Cost-effectiveness of emicizumab vs bypassing agents in the prevention of bleeding episodes in haemophilia A patients with anti-FVIII inhibitors in France.

INTRODUCTION: The development of an anti-FVIII inhibitor is the most serious complication of haemophilia A occurring in up to 30% of severe haemophilic patients. The current management of haemophilia A with inhibitor uses bypassing agents (BPA) and represents a significant therapeutic burden together with a limited adherence to prophylactic treatment. Emicizumab is the first monoclonal antibody developed in haemophilia A approved for the prevention of bleeding episodes in patients with anti-FVIII inhibitor. AIM: The purpose of this study is to evaluate the incremental cost-effectiveness ratio (ICER) of emicizumab versus BPAs. METHODS: A Markov model was developed over a five-year time horizon to estimate the comparative costs and benefits of the different therapeutic approaches in this rare disease. Model inputs were clinical, including annual bleeding rate and quality of life, and economical including mainly costs of prophylaxis, bleeds and adverse events. RESULTS: Emicizumab treatment is dominant, ie lest costly and more effective, in the base-case analysis saving 234 191 € for a gain of 0.88 QALY. This is confirmed by both the deterministic and probabilistic sensitivity analyses. The main limit of the study remains the absence of long-term clinical data allowing to relate treatment consumption to clinical benefit, especially in the progression of haemophilic arthropathy. CONCLUSION: Our results show that emicizumab is a cost-effective treatment allowing to consider an easy to implement prophylactic treatment for haemophilia A patients with anti-FVIII inhibitors.

Effectiveness and cost of contraception in France (FACET study): a cohort study from the French National Healthcare Insurance Database.

OBJECTIVE: To assess the effectiveness and costs associated with contraceptive methods based on real-world data in France. STUDY DESIGN: A cross-sectional cohort study based on data from a representative sample of the French National Healthcare Insurance Database (Echantillon Généralistes des Bénéficiaires (EGB)) was performed between January 1st 2006 and December 31st 2012. Women aged 15 years or older and users of at least one reimbursed contraceptive method between January 1st 2012 and December 31st 2012 were selected. The outcome of interest was unintended pregnancy, defined as pregnancies occurring after at least one month since the dispensation of a contraceptive method. The mean annual costs of contraceptive methods (in 2012 Euros) were collected in the database from a health system perspective. Costs were expressed for the first year of use, considering the next years of use and taking into account or not the cost of unplanned pregnancies. RESULTS: A population of 48,090 women representative of the 4,664,730 French women with a reimbursed contraceptive method was identified in the EGB in 2012: 68.6% used at least one reimbursed oral contraception (OC), 30.2% used at least one intrauterine devices (IUD) (LGN-IUS 52 mg, 17.6%; copper, 13.1%) and 5.1% used at least one etonogestrel implant. Unplanned pregnancies rates ranged from 0.6% with LNG-IUS 52 mg and 0.8% with the etonogestrel implant to 4.8% with 1st and 2nd generation combined OCs. The mean annual costs of contraception for the first year of use ranged from €145 for 1st-2nd generation combined oral contraceptions (COCs) to €308 for LNG-IUS 52 mg taking into account the next years of use, the etonogestrel implant was associated with the lowest mean annual cost (€88). When costs of unplanned pregnancies were taken into account, the mean annual cost of contraception for the first year of use was lower for progestin-only OC (€251) and copper IUD (€257) compared to etonogestrel implant (€300) and LNG-IUS 52 mg(€323). CONCLUSION: This real-world study suggests that Long-acting reversible contraceptives (LARCs) (i.e. implant and IUDs) should be considered for a broader use to prevent unplanned pregnancies and related abortions in France both from a public health and economic perspective.

Cost analysis of adverse events associated with non-small cell lung cancer management in France.

BACKGROUND: Adverse events (AEs) related to medical treatments in non-small cell lung cancer (NSCLC) are frequent and need an appropriate costing in health economic models. Nevertheless, data on costs associated with AEs in NSCLC are scarce, particularly since the development of immunotherapy with specific immune-related AEs. OBJECTIVE: To estimate the costs of grades 3 and 4 AEs related to NSCLC treatments including immunotherapy in France. METHODS: Grades 3 and 4 AEs related to treatment and reported in at least 1% of patients in Phase III clinical trials for erlotinib, ramucirumab plus docetaxel, docetaxel, pemetrexed plus carboplatin plus bevacizumab, platinum-based chemotherapies, nivolumab and pembrolizumab were identified. When no cost evaluation was reported in literature, estimates on standard treatments and medical resource use for each AE were obtained thanks to an expert panel. Total cost per AE was calculated from a French national health insurance perspective and updated in 2017 Euros. Hospital stay costs were estimated based on public and private weighted tariffs and data from the French Medical Information System (Programme de Médicalisation des Systèmes d'Information). Costs of tests, consultations and treatments were calculated based on national reimbursement tariffs. RESULTS: Overall, costs of grades 3 and 4 AEs related to treatment ranged from €46 per event to €7,742 per year. Fourteen out of 24 AEs identified had a mean estimated cost over €2,000. The highest mean costs were related to type 1 diabetes (€7,742 per year) followed by pneumonitis (€5,786 per event), anemia (€5,752 per event), dehydration (€5,207 per event) and anorexia (€4,349 per event). Costs were mostly driven by hospitalization costs. CONCLUSION: Among the AEs identified, a majority appeared to have an important economic impact, with a management cost of at least €2,000 per event mainly driven by hospitalization costs. This study may be of interest for economic evaluations of new interventions in NSCLC.

TREM2 mutations are rare in a French cohort of patients with frontotemporal dementia.

Homozygous mutations in TREM2 have been recently identified by exome sequencing in families presenting with frontotemporal dementia (FTD)-like phenotype. No study has evaluated the exact frequency of TREM2 mutations in cohorts of FTD patients so far. We sequenced TREM2 in 175 patients with pure FTD, mostly French, to test whether mutations could be implicated in the pathogenesis of the disease. No disease-causing mutation was identified in 175 individuals from the French cohort of FTD patients. We did not identify the polymorphism p.R47H (rs75932628), strongly associated with an increased risk of developing Alzheimer's disease. We conclude that TREM2 mutations are extremely rare in patients with pure FTD, although further investigation in larger populations is needed.

Dual functions of the Hsm3 protein in chaperoning and scaffolding regulatory particle subunits during the proteasome assembly.

The 26S proteasome, a molecular machine responsible for regulated protein degradation, consists of a proteolytic core particle (20S CP) associated with 19S regulatory particles (19S RPs) subdivided into base and lid subcomplexes. The assembly of 19S RP base subcomplex is mediated by multiple dedicated chaperones. Among these, Hsm3 is important for normal growth and directly targets the carboxyl-terminal (C-terminal) domain of Rpt1 of the Rpt1-Rpt2-Rpn1 assembly intermediate. Here, we report crystal structures of the yeast Hsm3 chaperone free and bound to the C-terminal domain of Rpt1. Unexpectedly, the structure of the complex suggests that within the Hsm3-Rpt1-Rpt2 module, Hsm3 also contacts Rpt2. We show that in both yeast and mammals, Hsm3 actually directly binds the AAA domain of Rpt2. The Hsm3 C-terminal region involved in this interaction is required in vivo for base assembly, although it is dispensable for binding Rpt1. Although Rpt1 and Rpt2 exhibit weak affinity for each other, Hsm3 unexpectedly acts as an essential matchmaker for the Rpt1-Rpt2-Rpn1 assembly by bridging both Rpt1 and Rpt2. In addition, we provide structural and biochemical evidence on how Hsm3/S5b may regulate the 19S RP association to the 20S CP proteasome. Our data point out the diverse functions of assembly chaperones.