PB0671 - Analysis of F8 Genotypes and Pharmacodynamic and Safety Biomarkers in People with Moderate or Mild Hemophilia A Receiving Emicizumab in the HAVEN 6 Trial

Monday, July 11, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: In-Person

Presenting Author(s)

Anna Kiialainen, PhD

Senior Scientist
F. Hoffmann-La Roche Ltd.
Basel, Basel-Stadt, Switzerland

Co-Author(s)

CN

Claude Negrier

Professor
Louis Pradel University Hospital, Claude Bernard University Lyon 1
Lyon, Auvergne, France
Steven W. Pipe, MD

Professor of Pediatrics and Pathology
University of Michigan, Ann Arbor, MI, USA
Ann Arbor, Michigan, United States
BB

Benjamin M Beckermann

Senior Clinical Scientist
F. Hoffmann-La Roche Ltd.
Basel, Basel-Stadt, Switzerland
OC

Olivier Catalani

Senior Statistical Scientist
F. Hoffmann-La Roche Ltd.
Basel, Basel-Stadt, Switzerland
CS

Christophe Schmitt

Clinical Pharmacologist
F. Hoffmann-La Roche Ltd.
Basel, Basel-Stadt, Switzerland
Cédric Hermans, Professor

Professor, Head of Hematology
Cliniques Universitaires Saint-Luc
Brussels, Brussels Hoofdstedelijk Gewest, Belgium
JO

Johannes Oldenburg

Director of the Institute of Experimental Haematology and Transfusion Medicine
University Clinic Bonn, Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany
Bonn, Berlin, Germany
ML

Michaela Lehle

Global Development Leader, Hematology
F. Hoffmann-La Roche Ltd.
Basel, Basel-Stadt, Switzerland

Background: Emicizumab, a bispecific antibody that substitutes for missing or deficient activated factor (F)VIII, demonstrated a favorable safety and efficacy profile in people with moderate/mild hemophilia A (HA) in the HAVEN 6 trial (Negrier, et al. Blood 2021).

Aims: To present: a F8 genetic analysis of people with moderate/mild HA; pharmacodynamics (PD) of emicizumab; and exploratory safety biomarkers in people receiving emicizumab, in HAVEN 6 (NCT04158648).

Methods: Informed consent and ethics committee approval were obtained. F8 coding regions and exon/intron boundaries were sequenced (Sanger sequencing) and rearrangements analyzed using inverse-shifting PCR. Variants were mapped against the EAHAD F8 database, ClinVar, and gnomAD. For PD, a chromogenic FVIII activity assay containing human factors, two thrombin generation (TG) assays (triggered by FXIa and tissue factor [TF]), and activated partial thromboplastin time (aPTT) were used. Endogenous FVIII was measured using a chromogenic FVIII activity assay containing bovine factors, and FVIII antigen concentration using ELISA. Plasma levels of the safety biomarkers fibrinogen, prothrombin fragment 1.2, and D-dimer were determined.

Results: F8 genetic analysis was conducted in 67 participants. Overall, one rearrangement and 64 unique short variants were identified: 13 benign, 42 likely pathogenic/unclassified, and nine novel. After excluding benign variants, most participants (81%) had one missense F8 variant.
PD and safety biomarkers were assessed in 72 participants throughout emicizumab exposure (median 54.3 weeks; data cut-off 30 October 2021). PD markers demonstrated emicizumab activity in addition to endogenous FVIII. Mean FVIII-like activity and TG peak height increased during loading and were maintained throughout exposure, but were below normal ranges. aPTT was normalized after first emicizumab dose. Endogenous FVIII activity, antigen levels, and safety biomarker concentrations were unaffected by emicizumab.

Conclusion(s): Identified F8 mutations were consistent with mutations in people with moderate/mild HA. Emicizumab improved coagulation parameters without showing abnormal signs of interaction with endogenous FVIII or affecting safety biomarkers.