Original Title: Réévaluation d’Hemlibra (émicizumab) – Hémophilie de type A sans inhibiteur

Authors' objectives: As requested by the manufacturer, the Institut national d’excellence en santé et en services sociaux (INESSS) proceeded to re-evaluat emicizumab (Hemlibra™), a bispecific monoclonal antibody indicated in Canada for hemophilia A (congenital factor VIII deficiency) patient with or without factor VIII inhibitors as routine prophylaxis to prevent bleeding or reduce the frequency of bleeding episodes. The requested indication for the re-evaluation is as follows: “For routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients of all ages with hemophilia A (congenital factor VIII deficiency), graded as severe or moderate, without factor VIII (FVIII) inhibitors:  Patients with severe hemophilia A who display trough FVIII levels of < 0,01 IU/ml or < 1% the normal concentration;  Patients with moderate hemophilia A who display trough FVIII levels of < 0,01 0,05 IU/ml or 1-5% the normal concentration and experience at least 4 spontaneous bleeding events per year; AND  Patients who cannot receive FVIII prophylaxis because of inappropriate venous access or an important limitation regarding adherence to FVIII prophylaxis.” Emicizumab was previously evaluated by INESSS (April and December 2019 reports) and is listed on the Liste des produits du système du sang du Québec for the following indication : “For routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients of all ages with hemophilia A (congenital factor VIII deficiency) with factor VIII (FVIII) inhibitors”. This is the second evaluation for the population of type A hemophilia without inhibitors. In the previous evaluation, INESSS issued an unfavourable recommendation since the therapeutic value of emicizumab was not recognized for this population. The recombinant FVIIIs Advate™, Adynovate™, Eloctate™, EsperoctTM, Kovaltry™, Nuwiq™, Xyntha™ (including Xyntha Solofuse™) and Zonovate™, all of which are listed on the Liste des produits du système du sang du Québec, were used as comparators. Nuwiq™ and Zonovate™ are currently distributed by Héma-Québec, and Eloctate™ is available under an MSSS directive.

Authors' results and conclusions: Efficacy results come from two new studies as well as two studies reported in the previous evaluation. • According to the network meta-analysis provided, the efficacy of emicizumab prophylaxis (both the every 7 and every 14 days regimens) to prevent treated bleeds is superior to FVIII prophylaxis. However, the weak methodological quality of the study, as well as the various biases make it impossible to assess this conclusion. • Two intraindividual comparisons, both encompassing a non-interventional phase of FVIII prophylaxis, suggested that emicizumab offers a better protection than FVIII against bleeds. Considering the risk of bias of the non-interventional phase, it is not possible to assess the efficacy of emicizumab over FVIII. Safety New safety data were gathered from a post-market report and an unpublished manuscript. The safety data from the product monograph and clinical studies evaluated in the precedent evaluation were also considered. • The most common adverse reactions (≥ 1%) observed in clinical studies were injection site reaction (21%), joint pain (16%), headache (14%), fever (6%), diarrhea (5%) and muscle pain (4%). • Ever since the warning was issued concerning the use of high doses of activated prothrombin complex concentrate (aPCC) for the treatment of breakthrough bleeding in patients treated with emicizumab, no thrombotic events linked to emicizumab have been reported. • Since the FDA authorized emicizumab in 2018, severe adverse events (including deaths and thrombotic events) have been reported post-marketing. Quality of life No new quality of life data were provided. The data from the previous evaluation were considered. • The available data on FVIII prophylaxis is insufficient to determine the impact of emicizumab on quality of life.

Authors' recommendations: In light of the available data, INESSS cannot recognize Hemlibra™ for the following indication: routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with moderate or severe hemophilia A (congenital factor VIII deficiency) without factor VIII (FVIII) inhibitors. It therefore recommends that this indication not be included in the list of products for Québec’s blood system. Comparative data of better methodological quality and relevant to the hemophilia context in Québec, and answers to the above-mentioned safety concerns raised are required to support the assessment of this drug’s therapeutic value in the proposed indication.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/reevaluation-dhemlibramc-emicizumab-hemophilie-de-type-a-sans-inhibiteur-mise-a-jour-de-la-liste-des-produits-du-systeme-du-sang-du-quebec-mars-2021.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/reevaluation-dhemlibramc-emicizumab-hemophilie-de-type-a-sans-inhibiteur-mise-a-jour-de-la-liste-des-produits-du-systeme-du-sang-du-quebec-mars-2021.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: L'Institut national d'excellence en sante et en services sociaux (INESSS)