Estimated Cost-effectiveness of Atezolizumab Plus Cobimetinib and Vemurafenib for Treatment of BRAF V600 Variation Metastatic Melanoma.

Importance: In the IMspire150 trial, triplet treatment with atezolizumab and vemurafenib plus cobimetinib significantly improved progression-free survival (PFS) compared with vemurafenib plus cobimetinib alone for treatment of BRAF V600 variation metastatic melanoma. However, considering high cost of this combination, it is unclear if the incremental cost is worth the additional survival benefit. Objective: To evaluate the cost-effectiveness of atezolizumab and vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone in patients with newly diagnosed unresectable BRAF V600 variation metastatic melanoma from the US health care perspective. Design, Setting, and Participants: This economic evaluation study used a 3-state partitioned survival model to assess the cost-effectiveness of the combination of atezolizumab with vemurafenib plus cobimetinib vs vemurafenib plus cobimetinib alone. The observed Kaplan-Meier curves for overall survival and PFS were digitized from the IMspire150 trial (January 2017-April 2018) and the long-term survivals (over a lifetime horizon) beyond the end of the trial were extrapolated using 7 different survival models. The cost and health preference data were collected from a literature review. This study was performed from March 2021 through June 2021. Main Outcomes and Measures: The outcomes of interest were expected life-years (LYs) gained and quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio (ICER), expressed as cost per LYs and per QALYs saved. Results: Adding atezolizumab to vemurafenib and cobimetinib provided an additional 3.267 QALYs compared with the doublet regimen of vemurafenib plus cobimetinib, at an ICER of $271 669 per QALY, which is not considered cost-effective at the willingness-to-pay threshold of $150 000 per QALY. However, the scenario analyses found that atezolizumab combined with vemurafenib plus cobimetinib could be cost-effective at 20-year (ICER, $121 432 per QALY) and 30-year ($98 092 per QALY) time horizons when both strategies were stopped after 2 years of treatments, and over a lifetime horizon ($122 220 per QALY) when only immunotherapy with atezolizumab was stopped after 2 years of treatment. Conclusions and Relevance: These findings suggest that the atezolizumab and vemurafenib plus cobimetinib regimen provides significant survival benefits over vemurafenib plus cobimetinib alone, and a price reduction would be encouraged to maximize the value of its survival gain.

A modeling framework for the economic evaluation of baricitinib in moderate-to-severe rheumatoid arthritis.

Objectives: The approval in more than 50 countries of baricitinib, an oral Janus Kinase inhibitor for the treatment of Rheumatoid Arthritis (RA), warrants a framework for corresponding economic evaluations. To develop a comprehensive economic model assessing the cost-effectiveness of baricitinib for the treatment of moderately-to-severely active RA patients in comparison to other relevant treatments, considering the natural history of the disease, real world treatment patterns, and clinical evidence from the baricitinib trials.Methods: A systematic literature review of previously developed models in RA was conducted to inform the model structure, key modeling assumptions and data inputs. Consultations with rheumatologists were undertaken to validate the modeling approach and underlying assumptions.Results: A discrete event simulation model was developed to international best practices with flexibility to assess the cost-effectiveness of baricitinib over a lifetime in a variety of markets. The model incorporates treatment sequencing to adequately reflect treatment pathways in clinical practice. Outcomes assessed include cost and quality-adjusted life years, allowing for a full incremental analysis of cost-effectiveness of competing treatments and treatment sequences.Conclusion: The economic model developed provides a robust framework for future analyses assessing the cost-effectiveness of baricitinib for the treatment of RA in specific country settings.

The Effectiveness and Value of Siponimod for Secondary Progressive Multiple Sclerosis.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Synnott and Pearson are employed by ICER. Bloudek and Carlson report a research agreement between the University of Washington and ICER; Bloudek reports consulting fees from Allergan, Seattle Genetics, Dermira, Sunovion, TerSera Therapeutics, Cook Regentech, and Mallinckrodt Pharmaceuticals; and Carlson reports personal fees from Bayer, unrelated to this report. Sharaf reports consulting fees from ICER.

Importance of Patient-Centered Outcomes When Evaluating Treatments for Secondary Progressive Multiple Sclerosis.

DISCLOSURES: No funding supported the writing of this commentary. The author has nothing to disclose.

A Budget Impact and Cost Per Additional Responder Analysis for Baricitinib for the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients with an Inadequate Response to Tumor Necrosis Factor Inhibitors in the USA.

BACKGROUND/OBJECTIVE: Baricitinib is a selective and reversible Janus kinase (JAK) inhibitor indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor inhibitors (TNFis) and has been shown to improve multiple clinical and patient-reported outcomes. However, it is unclear what the budgetary impact would be for US commercial payers to add baricitinib to their formulary and how the efficacy of baricitinib compares to other disease-modifying antirheumatic drugs (DMARDs) with a similar indication. METHODS: A budget impact model (BIM) was developed for a hypothetical population of 1 million plan members that compared a world without and with baricitinib. A retrospective observational study was carried out to estimate market utilization of advanced therapies. Number needed to treat (NNT) and cost per additional responder were calculated for American College of Rheumatology (ACR) 20%/50%/70% improvement criteria (ACR20/50/70) response outcomes combining cost estimates from the BIM and efficacy values from a network meta-analysis (NMA). The model included costs related to drug acquisition and monitoring costs. RESULTS: Adding baricitinib would save a commercial payer $US169,742 for second-line therapy and $US135,471 for third-line therapy over a 2-year time horizon (all costs correspond to 2019 US dollars). Cost savings were driven by baricitinib drawing market share away from more expensive comparators. The NMA, based on nine studies, found no statistically significant differences in the median treatment difference between baricitinib and comparators except for versus a conventional synthetic DMARD (csDMARD), and thus NNT versus a csDMARD was similar. The cost per additional responder for baricitinib in patients with inadequate response to a TNFi was substantially lower than all other treatments for all three ACR response criteria at 12 weeks (ACR20: $US129,672; ACR50: $US237,732; ACR70: $US475,464), and among the lowest at 24 weeks (ACR20: $US167,811; ACR50: $US259,344; ACR70: $US570,557). CONCLUSIONS: Baricitinib, compared to other DMARDs, was a less expensive option (- $US0.01 incremental cost per member per month in second- and third-line therapy over a 2-year time horizon) with comparable efficacy in patients with inadequate response to TNFi. Adding baricitinib to formulary would likely be cost saving for US payers and expands treatment options for these patients.

Custo-utilidade de terapias-alvo comparadas à dacarbazina para o tratamento de primeira linha do melanoma avançado não-cirúrgico e metastático no Sistema Único de Saúde do Brazil.

OBJECTIVE: To estimate the incremental cost-utility ratio (ICUR) of isolated and combined targeted therapy regimens compared to dacarbazine for first-line treatment of advanced and metastatic melanoma with BRAF V600 mutation. METHODS: A Markov model with three health states (no progression, progression and death), monthly duration cycle and 10-year time horizon was constructed to compare targeted therapy regimens (vemurafenib, dabrafenib, vemurafenib/cobimetinib and dabrafenib/trametinib) with dacarbazine chemotherapy under the Brazilian public health perspective. One-way and probabilistic sensitivity analyses were performed. RESULTS: Mean cost was R$5662.50 ($1490.13) for dacarbazine, R$175 937.18 (46 299.26) for vemurafenib, R$167 461.70 ($44 068.87) for dabrafenib, R$425 901 ($112 079.21) for vemurafenib/cobimetinib and R$411 799.81 ($108 368.37) for dabrafenib/trametinib, whereas QALY was 0.91 for dacarbazine, 1.08 for vemurafenib, 1.12 for dabrafenib, 1.64 for vemurafenib/cobimetinib and 1.56 for dabrafenib/trametinib. The ICUR was estimated from R$572 165.76 ($150 569.94) to R$1 012 524.56 ($266 453.83) per patient, and the most impactful parameters were risk of progression and death, and treatment cost. CONCLUSION: The incorporation of targeted therapies in the Brazilian public health system would produce an additional expenditure of at least 19 times the national GDP per capita to increase in one year the quality-adjusted survival of each patient with advanced/metastatic BRAF-mutant melanoma.

Baricitinib for Previously Treated Moderate or Severe Rheumatoid Arthritis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal process, the National Institute for Health and Care Excellence invited the manufacturer (Eli Lilly) of baricitinib (BARI; Olumiant®; a Janus kinase inhibitor that is taken orally) to submit evidence of its clinical and cost effectiveness for the treatment of moderate to severe rheumatoid arthritis (RA) after the failure of disease-modifying antirheumatic drugs (DMARDs). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company's submission (CS) to NICE. The clinical-effectiveness evidence in the CS for BARI was based predominantly on three randomised controlled trials comparing the efficacy of BARI against adalimumab or placebo, as well as one long-term extension study. The clinical-effectiveness review identified no head-to-head evidence on the efficacy of BARI against all the comparators within the scope. Therefore, the company performed network meta-analyses (NMAs) in two different populations: one in patients who had experienced an inadequate response to conventional DMARDs (cDMARD-IR), and the other in patients who had experienced an inadequate response to tumour necrosis factor inhibitors (TNFi-IR). The company's NMAs concluded BARI had comparable efficacy as the majority of its comparators in both populations. The company submitted a de novo discrete event simulation model that analysed the incremental cost-effectiveness of BARI versus its comparators for the treatment of RA from the perspective of the National Health Service (NHS) in four different populations: (1) cDMARD-IR patients with moderate RA, defined as a 28-Joint Disease Activity Score (DAS28) > 3.2 and no more than 5.1; (2) cDMARD-IR patients with severe RA (defined as a DAS28 > 5.1); (3) TNFi-IR patients with severe RA for whom rituximab (RTX) was eligible; and (4) TNFi-IR patients with severe RA for whom RTX in combination with methotrexate (MTX) is contraindicated or not tolerated. In the cDMARD-IR population with moderate RA, the deterministic incremental cost-effectiveness ratio (ICER) for BARI in combination with MTX compared with intensive cDMARDs was estimated to be £37,420 per quality-adjusted life-year (QALY) gained. In the cDMARD-IR population with severe RA, BARI in combination with MTX dominated all comparators except for certolizumab pegol (CTZ) in combination with MTX, with the ICER of CTZ in combination with MTX compared with BARI in combination with MTX estimated to be £18,400 per QALY gained. In the TNFi-IR population with severe RA, when RTX in combination with MTX was an option, BARI in combination with MTX was dominated by RTX in combination with MTX. In the TNFi-IR population with severe RA for whom RTX in combination with MTX is contraindicated or not tolerated, BARI in combination with MTX dominated golimumab in combination with MTX and was less effective and less expensive than the remaining comparators. Following a critique of the model, the ERG undertook exploratory analyses after applying corrections to the methods used in the NMAs and two programming errors in the economic model that affected the company's probabilistic sensitivity analysis (PSA) results. The ERG's NMA results were broadly comparable with the company's results. The programming error that affected the PSA of the severe cDMARD-IR population had only a minimal impact on the results, while the error affecting the severe TNFi-IR RTX-ineligible population resulted in markedly higher costs and QALYs gained for the affected comparators but did not substantially modify the conclusions of the analysis. The NICE Appraisal Committee concluded that BARI in combination with MTX or as monotherapy is a cost-effective use of NHS resources in patients with severe RA, except in TNFi-IR patients who are RTX-eligible.

[LDL cholesterol lowering therapy: no target value but personalised treatment]. / LDL-cholesterolverlagende therapie: geen streefwaarde maar behandeling op maat.

We previously recommended that LDL cholesterol lowering therapy be based on the risk for (recurrent) coronary events, rather than on arbitrary targets for serum LDL cholesterol concentration. We also recommended refraining from therapy with ezetimibe until its efficacy in preventing cardiovascular events had been documented. At the American Heart Association scientific sessions 2014 the results of the IMPROVE-IT study were reported. In this large, randomised trial, a modest benefit of the combination of simvastatin plus ezetimibe over simvastatin alone was reported after 7 years of treatment. The efficacy of such combination therapy was similar to the efficacy of high-dose statin therapy, while the combination therapy is much more expensive. Comparing the efficacy and costs of different preventive therapies, we recommend first prescribing aspirin and a moderate dose of statin, secondly an ACE inhibitor. A high-dose statin should be considered in high-risk patients. The combination of simvastatin and ezetimibe should be prescribed only in high-risk patients (e.g. diabetics after myocardial infarction) who do not tolerate high-dose statins.

Impact of the ENHANCE trial on the use of ezetimibe in the United States and Canada.

BACKGROUND: We previously found that the use of ezetimibe increased rapidly with different patterns between the United States (US) and Canada prior to the landmark Ezetimibe and Simvastatin in Hypercholesterolemia Enhance Atherosclerosis Regression (ENHANCE) trial, which was reported in January 2008, and failed to show that the drug slowed the progression of atherosclerosis. What is not known is how practice in the 2 countries changed after the ENHANCE trial. We examined ezetimibe use trends in the US and Canada before and after the reporting of the ENHANCE trial. METHODS: We conducted a population-based, retrospective, time-series analysis using the data collected by IMS Health in the US and CompuScript in Canada from January 1, 2002, to December 31, 2009. The main outcome measure was monthly number of prescriptions for ezetimibe-containing products. RESULTS: The monthly number of ezetimibe prescriptions/100,000 population rose from 6 to 1,082 in the US from November 2002 to January 2008, then significantly declined to 572/100,000 population by December 2009 after the release of the ENHANCE trial, a decrease of 47.1% (P < .001). In contrast, in Canada, use continuously rose from 2 to 495/100,000 population from June 2003 to December 2009 (P = .2). United States expenditures totaled $2.24 billion in 2009. CONCLUSIONS: Ezetimibe remains commonly used in both the US and Canada. Ezetimibe use has decreased in the US post-ENHANCE, whereas use has gradually but steadily increased in Canada. The diverging patterns of ezetimibe use in the US and Canada require further investigation, as they reveal that a common evidence base is eliciting very different utilization patterns in neighboring countries.

Use and misuse of ezetimibe: analysis of use and cost in Saskatchewan, a Canadian jurisdiction with broad access.

BACKGROUND: Saskatchewan is the only Canadian province that lists ezetimibe for open formulary access even though it is a second-line agent for lowering cholesterol. METHODS: A retrospective analysis of ezetimibe use in Saskatchewan between 2002 and 2011 was carried out using provincial health administrative databases. Overall use and costs of ezetimibe were described over time. Among new users of ezetimibe, the percentage who received the drug as first-line monotherapy was estimated. First-line monotherapy was defined as no statin dispensations in the 365 days before and the 60 days after the first ezetimibe dispensation. Potential predictors of first-line monotherapy were assessed using generalized linear mixed-effect models. RESULTS: In 2004, ezetimibe represented 2.5% of cholesterol-lowering dispensations. In 2011, its use increased to 8.8% of cholesterol-lowering dispensations and 13.2% of the total cost of cholesterol-lowering agents. Overall, ezetimibe was used as first-line monotherapy in 23% of all new users (4024 of 17,475 patients). Approximately half of all cases of first-line monotherapy were prescribed by 10.4% (112 of 1074) of prescribers in the cohort. Patients who had experienced previous acute coronary syndrome or who had undergone coronary revascularization procedures were significantly less likely to receive first-line monotherapy. CONCLUSIONS: A high proportion of ezetimibe's use is not in accordance with evidence-based recommendations. Suboptimal prescribing could partially explain current patterns of use; however, other factors such as medication nonadherence may have played an important role. Restricting ezetimibe use in the provincial formulary in addition to improving prescribers' awareness through academic detailing should be considered.

A case study of single-pill combination therapy: the ezetimibe/simvastatin combination for treatment of hyperlipidemia.

In recent years, combination therapy has received growing popularity as a powerful therapeutic tactic for the treatment of diseases. The justifications and benefits of combination therapy are far-reaching, including but not limited to addressing unmet medical needs such as cancer, malaria, and HIV/AIDS, improved clinical efficacy and safety with reduced dosage of a single medication, understanding the underlying science of the disease, alleviating pharmaco-economic impacts, and better drug life-cycle management. Using the ezetimibe/simvastatin combination therapy as a case study, a comprehensive overview of the successful discovery and development of the single-pill combination, Vytorin, is presented in this review. A cursory introduction to combination therapy and the rationale for the ezetimibe/simvastatin combination for the treatment of hyperlipidemia provides an instructive entry point. The discovery and mode of action of simvastatin and ezetimibe monotherapies set the scene for a detailed discussion on the discovery and development of Vytorin, with emphasis on bioequivalency studies, clinical efficacy and safety profile studies, and the economic consequences of the single-pill combination therapy. Large-scale outcome clinical trials are also discussed to demonstrate the long-term effects of Vytorin.

Combination of prescribing restrictions and policies to engineer low prices to reduce reimbursement costs.

OBJECTIVES: To primarily document the influence of recent changes in the pricing policies for generics and originators in Norway, coupled with prescribing restrictions for both the proton pump inhibitors (PPIs) and statins, on subsequent prescribing efficiency, to provide possible examples to other countries. Second, to review the impact of prescribing restrictions on ezetimibe utilization in Norway compared with other European countries, again to provide guidance. METHODS: A retrospective observational study using data from the Norwegian Drug Wholesales Statistics to evaluate changes in utilization patterns for the PPIs and statins from 2001 to 2009, and the Norwegian Prescription Database for expenditure data from January 2004 to 2009. Reforms validated with key personnel at the Norwegian Medicines Agency. RESULTS: Atorvastatin utilization as measured by defined daily doses decreased after prescribing restrictions. This, coupled with increased utilization of generic simvastatin at only 15% of prepatent loss prices in recent years, led to a 55% decrease in statin expenditure in Norway between 2004 and 2009 despite appreciably increased utilization. Utilization of esomeprazole also fell following prescribing restrictions, but to a lesser extent. This reduction, coupled with low prices for generics as a result of recent pricing policies, resulted in PPI expenditure decreasing by 27% during the same period despite again appreciably increased utilization. CONCLUSIONS: Policies to reduce the price of generics have been successfully introduced in Norway despite its small population size versus a number of other Western European countries. Prescribing restrictions have also been successfully introduced, mirroring the influence with multifaceted reforms in other European countries. The same applies to ezetimibe with utilization at only 1.9% of total statin and ezetimibe utilization in 2009. However, the difference in subsequent utilization patterns for atorvastatin versus esomeprazole makes it a challenge for health authorities to predict the ultimate impact of such measures. This requires further research.

Projected cost-effectiveness of ezetimibe/simvastatin compared with doubling the statin dose in the United Kingdom: findings from the INFORCE study.

OBJECTIVE: To evaluate the incremental cost-effectiveness ratio (ICER) of switching to ezetimibe/simvastatin (Eze/Simva) compared with doubling the submaximal statin doses, in patients with acute coronary syndrome (ACS) events in the INFORCE study. METHODS: Lifetime treatment costs and benefits were computed using a Markov model. Model inputs included each patient's cardiovascular risk factor profile and actual lipid values at baseline and 12 weeks (endpoint). Cardiovascular event and drug costs were discounted at 3.5%. Age-specific utilities were based on UK literature values and non-coronary heart disease mortality rates on the Office of National Statistics data. In the INFORCE study, 384 patients taking statins at stable doses for ≥6 weeks before hospital admission were stratified by statin dose/potency (low, medium, and high) and then randomized to doubling the statin dose or switching to Eze/Simva 10/40mg for 12 weeks. RESULTS: The Eze/Simva group (n=195) had a higher mean baseline total cholesterol than the double-statin group (n=189). Analyses were adjusted for baseline characteristics. In the INFORCE study, Eze/Simva reduced low-density lipoprotein cholesterol (LDL-C) by ∼30% (vs. 4% with doubling statin doses) and significantly enhanced LDL-C goal attainment. In the cost-effectiveness analysis, Eze/Simva conferred 0.218 incremental discounted quality-adjusted life year (QALY) at a discounted incremental cost of £2524, for an ICER of £11,571/QALY (95% confidence interval=£8181-£18,600/QALY). The ICER was £13,552/QALY, £11,930/QALY, and £10,148/QALY in the low-, medium-, and high-potency strata, respectively. CONCLUSIONS: Switching to Eze/Simva 10/40 mg is projected to be a cost-effective treatment (vs. double-statin) in UK patients with ACS.

Cost-effectiveness of rosuvastatin versus ezetimibe/simvastatin in managing dyslipidemic patients in Mexico.

OBJECTIVE: The purpose of this analysis was to study the effectiveness and cost-effectiveness of oral rosuvastatin (RSV) 10 mg/day vs. oral ezetimibe/simvastatin (E/S) 10/20 mg/day in patients who met the LDL-C goals set out in the National Cholesterol Education Program (NCEP), Adult Treatment Panel III (ATP III) 2001 and 2004 guidelines, and the percent change in the atherogenic lipid profile in daily outpatient practice in a high specialty Hospital in Mexico City. METHODS: From January 2004 to December 2005, outpatient medical records in the Cardiology Service were reviewed according to the following criteria: established dyslipidemia diagnosis, triglycerides and serum lipid measurements (TC, LDL-C, HDL-C) taken before receiving drug therapy with either oral RSV 10 mg/day or oral E/S 10/20 mg/day once daily, no other related lipid-lowering treatment administered, and lipid levels recorded at 8 weeks of treatment. A cost analysis was performed from an institutional perspective, using the exchange rate as of October 2006 of 10.9007 pesos / US dollar. A deterministic analysis was performed comparing treatment costs, proportion of patients achieving the ATP III goal, and the percentage decrease in LDL-C. In addition, a stochastic analysis was performed, considering the uncertainty around the estimations for mean cost and mean effectiveness estimations. RESULTS: Using the ATP III 2001 criteria, the percentage of patients who reached the LDL-C goals was 81.4% for patients who received RSV, while the proportion for patients who received E/S was 58.4% (p < 0.001). Results according to the ATP III 2004 criteria were: RSV, 46.4% vs. E/S, 31.4% (p = 0.04). The cost of a 1% reduction in LDL-C was $2.02 with RSV and $4.09 with E/S. The cost-effectiveness acceptability curve showed that RSV might be more cost-effective than E/S, based on patients who achieved the 2004 goals. CONCLUSIONS: According to this exploratory, non-controlled retrospective analysis, it can be said that in daily clinical practice in high-cardiovascular-risk Mexican patients, treatment with oral RSV 10 mg/day is more effective and less costly than treatment with the fixed-combination oral E/S 10/20 mg/day.