Authors' objectives: The academic technology assessment group (ATAG) reviewed a report on the additional benefit and cost-effectiveness of Inclisiran (Novartis Pharma K.K.) for patients with non-familial hypercholesterolemia (non-FH) and familial hypercholesterolemia (FH) with insufficient response to maximum-tolerated HMG-CoA reductase inhibitors. This report summarizes the results of the review and reanalysis by the ATAG. The target population was classified into four groups: (a) non-FH patients with a history of atherosclerotic cardiovascular disease (ASCVD) for whom treatments with evolocumab selfadministration are difficult for inevitable reasons such as limited physical or cognitive functions; (b) non-FH patients with ASCVD not categorized as the population (a); (c) FH patients with ASCVD; and (d) FH patients without ASCVD. The comparator was standard of care (SoC) in the population (a), and evolocumab + SoC in the populations (b)-(d). In evaluating the additional benefits of inclisiran, the manufacturer defined LDL-cholesterol (LDL-C) change and treatment discontinuation/adherence as outcomes. Regarding LDL-C change, while the systematic review conducted by the manufacturer identified randomized controlled trials (RCTs) comparing inclisiran to placebo and evolocumab to placebo, no RCT directly comparing inclisiran to evolocumab was identified. For the population (a), they used only the subgroup results of ORION-15, a trial for Japanese non-FH patients and concluded that inclisiran provided additional benefit through a significant reduction in LDL-C. For the population (b)- (d), they conducted network meta-analyses (NMA) with the placebo groups as common treatments. Although the NMAs did not show statistically significant superiority of inclisiran over evolocumab in LDL-C reduction, the manufacturer concluded inclisiran had additional benefits in populations (b)-(d) by also taking into account treatment discontinuation/adherence, based on an observational study of treatment discontinuation/adherence using medical claims data in the US. The ATAG considered LDL-C change was appropriate as an outcome for evaluating additional benefit. Regarding LDL-C changes, the SR by the ATAG identified the same clinical trials as the manufacturer. For the population (a), the academic group performed a meta-analysis of five RCTs (ORION-1, 10, 11, 15, 18) comparing inclisiran and placebo while the manufacturer used only ORION-15, since it is a phase two trial and no differences in the efficacy of inclisiran were observed by ethnicity. As a result, inclisiran significantly reduced LDL-C compared to placebo, indicating an additional benefit over SoC. For the populations (b)-(d), the ATAG did not perform NMAs due to heterogeneity between trials of inclisiran and evolocumab, but instead conducted pairwise meta-analyses comparing each drug to placebo using the same trials as the manufacturer. These results did not demonstrate that inclisiran was superior to evolocumab, and the ATAG concluded that there were no additional benefits of inclisiran over evolocumab for the populations (b)-(d). The manufacturer conducted cost-effectiveness analyses using a Markov model that predicted reductions in baseline cardiovascular event risk and then estimated cardiovascular-related deaths, direct medical costs, and health-related quality of life from LDL-C changes. The ATAG revised the parameters of direct medical costs after cardiovascular events and the efficacy parameter for inclisiran. For the populations (b)-(d), the ATAG conducted cost-minimization analyses. As a result, for the population (a), the base-case analysis showed that inclisiran led to an incremental cost of JPY 3,265,420 and 0.453 quality-adjusted life years (QALYs) gained compared to SoC, resulting in an incremental cost-effectiveness ratio (ICER) of JPY 7,212,577 per QALY. For the populations (b)-(d), inclisiran had an additional cost of JPY 781,886 compared to evolocumab. In conclusion, these results suggest that the ICERs for inclisiran compared to the comparators are likely to belong to the interval between JPY 5 and 7.5 million per QALY in the population (a), and inclisiran are likely to be "cost increase" in the populations (b)-(d) from the perspective of public healthcare payers in Japan.

Project Status: Completed

URL for project: https://c2h.niph.go.jp/en/

Year Published: 2025

URL for published report: https://c2h.niph.go.jp/en/results/C2H2305.html

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: Japan

Organisation Name: Center for Outcomes Research and Economic Evaluation for Health

Contact Address: 2-3-6 Minami, Wako-shi, Saitama 351-0197 Japan

Contact Name: Takeru Shiroiwa

Contact Email: t.shiroiwa@gmail.com