VPB0170 - Correlation of Factor VIII Activity Measured by One-Stage Clotting and Chromogenic Substrate Assays in a Phase III Study of Emicizumab Prophylaxis for Acquired Hemophilia A (AGEHA)

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

Koichiro Yoneyama, MSc

Pharmaceutical Science Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan

Co-Author(s)

KT

Kazuo Tokuda

Pharmaceutical Science Dept.
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
RO

Ryoto Ozaki

Biometrics Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
RK

Ryota Kobayashi

Specialty Clinical Development Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
YO

Yuki Oguchi

Primary Lifecycle Management Dept.
Chugai Pharmaceutical Co., Ltd.
Tokyo, Tokyo, Japan
Anna Kiialainen, PhD

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

Kagehiro Amano

Professor
Department of Laboratory Medicine, Tokyo Medical University
Tokyo, Tokyo, Japan
Midori Shima

Dean
Thrombosis and Hemostasis Research Center, Nara Medical University, Kashihara, Japan
Kashihara, Nara, Japan

Background: Emicizumab is a bispecific antibody mimicking the cofactor function of activated factor (F) VIII. In a phase III study of emicizumab in patients with acquired hemophilia A (PwAHA) (AGEHA), endogenous FVIII activity was monitored and restoration to >50 IU/dL was employed as a criterion for guiding completion of emicizumab prophylaxis. A one-stage clotting assay with emicizumab neutralization by adding anti-emicizumab antibodies (OSAwEN) was used for the measurement.

Aims: To assess whether chromogenic substrate assays using bovine or human coagulation factors (bCSA or hCSA) can be alternative methods for OSAwEN to measure FVIII activity for guiding completion of emicizumab prophylaxis in PwAHA.

Methods: FVIII activity was measured by OSAwEN, bCSA, and hCSA in AGEHA, and their correlations were evaluated. AGEHA was conducted in accordance with relevant ethical standards.

Results: When >50 (I)U/dL was defined as a positive result, bCSA and hCSA provided positive, negative, and overall percent agreements of ≥80% with OSAwEN (Table). A linear simple regression estimated a slope slightly above 0.9 for OSAwEN values against bCSA values. Given the reactivity of emicizumab in hCSA, a linear multiple regression was performed incorporating plasma emicizumab concentrations (Cemi) in addition to OSAwEN values as predictor variables against hCSA values, estimating a slope slightly below 0.9 for OSAwEN values. bCSA and hCSA were predicted to have Pearson’s correlation coefficients of ≥0.9 with OSAwEN and to derive 51.8 and 53.7 U/dL, respectively, corresponding to 50 IU/dL for OSAwEN in the absence of emicizumab. Add-on effect of emicizumab in hCSA was predicted to correspond to approximately 15 U/dL with the observed mean steady-state trough Cemi slightly above 35 μg/mL in AGEHA (Figure).

Conclusion(s): bCSA and hCSA showed good correlations with OSAwEN and may be applicable to measure FVIII activity for guiding completion of emicizumab prophylaxis in PwAHA. However, add-on effect of emicizumab should be considered when interpreting hCSA values.