WFH Guidelines for the Management of Hemophilia, 3rd edition

The term bispecific antibody (bsAb) is used to describe a large family of molecules designed to recognize two different epitopes or antigens. BsAbs come in many formats, ranging from relatively small proteins, merely consisting of two linked antigen-binding fragments, to large immunoglobulin G (IgG)-like molecules with additional domains attached. An attractive bsAb feature is their potential for novel functionalities - that is, activities that do not exist in mixtures of the parental or reference antibodies. In these so-called obligate bsAbs, the physical linkage of the two binding specificities creates a dependency that can be temporal, with binding events occurring sequentially, or spatial, with binding events occurring simultaneously, such as in linking an effector to a target cell. To date, more than 20 different commercialized technology platforms are available for bsAb creation and development, 2 bsAbs are marketed and over 85 are in clinical development. Here, we review the current bsAb landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.

Bispecific antibodies: a mechanistic review of the pipeline.

Although its origins date to 2006, the Institute for Clinical and Economic Review (ICER) gained prominence around 2015 when it focused its health technology assessment (HTA) efforts on a new highly effective, though expensive, treatment for hepatitis C. ICER, a small, private organization, seemed to fill a void in the United States because it offered a systematic value assessment approach and made its analyses publicly accessible. Drawing inspiration from England and Wales’ HTA body, ICER has used the quality-adjusted life year (QALY) and cost-effectiveness analysis. That decision gives ICER a powerful approach applicable to a wide range of technologies, but it has also spurred controversy. The organization has responded to criticisms by revising its “value framework.” Changes include separation of budget impact analysis from value determinations, introduction of other value measures beyond the QALY, increasing consideration of contextual elements, and adoption of a “societal perspective” where data support it.

Institute for Clinical and Economic Review

Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study

A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.

Background Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostas...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1803550

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors

Introduction Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis. Aim Describe health-related outcomes in PwHA with inhibitors in HAVEN 1. Methods PwHA with inhibitors aged ≥12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. Results At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ-VAS (-9.7 [-17.6, -1.82]; P = 0.017); and IUS (-0.16 [-0.25, -0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire-specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. Conclusions In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes.

/pdf/the-effect-of-emicizumab-prophylaxis-on-health-related-1f2p0lhmpy.pdf

Willem Bujan

Papers

Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors

The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study.