OC 50.5 - Mim8 is associated with improved thrombin generation vs. emicizumab in patients with haemophilia A, with and without inhibitors

Tuesday, July 12, 2022

11:45 AM – 12:00 PM

Location: ExCel Center, ICC Auditorium

Presentation Format: In-Person

Presenting Author(s)

Jerzy Windyga, MD, PhD

Professor
Department of Hemostasis Disorders and Internal Medicine, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Warsaw, Mazowieckie, Poland

Co-Author(s)

Pratima Chowdary, MD

Consultant Haematologist
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, United Kingdom
London, England, United Kingdom
Francisco José López Jaime, MD

Hematologist
Hemostasis and Thrombosis Unit, Regional University Hospital of Málaga, IBIMA, Málaga, Spain.
Málaga, Andalucia, Spain
CE

Christian Winther Eskelund

International Medical Manager
Novo Nordisk A/S
Søborg, Hovedstaden, Denmark
PJ

Pernille Juul Jørgensen

Senior Statistician
Novo Nordisk A/S
Søborg, Hovedstaden, Denmark
MK

Mads Kreilgaard

Principal Scientist
Novo Nordisk A/S
Søborg, Hovedstaden, Denmark
Johnny Mahlangu, MD, MMed

Professor in Haematology
University of the Witwatersrand and NHLS
Johannesburg, South Africa

Background: Factor VIII (FVIII) replacement is the standard of care for patients with haemophilia A (HA). Mim8 is a bispecific antibody bridging factor IXa/X (FIXa/FX), with enhanced haemostatic properties in vitro and in HA mouse models, compared with emicizumab. FRONTIER1 (NCT04204408) is a phase 1/2 study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of subcutaneous Mim8 in healthy participants and patients with severe HA, independent of FVIII inhibitor status.

Aims: We report on peak thrombin generation, and laboratory markers in response to Mim8 or emicizumab.

Methods: The phase 2 part of FRONTIER1 is open-label, with Mim8 administered subcutaneously over 12 weeks, across four multiple ascending dose cohorts, targeting average plasma exposure of 1–9 µg/ml, through dosing weekly (cohorts 1–3) or every four weeks (cohort 4); cohorts 3/4 targeted the same plasma exposure. FRONTIER1 is ongoing with a fifth ascending dose cohort. An additional cohort of patients treated with emicizumab was included for comparison. Informed consent and ethics committee approval were acquired.

Results: 32 patients on Mim8 (cohorts 1 [n=7], 2 [n=9], 3 [n=8], and 4 [n=8]) and 10 on emicizumab were included. Peak thrombin levels increased with Mim8 dose, at lower plasma concentrations than with emicizumab, indicating higher potency for Mim8 (Figure 1). Mean peak thrombin levels were comparable between patients on emicizumab and Mim8 in cohort 2. No dose-dependent changes in D-dimer, fibrinogen, platelets, or FIXa/FX antigen levels were observed; most values remained within the normal range. A relative increase in prothrombin fragments 1 and 2, with stabilisation at steady state, was seen for both Mim8- and emicizumab-treated patients, in correlation with the respective thrombin peak increase.

Conclusion(s): A dose-dependent increase in thrombin generation was observed in Mim8-treated patients, reaching higher peak thrombin levels than in emicizumab patients. Laboratory parameters showed no signs of exaggerated coagulation.