Fingolimod Research Articles

Adverse Drug Reactions with Drugs Used in Multiple Sclerosis: An Analysis from the Italian Pharmacovigilance Database.

Given the importance of inflammation at the onset of multiple sclerosis (MS), therapy is mainly based on the use of anti-inflammatory drugs including disease modifying therapies (DMTs). Considering the recent approval of some DMTs, pharmacovigilance becomes a fundamental tool for the acquisition of new safety data. The aim of the study was to analyze adverse drug reactions (ADRs) related to the use of drugs approved for MS. All national publicly-available aggregated ADR reports recorded from 2002 to 2020 into the Reports of Adverse Reactions of Medicines (RAM) system and all complete Sicilian data reported into the Italian spontaneous reporting system (SRS) database having as suspected drugs interferon β-1a (IFN β-1a), interferon β-1b (IFN β-1b), peginterferon β-1a (PEG-IFN β-1a), glatiramer acetate (GA), natalizumab (NTZ), fingolimod (FNG), teriflunomide (TRF), dimethyl fumarate (DMF), alemtuzumab (Alem), ocrelizumab (OCZ), or cladribine (Cladr), were collected. Descriptive analyses of national, publicly-available aggregated data and full-access regional data were performed to assess demographic characteristics and drug-related variables followed by a more in-depth analysis of all Sicilian ADRs with a case-by-case assessment and a disproportionality analysis of unexpected ADRs. A total of 13,880 national reports have been collected from 2002 to 2020: they were mainly not serious ADRs (67.9% vs. 26.1%) and related to females (71.7% vs. 26.3%) in the age group 18–65 years (76.5%). The most reported ADRs were general and administration site conditions (n = 6,565; 47.3%), followed by nervous (n = 3,090; 22.3%), skin (n = 2,763; 19.9%) and blood disorders (n = 2,180; 15.7%). Some unexpected Sicilian ADRs were shown, including dyslipidemia for FNG (n = 10; ROR 28.5, CI 14.3–59.6), NTZ (n = 5; 10.3, 4.1–25.8), and IFN β-1a (n = 4; 8.7, 3.1–24.1), abortion and alopecia for NTZ (n = 9; 208.1, 73.4–590.1; n = 3; 4.9, 1.5–15.7), and vitamin D deficiency for GA (n = 3; 121.2, 30.9–475.3). Moreover, breast cancer with DMF (n = 4, 62.8, 20.5–191.9) and hypothyroidism with Cladr (n = 3; 89.2, 25.9–307.5) were also unexpected. The reporting of drugs-related ADRs in MS were mostly reported in the literature, but some unknown ADRs were also found. However, further studies are necessary to increase the awareness about the safety profiles of new drugs on the market.

OP130 Economic Evaluation Of High-Cost Drugs For Relapsing-Remitting Multiple Sclerosis In Thailand

IntroductionDrugs for relapsing-remitting multiple sclerosis (RRMS) are costly and not included in the National List of Essential Medicines of Thailand yet. This study aims to conduct an economic evaluation of high-cost drugs for RRMS.MethodsThe Markov model was used to estimate lifetime costs and quality-adjusted life years (QALYs) gained. The treatment options include Interferon beta-1a (IFN) and Teriflunomide (TERI) (first-line), Fingolimod (FIN) and Natalizumab (NATA) (second-line), and Alemtuzumab (ALEM) (third-line) compared with usual care. The effectiveness of drugs was retrieved by network meta-analysis. The probability of health state transition was obtained from primary data. Treatment-related costs were derived from the national database. Other costs and utilities were obtained from the study in Thai RRMS patients.ResultsThe lowest lifetime costs option was usual care (THB2 million) (USD65,808), while the highest QALY gained option was IFN-NATA-ALEM (8.6 QALY gained). All treatment options were not cost-effective compared with usual care at the threshold of THB160,000 (USD5,300) per QALY gained. However, the option of IFN-NATA-ALEM yielded the lowest incremental cost-effectiveness ratio (ICER), which was THB4.4 million (USD144,778) per QALY gained.ConclusionsHigh-cost drugs were not cost-effective; nonetheless, the IFN-NATA-ALEM option could increase QALY gained with the lowest additional budget. The government should negotiate the price of IFN to decrease by eighty percent.

Efficacy of fingolimod in the 2nd line treatment of active relapsing-remitting multiple sclerosis: About a Tunisian cohort of 50 patients

Fingolimod (FING) is the first oral immunomodulatory treatment approved for the 2-line disease-modifying treatment of active relapsing-remitting (RR) forms of multiple sclerosis (MS). Observational post-marketing studies are important for clarifying the efficacy and safety of the product in current medical practice. The Aim of our study is to assess the effectiveness of FING in patients with RR-MS followed at the National institution of neurology in Tunis.

Two-year macular volume assessment in multiple sclerosis patients treated with fingolimod.

Fingolimod (FNG) is associated with the development of symptomatic macular edema (ME) in a small subset of multiple sclerosis (MS) patients. By using spectral domain optical coherence tomography (SD-OCT), an increase in the total macular volume (TMV) was rarely detected during the first months of treatment. The objective of this study is to assess whether FNG treatment leads to long-term macular changes in a real-life setting. Sixty RRMS patients starting FNG, according to therapeutic indication, were enrolled at three Italian MS centers and followed for 2years. The mean TMV did not change between baseline and the follow-up. No patients experienced visual acuity drop during the follow-up. Initiation of FNG in MS is associated with a modest, not significant, increase in macular volume followed by no further significant changes over 2years, highlighting the good safety profile of such treatment in MS.

Immunohistochemical analysis of protective effects of maternal fingolimod on the placenta and fetal lung and brain in chorioamnionitis-induced preterm birth rat model

Objectives Fingolimod (FIN) is used for multiple sclerosis treatment and has potential antiapoptotic and anti-inflammatory effects. We aimed at expanding our knowledge on various immunohistochemical markers for elucidating the possible mechanisms of action of fingolimod in the placenta and fetal lung and brain. Methods Sixteen pregnant rats were divided into four groups. On gestational day 17, lipopolysaccharide (LPS) was injected intraperitoneally to induce preterm fetal injury followed by intraperitoneal injection of fingolimod. Hysterotomy for preterm delivery was performed 6 h after fingolimod was injected. The study groups included (1) control, (2) LPS (1 mg/kg), (3) FIN (4 mg/kg), and (4) FIN + LPS. Fetal brain and lung and placenta samples were collected for histopathological examination. Moreover, fetal lungs (surfactant protein-A (SP-A), SP-B, SP-D, caspase-3, and caspase-8), fetal brains (interleukin-10, interleukin-1β, TNF-α, caspase-8, glial fibrillary acidic protein, vimentin, myelin basic protein, and receptor activator of nuclear factor kappa), and placenta tissues (interleukin-10, interleukin-1β, TNF-α, caspase-3, and caspase-8) were immunohistochemically evaluated. Results Maternal fingolimod treatment led to attenuation of LPS-induced fetal brain, lung, and placental injury, as indicated by lower immunoexpression of inflammatory markers compared to LPS group (p < .0001 for all comparisons). Conclusion The findings of the present study confirm the neuroprotective effects of antenatally administered fingolimod, which also significantly improved preterm fetal lung injury and placental inflammation in LPS-exposed preterm pregnancies by possible antiapoptotic and anti-inflammatory effects.

Effectiveness of Fingolimod versus Natalizumab as Second-Line Therapy for Relapsing-Remitting Multiple Sclerosis in Spain: Second-Line GATE Study

Background: There is a lack of head-to-head studies comparing the efficacy of fingolimod (FIN) and natalizumab (NTZ) as second-line therapy for relapsing-remitting multiple sclerosis (RRMS). Methods: Multicenter, observational study, in which, information of 388 patients randomly selected and treated with FIN or NTZ in routine clinical practice was retrospectively collected with the main objective of comparing the annualized relapse rate (ARR) over the first year, after FIN or NTZ treatment initiation. Results: Mean ARR during the first year of treatment was 0.28 in FIN group and 0.12 in NTZ group (p = 0.0064); nevertheless, the difference between groups lost statistical significance when the propensity score analysis was performed. Time to disability ­progression was similar in both treatment groups (12.3 ± 6.7 months in FIN, and 12.8 ± 0.1 months in NTZ; p = 0.4654). Treatment persistence after the first year of treatment was higher in patients treated with FIN (95%) than in those treated with NTZ (84%; p = 0.0014). Conclusions: After 12 months of treatment, both FIN and NTZ reduced the ARR, but ARR percent reduction was significantly higher with NTZ. Treatment persistence was higher in patients receiving FIN.

Second-Line Therapy in Multiple Sclerosis

Multiple sclerosis (MS) patients with breakthrough disease on immunomodulatory drugs are frequently offered to switch to second-line treatment (SLT). No head-to-head study has been performed yet to assess whether SLT is more effective than classical immunomodulators. We aim to retrospectively assess the moment of introduction, efficacity and tolerance of SLT. We retrospectively enrolled the patients in our department with relapsing-remitting MS (RRMS) who received first-line treatment (FLT) for more than 12 months than switched to SLT for 5 consecutive years. Outcome measures were Rio Score (RS) and modified Rio Score (MRS), annualized relapse rate (ARR) and changes in expanded disability status scale (EDSS) score. We also reported the side effects developed under SLT. We enrolled 20 patients, 6 males and 13 females. They all received interferon before switch. Twelve were switched to Natalizumab (NAT) and eight to Fingolimod (FIN). When switch was decided, 16 patients (80%) had high RS (2 or 3) and 19 (95%) had high MRS (2 or 3). Mean ARR was at 2.4 at the switch to SLT, it decreased significantly to 0.73 (70%) after 12 months and 0.4 (84%) after 5 years (p< 0.001). Nine patients were relapse-free after 12 months (75%) and 5 after 5 years (25%). Mean EDSS was at 3.36 at the switch to SLT, it significally decreased to 3 after 12 months and 1.5 after 5 years (p< 0.001). Side effects reported in 6 cases (30%); 3 cases of lymphopenia under FIN, 2 cases of lymphocytosis and on case of BK virus urinary infection under TYS. MRS was better to predict suboptimal interferon responders than RS in our study. SLT was more effective than interferon on disease progress and activity during the first 5 years of treatment. However, prospective head to head studies are needed to get higher evidence level.

Perniosis in a patient treated with fingolimod

Perniosis in a patient treated with fingolimod

Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis

Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS. Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models. A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ. In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.

In Ischemic Stroke, Adding Fingolimod Seems to Enhance Alteplase's Effects

In multiple sclerosis, fingolimod decreases egress of lymphocytes from the spleen and lymph nodes. In stroke, it has also been reported to decrease

Effects of fingolimod on sphingosine-1-phosphate signal in osteoclasts

Objective To study the effects of fingolimod (FTY720) on the sphingosine-1-phosphate (S1P) signaling pathway in osteoclasts. Methods Murine RAW 264.7 macrophages were induced into osteoclasts by dexamethasone and 1α,25-(OH)2VitD3 and identified by tartrate resistant acid phosphatase Trp staining. After the osteoclasts were divided into 2 groups, the experimental group was treated with 400 ng/mL FTY720-P while the control group was not. The signal expression of extracellular signal-regulated kinase 1 (ERK1), caspase9 and protein kinase(PKC) in the downstream of S1P pathway was detected at the gene and protein levels, and the expression of bone morphogenetic protein-2(BMP-2) and transforming growth factor-β1 (TGF-β1) , which are closely related to bone reconstruction, was detected. Results The RAW264.7 cells were successfully induced into osteoclasts identified by trataric acid phosphatase staining kit(TRAP). The expression of S1PR1 in osteoclasts was higher than that in other S1PRs. After culture for 48 hours, the expression of PKC mRNA in the experimental group was significantly lower than that in the control group while the expression of BMP-2 mRNA and TGF-β1 mRNA was significantly increased in the experimental group than in the control group (P 0.05). Conclusions FTY720-P can affect the expression of PKC signal in the downstream of osteoclasts by affecting S1P signaling pathway, mainly by binding to S1PR1 signal pathway, and can also promote the expression of TGF-β1 and BMP-2 in osteoclasts, ultimately affecting the function of osteoclasts. Key words: Protein kinase C; Osteoclasts; Bone morphogenetic proteins; Sphingosine-1-phosphate receptor 1

Are antioxidant parameters in serum altered in patients with relapsing-remitting multiple sclerosis treated with II-line immunomodulatory therapy?

So far little has been known about antioxidant properties of immunomodulatory drugs. The aim of the study was to evaluate the antioxidant status in serum of relapsing-remitting multiple sclerosis (RRMS) patients treated with II-line immunomodulatory therapy compared to de novo diagnosed patients, subjects treated with interferon (IFN) beta and healthy controls. We analyzed the relationships depending on the gender, age, disease duration, the Expanded Disability Status Scale, the annualised relapse rate, and MRI lesions in patients treated with II-line. One hundred and twenty one RRMS patients were enrolled in the prospective study. Patients were divided into the following groups: de novo, IFN, fingolimod (FG), natalizumab (NT), and the control. The total antioxidant capacity, sulfhydryl groups (SH groups, PSH groups), ceruloplasmin, and superoxide dismutase (SOD) activity were determined in serum. NT and FG groups presented with lower SOD activity compared to controls. The levels of antioxidants in NT- and FG-treated patients were not different from the IFN group. Antioxidant parameters increased with disease duration in the FG group. FG and NT could have an effect on the antioxidant system in multiple sclerosis (MS) patients. The results of this study propose a novel aspect of antioxidative properties of II-line immunomodulatory therapy in MS.

Natalizumab cost effective versus fingolimod for RRMS

Natalizumab cost effective versus fingolimod for RRMS

Fingolimod ameliorates neuropsychiatric lupus without reducing circulating autoantibodies or brain cytokine expression.

Abstract Although the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is still not well understood, autoantibodies, loss of brain barrier integrity, and pro-inflammatory cytokines have all been implicated in disease progression. Fingolimod (FL), an approved treatment for multiple sclerosis, improves neurologic disease through S1PR modulation and reducing passage of autoaggressive lymphocytes into the CNS. In initial studies, we found that FL treatment reduces lymphocytic infiltration of the choroid plexus in MRL/lpr lupus mice and attenuates memory impairment and depressive-like behavior. Here, we determined the effects of FL on systemic disease and pro-inflammatory cytokine expression in the CNS. Brain, spleen, lymph node, and serum samples were evaluated in MRL/lpr mice treated with FL three times weekly for 10 weeks starting at 10 weeks of age and from untreated controls (n=16/group). FL-treated mice exhibited a significant reduction in splenomegaly and lymphadenopathy. However, there was no change in serum titers of anti-double stranded DNA antibodies. Moreover, immunofluorescence staining revealed no difference in IgG deposition between treated and control mice, suggesting that autoantibody reduction is not critical for FL-mediated disease improvement. Surprisingly, quantification of brain cortical cytokine levels revealed a significant increase in IL-1a, IL-1b, IFNg, IFNb and IL-12p70 in FL-treated mice, while IL-1a, IL-1b and MCP-1 were increased in the hippocampus. These findings suggest that FL attenuates NPSLE, but the mechanism of improvement is not mediated by a reduction of autoantibodies or pro-inflammatory cytokine signaling.

Predictors of hematological abnormalities in multiple sclerosis patients treated with fingolimod and dimethyl fumarate and impact of treatment switch on lymphocyte and leukocyte count

BackgroundThere is limited data regarding the predictors of hematological abnormalities in multiple sclerosis (MS) patients treated with dimethyl fumarate (DMF) or fingolimod (FNG), and the impact of treatment switch on lymphocyte and leukocyte count MethodsWe identified 405 patients on DMF and 300 patients on FNG (treatment duration: at least 12 month) within a large prospective study of MS patients conducted at the Partners MS Center, Brigham and Women's Hospital (CLIMB study) between Jan 2011 to Feb 2016. Patients had complete blood counts with differentials at baseline and every 6 months while on treatment. Most participants had a clinical visit with complete neurologic examinations every 6 months and brain MRI scan every 12 months. T cell subset profile was available for subgroup of patients (n = 116). ResultsIn the FNG group, the risk of developing lymphopenia grade 4 (< 200) was higher in female patients (p = 0.0117) and those who were previously treated with natalizumab (p = 0.0116), while the risk of lymphopenia grade 3b+4 (< 350) was higher in female patients (p = 0.0009). DMF treated patients with lower baseline lymphocyte count had a higher chance of developing lymphopenia grade 2 (< 800) (p < 0.0001) or 2+3 (< 500) (p < 0.0001). We examined the effect of treatment switch between DMF and FNG. No significant recovery in lymphocyte and leukocyte count was observed after treatment switches. Reduced dosing of FNG in patients with lymphopenia led to increase in lymphocyte count but also increased disease activity in 25% of patients. ConclusionFemale sex and prior exposure to natalizumab increased the probability of lymphopenia on FNG, while low absolute lymphocyte count was associated with increased risk of lymphopenia on DMF. Parallel switch did not lead to recovery from hematological abnormalities. Long-term studies with larger number of patients are required to confirm our findings and to establish guidelines for prediction and management of hematological abnormalities.

Cost-Effectiveness of Peginterferon Beta-1a and Alemtuzumab in Relapsing-Remitting Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, affecting 2.5 million people globally and 400,000 people in the United States. While no cure exists for MS, the goal is to manage the disease using disease-modifying therapies (DMTs), which have been shown to slow disease progression and prevent relapses. Relapsing-remitting MS (RRMS) is the most common form of MS at the time of diagnosis. Peginterferon beta-1a (PEG) and alemtuzumab (ALT) were recently approved and have demonstrated good clinical outcomes, including reduced relapse rates in clinical trials. High costs associated with these DMTs necessitates cost-effectiveness analyses to understand their overall value in RRMS management. To assess the cost-effectiveness of (a) Model 1: PEG relative to intramuscular interferon beta-1a (IM IFN), subcutaneous interferon beta-1b (SC IFN), glatiramer acetate 20 mg per mL (GA), fingolimod (FIN), natalizumab (NAT), and dimethyl fumarate (DMF), and (b) Model 2: ALT relative to subcutaneous interferon beta-1a 44 μg (IFN beta-1a 44 μg). Both analyses were conducted from a U.S. third-party payer perspective. Two static decision models were used to compare the cost-effectiveness of PEG and ALT over a 1-year and a 2-year time horizon, respectively. Model inputs were drug acquisition costs (wholesale acquisition cost from RED BOOK); drug administration and monitoring costs (package inserts and Centers for Medicare & Medicaid Services 2015 Physician Fee Schedule); relapse rates and relapse rate reduction (clinical trials); and cost of managing relapses (published literature). All costs were adjusted to 2015 U.S. dollars using the medical care component of the Consumer Price Index. Outcomes measured were total cost of therapy per patient, cost per relapse avoided, and incremental cost-effectiveness ratios (ICERs) calculated as cost per relapse avoided. Sensitivity analysis was conducted to test model robustness given the uncertainty of model inputs and study assumptions. Model 1 results showed that PEG dominated IM IFN and GA, compared with SC IFN; PEG had an ICER of $1,978,000 per relapse avoided. Compared with FIN, NAT, and DMF, PEG was less expensive and less effective. Model 2 showed that ALT had an ICER of $25,276 per relapse avoided relative to IFN beta-1a 44 μg. In patients with RRMS, PEG is a viable alternative when compared with the DMTs in our model. Deciding whether to choose PEG over other DMTs would depend on multiple factors. On the other hand, ALT had an ICER of $25,276 cost per relapse avoided relative to IFN beta-1a 44 μg. The study results will assist payers in evaluating different medication choices for effective therapy. No outside funding supported this study. Kamal has received research funding from Novartis Pharmaceuticals and the College of Psychiatric and Neurologic Pharmacists and also serves as a consultant for the Lynx Group. Dashputre and Pawar report no conflicts of interest. Study concept and design were primarily contributed by Dashputre, along with Kamal and Pawar. Dashputre took the lead in data collection, along with Kamal, and data analysis was performed by Dashputre, Kamal, and Pawar. The manuscript was written and revised primarily by Dashputre, along with Kamal and Pawar.

Comparative Effectiveness of High-Efficacy Multiple Sclerosis Treatments

Head-to-head data exist for alemtuzumab versus thrice-weekly subcutaneous interferon beta 1a (IFN) and for fingolimod versus weekly intramuscular IFN. However, no trial data are available comparing alemtuzumab with natalizumab and with fingolimod. Researchers have now compared these treatments' effects on relapse rates and other outcomes using MSBase, a longitudinal international registry that prospectively collects observational data from multiple sclerosis (MS) clinical practices. Treatments are based on physician and patient preferences, …

Active brain changes after initiating fingolimod therapy in multiple sclerosis patients using individual voxel-based analyses for diffusion tensor imaging.

ABSTRACTVoxel-based analysis (VBA) of diffusion tensor images (DTI) and voxel-based morphometry (VBM) in patients with multiple sclerosis (MS) can sensitively detect occult tissue damage that underlies pathological changes in the brain. In the present study, both at the start of fingolimod and post-four months clinical remission, we assessed four patients with MS who were evaluated with VBA of DTI, VBM, and fluid-attenuated inversion recovery (FLAIR). DTI images for all four patients showed widespread areas of increased mean diffusivity (MD) and decreased fractional anisotropy (FA) that were beyond the high-intensity signal areas across images. After four months of continuous fingolimod therapy, DTI abnormalities progressed; in particular, MD was significantly increased, while brain volume and high-intensity signals were unchanged. These findings suggest that VBA of DTI (e.g., MD) may help assess MS demyelination as neuroinflammatory conditions, even though clinical manifestations of MS appear to be in complete remission during fingolimod.

Phase II Data Support Ongoing Study of Amiselimod in Relapsing Multiple Sclerosis

Fingolimod is an FDA-approved sphingosine 1-phosphate (S1P) modulator that acts on subreceptors S1P1,3,4,5. By contrast, the investigational drug

The cost-effectiveness of disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis

Background: The safety and efficacy of disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has been established; however, it is not clear which provides optimal value, given benefit-risk profiles and costs.Aims: To compare the cost-effectiveness of current DMTs for patients with RRMS in the US.Materials and methods: A Markov model predicting RRMS course following initiation of a DMT was created comparing outcomes (e.g. relapses, disease progression) and costs of natalizumab (NTZ), dimethyl fumarate (DMF), and peginterferon beta-1a (PEG) with fingolimod (FIN), glatiramer acetate (GA, 20 mg daily), and subcutaneous interferon beta-1a (IFN, 44 mcg), respectively, over 10 years. RRMS and secondary-progressive MS (SPMS) EDSS state transitions were predicted in 3-month cycles in which patients were at risk of death, relapse, or discontinuation. Upon DMT discontinuation, natural history progression and relapse rates were applied. Incremental cost-effectiveness ratios (ICERs) were estimated for the cost per relapse avoided, relapse-free years gained, progression avoided, and progression-free years gained. The impact of model parameters on outcomes was evaluated via one-way sensitivity analyses.Results: Costs ranged from $561,177 (NTZ) to $616,251 (GA). NTZ, DMF, and PEG were dominant (less costly and more effective) compared to FIN, GA, and IFN, respectively, for all ICERs. Variability in drug costs and parameters that affected drug cost accrual (e.g. discontinuation rates and the decision to drop out after SPMS conversion) had a considerable impact on ICERs.Limitations: Several simplifying assumptions were made that may represent potential limitations of this analysis (e.g. a constant treatment effect over time was assumed).Conclusions: The results from this analysis suggest that the NTZ, DMF, and PEG are cost-effective DMT choices compared to FIN, GA, and IFN, respectively. The actual impact on a particular plan will vary based on drug pricing and other factors affecting drug cost accrual.