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Supplements Multiple Sclerosis: A Review of Diagnosis and Management

Beyond Efficacy and Safety: Where We Go From Here in the Management of Multiple Sclerosis

The relationship between the mechanism of action of prior DMTs and subsequent therapies should be evaluated.4 In some cases, previous DMTs could potentially nullify or attenuate the mode of action of future therapies. The T-cell– and B-cell–depleting actions of alemtuzumab and ocrelizumab, respectively, occur immediately following the use of fingolimod if lymphocytes have not yet exited from secondary lymphoid tissue.

The development of PML has been associated with the use of several DMTs.4 The risk differs according to DMT. Natalizumab is associated with the highest risk for PML (incidence, 1/100 to 1/1000), followed by fingolimod (incidence, 1/18,000) and dimethyl fumarate (incidence, approximately 1/50,000).4 The risk for PML with other DMTs is either very low or unclear. It is currently not known whether or how the sequencing of DMTs might affect overall PML risks.

It is generally recommended that live vaccinations be avoided in patients with MS.1,4 The prescribing information for teriflunomide, fingolimod, daclizumab*, and alemtuzumab advise against the use of live attenuated vaccines during and for prespecified time periods after discontinuing therapy.20-23

Aside from glatiramer acetate and the interferon beta agents, all of other DMTs have been associated with a risk for infection, including both community-acquired infections and opportunistic infections.24 Patients should therefore be screened for latent viruses and other conditions (such as hepatitis B infections) prior to initiating therapy.

The High Cost of DMTs

MS is a disabling, chronic disease that imposes a substantial economic burden on both patients and on the US healthcare system.5 The single largest driver of MS-associated healthcare expenditures are prescription drugs, which account for more than half of all direct medical costs. In particular, the costs of DMTs have risen dramatically over the last 10 years.5 The price of some of these medications has increased nearly 10-fold (see Table 1). Acquisition costs for nearly all DMTs currently exceed $70,000 per year.5 This does not include costs incurred from the care of patients receiving these agents (such as laboratory monitoring, first-dose observation period, and physician visits), only the cost of the actual DMT itself.

It is important to note that patients with MS often require many medications in addition to DMTs. Use of these medications is responsible for additional costs in the healthcare system.

Generic formulations are available for both the glatiramer acetate 20 mg and 40 mg formulations.25,26 Fingolimod will lose exclusivity in 2019; it is anticipated that generic competition will occur soon thereafter.

The high cost of DMTs has a cascade of negative consequences for patients, ranging from excessive cost-sharing or deductible amounts to restrictive insurance barriers, which can negatively affect patient care.5

Unmet Needs

Although the currently approved DMTs are reliable, constantly being improved, effective in treating relapses, and capable of decreasing long-term disability, they have only limited efficacy for the treatment of progressive disease without the occurrence of additional inflammatory relapses.6 In fact, of all the currently approved DMTs, only 1 agent—ocrelizumab—has been approved for the treatment of patients with primary progressive MS.27

Because the neuroarchitectural damage that occurs during relapses accumulates over time and is associated with increasing patient disability, neuroprotective and regenerative therapies are needed.6 Specifically, agents that repair or regenerate neurons, oligodendrocytes, and supporting glia are critical components of the MS treatment armamentarium.7

Limiting disability among patients with MS will inevitably require a multidimensional approach that targets both the peripheral and the central nervous systems, focusing on specific immune components, as well as on those pathways that are thought to contribute significantly to neurodegenerative processes.28

The MS Pipeline

As noted earlier, several new medications are being investigated in late-phase clinical studies for the treatment of patients with relapsing or progressive forms of MS.8 These agents represent a variety of mechanisms of action, and are associated with lower relapse rates and improvements in disabilities. Several of these pipeline agents are selective sphingosine-1-phosphate (S1P) receptor immunomodulators, including laquinimod, ozanimod, ponesimod, and siponimod. These agents have similar efficacy to the currently approved S1P immunomodulator fingolimod, whereas ozanimod appears to have an improved safety profile compared with other drugs in its class.8 Ofatumumab is a CD20-positive B-cell–targeting monoclonal antibody, and masitinib is a mast-cell inhibitor.8 Phase 3 trials for some of these agents will conclude within the next 12 months, and their manufacturers are expected to apply for FDA approval soon thereafter. Table 2 describes a variety of agents in the MS pipeline.


In addition to efficacy and safety concerns, clinicians must also consider the optimal time to initiate MS therapy, adherence factors, switching strategies, and cost issues when prescribing DMTs to patients.2-5 These considerations are a reflection of the many unmet needs of the MS care spectrum. With more agents in the pipeline offering the potential to lower relapse rates and improve disabilities, however, the treatment landscape is poised for continued growth, giving clinicians increased opportunities to possibly improve treatment outcomes as well as quality of life.

  1. Bainbridge JL, Miravalle A, Wong PS. Multiple sclerosis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiological Approach, 10th ed. New York, NY: McGraw-Hill Education; 2017:815-836.
  2. Rojas JI, Patrucco L, Miguez J, Cristiano E. Brain atrophy in multiple sclerosis: therapeutic, cognitive and clinical impact. Arq Neuropsiquiatr. 2016;74(3):235-243.
  3. Doshi A, Chataway J. Multiple sclerosis, a treatable disease. Clin Med (Lond). 2017;17(6):530-536.
  4. Pardo G, Jones DE. The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J Neurol. 2017;264(12):2351-2374.
  5. Hartung DM. Economics and cost-effectiveness of multiple sclerosis therapies in the USA. Neurotherapeutics. 2017;14(4):1018-1026.
  6. Kremer D, Kury P, Dutta R. Promoting remyelination in multiple sclerosis: current drugs and future prospects. Mult Scler. 2015;21(5):541-549.
  7. Wingerchuk DM, Carter JL. Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. Mayo Clin Proc. 2014;89(2):225-240.
  8. Radick L, Mehr SR. The lastest innovations in drug pipeline for multiple sclerosis. Am Health Drug Benefits. 2015;8(8):448-453.
  9. Ziemssen T, Derfuss T, de Stefano N, et al. Optimizing treatment success in multiple sclerosis. J Neurol. 2016;263(6):1053-1065.
  10. Remington G, Rodriguez Y, Logan D, Williamson C, Treadaway K. Facilitating medication adherence in patients with multiple sclerosis. Int J MS Care. 2013;15(1):36-45.
  11. Crawford A, Jewell S, Mara H, McCatty L, Pelfrey R. Managing treatment fatigue in patients with multiple sclerosis on long-term therapy: the role of the multiple sclerosis nurses. Patient Prefer Adherence. 2014;8:1093-1099.
  12. Costello K, Kennedy P, Scanzillo J. Recognizing nonadherence in patients with multiple sclerosis and maintaining treatment adherence in the long term. Medscape J Med. 2008;10(9):225.
  13. Evans C, Marrie RA, Zhu F, et al. Adherence and persistence to drug therapies for multiple sclerosis: a population-based study. Mult Scler Relat Disord. 2016;8:78-85.
  14. Tan H, Cai Q, Agarwal S, Stephenson JJ, Kamat S. Impact of adherence to disease-modifying therapies on clinical and economic outcomes among patients with multiple sclerosis. Adv Ther. 2011;28(1):51-61.
  15. Treadaway K, Cutter G, Salter A, et al. Factors that influence adherence with disease-modifying therapy in MS. J Neurol. 2009;256(4):568-576.
  16. Devonshire V, Lapierre Y, Macdonell R, et al; GAP Study Group. The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis. Eur J Neurol. 2011;18(1):69-77.
  17. National Clinical Advisory Board of the National Multiple Sclerosis Society. 2007 disease management consensus statement. Accessed February 9, 2018.
  18. Farber RS, Sand IK. Optimizing the initial choice and timing of therapy in relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord. 2015;8(5):212-232.
  19. Goldenberg MM. Multiple sclerosis review. P T. 2012;37(3):175-184.
  20. Aubagio [package insert]. Cambridge, MA: Genzyme Corporation; November 2016.
  21. Gilenya [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; December 2017.
  22. Zinbryta [package insert]. Cambridge, MA: Biogen Inc; August 2017.
  23. Lemtrada [package insert]. Cambridge, MA: Genzyme Corporation; December 2017.
  24. Grebenciucova E, Pruitt A. Infections in patients receiving multiple sclerosis disease-modifying therapies. Curr Neurol Neurosci Rep. 2017;17(11):88.
  25. Glatiramer acetate 20 mg [package insert]. Morgantown, WV: Mylan Pharmaceuticals, Inc; April 2017.
  26. Glatiramer acetate 40 mg [package insert]. Morgantown, WV: Mylan Pharmaceuticals, Inc.
  27. Ocrevus [package insert]. South San Francisco, CA: Genentech, Inc; March 2017.
  28. Yong H, Chartier G, Quandt J. Modulating inflammation and neuroprotection in multiple sclerosis. published online June 5, 2017. J Neurosci Res.
  29. Comi G, Pulizzi A, Rovaris M, et al; LAQ/5062 Study Group. Effect of laquinimod on MRI-monitored disease activity in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;371(9630):2085-2092.
  30. Comi G, Jeffery D, Kappos L, et al; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Eng J Med. 2012;366(11):1000-1009.
  31. Vollmer TL, Sorensen PS, Selmaj K, et al; BRAVO Study Group. A randomized placebo-controlled phase III trial of oral laquinimod for multiple sclerosis. J Neurol. 2014;261(4):773-783.
  32. Multiple Sclerosis Discover Forum. Accessed February 14, 2018.
  33. Vermersch P, Benrabah R, Schmidt N, et al. Masitinib treatment in patients with progressive multiple sclerosis: a randomized pilot study. BMC Neurol. 2012;12:36.
  34. Sorensen P, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014;82(7):573-581.
  35. Tran JQ, Hartung JP, Olson AD, et al. Cardiac safety of ozanimod, a novel sphingosine-1-phosphate receptor modulator: results of a thorough QT/QTc study. published online August 7, 2017. Clin Pharmacol Drug Dev.
  36. Cohen JA, Arnold DL, Comi G, et al; RADIANCE Study Group. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016;15(4):373-381.
  37. Olsson T, Boster A, Fernández O, et al. Oral ponesimod in relapsing–remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014;85(11):1198-1208.
  38. Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. [published correction appears in Lancet Neurol. 2013:12(9):846]. Lancet Neurol. 2013 12(8):756-767.
  39. Vermersch P, Bar-Or A, Cree B, et al. The EXPAND study results: efficacy of siponimod in secondary progressive multiple sclerosis. Eur J Neurol. 2017;24(suppl 1):44.
  40. Giovannoni G, Bar-Or A, Cree B, et al. The EXPAND study results: safety and tolerability of siponimod in patients with secondary progressive multiple sclerosis. Eur J Neurol. 2017;24(suppl 1):495.
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