Long-Term Outcomes of Eladocagene Exuparvovec Compared with Standard of Care in Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Modelling Study.

INTRODUCTION: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare disease with symptoms including movement disorders, developmental delays, and autonomic symptoms starting from birth; further, patients with AADC deficiency are at a high risk of death in the first decade of life. Limited information on the impact of treatment with gene therapy on patients' disease trajectories and survival, quality-of-life, and resource usage benefits are available. METHOD: A cohort-based model with a lifetime horizon has been developed, based on motor milestones, to estimate the long-term benefits for patients after treatment with eladocagene exuparvovec compared to best supportive care (BSC). The model takes a National Health Service (NHS) perspective using a UK setting. The model comprises two parts: the developmental phase, in which patients with initially no motor function can progress to other motor milestone states, and a long-term projection phase. Efficacy for eladocagene exuparvovec is derived from clinical trial data with a duration up to 120 months. As the incidence of AADC deficiency is low, data for key model inputs is lacking; therefore estimates of survival by motor milestone were based on proxy diseases. A disease-specific utility study provided quality of life inputs and a burden of illness study informed inputs for disease management. RESULTS: The model indicates survival (25.25 undiscounted life years gained) and quality-of-life benefits (20.21 undiscounted quality-adjusted life years [QALYs] gained) for patients treated with eladocagene exuparvovec compared to BSC. Resource usage costs are greater for patients treated with eladocagene exuparvovec, mainly due to the increased life expectancy during which patients accrue additional healthcare resource usage. Scenario analyses indicate robust results. CONCLUSION: This study assessed long-term outcomes for patients with AADC deficiency. Patients treated with eladocagene exuparvovec were found to have improved survival and quality of life benefits compared to patients treated with BSC.

Cost-effectiveness analysis of KTE-X19 CAR T therapy versus real-world standard of care in patients with relapsed/refractory mantle cell lymphoma post BTKi in England.

AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) post-Bruton tyrosine kinase inhibitor (BTKi) treatment from a UK healthcare perspective. MATERIALS AND METHODS: A three-state partitioned survival model (pre-progression, post-progression and death) with a cycle length of one month was used to extrapolate progression-free and overall survival over a lifetime horizon. Population inputs along with KTE-X19 (brexucabtagene autoleucel) efficacy and safety data were derived from the single-arm trial ZUMA-2 (NCT02601313). The composition of SoC was informed by a literature-based meta-analysis, SoC efficacy data were obtained from the SCHOLAR-2 real-world study. Survival was modelled using standard parametric curves for SoC and a mixture-cure methodology for KTE-X19. It was assumed that patients whose disease had not progressed after five years experienced long-term remission. Costs, resource use and utility, and adverse event disutility inputs were obtained from published literature and publicly available data sources. An annual discount rate of 3.5% was applied to costs and health outcomes. Modelled outcomes for KTE-X19 and SoC included expected life years (LY), quality-adjusted life years (QALY) and total costs. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Estimated median survival was 5.96 years for KTE-X19 and 1.38 for SoC. Discounted LYs, QALYs and lifetime costs were 8.27, 5.99 and £385,765 for KTE-X19 versus 1.98, 1.48 and £79,742 for SoC, respectively. The KTE-X19 versus SoC cost per QALY was £67,713 and the cost per LY was £48,645. Influential scenario analyses use alternative KTE-X19 survival curves and discount rates, and shorter time horizons. CONCLUSION: Considering the survival and quality of life benefits compared to SoC, KTE-X19 for R/R MCL appears as a cost-effective treatment in the real-world UK setting.

Cost-effectiveness for KTE-X19 CAR T therapy for adult patients with relapsed/refractory mantle cell lymphoma in the United States.

AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients from a US healthcare perspective. MATERIALS AND METHODS: A three-state partitioned-survival model (pre-progression, post-progression, and death) with a cycle length of 1 month was used to extrapolate progression-free and overall survival (OS) over a lifetime horizon. Due to the long tail of the OS curve, OS was modeled applying a mixture-cure methodology, using the assumption that patients whose disease had not progressed after 5 years experienced long-term remission. Population inputs were derived from the ZUMA-2 trial. This was also the source of KTE-X19 efficacy and safety data, while this data was obtained from the literature for SoC. Costs and resource use inputs were derived from the published literature and publicly available data sources. Health state utilities were derived from the ZUMA-2 trial (NCT02601313), applying the US tariff. Adverse event disutilities were derived from the published literature. Costs and health outcomes were discounted at 3% per year. The model estimated expected life years (LY), quality-adjusted life years (QALY), and total costs for KTE-X19 vs SoC. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Median survival was 9.71 years for KTE-X19 and 2.13 for SoC. Discounted LYs, QALYs, and lifetime costs were 8.99, 7.39, and $693,832 for KTE-X19 vs 4.47, 3.65, and $574,263 for SoC, respectively. The KTE-X19 vs SoC cost per QALY was $31,985. The most influential model parameter was the utility for patients with long-term remission. At a willingness-to-pay threshold of $150,000 per QALY, the probability that KTE-X19 was cost-effective was 99%. CONCLUSION: The treatment of R/R MCL with KTE-X19 presents a potentially cost-effective alternative to the current SoC, deriving its value from incremental survival and health-related quality-of-life benefits.

Multiple imputation to deal with missing EQ-5D-3L data: Should we impute individual domains or the actual index?

PURPOSE: Missing data are a well-known and widely documented problem in cost-effectiveness analyses alongside clinical trials using individual patient-level data. Current methodological research recommends multiple imputation (MI) to deal with missing health outcome data, but there is little guidance on whether MI for multi-attribute questionnaires, such as the EQ-5D-3L, should be carried out at domain or at summary score level. In this paper, we evaluated the impact of imputing individual domains versus imputing index values to deal with missing EQ-5D-3L data using a simulation study and developed recommendations for future practice. METHODS: We simulated missing data in a patient-level dataset with complete EQ-5D-3L data at one point in time from a large multinational clinical trial (n = 1,814). Different proportions of missing data were generated using a missing at random (MAR) mechanism and three different scenarios were studied. The performance of using each method was evaluated using root mean squared error and mean absolute error of the actual versus predicted EQ-5D-3L indices. RESULTS: In large sample sizes (n > 500) and a missing data pattern that follows mainly unit non-response, imputing domains or the index produced similar results. However, domain imputation became more accurate than index imputation with pattern of missingness following an item non-response. For smaller sample sizes (n < 100), index imputation was more accurate. When MI models were misspecified, both domain and index imputations were inaccurate for any proportion of missing data. CONCLUSIONS: The decision between imputing the domains or the EQ-5D-3L index scores depends on the observed missing data pattern and the sample size available for analysis. Analysts conducting this type of exercises should also evaluate the sensitivity of the analysis to the MAR assumption and whether the imputation model is correctly specified.