OC 24.1 - Effect of the type of F9 mutation on the pharmacokinetic profile of patients with hemophilia B treated with extended half-life FIX concentrates.

Sunday, June 25, 2023

14:45 – 15:00 ET

Room: 520

Session Available As: On-Demand

Presenting Author(s)

Davide Matino, MD (he/him/his)

Assistant Professor
Department of Medicine, Division of Hematology, McMaster University, Hamilton, ON
Hamilton, Ontario, Canada

Co-Author(s)

PC

Pierre Chelle, PhD

Research Associate
University of Waterloo
Waterloo, Ontario, Canada
Shannon Jackson, MD (she/her/hers)

Hematologist, Providence Health Care
Providence Hematology, St. Paul’s Hospital, Vancouver, BC, Canada
Vancouver, British Columbia, Canada
Jerome Teitel, MD

Professor
St Michael's Hospital Haemophilia Treatment Centre, University of Toronto
Toronto, Ontario, Canada
Giancarlo Castaman, MD

Medical Director
Center for Bleeding Disorders and Coagulation, Careggi University Hospital, Florence, Italy
Florence, Toscana, Italy
AK

Arun Keepanasseril

Assistant Professor
Department of Health Research Methods, Evidence, and Impact (HEI), McMaster University, Hamilton, Canada
Hamilton, Ontario, Canada
EI

Emma Iserman

Statistical Analyst
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON
Hamilton, Ontario, Canada
David Lillicrap, MD

Professor
Department of Pathology and Molecular Medicine, Queen's University
Kingston, Ontario, Canada
Anthony KC. Chan, MBBS

Professor
McMaster University, McMaster Children’s Hospital, Hamilton, Canada
Hamilton, Ontario, Canada
AI

Alfonso Iorio

Professor
Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON
Hamilton, Ontario, Canada

Background: Previous pharmacokinetic (PK) studies have demonstrated that a significant extravascular distribution of FIX in both pre-clinical models and in hemophilia B (HB) patients can occur. Genotyping of hemophilia patients showed that a significant proportion carry missense mutations resulting in circulating, dysfunctional FIX protein (cross-reacting material; CRM). FIX can bind to type IV collagen in the subendothelial extracellular matrix in the extravascular space. In murine HB models the presence (CRM+) or absence (CRM-) of dysfunctional FIX can impact the PK (and in turn hemostatic efficacy) of the therapeutic FIX. We hypothesized that the PK parameters of EHL FIX products that have a significant (rFIX-Fc) or negligible (N9-GP) extravascular distribution might be differently influenced by the presence of FIX antigen in the extravascular space.

Aims: To investigate the effect of F9 mutations on the PK profile of patients treated with EHL FIX concentrates.

Methods: Bayesian PK estimates on patients > 12 yo from participating Canadian centers were extracted from the WAPPS-Hemo database. Genetic mutations for the same patients were obtained for the same patients from the Canadian Bleeding Disorders Registry. Patients with missense mutations were classified as CRM+, all the others were considered CRM-. Differences in PK parameter distributions between CRM+ and CRM- groups were analyzed by non-parametric Wilcoxon test.

Results: A total of 69 individual PK studies were available for analysis. Clearance, Terminal half-life, In vivo recovery, and Volume of distribution were all significantly reduced in CRM- patients that received rFIX-Fc (Fig. 1). No statistically significant differences were found between patients receiving N9-GP (Fig. 1).

Conclusion(s): Patients with F9 missense mutations may express levels of FIX antigen that could compete with the exogenous FIX and influence PK parameters. This phenomenon may not take place when a FIX product with an exclusive intravascular distribution is administered.

Learning Objectives:

Discuss the relationship between F9 gene mutations and circulating FIX antigen in HB patients
Describe the association between F9 gene mutation and key PK parameters in hemophilia B patients receiving EHL FIX concentrates
Summarize the current understanding of FIX pharmacokinetics and main differences among the available EHL FIX products