OC 21.1 - Novel FVIIIa-mimetic molecule with the potential to be the first oral treatment for severe hemophilia A

Sunday, June 23, 2024

14:45 – 15:00 ICT

Room: Ballroom B1

Presenting Author(s)

Jacob Lund, PhD

Principal Scientist, Rare Blood Disorders, Rare Disease Research
Novo Nordisk A/S, Måløv, Denmark
Måløv, Hovedstaden, Denmark

Co-Author(s)

JB

Jais R. Bjelke

Principal Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
DG

Daniele Granata

Specialist Modelling Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
TE

Thomas Egebjerg

Principal Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
EJ

Eva Johansson

Principal Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
WZ

Wang Zhuoran

Sr Scientist II
Novo Nordisk A/S
Beijing, Beijing, China (People's Republic)
PB

Pierre-Louis Bardonnet

Principal Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
PC

Pingping Chen

Sr Scientist
Novo Nordisk A/S
Beijing, Beijing, China (People's Republic)
MB

Mads Bjelke

Principal Scientist
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark
AV

Andreas Vegge

Project Vice President
Novo Nordisk A/S
Bagsvaerd, Hovedstaden, Denmark

Background: The FVIIIa-mimetic approach has enabled subcutaneous prophylactic treatment of hemophilia A (HA) with weekly to monthly dosing frequency, reducing the treatment burden for patients. An orally available treatment may constitute the next frontier in the management of severe to moderate HA, eliminating injections altogether. However, oral delivery of large molecules constitutes a great technical challenge and requires extensive optimization of potency, biophysical properties and formulation. Novo Nordisk is developing Inno8, a novel VHH-based FVIIIa-mimetic molecule with ultra-high potency to enable once-daily oral treatment of HA.

Aims: To develop the first ever oral FVIIIa mimetic treatment for hemophilia A

Methods: In vitro potency was assessed using thrombin generation assay with HA plasma and thromboelastography with FVIII-neutralized healthy whole blood. Inno8 was formulated with sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) for peroral delivery. Oral absorption and systemic plasma half-life were estimated in beagle dogs.

Results: Inno8 was made by connecting two heavy-chain only VHH fragments recognizing human FIXa and FX, respectively, followed by extensive protein engineering to enhance the in vitro potency. With a total molecular weight of approximate 30 kDa, Inno8 is five times smaller than an IgG antibody. Inno8 was further engineered to bind human serum albumin in circulation thereby extending the plasma half-life. Using in vitro global hemostatic assays, Inno8 was demonstrated to achieve similar in vitro activity as the sequence-identical analogue of emicizumab at approximately 90-fold lower concentrations (figure 1). Moreover, Inno8 was shown to be orally available and exhibited a long systemic half-life of approximately 113 hours in beagle dogs. The Inno8 profile may thus allow for prophylactic once-daily oral treatment of HA.

Conclusion(s): Inno8 is a novel, small FVIIIa-mimetic bi-domain antibody with ultra-high potency, long plasma half-life and oral absorption demonstrating potential as the first ever oral treatment of severe HA.