Comparative efficacy of ofatumumab versus oral therapies for relapsing multiple sclerosis patients using propensity score analyses and simulated treatment comparisons.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

Disutility of Cognitive Processing Speed (CPS) Impairment in the Context of Multiple Sclerosis: A Time Trade-Off (TTO) Elicitation Study.

Introduction: Cognitive impairment, especially relating to cognitive processing speed, is a major cause of disability in people with multiple sclerosis (MS). Utility values are quantitative estimates of the quality of life experienced in specific health states and are a key component of cost-effectiveness modelling. However, existing health state utility values in MS typically focus on physical ability and are generally derived using generic (not disease-specific) measures of quality of life. The objective of the current study was to generate health state utility values for levels of cognitive impairment. We used a direct utility elicitation approach called the time trade-off (TTO) methodology. Materials and Methods: Health state descriptions were created following interviews with healthcare professionals, patients, and caregivers in the United States (n=35), and with healthcare professionals in the UK (n=5). Three health states (mild, moderate, and severe impairment) were defined based upon a well-established and validated test for cognitive dysfunction called the Symbol Digit Modalities Test (SDMT) and described using qualitative interview findings. Next, interviews with members of the general public in the UK were conducted to estimate utility values for each health state using the TTO methodology. The procedure was based on the established Measurement and Valuation of Health (MVH) protocol, which generates values on a scale from 0.0 to 1.0. Results: Mean health state utility values were 0.77 ± 0.24 in "mild impairment" (SDMT 43-40), 0.57 ± 0.26 in "moderate impairment" (SDMT 39-32), and 0.34 ± 0.28 in "severe impairment" (SDMT ≤ 31). Discussion: Results indicate that the public perceives that health states of cognitive slowing (as observed in MS) are associated with a substantial reduction in affected individuals' health-related quality of life, quantified using the TTO methodology. Future economic modeling should consider how utility impacts of both cognitive and physical disability can be appropriately incorporated.

Does the Multiple Sclerosis Impact Scale-29 (MSIS-29) have the range to capture the experience of fully ambulatory multiple sclerosis patients? Learnings from the ASCLEPIOS studies.

Background: Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits. Objective: To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide). Methods: Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS (N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores. Results: Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3. Conclusion: The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Cost-consequence analysis of ofatumumab for the treatment of relapsing-remitting multiple sclerosis in Canada.

Aim: The costs and consequences of initial and delayed ofatumumab treatment were evaluated in relapsing-remitting multiple sclerosis with active disease in Canada. Materials & methods: A Markov cohort model was used (10-year horizon, annual cycle length, 1.5% discounting). Scenario analyses examined ofatumumab as first-line treatment versus 3 and 5 years following switch from commonly used first-line therapies. Results: Ofatumumab resulted in improvements in clinical outcomes (relapses and disease progression) and productivity (employment and full-time work), and reduction of economic burden (administration, monitoring and non-drug costs) that were comparable to other high-efficacy therapies (ocrelizumab, cladribine and natalizumab). Switching to ofatumumab earlier in the disease course may improve these outcomes. Conclusion: Results highlight the value of a high-efficacy therapy such as ofatumumab as initial treatment (i.e., first-line) in newly diagnosed relapsing-remitting multiple sclerosis patients with active disease.

Comparative efficacy of therapies for relapsing multiple sclerosis: a systematic review and network meta-analysis.

Aim: To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Materials & methods: Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. Results: For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. Conclusion: The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).

Individual Differences in the Patient Experience of Relapsing Multiple Sclerosis (RMS): A Multi-Country Qualitative Exploration of Drivers of Treatment Preferences Among People Living with RMS.

AIMS: The aim of this study was to explore the experiences, values and preferences of people living with relapsing multiple sclerosis (PLwRMS) focusing on their treatments and what drives their treatment preferences. METHODS: In-depth, semi-structured, qualitative telephone interviews were conducted using a purposive sampling approach with 72 PLwRMS and 12 health care professionals (HCPs, MS specialist neurologists and nurses) from the United Kingdom, United States, Australia and Canada. Concept elicitation questioning was used to elicit PLwRMS' attitudes, beliefs and preferences towards features of disease-modifying treatments. Interviews with HCPs were conducted to inform on HCPs' experiences of treating PLwRMS. Responses were audio recorded and transcribed verbatim and then subjected to thematic analysis. RESULTS: Participants discussed numerous concepts that were important to them when making treatment decisions. Levels of importance participants placed on each concept, as well as reasons underpinning importance, varied substantially. The concepts with the greatest variability in terms of how much PLwRMS found them to be important in their decision-making process were mode of administration, speed of treatment effect, impact on reproduction and parenthood, impact on work and social life, patient engagement in decision making, and cost of treatment to the participant. Findings also demonstrated high variability in what participants described as their ideal treatment and the most important features a treatment should have. HCP findings provided clinical context for the treatment decision-making process and supported patient findings. CONCLUSIONS: Building upon previous stated preference research, this study highlighted the importance of qualitative research in understanding what drives patient preferences. Characterized by the heterogeneity of the RMS patient experience, findings indicate the nature of treatment decisions in RMS to be highly individualized, and the subjective relative importance placed on different treatment factors by PLwRMS to vary. Such qualitative patient preference evidence could offer valuable and supplementary insights, alongside quantitative data, to inform decision making related to RMS treatment.

Proportion and characteristics of secondary progressive multiple sclerosis in five European registries using objective classifiers.

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported. Materials and methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published. Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned. Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs.

Evaluating the impact of early vs delayed ofatumumab initiation and estimating the long-term outcomes of ofatumumab vs teriflunomide in relapsing multiple sclerosis patients in Spain.

OBJECTIVES: To evaluate the impact of early (at first-line) vs delayed (3-year delay) ofatumumab initiation and long-term clinical, societal, and economic outcomes of ofatumumab vs teriflunomide in relapsing multiple sclerosis (RMS) patients from a Spanish societal perspective. METHODS: A cost-consequence analysis was conducted using an Expanded Disability Status Scale (EDSS)-based Markov model. Inputs were sourced from ASCLEPIOS I and II trials and published literature. RESULTS: At the end of 10 years, compared with first-line teriflunomide treatment, early first-line ofatumumab initiation was projected to result in 35.6% fewer patients progressing to EDSS ≥ 7 and 27.8% fewer relapses. The ofatumumab cohort required 7.3% reduced informal care time and had 19% fewer disability-adjusted life years (DALYs) than the teriflunomide cohort. A 3-year delay in ofatumumab treatment (3-year teriflunomide + 7-year ofatumumab) was projected to result in 32.2% more patients progressing to EDSS ≥ 7, 20.2% more relapses, 5.4% increased informal care time, and 16.6% more DALYs compared with early ofatumumab initiation. Early ofatumumab initiation was associated with total annual cost savings (excluding disease-modifying-therapies' acquisition costs) of €35,328 ($34,549; conversion factor 1€= $1.02255) and €24,373 ($23,836) per patient vs teriflunomide and 3-year delayed ofatumumab initiation, respectively. CONCLUSIONS: This study highlights the benefits of early initiation of high-efficacy therapy such as ofatumumab vs its delayed initiation for improving the outcomes in RMS patients (having characteristics similar to those of patients included in the ASCLEPIOS trials). Ofatumumab treatment was projected to provide improved long-term clinical, societal, and economic outcomes vs teriflunomide treatment in RMS patients from a Spanish societal perspective.

The therapeutic benefits of ofatumumab in relapsing multiple sclerosis (RMS) patients have been reported in the ASCLEPIOS I and II trials. Using an Expanded Disability Status Scale-based Markov model, this study aimed to assess the impact of early (i.e. at first-line, as the first treatment after diagnosis) vs delayed (i.e. 3-year delay) ofatumumab initiation in RMS patients from a Spanish societal perspective. In addition, the long-term clinical, societal, and economic outcomes of ofatumumab vs teriflunomide treatment were assessed. Evidence from this study suggests that early initiation of a high-efficacy therapy such as ofatumumab, compared with its delayed initiation, is an effective and cost-saving strategy for improving outcomes in RMS patients. Furthermore, patients receiving ofatumumab for 10 years are projected to experience comparatively better outcomes (clinical, societal, and economic) than those receiving teriflunomide.

Cost-Effectiveness Analysis of Ofatumumab for the Treatment of Relapsing-Remitting Multiple Sclerosis in Canada.

BACKGROUND: Ofatumumab is a high-efficacy disease-modifying therapy (DMT) approved for first-line treatment of relapsing-remitting multiple sclerosis (RRMS) in Canada. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of ofatumumab from a Canadian healthcare system perspective. METHODS: A Markov cohort model was run over 65 years using annual cycles, 1.5% annual discount rate, and 100% treatment discontinuation at 10 years. The British Columbia database informed natural history transition probabilities. Treatment efficacy for DMTs were sourced from a network meta-analysis. Clinical trial data were used to estimate probabilities for treatment-related adverse events. Health utilities and costs were obtained from Canadian sources (if available) and the literature. RESULTS: Among first-line indicated therapies for RRMS, ofatumumab was dominant (more effective, lower costs) over teriflunomide, interferons, dimethyl fumarate, and ocrelizumab. Compared with glatiramer acetate and best supportive care, ofatumumab resulted in incremental cost-effectiveness ratios (ICERs) of $24,189 Canadian dollars per quality-adjusted life-year (QALY) and $28,014/QALY, respectively. At a willingness-to-pay threshold of $50,000/QALY, ofatumumab had a 64.3% probability of being cost effective. Among second-line therapies (scenario analysis), ofatumumab dominated natalizumab and fingolimod and resulted in an ICER of $50,969 versus cladribine. CONCLUSIONS: Ofatumumab is cost effective against all comparators and dominant against all currently approved and reimbursed first-line DMTs for RRMS, except glatiramer acetate.

How do patients with secondary progressive multiple sclerosis enrolled in the EXPAND randomized controlled trial compare with those seen in German clinical practice in the NeuroTransData multiple sclerosis registry?

Background: In EXPAND (NCT01665144), a phase 3 randomized clinical trial, siponimod reduced disability progression versus placebo in patients with secondary progressive multiple sclerosis (SPMS). Aim: To understand how a real-world population with SPMS relates to that in EXPAND, we conducted a retrospective, observational cohort study using the German NeuroTransData (NTD) multiple sclerosis (MS) registry. Methods: The NTD MS registry is run by a Germany-wide network of physicians. Two cross-sectional analyses were performed using the NTD MS registry. The first included patients with SPMS, as recorded in the registry, and compared their characteristics between 1 January 2018 and 31 December 2018 with patients in EXPAND. The second described the characteristics of patients in the registry at the time of diagnosis of SPMS between 1 January 2010 and 31 December 2018. Results: The first analysis included 773 patients: patients were older in the NTD MS registry than in EXPAND (mean age, 57.9 vs 48.0 years) and had a longer duration of SPMS (mean, 6.2 vs 3.8 years). In the NTD MS registry, median Expanded Disability Status Scale (EDSS) scores were comparable to EXPAND (6.0 versus 6.0), although fewer patients had relapses in the previous 24 months (16% vs 36% [siponimod] and 37% [placebo]). Data on gadolinium-enhancing lesions were only available for 5.8% of patients in the NTD MS registry. The second analysis included 916 patients: at the time of SPMS diagnosis, the mean age was 53.2 years and the median EDSS score was 5.0. Conclusion: The population in the NTD MS registry was older to that in EXPAND, but were similar in terms of disability. Differences likely reflect the inclusion criteria of EXPAND but also highlight that real-world populations encompass a wider range of patient characteristics.

Systematic literature review and meta-analysis of the prevalence of secondary progressive multiple sclerosis in the USA, Europe, Canada, Australia, and Brazil.

BACKGROUND: Secondary progressive multiple sclerosis (SPMS) is a subtype of multiple sclerosis (MS), which is a chronic neurological disease, characterised by inflammation of the central nervous system. Most of MS patients eventually progress to SPMS. This study estimates the prevalence of SPMS in the United States of America, Europe, Canada, Australia, and Brazil. METHODS: A systematic literature search of the Medline and Embase databases was performed using the OVID™ SP platform to identify MS epidemiological studies published in English from database inception to September 22, 2020. Studies reporting the prevalence of MS and proportion of SPMS patients in the included population were selected. The pooled prevalence of SPMS was calculated based on the proportion of SPMS patients. The Loney quality assessment checklist was used for quality grading. A meta-analysis of the proportions was conducted in RStudio. RESULTS: A total of 4754 articles were retrieved, and prevalence was calculated from 97 relevant studies. Overall, 86 medium- and high-quality studies were included in the meta-analysis. Most studies were conducted in European countries (84 studies). The estimated pooled prevalence of SPMS was 22.42 (99% confidence interval: 18.30, 26.95)/100,000. The prevalence of SPMS was more in the North European countries, highest in Sweden and lowest in Brazil. A decline in SPMS prevalence was observed since the availability of oral disease-modifying therapies. We also observed a regional variation of higher SPMS prevalence in urban areas compared with rural areas. CONCLUSION: High variability was observed in the estimated SPMS prevalence, and the quality of the studies conducted. The influence of latitude and other factors known to affect overall MS prevalence did not fully explain the wide range of inter-country and intra-country variability identified in the results.

Simulated treatment comparison of efficacy outcomes for ofatumumab in ASCLEPIOS I/II versus ocrelizumab in OPERA I/II for the treatment of patients with relapsing multiple sclerosis.

BACKGROUND: Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab. METHODS: Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change). RESULTS: Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes. CONCLUSION: Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

ENTIMOS: A Discrete Event Simulation Model for Maximising Efficiency of Infusion Suites in Centres Treating Multiple Sclerosis Patients.

BACKGROUND: Improved multiple sclerosis (MS) diagnosis and increased availability of intravenous disease-modifying treatments can lead to overburdening of infusion centres. This study was focused on developing a decision-support tool to help infusion centres plan their operations. METHODS: A discrete event simulation model ('ENTIMOS') was developed using Simul8 software in collaboration with clinical experts. Model inputs included treatment-specific clinical parameters, resources such as infusion chairs and nursing staff, and costs, while model outputs included patient throughput, waiting time, queue size, resource utilisation, and costs. The model was parameterised using characteristics of the Charing Cross Hospital Infusion Centre in London, UK, where 12 infusion chairs were deployed for 170 non-MS and 860 MS patients as of March 2021. The number of MS patients was projected to increase by seven new patients per week. RESULTS: The model-estimated waiting time for an infusion is, on average, 8 days beyond clinical recommendation in the first year of simulation. Without corrective action, the delay in receiving due treatment is anticipated to reach 30 days on average at 30 months from the start of simulation. Such system compromise can be prevented either by adding one infusion chair annually or switching 7% of existing patients or 24% of new patients to alternative MS treatments not requiring infusion. CONCLUSION: ENTIMOS is a flexible model of patient flow and care delivery in infusion centres serving MS patients. It allows users to simulate specific local settings and therefore identify measures that are necessary to avoid clinically significant treatment delay resulting in suboptimal care.

Comparing the long-term clinical and economic impact of ofatumumab versus dimethyl fumarate and glatiramer acetate in patients with relapsing multiple sclerosis: A cost-consequence analysis from a societal perspective in Germany.

Background: Evidence suggests that early highly efficacious therapy in relapsing multiple sclerosis is superior to escalation strategies. Objective: A cost-consequence analysis simulated different treatment scenarios with ofatumumab (OMB), dimethyl fumarate (DMF) and glatiramer acetate (GA): immediate OMB initiation as first treatment, early switch to OMB after 1 year on DMF/GA, late switch after 5 years or no switch. Methods: An EDSS-based Markov model with a 10-year time horizon was applied. Cycle transitions included EDSS progression, improvement or stabilization, treatment discontinuation, relapse or death. Input data were extracted from OMB trials, a network meta-analysis, published literature, and publicly available sources. Results: The late switch compared to the immediate OMB scenario resulted in a lower proportion of patients with EDSS 0-3 (Δ - 7.5% DMF; Δ - 10.3% GA), more relapses (Δ + 0.72 DMF; Δ + 1.23 GA) and lower employment rates (Δ - 4.0% DMF; Δ - 5.6% GA). The same applies to late versus early switches. No switch scenarios resulted in worse outcomes. Higher drug acquisition costs in the immediate OMB and early switch scenarios were almost compensated by lower costs for patient care and productivity loss. Conclusion: Immediate OMB treatment and an early switch improves clinical and productivity outcomes while remaining almost cost neutral compared to late or no switches.

Indirect comparisons of siponimod with fingolimod and ofatumumab in multiple sclerosis: assessing the feasibility of propensity score matching analyses.

OBJECTIVE: Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes. METHODS: One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM). RESULTS: An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20; p-value = .240] and hazard ratio 0.80 [95% confidence interval 0.52-1.22; p-value = .300], respectively). CONCLUSIONS: For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.

How have Economic Evaluations in Relapsing Multiple Sclerosis Evolved Over Time? A Systematic Literature Review.

INTRODUCTION: The introduction of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) over the last two decades has prompted the economic assessments of these treatments by reimbursement authorities. The aim of this systematic literature review was to evaluate the modeling approach and data sources used in economic evaluations of DMTs for RMS, identify differences and similarities, and explore how economic evaluation models have evolved over time. METHODS: MEDLINE®, Embase®, and EBM Reviews databases were searched using Ovid® Platform from database inception on 25 December 2019 and subsequently updated on 17 February 2021. In addition, health technology assessment agency websites, key conference proceedings, and gray literature from relevant websites were screened. The quality of included studies was assessed using the Drummond and Philips checklists. RESULTS: A total 155 publications and 30 Health Technology Assessment (HTA) reports were included. Most of these were cost-utility analysis (73 studies and 25 HTA reports) and funded by medicines manufacturers (n = 65). The top three countries where studies were conducted were the USA (n = 29), the UK (n = 16), and Spain (n = 10). Studies predominantly used Markov cohort models (94 studies; 25 HTAs) structured based on the Expanded Disability Status Scale (EDSS) with 21 health states (20 studies; 12 HTA reports). The London Ontario and British Columbia data sets were commonly used sources for natural history data (n = 33; n = 13). Twelve studies and ten HTAs from the UK assumed a waning of DMT effect over the long term, while this was uncommon in studies from other countries. Nineteen studies adjusted for multiple sclerosis (MS)-specific mortality estimates, while 18 studies used data from the national life table without adjustment. Studies prominently referred to mortality data that were about two decades old. The data on treatment effect was generally obtained from randomized controlled trials (43 studies; 7 HTAs) or from published evidence synthesis (23 studies; 24 HTAs). Utility estimates were derived from either published studies and/or supplemented with data from RCTs. Most of the models used the lifetime horizon (n = 37) with a 1-year cycle length (n = 63). CONCLUSION: As expected, similarities as well as differences were observed across the different economic models. Available evidence suggests models should continue using the Markov cohort model with 21 EDSS-based states, however, allowing the transition to a lower EDSS state and assuming a sustained treatment effect. With reference to the data sources, models should consider using a contemporary MS-specific mortality data, recent natural history data, and country-specific utility data if available. In case of data unavailability, a sensitivity analysis using multiple sources of data should be conducted. In addition, future models should incorporate other clinically relevant outcomes, such as the cognition, vision, and psychological aspects of RMS, to be able to present the comprehensive value of DMTs.

Cost Effectiveness and Budget Impact of Siponimod Compared to Interferon Beta-1a in the Treatment of Adult Patients with Secondary Progressive Multiple Sclerosis with Active Disease in Switzerland.

OBJECTIVE: The study aim was to evaluate the cost effectiveness and budget impact of siponimod compared to interferon beta-1a for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, from a Swiss health insurance perspective. METHODS: We conducted an analysis using a Markov cohort model with a cycle length of 1 year, life-long time horizon, and discount rate of 3% for cost and health outcomes. We used a matching-adjusted indirect comparison to estimate clinical outcomes using data from the EXPAND randomised controlled trial of siponimod vs placebo and the Nordic SPMS randomised controlled trial of interferon beta-1a vs placebo as the basis for estimates of disability progression and relapse outcomes. We used 6-month confirmed disability progression results to estimate disability progression in the base-case analysis. We calculated quality-adjusted life-years (QALYs) based on an external study that administered the EQ-5D-3L questionnaire to European patients with multiple sclerosis. We included costs (Swiss Franc (CHF), year 2020) of drug acquisition/administration, adverse events and disease management. We also performed a budget impact analysis to estimate the cost over the first 3 years of introducing siponimod. RESULTS: For the base case, siponimod resulted in mean incremental costs of CHF 84,901 (siponimod: CHF 567,838, interferon beta-1a: CHF 482,937) and mean incremental QALYs of 1.591 (siponimod: 7.495, interferon beta-1a: 5.905), leading to an incremental cost-effectiveness ratio of CHF 53,364 per QALY gained. In the probabilistic sensitivity analysis, the probability of the cost effectiveness of siponimod assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained was 90%. Siponimod was projected to result in drug administration costs for siponimod of CHF 23,817,856 in the first 3 years after introduction, accompanied by large cost offsets in drug acquisition of other multiple sclerosis drugs. Considering drug administration, monitoring and adverse event management costs, it was estimated to result in additional healthcare costs in Switzerland of CHF 2,177,021. CONCLUSIONS: In the base-case analysis, we found that siponimod may be cost effective for treating Swiss adult patients with SPMS with active disease. The results of the cost-effectiveness analyses are valid under the assumption that the efficacy of siponimod and the comparators on disability progression for the overall SPMS population would be the same in the active SPMS population. CLINICAL TRIAL IDENTIFIER: NCT01665144. This economic evaluation was based on the EXPAND trial.

Secondary progressive multiple sclerosis: a systematic review of costs and health state utilities.

Objective: To identify evidence in the literature presenting the economic and humanistic (based on health state utility values [HSUVs]) burden of multiple sclerosis (MS) and report the incremental burden of secondary progressive MS (SPMS) compared with relapsing-remitting MS (RRMS).Methods: Electronic databases (Embase, MEDLINE, MEDLINE In-Process, Cochrane Library) and other relevant repositories were systematically searched from the date of inception until November 2019 for evidence on the economic burden of MS, or HSUVs in patients with MS. Data were extracted from studies investigating cost data or HSUVs for patients with SPMS compared with RRMS.Results: In total, 25 studies were identified that reported data on the economic and HSUV burden of SPMS versus RRMS: 18 studies reported cost data and nine presented HSUVs. Overall, costs associated with SPMS were consistently higher than those for RRMS. Major cost drivers appeared to shift following transition from RRMS to SPMS, with higher direct medical costs associated with RRMS than with SPMS, while the opposite was true for direct non-medical costs and indirect costs. In all studies presenting HSUVs specifically in patients with SPMS, the disease burden was greater (indicated by lower HSUV scores or a negative regression coefficient vs RRMS) for patients with SPMS than for those with RRMS. Fatigue and psychological stress (including depression) were identified as key drivers of this reduced health-related quality of life (HRQoL).Conclusions: Our findings indicate that SPMS is associated with higher costs and more substantial HRQoL decrements than RRMS. These results highlight the substantial unmet need for effective treatments that can slow disease progression in patients with SPMS, which, in turn, would reduce the rate of HRQoL deterioration and increasing healthcare costs.

Efficacy classification of modern therapies in multiple sclerosis.

Background: The Association of British Neurologists (ABN) 2015 guidelines suggested classifying multiple sclerosis therapies according to their average relapse reduction. We sought to classify newer therapies (cladribine, ocrelizumab, ofatumumab, ozanimod) based on these guidelines. Materials & methods: Therapies were classified by using direct comparative trial results as per ABN guidelines and generating classification probabilities for each therapy based on comparisons versus placebo in a network meta-analysis for annualized relapse rate. Results: For both approaches, cladribine and ofatumumab were classified as high efficacy. Ocrelizumab and ozanimod (1.0 mg) were classified as moderate or high efficacy depending on the approach used. Conclusion: Cladribine and ofatumumab have an efficacy comparable with therapies classified in the ABN guidelines as high efficacy.