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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.

Conclusions

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.

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