4/30/2014

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

Published on Formulary Journal (http://formularyjournal.modernmedicine.com)

Disease-modifying therapies for multiple

sclerosis: Focus on future direction
Publish Date: NOV 01,2012
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;
47:392399.)
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, firstdegree 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
http://formularyjournal.modernmedicine.com/print/29793

1/7

4/30/2014

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

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

In 1993, FDA approved interferon (IFN)-beta 1b as the first diseasemodifying 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
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

Table 2: Current
disease-modifying
agents

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
Table 3: Multiple
manufacturer recently announced that it is pulling the drug for this
sclerosis pipeline
use in preparation of its launch of alemtuzumab for the treatment of
products
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 g) 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-nave patients, and CARE-MS II,
studying patients who have experienced relapse episodes while on currently available diseasemodifying 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
http://formularyjournal.modernmedicine.com/print/29793

2/7

4/30/2014

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

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 gadoliniumenhancing (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
http://formularyjournal.modernmedicine.com/print/29793

3/7

4/30/2014

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

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.
REFERENCES
1. Calabresi PA. Multiple sclerosis and demyelinating conditions of the central nervous system.
In: Goldman L, Schafer AI, eds. Goldman's Cecil Medicine, 24th ed. Philadelphia, PA: Saunders
Elsevier, 2011:23472355.
2. National Multiple Sclerosis Society. Who gets MS? http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/who-gets-ms/index.aspx/. Accessed August 27,
2012.
3. Courtney AM, Treadaway K, Remington G, Frohman E. Multiple sclerosis. Med Clin N Am.
2009;93:451476.
http://formularyjournal.modernmedicine.com/print/29793

4/7

4/30/2014

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

4. National Multiple Sclerosis Society. Fact sheet: MS research.

http://www.nationalmssociety.org/chapters/mnm/mediacenter/fact-sheet-msresearch/index.aspx/. Accessed August 27, 2012.
5. Zhou J, Allen PD, Pessah IN, Naguib M. Neuromuscular disorders and malignant hyperthermia.
In: Miller RD, Eriksson LI, Fleisher LA, et al, eds. Miller's Anesthesia, 7th ed. Philadelphia, PA:
Churchill Livingstone Elsevier, 2009:11711195.
6. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:15021517.
7. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med.
2000;343:938952.
8. Ramagopalan SV, Sadovnick AD. Epidemiology of multiple sclerosis. Neurol Clin. 2011;29:207
217.
9. Sadovnick AD, Armstrong H, Rice GP, et al. A population-based study of multiple sclerosis in
twins: Update. Ann Neurol. 1993;33:281285.
10. Lublin FD. Clinical features and diagnosis of multiple sclerosis. Neurol Clin. 2005;23:115.
11. Schapiro RT. Managing symptoms of multiple sclerosis. Neurol Clin. 2005;23:177187.
12. Warnke C, Meyer zu Hrste G, Hartung HP, Stve O, Kieseier BC. Review of teriflunomide
and its potential in the treatment of multiple sclerosis. Neuropsychiatr Dis Treat. 2009;5:333
340.
13. National Multiple Sclerosis Society. The MS diseasemodifying medications. February 2012.
http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-aboutms/treatments/index.aspx/. Accessed September 17, 2012.
14. Giovannoni G. Promising emerging therapies for multiple sclerosis. Neurol Clin. 2011;435
448.
15. Klotz L, Meuth SG, Wiendl H. Immune mechanisms of new therapeutic strategies in multiple
sclerosisA focus on alemtuzumab. Clin Immunol. 2012;142:2530.
16. Button T, Coles A. Alemtuzumab for the treatment of multiple sclerosis. Future Neurology.
2010;5:177188.
17. Thomson Reuters. Sanofi pulls leukaemia drug ahead of possible OK for Lemtrada. August
20, 2012.
18. CAMMS223 Trial Investigators, Coles AJ, Compston DA, Selmaj KW, et al. Alemtuzumab vs.
interferon beta-1a in early multiple sclerosis. N Engl J Med. 2008;359:17861801.
19. Thomson Reuters Pharma. http://www.thomson-pharma.com/. Accessed August 29, 2012.
20. Efficacy and safety results from CARE-MS I: A phase 3 study comparing alemtuzumab and
interferon beta-1a. Sanofi-Aventis. Data on file. August 28, 2012.
21. Efficacy and safety results from CARE-MS II: A phase 3 study comparing alemtuzumab and
interferon beta-1a. Sanofi-Aventis. Data on file. August 28, 2012.
22. Claussen MC, Korn T. Immune mechanisms of new therapeutic strategies in MS:
Teriflunomide. Clin Immunol. 2012;142:4956.
23. O'Connor P, Wolinsky JS, Confavreux C, et al; TEMSO Trial Group. Randomized trial of oral
teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365:12931303.
24. Business wire. Genzyme reports positive top-line results of TOWER, a pivotal phase III trial
for Aubagio (teriflunomide) in relapsing multiple sclerosis. June 1, 2012.
25. Gold R, Wolinsky JS. Pathophysiology of multiple sclerosis and the place of teriflunomide.
Acta Neurol Scand. 2011;124:7584.
http://formularyjournal.modernmedicine.com/print/29793

5/7

4/30/2014

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

26. Giacomini PS, Bar-Or A. Laquinimod in multiple sclerosis. Clin Immunol. 2012;142:3843.
27. Jeffery DR. Development of laquinimod for relapsing-remitting multiple sclerosis. Future
Neurology. 2008;3:641648.
28. Comi G, Pulizzi A, Rovaris M, et al; LAQ/5062 Study Group. Effect of laquinimod on MRImonitored disease activity in patients with relapsing-remitting multiple sclerosis: A multicentre,
randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371:20852092.
29. Comi G, Jeffery D, Kappos L, et al; ALLEGRO Study Group. Placebo-controlled trial of oral
laquinimod for multiple sclerosis. N Engl J Med. 2012;366:10001009.
30. ClinicalTrials.gov/. BRAVO study: Laquinimod double blind placebo controlled study in RRMS
patients with a rater blinded reference arm of interferon -1a (Avonex).
http://www.clinicaltrials.gov/ct2/show/NCT00605215?term=bravo&rank=5/. Accessed
September 24, 2012.
31. ClinicalTrials.gov/. A study to evaluate the long-term safety, tolerability and effect of daily
oral laquinimod 0.6 mg on disease course in subjects with relapsing multiple sclerosis; A study
to evaluate the long-term safety, tolerability and effect on disease course.
http://www.clinicaltrials.gov/ct2/results?intr=%22Laquinimod%22&phase=2/. Accessed
September 17, 2012.
32. MacManus DG, Miller DH, Kappos L, et al. BG-12 reduces evolution of new enhancing lesions
to T1-hypointense lesions in patients with multiple sclerosis. J Neurol. 2011;258:449456.
33. Kappos L, Gold R, Miller DH, et al; BG-12 Phase Iib Study Investigators. Efficacy and safety
of oral fumarate in patients with relapsing-remitting multiple sclerosis: A multicenter,
randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372:14631472.
34. Perumal J, Khan O. Emerging disease-modifying therapies in multiple sclerosis. Curr Treat
Options Neurol. 2012;14:256263.
35. Martin R. Anti-CD25 (daclizumab) monoclonal antibody therapy in relapsing-remitting
multiple sclerosis. Clin Immunol. 2012;142:914.
36. Jones JL, Coles AJ. New treatment strategies in multiple sclerosis. Exp Neurol.
2010;225:3439.
37. Wynn D, Kaufman M, Montalban X, et al; CHOICE Investigators. Daclizumab in active
relapsing multiple sclerosis (CHOICE study): A phase 2, randomised, double-blind, placebocontrolled, add-on trial with interferon beta. Lancet Neurol. 2010;9:381390.
38. Kim SE. Daclizumab treatment for multiple sclerosis. Pharmacotherapy. 2009;29:227235.
39. ClinicalTrials.gov/. Efficacy and safety of daclizumab high yield process versus interferon 1a
in patients with relapsing-remitting multiple sclerosis ([DECIDE]).
http://www.clinicaltrials.gov/ct2/show/NCT01064401?term=decide&phase=2&rank=1/.
Accessed August 27, 2012.
40. Fox EJ, Rhoades RW. New treatments and treatment goals for patients with relapsingremitting multiple sclerosis. Curr Opin Neurol. 2012;25(Suppl):S11S19.
41. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: A
phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378:17791787.
42. Elovaara I. Early treatment in multiple sclerosis. J Neurol Sci. 2011;311(S1):S24S28.
43. Goodin DS, Frohman EM, Garmany GP Jr, et al; Therapeutics and Technology Assessment
Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice
Guidelines. Disease modifying therapies in multiple sclerosis: Report of the Therapeutics and
Technology Assessment Subcommittee of the American Academy of Neurology and the MS
Council for Clinical Practice Guidelines. Neurology. 2002;58:169178.
http://formularyjournal.modernmedicine.com/print/29793

6/7

4/30/2014

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

About formulary | Contact Us | About Us | Advertise with Formulary | Search | Mediwire

| All Content | Modern Medicine Formulary | Privacy Policy | Terms of Use | Advertiser
Terms | Linking and RSS Policy
2014 Advanstar Communications, Inc. All rights reserved.
Reproduction in whole or in part is prohibited.
Please send any technical comments or questions to our webmaster.
Source URL: http://formularyjournal.modernmedicine.com/formulary-journal/news/clinical/clinicalpharmacology/disease-modifying-therapies-multiple-sclerosis

http://formularyjournal.modernmedicine.com/print/29793

7/7