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    Disease-modifying therapies for multiple sclerosis: Focus on future direction

    Abstract

    Multiple sclerosis (MS) is a neurologic disorder of chronic inflammation and demyelination of the central nervous system. The disease affects an estimated 400,000 people in the United States, with an onset in young adulthood. The exact cause of MS is unknown; however, both genetic and environmental factors are believed to be involved. Although there is no cure for MS, drug treatments are available with the goal of decreasing relapses and further disability. Nine agents are currently approved for MS, with interferon and glatiramer established as first-line therapies, although their routes of administration may hamper compliance. Several additional agents, including oral products, are now under investigation for the future treatment of MS. (Formulary. 2012; 47:392–399.)

    Multiple sclerosis (MS) is a disabling neurologic disease characterized by chronic inflammation and demyelination of the central nervous system (CNS). The disease most often presents in the third to fourth decades of life and is second only to trauma as the most common cause of neurologic disability in young adults.1 According to the National Multiple Sclerosis Society, MS affects approximately 2.1 million people worldwide, including an estimated 400,000 individuals with a diagnosis of MS in the United States.2 Women are 2 to 3 times more likely to be diagnosed with MS; however, men experience a more progressive clinical course.2,3 Due to its chronic and progressive nature the economic impact of MS is considerable. In the United States, the average annual cost, including direct and indirect variables, is estimated at $69,000 per person with total costs of MS care approximately $28 billion annually.4

    MS is an autoimmune disorder in which the body's own defenses attack myelin, a fatty substance that surrounds and protects nerve fibers.5 The process is believed to start after autoreactive T cells cross the blood-brain barrier.6 A cascade of events ensues with injury to the myelin membrane resulting in denuded axons that are unable to transmit action potentials efficiently.7 This slowed or blocked nerve conduction results in the variety of symptoms seen in MS. Symptoms may regress as inflammation subsides or as partial remyelination occurs; however, eventual irreversible axonal injury, scarring, and exhaustion of the oligodendrocyte (mature cells that synthesize myelin) progenitor pool leads to a progressive loss of neurologic function.6,7 The pathologic hallmark of MS is CNS plaque or lesions representing the end stage of the inflammation, demyelination and neuronal and axonal degeneration processes.6

    The pathology of MS is presumed to result from dysregulation of the immune system, which is influenced by genetic and environmental factors. Compared to the general population, first-degree relatives are at a 15- to 35-times greater risk of developing MS.8 A 7.5-year follow-up of a population-based study of twins found a 31% concordance rate in monozygotic twins compared to a 5% rate among dizygotic twins, suggesting an important implication for environmental factors in MS.9 MS is more common in people living in northern latitudes, and low levels of vitamin D have been linked to MS possibly due to the beneficial effects of cholecalciferol on regulating the responses of the immune system.1


    Table 1: Types of multiple sclerosis
    The course of MS and its symptoms vary widely among individuals, dependent on the location and extent of the lesions. The disease is characterized by a relapsing-remitting course and can be classified into 4 types as outlined in Table 1.10 Diagnosis of MS is based on symptoms and magnetic resonance imaging (MRI); an evaluation of the cerebral spinal fluid may assist in the diagnosis. MS is in general a diagnosis of exclusion after exhausting other plausible explanations for the symptoms. The symptoms of MS typically begin with sensory disturbances, diplopia, Lhermitte's sign (electrical sensation down the spine evoked by the bending of the neck), limb weakness, balance and coordination problems, and neurogenic bladder and bowel symptoms.7,11 The most common and disabling symptom of MS is fatigue.11

    CURRENT THERAPIES


    Table 2: Current disease-modifying agents
    In 1993, FDA approved interferon (IFN)-beta 1b as the first disease-modifying therapy for MS. Since then treatment for MS has drastically improved with IFN-beta and glatiramer acetate considered first-line agents.12 Table 2 lists all 9 of the disease-modifying therapies that are currently approved for MS.13

    FUTURE DIRECTION


    Table 3: Multiple sclerosis pipeline products
    Various oral and intravenous (IV) pharmacologic agents are in the pipeline for MS treatment. Table 3 summarizes these new products, but a detailed summary is provided herein.14

    Alemtuzumab, a recombinant, humanized, monoclonal antibody, targets human CD52, a surface protein expressed on T and B lymphocytes, resulting in a very rapid and almost complete depletion of these cells in circulation.15,16 This drug is currently FDA approved for treatment of B-cell chronic lymphocytic leukemia; however, the manufacturer recently announced that it is pulling the drug for this use in preparation of its launch of alemtuzumab for the treatment of MS.17 The rationale for alemtuzumab use in MS is that lymphodepletion would disable the abnormal immune response better than standard immunosuppressive therapy.15 Alemtuzumab is administered via IV infusion and as with other antibody-mediated therapies, the first dose is associated with an induction of cytokines, resulting in infusion reactions that can be managed with pretreatment medications. A phase 2, randomized, blinded trial (CAMMS223) studied alemtuzumab (at a dose of either 12 mg/d or 24 mg/d) versus IFN beta-1a (at a dose of 44 μg) for 36 months.18 Compared to IFN beta-1a, alemtuzumab showed a significant reduction of 71% in sustained accumulation of disability (SAD), as measured by Expanded Disability Status Scale (EDSS) scores, and of 74% in the annualized rate of relapse (ARR). In this study alemtuzumab was associated with autoimmunity, most seriously manifesting as immune thrombocytopenic purpura (ITP). Two phase 3 trials have been completed. These are CARE-MS I, comparing the safety and efficacy of alemtuzumab to IFN beta-1a in relapsing-remitting MS (RRMS) treatment-na´ve patients, and CARE-MS II, studying patients who have experienced relapse episodes while on currently available disease-modifying therapies.19 CARE-MS I met one of its primary end points; the study showed that alemtuzumab treatment reduced relapse rate by 55% compared with IFN beta-1a.20 No significant difference between treatments was seen, however, in the second end point of time to SAD, as measured by EDSS-based endpoints. Results from CARE-MS II showed a 47% reduction in relapse rates and a 42% reduction in SAD at 2 years.21 Both reductions were significant. In both studies, infections were common in all treatment groups; however, a higher incidence was observed in those treated with alemtuzumab.20,21 Infections were mostly mild to moderate in severity with no life-threatening or fatal infections observed. Three cases and 5 cases of serious ITP adverse events were observed in the alemtuzumab group in CARE-MS I and CARE-MS II, respectively.

    Teriflunomide is an active metabolite of leflunomide, an approved treatment for rheumatoid arthritis. Since the initial writing of this article, teriflunomide received FDA approval on September 12, 2012, for the treatment of relapsing forms of MS.13 An oral treatment, teriflunomide reversibly inhibits dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in the de novo pyrimidine synthesis.22 This inhibition of DHODH results in a cytostatic effect on proliferating T and B cells.12 A 2-year, placebo-controlled, phase 3 trial (TEMSO) studied patients randomized to either 7 mg/day or 14 mg/day of teriflunomide or placebo (1:1:1).23 Compared to placebo, teriflunomide treatment of 7 mg/day and 14 mg/day resulted in a 31.2% and 31.5% relative risk reduction in ARR, respectively, the primary end point of the study. In the 7-mg and 14-mg groups, the risk for disability progression was reduced by 23.7% and 29.8%, respectively. Treatment-emergent adverse events were comparable in all 3 groups and teriflunomide was well tolerated. Results from another phase 3 trial (TOWER) were recently reported.24 This double-blind, multicenter trial studied once-daily 7 mg or 14 mg teriflunomide to placebo in patients with relapsing-remitting disease. A 36.3% reduction in ARR, the primary end point, was observed in patients receiving teriflunomide 14 mg/day compared to placebo (P<.0001). The dose of 7 mg/day resulted in a 22.3% reduction in ARR compared to placebo but did not show statistical significance. The most common side effects reported in this study included headache, alanine transaminase elevations, hair thinning, diarrhea, nausea, and neutropenia. Additional phase 3 trials are ongoing including a study (TENERE) comparing the safety and efficacy of teriflunomide with IFN beta-1a in patients with relapsing MS.25 Because the parent compound leflunomide has known teratogenic properties, concern exists over use of teriflunomide in women of child-bearing potential.

    Laquinimod is an orally administered agent that is structurally related to linomide, a quinolone previously studied in MS.26 The exact mechanism of action is unknown; however, studies have shown laquinimod substantially reduced lymphocyte infiltration into the CNS of treated animals.26 Additionally laquinimod inhibited production of proinflammatory cytokines and promoted production of interleukin (IL)-4, an anti-inflammatory cytokine.27 A phase 2, randomized, double-blind trial studied laquinimod 0.3 mg and 0.6 mg daily versus placebo in reducing MRI-measured disease activity.28 Treatment with laquinimod 0.6 mg daily resulted in a significant reduction of 40.4% compared to placebo in mean cumulative number of gadolinium-enhancing (GdE) lesions. No significant treatment effect was seen with the lower dose of 0.3 mg. Both doses of laquinimod were well tolerated; transient and dose-dependent increases in liver enzymes occurred, with 1 case of Budd-Chiari syndrome (in a patient with underlying hypercoagulability) reported. Two phase 3 trials have completed. The first trial (ALLEGRO) evaluated the safety and efficacy of laquinimod 0.6 mg daily in RRMS compared to placebo.29 During the 24-month treatment period, a significant reduction in the mean ARR (the primary end point) was observed in the laquinimod treatment arm compared to the placebo group, with a 21% reduction in the number of confirmed relapses for the laquinimod group. In addition to the 3 most common adverse events of abdominal pain, back pain, and cough, elevation of alanine aminotransferase levels occurred 2 times more frequently in the laquinimod group. The elevated liver enzymes were transient and were not associated with clinical signs or objective measures of liver failure. The second trial (BRAVO) assessed the efficacy, safety, and tolerability of laquinimod 0.6 mg daily compared to placebo, with an IFN beta-1a reference arm. Data analysis is ongoing for BRAVO.30 Two additional phase 3 trials are also ongoing.31

    An oral formulation of dimethyl fumarate (BG00012, BG-12) has now been created. Its exact mechanism of action in MS is not known; however, anti-inflammatory and neuroprotective effects have been demonstrated in in vitro cell cultures and in vivo experimental autoimmune encephalomyelitis models.32 A phase 2b study randomly assigned patients with relapsing MS to receive oral dimethyl fumarate at doses of 120 mg once daily, 120 mg 3 times daily, 240 mg 3 times daily, or placebo.33 The treatment dose of 240 mg 3 times daily resulted in a 69% reduction in GdE compared to placebo. Additionally, 2 phase 3 studies have reported significant reductions in ARR.34 Compared to placebo, the first study (DEFINE) reported 53% and 48% significant reductions in ARR for doses of 240 mg 3 times daily and twice daily, respectively. Similarly the second trial (CONFIRM) compared oral dimethyl fumarate dosed at 240 mg twice daily or 240 mg 3 times daily to placebo. Both doses resulted in statistically significant reductions in ARR (44% with dosing twice daily and 51% with dosing 3 times daily). A phase 3 extension trial is ongoing.19

    Daclizumab is a humanized monoclonal antibody that targets CD25, the IL-2 receptor alpha.35 IL-2 is critical for the expansion and viability of activated T cells.36 Daclizumab was FDA approved for the prophylaxis of acute organ rejection in patients receiving renal transplants; however, due to diminished market demand, the product was discontinued in the United States in 2009. A phase 2, randomized, double-blind, placebo-controlled trial (CHOICE) studied daclizumab in RRMS patients taking IFN beta.37 Patients were randomly assigned to receive daclizumab 2 mg/kg every 2 weeks, daclizumab 1 mg/kg every 4 weeks, or placebo in addition to IFN beta. At 24 weeks, patients receiving daclizumab 2 mg/kg showed a 72% reduction in new or enlarged GdE lesions compared to patients receiving placebo. According to phase 2 safety information daclizumab had comparable rates of infections, higher rates of injection-site reactions, and higher rates of cutaneous events in comparison to placebo.38 A phase 3 trial (DECIDE) to assess the efficacy and safety of daclizumab monotherapy (150 mg once every 4 weeks) versus IFN beta-1a is ongoing.39

    Ocrelizumab, a humanized monoclonal antibody, targets CD20 resulting in B-cell depletion.40 A phase 2, randomized, placebo-controlled trial studied ocrelizumab in patients with RRMS.41 Patients received either placebo or ocrelizumab dosed at either 600 mg IV or 2,000 mg IV, or IFN beta-1a. The trial results showed an 89% and 96% reduction in brain lesions in the 600-mg and 2,000-mg groups, respectively. To reduce the risk of infusion-related reactions pretreatment with methylprednisolone was given. No opportunistic infections were noted in this trial; 1 death occurred in the group receiving 2,000 mg to which a contribution of ocrelizumab cannot be excluded. A phase 3 trial studying the efficacy and safety of ocrelizumab is ongoing.19

    Since 1993, many disease-modifying agents have been approved for the treatment of MS. All FDA-approved products treat relapsing forms of MS, with little or no effect on progressive disease. The decision of whether to treat, and with what therapy, should be made with the patient. The discussion should involve the prognosis, associated risk factors, and the efficacy, safety, and tolerability of the treatment options available.42 No cure exists for MS. Preventing or delaying long-term disability is the most important therapeutic goal.43 Evidence suggests that suppression of acute inflammatory activity has a beneficial impact on long-term disability only if administered early in the disease. Given that the route of administration can adversely affect compliance and early treatment of MS, oral products may become an important part of the armamentarium of MS treatment.

    Dr Wilbanks is a drug information specialist, Catamaran, Lisle, IL, and adjunct professor, Ferris State University, Big Rapids, MI.

    Disclosure Information: The author reports no financial disclosures as related to products discussed in this article.

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