Choosing the Best Treatment for Multiple Sclerosis: Comparative Effectiveness, Safety, and Other Factors Involved in Disease-Modifying Therapy Choice

Comparative effectiveness research (CER) has emerged as a priority for outlining the advantages and disadvantages of disease-modifying therapies (DMTs) for multiple sclerosis (MS). CER can provide physicians with valuable information to assist them in selecting the most appropriate therapeutics for their patients with MS. For payers, data from CER could inform decisions regarding the level of coverage for current and developing MS therapeutics, and drive the use of the most effective treatments for patients with MS. The base of CER data for DMTs has been expanding, and findings from a number of CER studies for currently available DMTs have been published, while further CER studies are planned to evaluate currently available and new DMTs or DMTs in development. While CER can be used to guide DMT selection for physicians and payers, the safety and tolerability of these treatments must be considered as well. Other emerging factors (eg, biomarkers and patient-specific factors) may also serve as important determinants of DMT choice in the future.

(Am J Manag Care. 2013;19:S332-S342)Clinical and coverage-related decisions in the multiple sclerosis (MS) therapeutic category are growing increasingly complex. Comparative effectiveness research (CER) can aid decision makers in navigating these multifaceted issues. The Institute of Medicine (IOM) defines CER as “the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or to improve the delivery of care.”¹ This type of information helps physicians and payers alike in evaluating the advantages and disadvantages of one product relative to other available treatments.²

Multiple factors contribute to the increasing complexity of decision making in the MS category, including the advent of novel MS treatments, increasing costs of therapy, and a lack of up-to-date clinical practice guidelines. In a category historically dominated by injectable therapies, approval of the first oral agents (fingolimod in 2010, teriflunomide in 2012, and dimethyl fumarate in 2013) represents a landmark advancement. In addition to these agents, other oral disease-modifying therapies (DMTs) and monoclonal antibodies are currently in phase 3 development or are awaiting US Food and Drug Administration approval.^3,4

These advances in MS therapies come at a price. A study of 361 commercially insured patients with MS showed an 8.2% compounded annual growth rate in per patient per year costs since 2006.⁵ The authors attribute this rise in costs to drug price inflation, citing an increase in member cost share per 30-day supply from $48 in 2006 to $114 in 2010. This increasing member cost share can be detrimental to the fragile population of patients with MS. In addition to the debilitating effects of the disease, persons newly diagnosed with MS are 3.5 times more likely to be hospitalized and twice as likely to go to the emergency department compared with their non-MS counterparts.⁶ Increased utilization of medical resources is reflected in the total medical costs incurred by MS patients, which can be nearly 5 times greater than those of healthy individuals. For newly diagnosed MS patients, one-fourth of these incremental costs have been attributed to drug prices.⁶

As a consequence of new product approvals and escalating drug costs, health plan decision makers are viewing the MS category with increased scrutiny. Jeremy Schaefer, PharmD, MBA, director benefit manager, stated that “Opportunities exist for payers to manage the MS categories and control costs. Preferring select agents on formulary, developing utilization management programs to promote patient safety, and encouraging use of preferred agents and specialty pharmacies all provide opportunities to optimize clinical and service outcomes at the lowest cost.”⁵ Payers are definitively operationalizing the management of this category. A survey of 93 health plans covering more than 115 million lives revealed that 81% to 86% of plans apply prior authorizations to MS agents and 65% have preferred agents.⁷ Furthermore, consensus statements from a panel of US managed care pharmacists and physicians have been published in order to aid health plan decision makers in managing this class.8 These statements recommend prior authorizations and preferred agents as viable strategies to appropriately manage the MS category. The article highlighted the lack of comprehensive, up-to-date US-based treatment guidelines as a distinct gap in evidencebased information available to payers to support decision making. Specifically, the most recent MS clinical treatment guidelines from the American Academy of Neurology were published in 2002 (and reaffirmed in 2008) and do not address several of the most recent drug approvals.⁹ In the absence of definitive guidance from physician associations, health plan decision makers must conduct their own assessments of the available literature and data to inform policies.

Because CER evaluates products in relation to one another, it can help payers determine whether a treatment should be elevated to first-line status, be assigned to a given copayment tier, or require a prior authorization for use.² MS is on the list of the top 100 initial priority CER topics published by the IOM and funded under the American Recovery and Reinvestment Act.¹ Although the full benefits of the prioritization of MS are yet to be realized, there is a growing body of CER on MS therapeutics. This article provides an overview of the available and emerging CER for MS.

Comparative Effectiveness and Relative Safety of MS TherapeuticsRelative Effectiveness Outcomes of Current DMTs

The Drug Effectiveness Review Project (DERP) published a drug class review of the comparative effectiveness of DMTs for MS in 2010, and provided an addendum for fingolimod in 2011.^10,11 Five studies that evaluated the comparative effectiveness of interferon beta-1a (intramuscular [IM] or subcutaneous [SC] injection) or interferon beta-1b SC were identified in the 2010 drug class review of DMTs in relapsingremitting MS (RRMS).¹¹ Given the existence of this body of work and, in contrast, the lack of comparative effectiveness data on primary progressive or secondary progressive MS, this review will focus on RRMS. The CER studies for current DMTs are summarized in Table 1.^12-30

Three controlled clinical trials directly compared interferon beta-1b SC with interferon beta-1a SC in patients with RRMS and showed no clinically important differences in Expanded Disability Status Scale (EDSS) scores, disease progression, or relapse rates between the 2 DMTs.^14-16 Findings from the 3 controlled clinical trials that have directly compared interferon beta-1a IM with interferon beta-1a SC suggest that relapse outcomes were better with interferon beta-1a SC treatment than with interferon beta-1a IM.^13-15 Because all of these studies evaluated high-dose or highfrequency administration of the interferon beta-1a/1b SC products relative to a once-weekly dosing schedule of interferon beta-1a IM, these findings indicate a dose, or at least a dose-frequency, effect of the interferons.¹⁶ No significant differences were shown between interferon beta-1a SC and interferon beta-1a IM with respect to disability-related outcomes or disease progression in patients with RRMS.^13-15 In 2 direct comparative studies that evaluated relapse outcomes, the percentage of patients with RRMS who were relapse free at 2 years was higher with interferon beta-1b SC than with interferon beta-1a IM (pooled relative risk, 1.51 [95% confidence interval (CI), 1.11-2.07]).^11,12,14

In addition to direct comparative studies of interferon beta products, at least 200 large-scale, comparative, observational studies of 1 year or longer in duration have been conducted in populations of patients taking interferon beta- 1b SC, interferon beta-1a SC, or interferon beta-1a IM.^17-20 In 2 of these studies, significant reductions from baseline were observed in relapse rates with all 3 interferon beta products (P <.0001).^18,19 No significant differences in relapse rates were observed between treatment groups.^18,19 In the largest observational study (N = 4754), the annualized relapse rate was lower for patients who received interferon beta as initial therapy than for those who received interferon beta as followup therapy, and all interferon beta products demonstrated similar efficacy with respect to reduction in relapses.20 The percentage of progression-free patients at 2 years was significantly higher in the interferon beta-1a IM group (83.4%) than in the interferon beta-1b SC (76.2%) or interferon beta-1a SC (69.4%) groups (P <.001).²⁰

Three head-to-head trials comparing glatiramer acetate with interferon beta-1b SC or interferon beta-1a SC in patients with RRMS showed no significant differences in relapse outcomes or disease progression for glatiramer acetate compared with either interferon beta.^21-23 In contrast, results from 2 comparative observational studies of glatiramer acetate of formulary development at Prime Therapeutics, a pharmacy and interferon betas employing data from clinical databases showed significant improvements in the annualized relapse rate with glatiramer acetate versus interferon betas.^24,25

Natalizumab has been compared with interferon beta and with glatiramer acetate in retrospective and case-controlled studies.^26,27 In a retrospective study comparing natalizumab with interferon beta-1a in patients with RRMS, patients in the natalizumab group had a significantly lower annualized relapse rate and significantly greater improvements in EDSS scores from baseline during the first and second year of treatment compared with patients in the interferon beta-1a group (P <.02 for all comparisons).²⁶ In a separate case-controlled study, patients who received natalizumab had a significantly lower annualized relapse rate than those who received interferon beta or glatiramer acetate (P <.0001).²⁷

The efficacy of fingolimod has been compared with that of interferon beta-1a in a year-long, randomized, doubleblind trial, and in a 1-year open-label extension study.^28,29 During 1 year of treatment, fingolimod was associated with a significantly lower annualized relapse rate than interferon beta-1a IM (P <.001 for both comparisons) in patients with RRMS; no significant difference between treatment groups was observed in the progression of disability.²⁸ In the 1-year extension study, patients who received interferon beta-1a in the parent study were switched to fingolimod; the annualized relapse rate was significantly lower after switching to fingolimod compared with the previous year on interferon beta-1a treatment (P <.049).²⁹

Dimethyl fumarate has been compared with glatiramer acetate in a 2-year randomized study in patients with RRMS.30 Although the study was not designed to evaluate the noninferiority or superiority of dimethyl fumarate compared with glatiramer acetate, post hoc analyses revealed that dimethyl fumarate taken 3 times daily was associated with a significantly lower annualized relapse rate (nominal P = .02), significantly lower numbers of new or enlarging T2-weighted hyperintense lesions (nominal P = .002), and significantly lower numbers of new T1-weighted hypointense lesions (nominal P = .003).³⁰

The efficacy of 2 doses of teriflunomide has been compared with that of interferon beta-1a SC in patients with relapsing MS treated for 48 weeks to longer than 2 years.^31,32 Data for the primary efficacy outcome and other secondary efficacy outcomes have recently become available (Table 2^33-37). The annualized relapse rate for the higher dose of teriflunomide evaluated (14 mg) was comparable to that for interferon beta-1a, but the annualized relapse rate for the lower dose of teriflunomide (7 mg) was significantly higher than that for interferon beta-1a (P = .03).^31,32 There were, however, no statistically significant differences between treatment groups with regard to the primary efficacy outcome (time to failure, with failure defined as the first occurrence of confirmed relapse or treatment discontinuation).^31,32

In addition to the CER studies described in this section, there is an ongoing observational study designed to assess the efficacy and safety of glatiramer acetate compared with interferon beta-1a IM or interferon beta-1b, an ongoing direct comparative study designed to evaluate the efficacy and safety of fingolimod compared with interferon beta-1b, and a recently completed study that evaluated the efficacy and safety of fingolimod compared with glatiramer acetate, interferon beta-1a IM, interferon beta-1a SC, and interferon beta-1b (Table 2^33-37).

Relative Safety of Currently Available DMTs

Although CER can help guide decisions related to prioritizing DMTs for MS, the relative safety and tolerability profiles of these therapeutics play an important role in decision making regarding treatment preferences.⁸ Interferon beta and glatiramer acetate, which are considered to be first-line DMTs, have generally favorable safety and tolerability profiles.^38,39 The most common side effects associated with interferon beta therapy are flu-like symptoms (eg, fever, chills, myalgias, headache).^38,39 The 2010 updated DERP drug class review summarized the pooled rates of selected adverse events (AEs) and discontinuations for interferons (Figure).¹¹

The most common side effects associated with glatiramer acetate treatment are typically inflammatory injection site reactions.^38,39 In a comparative study of glatiramer acetate and interferon beta-1b SC in patients with RRMS, the percentage of patients experiencing any injection site reaction was significantly higher with glatiramer acetate than with interferon beta-1b (P = .0005).²¹ In a separate comparative study of glatiramer acetate and interferon beta-1a SC in patients with RRMS, the rates of injection site swelling, injection site induration, and injection site pruritus were all significantly higher with glatiramer acetate than with interferon beta-1a SC (P <.005 for all comparisons).²² In contrast, the occurrence of flu-like syndrome was reported significantly more frequently with both interferon beta-1a SC and interferon beta 1-b SC than with glatiramer acetate (P <.0001).^21,22

Direct comparative evidence regarding the tolerability of natalizumab compared with other DMTs is lacking. Natalizumab, although generally well tolerated, has been associated with the development of progressive multifocal leukoencephalopathy (PML), a rare and typically fatal infection of the central nervous system.^39,40 With regard to comparative tolerability, results from a small case-controlled study of natalizumab compared with interferon beta or glatiramer acetate showed that the incidence of severe fatigue was significantly lower with natalizumab than with interferon beta or glatiramer acetate (P = .04).²⁷

The comparative tolerability of fingolimod has been evaluated in a 1-year, randomized, double-blind study of 2 doses of fingolimod and interferon beta-1a IM in patients with RRMS.²⁸ The incidences of flu-like illness and of myalgia were higher with interferon beta-1a IM than with either dose of fingolimod (1.25 mg or 0.5 mg),²⁸ while the incidence of herpes virus infection and of AEs leading to treatment discontinuation were both higher with fingolimod 1.25 mg than with fingolimod 0.5 mg or interferon beta-1a IM.²⁸ The primary safety concern with fingolimod is the potential for cardiovascular effects following administration of the first dose. Accordingly, the prescribing information warns against using fingolimod in patients with certain preexisting or recent (within the last 6 months) heart conditions or stroke, or in patients who are taking certain antiarrhythmic medications.⁴¹

The most common side effects associated with dimethyl fumarate treatment are flushing and gastrointestinal side effects.^30,42 In a study comparing dimethyl fumarate with glatiramer acetate, the incidence of flushing (which included hot flush and flushing) was 35% with twice-daily dimethyl fumarate, 28% with dimethyl fumarate taken 3 times daily, and 3% with glatiramer acetate. The incidence of gastrointestinal side effects (eg, nausea, diarrhea) was 36% with twice-daily dimethyl fumarate, 41% with dimethyl fumarate taken 3 times daily, and 15% with glatiramer acetate.30 According to the prescribing information, dimethyl fumarate may cause lymphopenia, and a complete blood count should be available before initiating treatment.⁴³

In a randomized, placebo-controlled, phase 3 study of teriflunomide, side effects reported to occur in more patients receiving teriflunomide than placebo included diarrhea, nausea, hair loss, and elevated alanine aminotransferase levels, while the incidence of elevated alanine aminotransferase levels that were at least 3 times the upper limit of normal were comparable for the teriflunomide and placebo groups.⁴⁴ In the comparative study of teriflunomide and interferon beta-1a SC, the safety and tolerability profiles of teriflunomide were consistent with those observed in previous clinical studies; the most common side effects associated with teriflunomide treatment were nasopharyngitis, diarrhea, hair thinning, and back pain.³¹ Teriflunomide is contraindicated in patients with severe hepatic impairment and in women who are pregnant or of childbearing potential and not using reliable contraception.⁴⁵

New Therapeutics and Therapeutics in Development for Multiple Sclerosis

In addition to the currently available oral DMTs, laquinimod, an oral immunomodulatory drug with neuroprotective effects, and a number of monoclonal antibodies, including daclizumab, alemtuzumab, and ocrelizumab, are in phase 3 development for the treatment of relapsing MS.^4,46-49 There is, however, a paucity of CER comparing these agents with currently available DMTs. Three direct comparative studies of alemtuzumab with interferon beta-1a have been completed, and several CER studies comparing new and developing DMTs with approved therapeutics are ongoing (Table 2^33-37). A direct comparative randomized, double-blind, phase 2 study of the monoclonal antibody alemtuzumab and interferon beta-1a SC in patients with early RRMS showed that alemtuzumab treatment was associated with significant reductions in the annualized relapse rate, the rate of sustained disability accumulation, and lesion burden, as compared with interferon beta-1a treatment (P <.005 for all comparisons).³⁵ Results from subsequent direct comparative randomized, controlled, phase 3 studies supported these findings, showing significantly lower relapse rates with alemtuzumab than with interferon beta-1a SC (P <.0001).^33,34

Emerging Factors Involved in DMT Selection

In addition to using data regarding the relative efficacy and safety of DMTs for MS to prioritize these treatments, some patient-specific factors, including gender, race, and genetics, may be considered when choosing a DMT for individual patients. A post marketing analysis of the effects of gender on the response to interferon beta treatment in patients with RRMS showed that female patients had a significantly higher risk of experiencing a first relapse than did male patients (P = .0097).⁵⁰ A separate post hoc analysis of data from a randomized, controlled trial of interferon beta-1a SC and interferon beta-1a IM showed that African American patients were more likely to experience relapses than white Americans.⁵¹ Although the results of these analyses suggest that female and African American patients may be less responsive to interferon beta treatment than males or white Americans, these results may instead be indicative of differences in the disease course based on gender and race, rather than differences in the response to treatment. In contrast to these results, no gender-related differences in treatment effects of glatiramer acetate have been observed in patients with MS,^52,53 and natalizumab has been shown to provide significant efficacy regardless of race or gender.^54,55

In addition to these patient characteristics, the identification of biomarkers that are indicative of the clinical response to beta interferons, glatiramer acetate, and natalizumab and the safety of these treatments is a growing field of research. Although routine screening for these biomarkers is not currently employed in the clinical setting, they may ultimately find utility in helping to develop MS management schemes tailored to the individual patient.^56-64 As an example, the interferon beta is an immunomodulator that induces a cellular response that results in the upregulation of numerous genes.⁶⁵ Patient-to-patient differences in the response to interferon beta may potentially be predicted early by differential expression of select interferon-inducible genes.⁶⁵ In addition to allowing for the determination of patients with poorer response to DMTs, biomarkers may provide an early indication of potential safety risks of DMTs. For example, the presence of JCV-specific antibodies in the blood or the presence of polyomavirus (JCV and the closely related BK virus) DNA in the cerebrospinal fluid may be useful markers for detecting patients who are at a heightened risk for the development of PML.^40,66,67

Conclusion

The base of CER data and comparative safety data for DMTs has been expanding, and further CER studies are planned to evaluate currently available and new or developing DMTs. In addition to safety and efficacy, other emerging factors, such as biomarkers and patient demographics, may serve as important determinants of DMT choice in the future.Author affiliation: Department of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC.

Funding source: This supplement was supported by Sanofi-Aventis. Editorial support for the writing of this manuscript was provided by Megan Knagge, PhD, of MedErgy, and was funded by Sanofi-Aventis. The author retained full editorial control over the content of this manuscript.

Author disclosure: Dr Happe reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: LEHappe@presby.edu.

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