Author(s): Tiffany Chang, MD, MAS, Genentech, Inc.; Charles R.M. Hay, MbChB, MD, FRCP, FRCPath, UK National Haemophilia Database and Manchester Royal Infirmary; Fabian Sanabria, MD, F. Hoffmann-La Roche Ltd; Flora Peyvandi, MD, PhD, IRCCS Ca Granda Foundation, Ospedale Maggiore Policlinico; Glenn F. Pierce, MD, PhD, World Federation of Hemophilia; Johnny N. Mahlangu, BSc, MBBCh, University of the Witwatersrand and NHLS; Richard H. Ko, MD, MHS, MS, Genentech, Inc.; Peter Kuebler, PharmD, Genentech, Inc.; Rebecca Kruse-Jarres, MD, University of Washington and Washington Center for Bleeding Disorders, Bloodworks Northwest; Steven W. Pipe, MD, University of Michigan

Research Category: Clinical Research/Clinical Trials

Description:

Objective:

The treatment landscape of hemophilia is evolving at an unprecedented pace and non-factor replacement therapies offer the prospect of improved efficacy, improved quality of life and decreased treatment burden. However, compared to traditional clotting factor concentrates, the experience with safety profiles with newer agents can belimited, and may differ. Post-marketing safety reports often lack key contextualizing details making safety data interpretation complex. We aim to provide a contemporary understanding of causes of death in PwcHA and a framework allowing for the consistent interpretation of safety events and meaningful analyses of mortality trends of current and forthcoming hemophilia therapeutics.

Methods:

We analyzed known causes of mortality in PwcHA through a systematic literature review, an analysis of the FDA Adverse Event Reporting System (FAERS) database, and expert clinical insights; the Centers for Disease Control and Prevention and World Health Organization provided leading causes of death in the US and worldwide non-hemophiliac populations. These were assembled into an algorithm for assessing fatalities in PwcHA.

Summary:

Life expectancy and causes of mortality in PwcHA have evolved towards approximating the general male population, yet are still not the same. PwcHA share mortality risks with the general population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and suicide. PwcHA also retain unique risks associated with complications from hemophilia or associated treatment, including hemorrhage, thrombosis, human immunodeficiency virus (HIV), hepatitis C virus (HCV), and liver dysfunction. Traditionally, thrombosis has been thought to pose a low mortality risk in PwcHA, though the evidence surrounding this has been inconsistent. Notably, as PwcHA are living longer, thrombotic risks are becoming more widely recognized. We propose a framework consisting of two overarching categories: hemophilia A-associated mortality and non-hemophilia A-associated mortality and an algorithm for categorizing fatalities into the aforementioned classes (figure).

Conclusions:

The introduction of non-factor replacement therapies has the potential to positively impact overall survival as well as impact the previously recognized causes of death in PwcHA in the coming decades. A conceptual framework for cross-examining mortality in PwcHA receiving any hemophilia therapy is needed to fully interpret reported fatalities in PwcHA and is expected to enable a new baseline for retrospective, as well as prospective analyses. Crucial factors required for a complete assessment of HA fatalities have been identified and can be used to provide guidance on future reporting of these events. Importantly, this presents a rare opportunity to document the public health impact of innovation in drug development.