OC 07.4 - HMB-001, a bispecific anti-FVIIa/anti-TLT-1 antibody, demonstrates effect in models of FVII deficiency

Saturday, June 24, 2023

13:45 – 14:00 ET

Room: 524

Session Available As: On-Demand

Presenting Author(s)

Henrik Ostergaard, PhD

Vice President Research
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark

Co-Author(s)

PF

Paolo Ferraresi

Research Technician
University of Ferrara, Department of Life Sciences and Biotechnology
Ferrara, Emilia-Romagna, Italy
MB

Marcello Baroni

Assistant Professor
University of Ferrara, Department of Life Sciences and Biotechnology
Ferrara, Emilia-Romagna, Italy
ET

Elena Tonetto

Ph.D. student
University of Ferrara, Department of Life Sciences and Biotechnology
Ferrara, Emilia-Romagna, Italy
AC

Amalie Carnbring Bonde

Research Scientist
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
Catherine J. Rea, MA, PhD

Medical Director
Hemab Therapeutics
41 King George Square, Richmond, England, United Kingdom
Minka Zivkovic, MSc

Ph.D. candidate
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands
Rolf T. Urbanus, PhD

Associate professor
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Utrecht, Utrecht, Netherlands
JF

Johan H. Faber

Co-founder & CTO
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark
BS

Benny Sorensen

CEO
Hemab Therapeutics
Cambridge, Massachusetts, United States
MP

Mirko Pinotti

Professor
University of Ferrara, Department of Life Sciences and Biotechnology
Ferrara, Emilia-Romagna, Italy
FB

Francesco Bernardi

Professor
University of Ferrara, Department of Life Sciences and Biotechnology
Ferrara, Emilia-Romagna, Italy
PG

Prafull S. Gandhi

Scientific Director
Hemab Therapeutics
Copenhagen, Hovedstaden, Denmark

Background: HMB-001 is a bispecific antibody with a mode of action relying on accumulation of endogenous FVIIa and delivery of bound FVIIa to activated platelets at sites of vascular injury. FVIIa localization is mediated by the simultaneous binding of HMB-001 to the TLT-1 receptor on activated platelets resulting in enhanced downstream thrombin generation. HMB-001 is currently being investigated in a Phase 1/2, first-in-human, clinical trial for its safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy in patients with Glanzmann Thrombasthenia. By enriching FVIIa at sites of vascular injury, we hypothesized that HMB-001 could also represent a subcutaneous prophylactic treatment option for FVII deficient patients with residual levels of functional protein and retained HMB-001 binding.

Aims: Investigate key mechanistic features of HMB-001 in models of FVII deficiency.

Methods: Binding of HMB-001 to recombinant FVII deficiency-causing variants was explored with ELISA-based assays using HMB-001 as secondary antibody. A PK/PD study was performed in cynomolgus monkey with HMB-001 and FVII/FVIIa quantification through ELISA and activity assays.

Results: A panel of 17 FVII variants from the EAHAD database were selected based on high prevalence, association with a moderate/severe clinical phenotype and proximity to the HMB-001 binding site. Among these, 12 were secreted at detectable levels upon expression and, noticeably, all were found to be recognized by HMB-001 at a clinically relevant concentration. With confirmed binding, we then explored in cynomolgus monkey the ability of HMB-001 to accumulate FVII/FVIIa from baseline levels mimicking FVII deficiency. Using siRNA, circulating FVII was initially knocked down to 10-30% residual levels followed by administration of HMB-001. Initial data from this study demonstrated a time-dependent accumulation of total FVII/FVIIa in plasma upon exposure to HMB-001.

Conclusion(s): HMB-001 demonstrates ability to bind prevalent FVII deficiency-causing variants and to accumulate FVII/FVIIa under conditions of impaired endogenous synthesis, positioning HMB-001 as a potential prophylactic therapy for FVII deficiency.

Learning Objectives:

Upon completion, participants will be able to understand the mechanism of action of HMB-001, a bispecific anti-FVIIa/anti-TLT-1 antibody with the ability to accumulate endogenous FVIIa and deliver it to the activated platelet to restore haemostasis
Upon completion, participants will understand the mode of binding of HMB-001 to coagulation FVII in relation to the location of the most prevalent FVII-deficiency causing mutations
Upon completion, participants will be familiar with the ability of HMB-001 to accumulate FVIIa under conditions mimicking FVII deficiency achieved through siRNA-mediated knock-down in cynomolgus monkey