, and 33% with IFN beta-1a (P <.001). Fingolimod also was more effective than IFN beta-1a at reducing MRI lesion activity and loss of brain volume. Serious AEs that led to discontinuation of treatment occurred more frequently in patients receiving fingolimod 1.25 mg than in those receiving fingolimod 0.5 mg or IFN beta-1a.
      Teriflunomide, a pyrimidine synthesis inhibitor, targets DNA immune cell replication by inhibiting mitochondrial dihydroorotate dehydrogenase, an enzyme involved in de novo synthesis of pyrimidine nucleotides in proliferating cells.35 Although the exact mechanism by which teriflunomide exerts its therapeutic effect is not known, it is presumed to involve a reduction in the number of activated lymphocytes in the CNS.25 Teriflunomide is another DMT that has introduced the possibility of drug-drug interactions. It is a breast cancer resistance protein (BCRP) substrate that is hydrolyzed to minor metabolites and is highly protein-bound. It is also an inducer of CYP1A2 and an inhibitor of BCRP, CYP2C8, and organic anion-transporting polypeptide (OATP) 1B1. Teriflunomide’s ability to induce CYP1A2 causes clinically significant drug-drug interactions with several other medications (eg, warfarin, clozapine, olanzapine, tizanidine, fluvoxamine, haloperidol,
imipramine, naproxen, duloxetine, cyclobenzaprine), and due to teriflunomide’s inhibition of CYP2C8, serum concentrations of pioglitazone would likely increase.25 Teriflunomide was compared with placebo in 4 clinical trials in patients with RRMS. In the largest trial of 1185 patients, the annualized relapse rate was 39% with teriflunomide 7 mg, 32% with teriflunomide 14 mg, and 50% with placebo. The relative risk reduction in annualized relapse rate was 22% with teriflunomide 7 mg, and 36% with teriflunomide 14 mg, compared with placebo.
      Teriflunomide undergoes extensive enterohepatic recirculation, which exposes the liver to high drug concentrations that may lead to hepatotoxicity.25 Moreover, the extended 18-day half-life of teriflunomide may have clinical implications in cases of pregnancy or serious AEs, when rapid elimination of the drug is required.

Intravenous Agents: Alemtuzumab, Natalizumab, and Mitoxantrone
The monoclonal antibodies alemtuzumab and natalizumab are the most effective DMTs currently available for the treatment of MS.8 However, both agents are associated with possible significant risks.16,18
Alemtuzumab is a humanized monoclonal antibody that depletes immune cells.16 Although its exact mechanism of action in MS is unclear, it presumably binds to CD52 on several mature leukocyte subpopulations, resulting in rapid lysis of CD4 and CD8 T cells, B cells, natural killer cells, eosinophils, macrophages, and monocytes. Alemtuzumab is associated with possible AEs, including frequent development of secondary autoimmune thyroid diseases, autoimmune cytopenias, and increased risk of infection. It is recommended that patients receiving alemtuzumab be premedicated with high-dose corticosteroids, such as 1000 mg of methylprednisolone.
       Alemtuzumab was compared in 2 head-to-head trials with IFN beta-1a 44 mcg 3 times weekly, and showed superior efficacy in both trials.16 In one trial, the annualized relapse rate was 52% for patients receiving IFN beta-1a and 26% for alemtuzumab. In a second trial, annualized relapse rates were 39% in the IFN beta-1a group and 18% in the alemtuzumab group. MRI outcomes were not significantly different.
        Natalizumab, a recombinant humanized monoclonal antibody, is another monoclonal antibody approved for use in RRMS.18 In MS, lesions presumably develop when activated immune cells responsible for inflammation, including T-lymphocytes, cross the blood-brain barrier. Natalizumab prevents the transmigration of these immune cells across the blood-brain barrier by blocking the alpha-4 subunit of integrin molecules that are involved in the adhesion and migration of cells from the vasculature into inflamed tissues. Since natalizumab strictly blocks migration of these cells and does not deplete them, there is a risk of rebound disease activity once the drug is stopped. The primary safety concern associated with the use of natalizumab is the increased risk of PML, for which it carries a black box warning.
        Natalizumab was evaluated in 2 placebo-controlled trials.18 One trial enrolled patients who had not received any IFN or GA for at least the previous 6 months; approximately 94% of patients were treatment-naïve to these agents. A second trial enrolled individuals who experienced 1 or more relapses while taking IFN beta-1a 30 mcg once weekly during the year prior to study entry; however, the efficacy of natalizumab monotherapy was not compared with the efficacy of natalizumab plus IFN beta-1a. Natalizumab reduced relapse rates and progression to disability and improved MRI outcomes in both trials. The annualized relapse rate was 22% with natalizumab monotherapy and 67% with placebo. In the second trial, the annualized relapse rate was 33% with natalizumab plus IFN beta-1a, and 75% with placebo plus IFN beta-1a.
       Mitoxantrone is a synthetic antineoplastic anthracenedione that targets immune cell replication.35 As an inhibitor of topoisomerase II-Hsp90 (heat shock protein 90) complex, mitoxantrone onselectively affects all proliferating cells, inhibiting B cells more than T cells. It is used as an antineoplastic agent in the treatment of metastatic breast cancer, acute myeloid leukemia, and non-Hodgkin lymphoma. Mitoxantrone is approved for use in secondary-progressive (chronic), progressive-relapsing, or worsening RRMS.17 However, postmarketing surveillance has shown that longterm
treatment with mitoxantrone is associated with dosedependent cardiomyopathy and acute leukemia, and use of this agent has fallen out of favor.35

Off-Label Medications
Rituximab is a chimeric CD20-directed cytolytic monoclonal antibody indicated for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, and granulomatosis with polyangiitis.36 In patients with RRMS, rituximab reduced relapse rates and inflammatory MRI lesions compared with placebo, but its effect on disability progression was marginal. Most AEs are infusion-or infection-related reactions.37,38 Severe infections have been observed in patients receiving rituximab, and a few rituximab-treated patients with hematologic malignancies or autoimmune disease have developed PML.36 A phase 2/3 study of rituximab in primary-progressive MS (PPMS) and a phase 2 study in RRMS have been completed, but results have yet to be reported.39,40
Azathioprine, a generic immunosuppressant, has been used off-label to treat all types of MS for decades, but with marginal efficacy. With the introduction of IFN beta, use of azathioprine declined. Azathioprine was associated with a 23% relative risk reduction in the frequency of relapses over 2 years, but its effect on disability progression was not demonstrated.3,41 AEs include gastrointestinal symptoms, photosensitivity, menstrual irregularity, and reduced fertility. Safety issues include myelotoxicity, hepatotoxicity, lymphopenia, infections, acute pancreatitis, increased toxicity in patients with thiopurine methyltransferase deficiency, and malignancies with cumulative doses above 600 g.9
       Cyclophosphamide has been used for progressive forms of MS; however, it is used less often because of its severe toxicity.9,42 Results from a meta-analysis showed that cyclophosphamide has no significant effect on disability progression at 12, 18, and 24 months.43 AEs include nausea, vomiting, amenorrhea, infertility, and alopecia. Safety concerns include myelotoxicity, hepatotoxicity, infections, hemorrhagic cystitis, and bladder cancer.9
Methotrexate has been evaluated in patients with progressive types of MS, and intravenous immunoglobulins have been used for all types of MS.42 However, the evidence supporting the use of these agents is of poor quality, and neither agent has been shown to prevent disability progression. Both methotrexate and intravenous immunoglobulins are associated with severe toxicity. 
Emerging Treatments for MS
Ocrelizumab is a humanized anti-CD20 monoclonal antibody in phase 3 clinical development for both RRMS and progressive forms of MS.44 Ocrelizumab selectively targets CD20-positive B cells, key contributors to myelin and axonal damage. Its effect in MS has been attributed to loss of B-cell-mediated cellular immunity.36
In 2 phase 3, randomized, double-blind, global multicenter trials in 1656 patients with RRMS, OPERA I and OPERA II, ocrelizumab (600 mg intravenously every 6 months) significantly reduced the annualized relapse rate by almost 50% over a 2-year period compared with IFN beta 1-a 44 mcg 3 times weekly.44 Progression of clinical disability also was delayed. Ocrelizumab was associated
with a significant reduction in the number of MRI detected lesions compared with IFN beta-1a (P <.0001).
      Overall incidence of AEs was 83.3% in both groups44; however, serious AEs occurred in 6.9% of patients given ocrelizumab and 8.7% of patients given IFN beta-1a. Infusion-related reactions were the most common AEs in patients treated with ocrelizumab; 34.3% of patients receiving ocrelizumab had at least 1 infusion-related reaction.
      In the ORATORIO study in patients with PPMS,compared with placebo, ocrelizumab (600 mg intravenously every 6 months given as two 300-mg doses 2 weeks apart) significantly reduced the risk of progression of clinical disability for at least 12 weeks by 24% (P = .0321) and for at least 24 weeks by 25% (P = .0365).44 Overall incidence of AEs was 95% in the ocrelizumab group and 90%
in the placebo group. Serious AEs developed in 20.4% of patients given ocrelizumab and 22.2% of patients given placebo. Infusion-related reactions developed in 39.9% of patients in the ocrelizumab group compared with 25.5% in the placebo group.

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