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Understanding the Mechanisms of Multiple Sclerosis Treatments

Individualized Care and Formulary Management in Multiple Sclerosis

Since the advent of the first multiple sclerosis (MS) disease-modifying therapy (DMT) almost 30 years ago, the range of treatments has significantly expanded. With many DMT options available and more DMTs winning FDA approval, it is important to understand the drug mechanisms of actions and evaluate the risks and benefits of each therapeutic option.

Despite our increased understanding of MS over the last several decades, unmet needs remain with regard to treatment selection. As demonstrated through clinical trials, there are varying degrees of treatment response among patients, demonstrating that there is no one-size-fits-all approach to MS treatment. Various responses to therapy are likely dependent on disease characteristics and genetic factors; however, no genetic markers for disease course, severity, or response to therapy have been identified. Therefore, optimizing an individualized approach is necessary in order to provide effective and safe treatment for each patient.1-3

“Window of Opportunity” for Early Intervention

When an MS diagnosis is made, the time at which therapy is initiated is critical. MS is a disease in which approximately 80% of patients will develop severe disability, and life expectancy is reduced by 10 years. This irreversible disability is determined by damage to the axons, which has been demonstrated to occur early in the disease course during a patient’s first clinical relapse. Importantly, disease activity in the early phases of the disease can predict long-term disability.2

Evidence continues to accumulate in support of early intervention being essential for maintaining long-term neurological function and preventing disability and premature mortality.4 It has been reported that patients who receive treatment after their first clinical attack but before an official MS diagnosis, also known as clinically isolate syndrome, have a 40% lower risk of disability progression compared with patients who did not receive early intervention.4 Further evidence for this emerged during a clinical trial for fingolimod, in which patients who were switched from a placebo to fingolimod mid-trial did not receive the same benefits as patients who received fingolimod from the start of the trial.4 In addition to early treatment, it is also believed that this window of opportunity is applicable in the transition of relapsing forms of MS to secondary progressive MS (SPMS) because treatment options are limited as the disease progresses.5

The Importance of Individualized Care

In addition to the importance of starting therapy as soon as possible, tailoring the therapy to the individual patient is critical. Before 2010, treatment options for MS were primarily limited to either interferon beta or glatiramer acetate for patients who were early in their disease course. If patients either did not respond or experienced breakthrough disease, they could be prescribed natalizumab, which was a more efficacious treatment option but had safety concerns. However, many new modalities of DMTs have since emerged, prompting health care professionals (HCPs) to individualize treatment decisions, which can be a complex undertaking.6

Individualizing treatment allows for effective and safer treatment regimens to be implemented, because certain patients have been shown to respond differently to the same treatment.2 Furthermore, finding the correct treatment option for an individual patient is critical to prevent further disease progression; treatment failure is associated with an increased risk of progression to SPMS.7 Currently, no biomarker is known that can be used to select the optimal treatment regimen; however, this area of research is still in its infancy.1,6 Theoretically, an effective biomarker would allow HCPs to carefully select a DMT with a specific mechanism of action to garner the greatest therapeutic benefit with the lowest safety risk.8

Several factors should be considered when selecting therapy, including efficacy, safety, mode of administration, economic components, and individual patient variables. Such individual patient variables can include practical aspects of adherence and administration, such as whether the patient can administer an injection on their own (or have familial support to assist) and whether they have access to transportation to infusion centers for intravenous treatments. Educating patients on therapy adherence, potential risks, and adverse effects (AEs) should also be factored into selecting a therapy.9,10

When customizing a treatment program for an individual patient, it is essential to complete a benefit/risk assessment. This assessment should include numerous factors, including DMT efficacy, to reduce disease activity; short- and long-term safety profiles of each DMT; criteria for switching treatment; and risk tolerance.6 Recommendations for selecting and switching DMTs have been released by the American Academy of Neurology, among other groups, to address several considerations. Such guidelines are highly data-driven, and no recommendations to choose one DMT over another are provided. Instead, the choice of the appropriate DMT should be made with the goal of providing the level of efficacy warranted by the patient’s current level of disease activity, carefully balanced with the patient’s preferences and maintenance of patient safety.6,11

Understanding the mechanism of action of a specific therapy is especially important if a change of therapy is deemed necessary. Recommendations for subsequent therapies include (1) selecting a different mechanism, and (2) considering the first therapy’s effects on the immune system, which can impact the efficacy and safety of a new therapy.6,11 Switching therapies may be considered necessary if the patient experiences breakthrough disease or if there are safety concerns regarding AEs or new patient comorbidities.9,11 For more information on drug mechanisms and drug classes within the MS treatment landscape, see the article on page 9.

Shared Decision-Making

Among the most important aspects of selecting treatment is allowing the patient a voice in the decision-making process, particularly given the chronic, lifelong nature of MS. One survey found that 79% of patients with MS preferred having an active role in decisions; another study reported that 90% of MS patients and physicians preferred shared decision-making or informed-choice decision-making approaches.10 Additionally, survey data indicate a significant connection between shared decision-making and higher treatment adherence rates.

Adhering to DMT therapy is essential for treatment efficacy; worse adherence can lead to increased risk of relapse and relapse-associated hospitalization. Patients who adhere to therapy are also reported to have an overall better quality of life.12 Reasons for nonadherence to medication can vary, but the most commonly reported include forgetfulness, injection-site pain, and AEs. Other reported reasons include treatment fatigue, practical issues related to self-injection, perceived lack of efficacy, and nonclinical factors, such as costs and health care barriers.12 Real-world adherence estimates can admittedly be difficult due to a lack of standardized measures, although simple steps, such as checking whether pills are dispensed or a prescription was filled, could be used.12

The success of shared decision-making relies on a positive patient–provider relationship, which begins at the initial HCP visit and with diagnosis. Active communication is crucial, and both the clinician and patient should understand their roles, responsibilities, and goals. In particular, the HCP should adequately communicate the risks and benefits of each DMT, and the patient should communicate their treatment preferences and lifestyle factors so the optimal DMT can be selected.12 Although a survey found that only 7.7% of responding patients with MS reported having no insurance, patients can still encounter issues with regard to coverage for specific medications, due to plan variations. If a specific drug is not covered, patients have the right to request an appeal for coverage.13

Building a long-term relationship with a patient is, of course, important beyond initial treatment selection. This can be especially true should a patient develop SPMS. Communication is a key to detecting these subtle disease changes.5

Formulary Management: Best Practices

Although specialty drugs such as DMTs for MS treatment account for only 1% of prescriptions in the United States, they account for 45% of total drug spending. It has been estimated that MS treatment costs $10 billion per year in the United States primarily due to the high cost of drugs. Because MS has many different treatment options, and because these comprise the fourth most expensive drug therapy category, “outcomes-based contracts” have been suggested between payers and pharmaceutical companies in the MS treatment landscape.2,14 These contracts state that the payment terms for medications are tied to the agreed-upon clinical circumstances, patient outcomes, or measures. These agreements can be used when there is uncertainty regarding clinical outcomes, but those outcomes are likely dependent on specialty high-cost medications, such as therapeutics for MS.14 These agreements have become more common over the last decade. Sixty-two outcomes-based contracts were publicly announced in the United States between 2009 and 2019, and more than 25% of health plans have an outcomes-based contract in place. Of these health plans, 85% expressed interest in pursuing additional contracts.14

In a recent series of market research interviews about the use of outcomes-based contracts in the field of MS therapeutics, 17 individuals representing payers, drug manufacturers, and industry consultants participated. They agreed that outcomes-based contracts can effectively mitigate risk and deliver value for DMTs in MS patients; however, they noted that widespread adoption of these contracts is limited by several challenges, including how to measure outcomes.14 Although all respondents agreed that end points must be measurable, clearly defined, objective, and noticeable within a relatively short period of time, there were several differences of opinion regarding what end points should be used to measure the success or failure of a drug.

These end points are particularly difficult in MS, as relapse rate can be considered too subjective and MRI results do not always directly correlate with disease progression, especially in the disease’s advanced stages. Consequently, respondents agreed that identifying a biomarker that correlates with clinical outcomes would be necessary for outcomes-based contracts to be widely adopted for MS therapies.14 Other challenges that were addressed in these interviews were data-related issues, patient adherence to therapy, regulatory barriers, and levels of risk mitigation.14

Future Directions

As many new therapeutics are introduced to the market, more precise procedures need to be developed for individualized DMT selection in order to prescribe patients the best treatment as early as possible in their disease course. Biomarkers are very much needed to further optimize treatment selection and to ascertain relatively quickly whether a treatment is working effectively. Once such biomarkers are identified, doors will open for the implementation of outcomes-based contracts between payers and pharmaceutical companies, further advancing the availability of optimized treatment outcomes in MS patients.


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  2. Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet. 2017;389(10076):1347-1356. doi:10.1016/S0140-6736(16)32388-1
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  8. The AJMC Institute for Value-Based Medicine. Contemporary management of multiple sclerosis: a stakeholder interchange report. The American Journal of Managed Care®. 2019. Accessed July 20, 2020.
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  12. Ben-Zacharia A, Adamson M, Boyd A, et al. Impact of shared decision making on disease-modifying drug adherence in multiple sclerosis. Int J MS Care. 2018;20(6):287-297. doi:10.7224/1537-2073.2017-070
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