Introduction
Multiple sclerosis (MS) is a chronic, immune-mediated neurodegenerative disease of the central nervous system that causes inflammation, demyelination, and axonal degeneration [
1,
2]. MS is estimated to affect over 2.8 million people globally and 400,000 people in the USA [
3,
4]. Although the course of MS is highly heterogeneous, most patients experience episodes of new or worsening neurological deficits and accumulation of unremitting disability which are both present from the very earliest stages of the disease [
1,
5]. Relapsing–remitting MS (RRMS) is the most common form of MS, accounting for roughly 85% of cases [
1]. RRMS is characterized by relapses, in which symptoms flare up, followed by periods of remission [
1].
Although there is no curative treatment for MS, several disease-modifying therapies (DMTs) have been developed to reduce the frequency and severity of relapses, delay disease progression, and limit new disease activity [
6‐
8]. There are currently more than 15 approved therapies available, with various routes of administration (injection, intravenous infusion, and oral), modes of action, and dosing schedules [
5]. With so many therapies available, the appropriate choice for a given patient will depend on several considerations, including level of disease activity, disease progression, medication-related factors (tolerability profile, administration method, efficacy, and cost), and patient characteristics and preferences [
9].
For medications to reach optimal therapeutic efficacy, they must be taken as prescribed. However, like those with many chronic illnesses, patients with MS may struggle with persistence (the duration of time from initiation to discontinuation of therapy) and adherence (the degree to which they follow their treatment plan) [
7,
10‐
12]. Factors impacting persistence and adherence of MS DMTs include patient-perceived lack of efficacy, adverse effects, inconvenience, and forgetfulness [
7,
12]. Real-world studies have shown that nonpersistence and nonadherence to DMTs can lead to negative clinical and economic outcomes for patients with MS, including higher rates of relapse, disease progression, hospitalization, and increased medical costs [
7,
13]. Furthermore, patients who are dissatisfied with their treatment are more likely to switch therapies. Previous studies have shown that up to 30% of patients with MS switch to an alternative DMT at least once within 2 years of initiating treatment [
14,
15], with lack of efficacy and adverse effects cited as the most common reasons for switching [
16]. As with nonpersistence and nonadherence, DMT switching is associated with higher rates of relapse and healthcare costs [
15‐
17].
Previous studies have compared treatment persistence and adherence between available oral DMTs excluding diroximel fumarate, and injectable DMTs, with results suggesting that oral DMTs have improved persistence and adherence. A retrospective study of hospitalization and outpatient data from 10,240 patients with MS newly initiated on a first-line DMT for RRMS reported significantly higher persistence and adherence with oral DMTs (teriflunomide and dimethyl fumarate) than injectable DMTs (interferons and glatiramer acetate) [
9]. Another retrospective database study also found that patients who received injectable DMTs discontinued significantly sooner than oral DMT users [
18].
Oral DMTs are convenient and easy to administer and have similar or superior efficacy to platform injectable therapies [
6,
19]. Recent studies suggest that orally administered products are preferred over all parenteral routes of administration [
20‐
22]. The first oral agents to treat RRMS were approved in the USA between 2010 and 2013 and include teriflunomide, dimethyl fumarate, and fingolimod [
19,
23‐
25]. A fourth oral treatment, diroximel fumarate was approved in the USA in 2019 and recently in the European Union (EU) in 2021 for the treatment of RRMS [
26]. Diroximel fumarate is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate. As a result of diroximel fumarate’s chemical structure, it may have a similar efficacy and safety profile to dimethyl fumarate with fewer gastrointestinal (GI) tolerability issues [
27]. The extent to which diroximel fumarate may differ in treatment persistence and adherence to other oral DMTs is inexplicit and needs to be confirmed in real-world settings.
Previous real-world studies have measured persistence and adherence to teriflunomide, dimethyl fumarate, and fingolimod; however, there is a lack of real-world evidence on diroximel fumarate. Therefore, the objective of this study was to measure persistence, adherence, and time to switching to a higher-cost therapy among patients with MS initiating treatment with these four oral DMTs.
Discussion
This retrospective real-world database study is the first to measure persistence, adherence, and time to switching to a higher-cost therapy (ocrelizumab, natalizumab, or cladribine) among patients with MS initiating treatment with the recently approved medication diroximel fumarate alongside three commonly used oral DMTs (teriflunomide, dimethyl fumarate, and fingolimod).
In this study, patients with MS newly initiated on teriflunomide and fingolimod had higher persistence rates and mean adherence at 6 and 12 months than patients treated with dimethyl fumarate and diroximel fumarate. Patients newly initiated on the fumarates (dimethyl fumarate and diroximel fumarate) had a larger percentage of patients switching and a shorter time to switching to a higher-cost therapy than patients newly initiated on the other oral DMTs.
Our findings are generally consistent with results from previous real-world studies of persistence and adherence to DMTs in patients with MS [
9,
29]. A retrospective French database study analyzed adherence to first-line DMTs in 10,240 patients with RRMS newly initiating therapy [
9]. Persistence and adherence were found to be higher overall in patients initiating therapy with an oral DMT, with better persistence observed in patients receiving teriflunomide than those receiving dimethyl fumarate. Likewise, a retrospective US database study of 1498 patients newly prescribed oral DMTs for MS reported significantly greater persistence and adherence among patients receiving fingolimod compared with patients receiving other oral DMTs over a 12-month period [
6].
Nonpersistence and nonadherence can occur for a variety of reasons, including administration method, efficacy, tolerability profile, cost, and treatment satisfaction[
9]. Additionally, previous adherence studies have reported greater DMT adherence for patients with RMS with once daily administration over other dosing schemes [
6,
9,
29], which may partially explain the higher adherence observed for teriflunomide and fingolimod (administered once daily) versus dimethyl fumarate and diroximel fumarate (administered twice daily) in this study.
Regarding tolerability, among oral DMTs for MS, the fumarates are associated with GI adverse events that can lead to premature discontinuations [
30‐
32]. A systematic review and meta-analysis that compiled data from 12,380 patients treated with dimethyl fumarate found that GI symptoms were the most common adverse event (occurring in 36% of patients), as well as the most commonly stated reason for discontinuing treatment (9% of all patients) [
30]. A recent randomized, double-blind, phase 3 study demonstrated fewer GI tolerability issues with diroximel fumarate compared with dimethyl fumarate. Among the 500 patients included in the study, lower rates of GI adverse events were experienced with diroximel fumarate than dimethyl fumarate (34.8% vs 49.0%) and lower discontinuation rates due to GI adverse effects (1.6% vs 5.6%) [
27]. However, findings from our real-world study of 6934 patients suggest that persistence and adherence among patients receiving diroximel fumarate and dimethyl fumarate were similar.
In addition to medication tolerability, greater satisfaction with treatment has been associated with higher adherence across a range of chronic conditions [
33], including RRMS [
34]. A large, global, phase 4 study measuring patient-reported outcomes (treatment satisfaction, disability, tolerability, clinical effectiveness, and quality of life) using the Treatment Satisfaction Questionnaire for Medication (TSQM) in patients with MS treated with teriflunomide reported high levels of treatment satisfaction, including patients who switched from other oral or injectable DMTs [
35]. In addition, teriflunomide maintained effectiveness over the course of the study on two patient-reported disability scales [
35]. Although approximately 82% of patients experienced adverse events, these were mostly mild to moderate in nature and led to treatment discontinuation in only a subset (10.9%) of patients [
35].
There are limited real-world studies investigating the rates and reasons of switching DMTs. Our switching analyses focused on higher-cost agents given switching due to efficacy concerns, the most common reason for switching in MS, generally results in the choice of a high efficacy, thus often higher-cost, therapy [
16,
36]. A retrospective, multicenter, Italian study of data from 2954 patients newly diagnosed with RRMS found that 48% of patients switched therapy within 3 years, with poor efficacy listed as the most common reason for switching [
37]. Switching may also vary with symptom severity. A cross-sectional German study of 595 patients with MS reported higher rates of switching to an alternate DMT in patients with mild to moderate MS (54.3%) compared with patients with active or highly active MS (43.5%) [
16].
Treatment persistence and adherence can result in better clinical and economic outcomes, including lower rates of relapses, risks for MS-related hospitalization, and MS-related medical costs [
13,
38,
39]. A retrospective claims database study of 12,431 patients with MS calculated the predicted mean cost savings among adherent patients in the 12 months after initiation of a DMT [
13]. They reported a total reduction in medical (nondrug) costs per patient of $5815.47 (− 41.7%), hospitalization costs of $1953.01 (− 58.5%), emergency department costs of $171.40 (− 46.9%), and outpatient admission costs of $2801.63 (− 32.9%). Likewise, studies have shown that patients who switched or discontinued their DMT had higher medical utilization and costs, suggesting that disruptions in therapy may result in serious unintended consequences [
17,
40].
Treatments that overcome some of the challenges associated with MS therapies (side effects, lack of treatment satisfaction, and perceived effectiveness) may improve persistence and adherence, delay time to switch, and consequently result in better therapeutic outcomes and reduced costs.
Limitations
Our results were obtained from a claims database, which has several inherent limitations. Claims data provide only an indirect measure of medication-taking behavior, and details on the patient’s clinical presentation and demographic characteristics are constrained to what can be extracted from health records. To obtain the largest and most representative sample, we included all patients who initiated treatment on the four study products during the study period, which included unequal numbers of patients in each analysis. However, unequal numbers across analyses were a necessary component of capturing patients who switched to higher-cost DMTs. Additionally, our outcomes are largely reported using descriptive measures, and no adjustments were made for possible confounding variables, such as any potential baseline differences between groups, e.g., age or MS severity. Other factors which may further contextualize our findings, such as information on treatment efficacy, and reasons for nonpersistence, nonadherence, and switching were not available in the database.