Oral Disease-modifying Agents Research Articles

Association of oral disease-modifying agents and their adherence trajectories with annual relapses in multiple sclerosis

BackgroundReal-world effectiveness can vary across oral disease-modifying agents (DMAs) and their adherence trajectories in patients with multiple sclerosis (MS). However, previous studies have not considered longitudinal adherence patterns while evaluating oral DMAs. ObjectivesThis study aimed to evaluate the association of oral DMAs and their adherence trajectories with annualized relapse rate (ARR) in patients with MS. MethodsThis retrospective observational cohort study based on the 2015–2019 MarketScan Commercial Claims and Encounters Database involved continuous enrolled adults (18–64 years) with ≥1 MS diagnosis (ICD-9/10-CM:340/G35) and ≥ 1 oral DMA prescription. Patients were grouped into incident fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) users based on the index DMA with a one-year washout period. Annual DMA adherence trajectories based on the monthly Proportion of Days Covered (PDC) one year after treatment initiation were identified using Group-Based Trajectory Modeling (GBTM). The validated claims-based ARR was evaluated during the one-year follow-up period using generalized boosted model-based inverse probability treatment weights with negative binomial regression model. ResultsThe study cohort consisted of 994 MS patients who initiated with FIN (23.0%), TER (22.3%), and DMF (54.7%) during the study period. GBTM grouped eligible patients into three adherence trajectories: complete adherers (59.2%), slow decliners (23.8%), and rapid decliners (17.0%). The proportion of complete adherers varied across the oral DMAs (FIN: 67.1%, TER: 55.4%, and DMF: 57.4%). The negative binomial regression modeling revealed that, while there was no difference in ARR across the three DMAs, rapid decliners (adjusted incidence rate ratio[aIRR]: 1.6, 95% CI: 1.1–2.4) had a higher rate of relapses compared to completely adherent patients. The type of oral DMAs did not moderate the relationship between ARR and the adherence trajectory groups. ConclusionsAdherence trajectories classified as rapid decliners were associated with a higher ARR than complete adherers after adjusting for their type of oral DMAs. Longitudinal medication adherence patterns are critical in reducing relapse rates in MS.

Comparative adherence trajectories of oral disease-modifying agents in multiple sclerosis.

Oral Disease-Modifying Agents (DMAs) such as fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) are convenient alternatives to injectable DMAs for multiple sclerosis (MS). However, there is limited evidence regarding the comparative adherence patterns of different oral DMAs. This study compared the adherence trajectories between FIN, TER, and DMF users with MS. A retrospective longitudinal study was conducted involving adults (≥18 years) identified with MS (International Classification of Diseases [ICD]-9/10-Clinical Modification [CM]:340/G35) and a DMA prescription from the 2015-2019 IBM MarketScan Commercial Claims Database. Patients were classified as incident FIN-, TER-, or DMF-users based on the index DMA with 1 year of washout period. The DMA adherence trajectories based on the proportion of days covered (PDC) were examined using the Group-Based Trajectory Modeling (GBTM) 1 year after the treatment initiation. Generalized boosting models (GBM)-based Inverse Probability Treatment Weights (IPTW) were incorporated in multinomial logistic regression to assess the comparative adherence trajectories across oral DMAs with FIN group as a reference category. The study cohort consisted of 1,913 patients with MS who were initiated with FIN (24.2%, n=462), TER (24.0%, n=458), and DMF (51.9%, n=993) during 2016-2018. The adherence rate (PDC≥0.8) among FIN, TER, and DMF users was found to be 70.8% (n=327), 59.6% (n=273), and 61.0% (n=606), respectively. The GBTM grouped patients into three adherence trajectories: Complete Adherers-59.1%, Slow Decliners-22.6%, and Rapid Discontinuers-18.3%. The multinomial logistic regression model involving GBM-based IPTW revealed that DMF (adjusted odds ratio [aOR]: 2.32, 95% confidence interval [CI]:1.57-3.42) and TER (aOR: 2.50, 95% CI:1.62-3.88) users had higher odds to be rapid discontinuers relative to FIN users. In addition, TER users were more likely (aOR: 1.50, 95% CI:1.06-2.13) to be slow decliners compared to FIN. TER and DMF were associated with poorer adherence trajectories than FIN. More research is needed to evaluate the clinical implications of these adherence trajectories of oral DMAs to optimize the management of MS.

P76 Comparative Adherence Trajectories across Oral Disease-Modifying Agents in Multiple Sclerosis

The oral Disease-Modifying Agents (DMAs) such as fingolimod (FIN), teriflunomide (TER), and dimethyl fumarate (DMF) are convenient alternatives to injectable DMAs for Multiple Sclerosis (MS). However, there is limited evidence regarding the comparative adherence patterns across different oral DMAs. This study compared the adherence trajectories between FIN, TER, and DMF users with MS.

HSD13 Factors Associated with Prescribing of Teriflunomide and Dimethyl Fumarate Versus Fingolimod in Multiple Sclerosis

The oral Disease-Modifying Agents (DMA) provided additional options to neurologists beyond injectable DMAs for Multiple Sclerosis (MS). This study examined the factors associated with prescribing teriflunomide (TER) and dimethyl fumarate (DMF) compared to fingolimod (FIN) in patients with MS.

FACTORS ASSOCIATED WITH SWITCHING FROM INJECTABLE TO ORAL DISEASE MODIFYING AGENTS AMONG PATIENTS WITH MULTIPLE SCLEROSIS

BackgroundSince the introduction of oral disease-modifying agents (DMA) in 2010, the treatment options for multiple sclerosis (MS) have changed significantly. There is limited information regarding the factors associated with switching to oral DMA among prevalent injectable DMA users. ObjectiveThis study evaluated the factors associated with switching to oral DMAs among prevalent injectable DMA users with MS. MethodsA retrospective observational cohort study using the TriNetX electronic medical records (EMR) data was conducted among patients with MS. The study included prevalent injectable DMA users with at least two injectable DMA (interferon beta-1a, interferon beta-1b, peginterferon beta-1a, or glatiramer acetate) prescription records within 6 months between September 2010 and May 2018. The second injectable DMA prescription date was considered as the index date. Switching was defined as any oral DMA prescription record (fingolimod, dimethyl fumarate, or teriflunomide) within 12 months after the index date. Patients with any infusion DMA prescription after the first injectable DMA prescription, and those less than 18 years of age were excluded from the study. The Andersen Behavioral Model was used as the conceptual framework to identify predisposing, enabling, and need factors measured during the 1-year baseline period before the index date. A multivariable logistic regression model was used to examine the predisposing (age, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, MS-related medication, and healthcare utilization) associated with switching from injectable to oral DMAs. ResultsAmong 2,943 prevalent injectable users included in this study, 8.09% (n=238) patients switched to oral DMAs. Patients who switched to oral DMAs were primarily younger adults aged 18-44 years (64.29%), females (82.77%), had sensory and visual symptoms, and had corticosteroid utilization during the one-year look-back period compared to non-switchers. Results from multivariable logistic regression model revealed that middle-aged adults (45-64 years, adjusted odds ratio [aOR]: 0.43, 95% Confidence Interval [CI]: 0.32-0.58), old adults (≥65 years, aOR: 0.30, 95% CI: 0.13-0.66) and men (aOR: 0.67, 95% CI: 0.47-0.96) were associated with decreased odds of switching to oral DMAs. Presence of MS-related sensory symptoms (aOR: 1.52, 95% CI: 1.07-2.16), visual symptoms (aOR: 1.59, 95% CI: 1.10-2.31), and corticosteroids usage (aOR: 1.44, 95% CI: 1.04-1.98) were associated with increased odds of switching to oral DMAs. ConclusionThe study found that about one in twelve prevalent injectable DMA users switched to oral DMA. Both demographic and clinical factors were associated with switching to oral DMAs. Further research is needed to evaluate the outcomes of switching to inform treatment decisions for MS management.

Prescribing of disease modifying agents in older adults with multiple sclerosis

BackgroundThe use of disease-modifying agents (DMAs) to treat Multiple Sclerosis (MS) in older adults is debated as the disease activity decreases with aging. However, limited data exist regarding prescribing patterns of DMAs among older adults with MS. ObjectiveTo examine prescribing patterns of DMAs and the factors associated with DMA prescribing practices among older adults with MS using electronic medical records (EMR) data. MethodsA retrospective longitudinal cohort study was conducted using the TriNetX, a federated EMR network from the US, data from 2016 to 2019. The study included older adults (≥60 years) with MS diagnosis and at least one prescription record during the study period. Patients with DMA prescriptions were identified and further classified into injectable, oral, or infusion users based on their last DMA prescription. A multivariable logistic regression model was used to evaluate the factors associated with prescribing of DMAs. A multinomial logistic regression model was also used to determine the factors associated with prescribing a particular dosage form of DMA. ResultsThe study cohort consisted of 12,922 older adults with MS, with 2,455 (18.99%) receiving DMA prescriptions. The commonly prescribed DMAs were injectables (10.46%), followed by orals (6.06%) and infusions (2.40%). Multivariable logistic regression revealed that older adults between 60– to 64 years (Adjusted Odds Ratio [aOR]= 2.38) and 65–69 years (aOR=1.60) had higher odds of receiving DMA compared to older adults of 70 years and above. African Americans (aOR=1.71) had higher odds of receiving DMA prescriptions compared to Caucasians. The presence of symptoms (pain, fatigue, speech, walking difficulty) and use of symptomatic medication (anti-fatigue medication, bladder dysfunction medication, antispasmodics, antidepressants, and relapse medication) increased the odds of being prescribed DMAs. Multinomial logistic regression found that patients 60–64 years of age had higher odds of being prescribed infusion (aOR, 95% Confidence Interval [CI] =2.06, 1.35–3.15) and oral (65–69 years: aOR=1.60, 1.24–2.07) over injectable DMAs compared to the older adults aged 70 years and above.Older males (aOR=1.68, 95% CI: 1.23–2.30) were associated with increased odds of being prescribed infusion DMA over injectable DMA compared to females. The presence of comorbidities such as coagulopathy and peripheral vascular disorders decreased the odds of being prescribed oral DMA over injectable DMA. Patients with cerebellar symptoms had an increased likelihood of being prescribed with an infusion DMA over injectable DMA. Patients using drugs for treating relapses had higher odds of being prescribed an infusion DMA over an injectable DMA. In terms of healthcare utilization, older adults with outpatient visits had higher odds of being prescribed an infusion DMA over an injectable DMA, while older adults with inpatient visits had lower odds of being prescribed an infusion DMA over an injectable DMA. ConclusionNearly one in five older adults with MS are prescribed DMAs, with a majority receiving injectable DMAs. Several demographic and clinical factors were associated with DMA prescribing . This study fills the data gap regarding the utilization of DMAs in older adults with MS.

Factors associated with oral fingolimod use over injectable disease- modifying agent use in multiple sclerosis

BackgroundFingolimod is the first approved oral disease-modifying agent (DMA) in 2010 to treat Multiple Sclerosis (MS). There is limited real-world evidence regarding the determinants associated with fingolimod use in the early years. ObjectiveThe objective of this study was to examine the factors associated with fingolimod prescribing in the initial years after the market approval. MethodsA retrospective, longitudinal study was conducted involving adults (≥18 years) with MS from the 2010–2012 IBM MarketScan. Individuals with MS were selected based on ICD-9-CM: 340 and a newly initiated DMA prescription. Based on the index/first DMA prescription, patients were classified as fingolimod or injectable users. All covariates were measured during the six months baseline period prior to the index date. Multivariable logistic regression was performed to determine the predisposing, enabling, and need factors, conceptualized as per the Andersen Behavioral Model (ABM), associated with prescribing of fingolimod versus injectable DMA for MS. ResultsThe study cohort consisted of 3118 MS patients receiving DMA treatment. Of which, 14.4% of patients with MS initiated treatment with fingolimod within two years after the market entry, while the remaining 85.6% initiated with injectable DMAs. Multivariable regression revealed that the likelihood of prescribing oral DMA increased by 2–3 fold during 2011 and 2012 compared to 2010. Patients with ophthalmic (adjusted odds ratio [aOR]-2.60), heart (aOR-2.21) and urinary diseases (aOR-1.37) were more likely to receive fingolimod. Patients with other neurological disorders (aOR-0.50) were less likely to receive fingolimod than those without neurological disorders. Use of symptomatic medication (for impaired walking (aOR-2.60), bladder dysfunction (aOR-1.54), antispasmodics (aOR-1.48), and neurologist consultation (aOR-1.81) were associated with higher odds of receiving fingolimod. However, patients with non-MS associated emergency visits (aOR-0.64) had lower odds of receiving fingolimod than those without emergency visits. ConclusionsDuring the initial years after market approval, patients with highly active MS were more likely to receive oral fingolimod than injectable DMAs. More research is needed to understand the determinants of newer oral DMAs.

Comparative Adherence Trajectories of Oral Fingolimod and Injectable Disease Modifying Agents in Multiple Sclerosis.

BackgroundOral fingolimod is convenient to use than injectable disease modifying agents (DMAs) in patients with multiple sclerosis (MS). However, the existing literature regarding the comparative adherence trajectories between oral fingolimod and injectable DMAs is limited.ObjectiveTo compare the adherence trajectories between oral DMA, fingolimod, and injectable DMAs in patients with MS.MethodsA retrospective longitudinal study was conducted using adults (≥18 years) with MS (ICD-9-CM: 340 and a DMA prescription) from the IBM MarketScan Commercial Claims and Encounters Database between 2010 and 2012. Patients were grouped into oral fingolimod or injectable DMA users based on the index DMA among patients with MS. The annual DMA adherence trajectories, based on the proportion of days covered (PDC), were examined using group-based trajectory modeling (GBTM) during the one-year follow-up period after treatment initiation. Multivariable multinomial logistic regression using stabilized inverse probability treatment weights (IPTW) was performed to assess the association between the DMA route of administration (Oral vs Injectable) and the adherence trajectory groups. The balance of covariates between oral and injectable DMAs before and after IPTW was checked against a standardized difference threshold of 0.25.ResultsThe study cohort consisted of 1,700 MS patients who were initiated with oral (15.8%) or injectable (84.2%) DMAs between 2010 and 2012. The adherence rates (PDC≥0.8) in oral fingolimod and injectable DMA users were found to be 64.7% and 50.8%, respectively. The GBTM grouped individuals in the study cohort into three adherence trajectories – rapid discontinuers (23.5%), complete adherers (49.9%), and slow decliners (26.6%). The multinomial logistic regression model with stabilized IPTW revealed that oral fingolimod users had higher odds to be a complete adherer (adjusted odds ratio [AOR]: 2.78, 95% CI: 1.85–4.16) or a slow discontinuer (AOR: 2.62, 95% CI: 1.70–4.05) than injectable DMA users.ConclusionsOral DMA fingolimod was associated with better adherence than injectable DMAs across group-based trajectories. Further research is warranted to evaluate the adherence trajectories with newer oral DMAs introduced in the last decade for MS.

Factors Associated with Prescribing Oral Disease Modifying Agents in Multiple Sclerosis: a Real-world Analysis of Electronic Medical Records

BackgroundLittle is known about the factors associated with the selection of Disease Modifying Agents (DMA) for the management of Multiple Sclerosis (MS) since the introduction of oral DMAs in 2010. ObjectivesTo examine the factors associated with initiation of oral DMAs in patients with MS using data from electronic medical records (EMR). MethodsA retrospective longitudinal study was conducted using TriNetX, a federated EMR network of over 38 million patients from the US, from 2009–2019. Adult (≥18 years) patients with MS from the United States were identified using a MS diagnosis (ICD-9-CM: 340 or ICD-10-CM: G35) and a newly prescribed DMA with a one-year baseline period. Patients with new DMA prescriptions were classified as oral or injectable users based on their index medication. A multivariable logistic regression model was used to determine the predisposing (age category, sex, race, and ethnicity), enabling (time-period), and need factors (comorbidities, MS symptoms, symptomatic medication, and healthcare utilization) associated with initiation of an oral versus injectable DMA. ResultsThe study cohort consisted of 7,511 MS patients with a newly prescribed DMA, of whom most were 18-44 years old (48.33%), female (75.18%), and white (80.92%). About 42.32% of MS patients were diagnosed with at least one comorbidity (mean±SD: 0.86±1.37). Two thirds (66.32%) of the patients with MS started injectable DMAs, and the remaining one third (33.68%) started oral DMAs. Multivariable regression revealed that middle-aged (45–64 years; Adjusted Odds Ratio [aOR]=0.88; 95% Confidence Interval [CI]: 0.79–0.98) and older adults (≥65 years; aOR=0.67, 95% CI: 0.53–0.84) were associated with a decreased likelihood of receiving oral DMAs. The presence of general symptoms (aOR=1.26, 95% CI: 1.10-1.45) and cerebellar symptoms (aOR=1.56, 95% CI: 1.26-1.93) was associated with an increased likelihood of an oral DMA. However, the presence of sensory symptoms (aOR: 0.72, 95% CI: 0.59-0.88) was associated with a decreased likelihood of an oral DMA. Comorbidities such as renal failure (aOR=0.16, 95%% 0.04-0.62), obesity (aOR=0.60, 95% CI: 0.45-0.80), drug abuse (aOR=0.61, 95% CI: 0.38-0.99), and other neurological disorders (aOR=0.82, 95% CI: 0.69-0.96) were associated with a decreased likelihood of receiving an oral DMA prescription. While the use of analgesics (aOR=0.78, 95% CI: 0.69-0.88) was associated with decreased likelihood, the use of antispasmodics (aOR=1.14, 95% CI: 1.01-1.28) was associated with an increased likelihood of receiving an oral DMA. Relative to the time-period when first oral DMAs entered into the market (2010-11), with time, the likelihood of prescribing oral DMA increased by multiple folds (2012-13, aOR=4.30, 95% CI: 3.08-6.00; 2014-15, aOR=19.34, 95% CI: 14.10-26.54; 2016-17, aOR=17.63, 95% CI: 12.76-24.35; and 2018-19, aOR=20.73, 95% CI: 14.64-29.37). ConclusionsOral DMA use steadily increased over the years, with one in three MS patients receiving oral agents. Both demographic and clinical factors were associated with the initiation of oral DMA over injectable DMA.

PND104 COMPARATIVE ADHERENCE TRAJECTORIES OF ORAL FINGOLIMOD AND INJECTABLE DISEASE MODIFYING AGENTS IN MULTIPLE SCLEROSIS

Oral fingolimod is supposed to be more effective and convenient to be administered by individuals with Multiple Sclerosis (MS) than injectable disease Modifying Agents (DMAs). However, existing evidence regarding the comparative adherence trajectories between oral and injectable DMAs is not yet explored. Hence, the objective of this study was to compare the adherence trajectories between oral fingolimod and injectable DMA users with MS. A retrospective longitudinal study was conducted using adults (≥18 years) identified with MS (ICD-9-CM: 340 and a DMA prescription) from IBM MarketScan Commercial Claims and Encounters Database during 2010–2011. Patients were classified as oral fingolimod or injectable users based on the index DMA among patients with MS. The DMA adherence trajectories based on Proportion Days Covered (PDC) were examined using Group-Based Trajectory Modeling (GBTM) during the one year after treatment initiation. Multivariable multinomial regression using stabilized Inverse Probability Treatment Weights (IPTW) was preformed to assess the association between the route of administration (Oral vs. Injectable) and adherence trajectory group. The study cohort consisted of 1,700 MS patients who were initiated with oral (15.82%) or injectable (84.18%) DMAs during 2010-2012. The adherence rate (PDC≥0.8) among oral fingolimod and injectable DMA users was found to be 64.68% and 50.80%, respectively. GBTM grouped study subjects into three adherence trajectories – Complete Adherers-55.76%, Slow Decliners-37.24% and Rapid Discontinuers-7.00%. The multinomial regression model with stabilized IPTW revealed that fingolimod users had lesser odds to be a rapid discontinuer (adjusted odds ratio [AOR]-0.38, 95% CI:0.20-0.73) or a slow discontinuer (AOR-0.53; 95% CI:0.40-0.71) relative to injectable DMA users. Oral fingolimod use was associated with better adherence trajectory than injectable DMAs. More research is needed to evaluate the adherence trajectories with other newer oral DMAs introduced in the last decade among individuals with MS.

Use of disease modifying agents in patients with multiple sclerosis: Analysis of ten years of national data.

Disease modifying agents (DMAs) are used to reduce relapses and decrease disability progression in Multiple Sclerosis (MS) patients. However, limited national level data exists regarding the prescribing patterns for MS, especially after the introduction of oral DMAs. This study examined the prescribing patterns and trends of DMAs using national level data and determined the factors associated with prescribing DMAs among MS patients in the United States. This cross-sectional study utilized 2006-2015 National Ambulatory Medical Care Survey (NAMCS) data to examine office-based visits involving MS (ICD-9-CM code 340). Descriptive weighted analyses were performed to assess the prescribing patterns of DMAs. Multivariable logistic regression model within the conceptual framework of Andersen Behavioral Model was used to determine the factors associated with prescribing of DMAs among MS patients. An estimated 8.5 million (95% Confidence Interval [CI] 7.01-10.09 million) MS patient visits were identified from 2006 to 2015. During the ten-year study period, 3.84 million (45%) MS visits involved prescribing of DMAs. The majority of DMA prescriptions were injectables (78%), followed by infusions (11%) and orals (11%). Oral DMAs use increased (from 11% in 2010-2011 to 40% in 2014-2015), whereas the use of injectable DMAs decreased (from 96% in 2006-2007 to 52% in 2014-2015) during the study period. Multivariable analyses revealed that predisposing (age and region) and enabling (physician specialty) factors were significantly associated with prescribing of DMAs among MS patients. Visits to neurologists (Odds Ratio [OR] 6.61, 95% CI 3.66-11.93) were associated with higher odds of being prescribed with DMAs. During the ten-year study period, increasing use of oral DMAs and declining use of injectable DMAs was observed. Both predisposing and enabling factors influenced the prescribing of DMAs. With increasing availability of oral DMAs, the DMAs use is likely to increase among MS patients.

An Overview of DRF in the treatment of Multiple Sclerosis

Diroximel fumarate (DRF) is an oral disease-modifying agent indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS), which is taken twice a day. In EVOLVE-MS-1, Phase 3, a two-year safety study evaluating DRF in patients with RRMS, it is shown that the occurrence of flushing and gastrointestinal treatment-emergent adverse events is comparatively low. This results in a low rate of discontinuation due to treatment-emergent adverse events as compared to dimethyl fumarate (DMF). Monomethyl fumarate (MMF) is a common active metabolite of DMF and DRF. This active metabolite is responsible for the mechanism of actions of the drugs since it crossed the blood-brain barrier. Methanol is the primary metabolite of DMF metabolism but a minor metabolite of DRF metabolism, which results in a lower risk of gastrointestinal symptoms. Both DMF and DRF show similar Tmax and Cmax, which indicate similarity in the efficacy of both the drugs. Therefore, DRF has a similar safety and efficacy profile but better tolerability of treatment-emergent adverse events when compared to DMF. This article provides an updated overview of the pharmacological, therapeutic efficacy, and tolerability of DRF.

Dimethyl Fumarate: A Review in Relapsing-Remitting MS.

Dimethyl fumarate (Tecfidera(®)) is an oral disease-modifying agent indicated for the twice-daily treatment of relapsing forms of multiple sclerosis (MS) and relapsing-remitting MS (RRMS). It displays immunomodulating and neuroprotective properties, both of which may contribute to its efficacy in these settings. In two phase III trials of 2years' duration (DEFINE and CONFIRM), twice-daily dimethyl fumarate reduced clinical relapse (both the proportion of patients with MS relapse and the annualized relapse rate), as well as MRI measures of disease activity, versus placebo in adults with RRMS; the drug also reduced disability progression relative to placebo in one of the two studies (DEFINE). Dimethyl fumarate had an acceptable tolerability profile in these trials, with the most common tolerability issues being flushing and gastrointestinal events, which appear to be largely manageable. In the DEFINE and CONFIRM extension (ENDORSE), a minimum of 5years of treatment with the drug was associated with continued benefit and no new/worsening tolerability signals. Although additional active comparator data are needed, dimethyl fumarate is an effective twice-daily treatment option for use in adults with RRMS, with the convenience of oral administration and an acceptable long-term tolerability profile.

Oral agents in multiple sclerosis.

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. Disease-modifying drugs licensed for MS treatment have been developed to reduce relapse rates and halt disease progression. The majority of current MS drugs involve regular, parenteral administration, affecting long-term adherence and thus reducing treatment efficacy. Over the last two decades great progress has been made towards developing new MS therapies with different modes of action and biologic effects. In particular, oral drugs have generated much interest because of their convenience and positive impact on medication adherence. Fingolimod was the first launched oral treatment for relapsing-remitting MS; recently, Teriflunomide and Dimethyl fumarate have also been approved as oral disease-modifying agents. In this review, we summarize and discuss the history, pharmacodynamics, efficacy, and safety of oral agents that have been approved or are under development for the selective treatment of MS.

Safety, Tolerability, and Efficacy of Oral Therapies for Relapsing-Remitting Multiple Sclerosis

Treatment options for relapsing-remitting multiple sclerosis (RRMS) have been continuously expanding in recent years, and the emergence of a number of oral disease-modifying agents (DMAs) has significantly changed the landscape of therapeutic options for MS patients. Many of these oral DMAs have demonstrated satisfactory safety and tolerability profiles in clinical trial settings, but the long-term safety of these agents is an important concern. This review discusses salient points on the safety and clinical efficacy of the approved and emerging novel oral therapies in RRMS, including fingolimod, teriflunomide, dimethyl fumarate, laquinimod, and cladribine.

Fingolimod: A Novel Oral Immunomodulatory Treatment For Multiple Sclerosis

Fingolimod (FTY720), an immunomodulator that acts on sphingosine-1-phosphate receptors, is the first oral disease-modifying agent to be approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). Compared with other disease-modifying agents, fingolimod is unique in its mechanisms of action: it sequesters lymphocytes into lymph nodes without directly inhibiting effector functions, and it exerts pleiotropic actions on cultured oligodendrocytes and oligodendrocyte progenitors. Whether the latter contributes to the favorable response to this drug is currently being investigated. Results from Phase II and III clinical trials demonstrate that fingolimod is highly effective in relapsing–remitting MS. In this article, we review the background on MS therapy, the mechanisms and pharmacology of fingolimod and its benefit–risk profile as a novel therapy in MS.

Multiple Sclerosis Therapeutic Pipeline: Opportunities and Challenges

The year 2010 marked the beginning of the era of oral medications for the treatment of multiple sclerosis, with the approval of dalfampridine to improve walking and fingolimod as the first oral disease-modifying agent. This review provides an overview of these and other emerging therapies, with an emphasis on the opportunities for new treatment paradigms they have the potential to offer, followed by a discussion of the challenges they will pose in the new era of multiple sclerosis management. Therapeutics in late-stage development for MS include non-selective immunosupressants, targeted immune-modulators, and monoclonal antibodies. Oral agents including cladribine, teriflunomide, laquinimod, and dimethyl fumarate, as well as monoclonal antibodies alemtuzumab, daclizumab, and rituximab are considered. Potential side effects and adverse event monitoring, including opportunistic infections, emergent malignancies, and other systemic consequences of immunosuppression are discussed in a unified section. Challenges of optimally staging, sequencing, and combining treatments in the expanding multiple sclerosis armamentarium are discussed. This review emphasizes the multifactorial decision making that these new therapeutics will warrant in terms of patient selection and personalization/individualization of therapy, and the increasingly interdisciplinary approach that will be necessitated by the new generation of agents.

Immune mechanisms of new therapeutic strategies in MS — Teriflunomide

At present, a series of oral disease-modifying agents is being introduced for the treatment of multiple sclerosis. With the exception of laquinimod, the "new" oral compounds have already been approved for other indications such as organ transplantation (FTY720), psoriasis (dimethylfumarate), hairy cell leukemia (cladribine), and rheumatoid arthritis (leflunomide). Leflunomide is the prodrug of teriflunomide which is the latest compound that has successfully been tested in a large phase III clinical trial in relapsing MS. Due to its favorable safety profile and its efficacy in rheumatoid arthritis where the aberrant immune response is in various aspects similar to the autoimmune reaction in MS patients, teriflunomide is a promising treatment option for MS patients. Here, we review the most important cell biological and immunological modes of action of teriflunomide, report on the available data on its pharmacokinetics in humans, and summarize the recent clinical trials of teriflunomide in relapsing MS.