321.

BLOOD COAGULATION AND FIBRINOLYTIC FACTORS: POSTER II | NOVEMBER 29, 2018

Efficacy of Anti-TFPI Antibody PF-06741086 Alone and

in Combination with Activated Prothrombin Complex
Concentrates in Mouse Hemophilia a Bleeding Model
*,1 1 1 1
Amey Barakat, Reema Jasuja, PhD, John E. Murphy, PhD, Debra D Pittman, MS
1
Rare Disease Research Unit, Pfizer Inc., Cambridge, MA

Blood (2018) 132 (Supplement 1) : 2460.

http://doi.org/10.1182/blood-2018-99-118431

Abstract
BACKGROUND: Tissue Factor Pathway inhibitor (TFPI) is a plasma serine protease inhibitor that
modulates the initiation of coagulation by directly binding and inhibiting the Tissue Factor (TF)/Factor VIIa/
Factor Xa complex. TFPI is a multi-Kunitz domain protein that directly binds to and inhibits both activated
Factor Xa (FXa) and FVIIa. Blocking TFPI can act as a bypass therapy by facilitating hemostasis initiated
by tissue factor/FVIIa, thereby, compensating for loss of Factor VIII or Factor IX (in hemophilia A or B).
PF-06741086, a fully human antibody engineered to inhibit TFPI, exhibits broad cross reactivity to TFPI
from numerous species, including mouse. PF-06741086 is being developed as a potential treatment for
bleeding disorders including hemophilia A and hemophilia B with and without inhibitors. aPCC (activated
Prothrombin complex concentrates or FEIBA, Factor Eight Inhibitor Bypass Agent) is a bypass agent for
to control bleed in Hemophilia patients with inhibitors. Since it is a plasma-derived concentrate containing
various prothrombin complex coagulation factors in their enzymatic or zymogen form, it is possible that
FEIBA could potentially impact the activity of PF-06741086.

AIMS: Here, we directly compare the hemostatic effect of PF-06741086 alone, and in combination with
aPCC in Hemophilia A mouse model using severe tail vein transection.

METHODS: Male hemophilia A mice were dosed with a single intravenous dose of PF-06741086 (0.5,
1, 2 or 6 mg/kg) 30 minutes prior to a 3mm tail clip, or aPCC (50, 100 or 200 U/kg) was administered
5 minutes before the tail clip. Mice were also treated with a combined dose of 0.5 mg/kg anti-TFPI
PF-06741086 and aPCC at 50, 100 or 200 U/kg. Blood was collected for 10 minutes and quantified
against a standard curve of hemoglobin as volume blood loss.
RESULTS: PF-06741086 demonstrated a dose dependent response in improving hemostasis in
Hemophilia A mice after tail clip. PF-06741086 was able to restore hemostasis at 1 mg/kg (49%),
and higher doses further improved hemostasis at 2 mg/kg (63%), and 6 mg/kg (78%). aPCC also
demonstrated a dose dependent reduction in blood loss and improved hemostasis with all tested doses of
50 U/kg (25%), 100 U/kg (23%) and 200 U/kg (66%). At a dose of 0.5 mg/kg, PF-06741086 did not show
any improvement in hemostasis over vehicle control. We used this dose for all combination studies with
aPCC. Combined use of low dose PF-06741086 (0.5 mg/kg) and 100 U/kg aPCC shows a trend towards
improvement in hemostasis compared to either drug alone. A higher dose of aPCC (200 U/kg) combined
with low dose PF-06741086 (0.5 mg/kg) significantly reduces blood loss (86%) in Hemophilia A mice in
tail clip model compared to saline, TFPI or aPCC alone used at the same dose of 0.5 mg/kg or 200 U/kg
respectively.

CONCLUSIONS: Prophylactic administration of PF-06741086 exhibits a dose response and improves

hemostasis in an injury model in Hemophilia A mice. The addition of aPCC alone restores hemostasis at
200 U/kg and this effect was enhanced in combination with PF-06741086 in this mouse model.

Disclosures

Barakat: Pfizer: Employment. Jasuja: Pfizer: Employment. Murphy: Pfizer: Employment. Pittman:
Pfizer: Employment.

Author notes
* Asterisk with author names denotes non-ASH members.

© 2018 by the American Society of Hematology