PII-106 - POPULATION PK AND PK/PD MODELING OF MARSTACIMAB, AN ANTI-TFPI MONOCLONAL ANTIBODY, IN ADULT AND ADOLESCENT HEMOPHILIA PATIENTS WITHOUT INHIBITORS

S. Nayak¹, A. Suzuki², P. Ravva³, S. Raje³; ¹Pfizer Inc., Cambridge, MA, United States, ²Pfizer Inc., Tokyo, Japan, ³Pfizer Inc., Collegeville, PA, United States.

Background: Hemophilia is an X-linked recessive genetic disorder which is characterized by a reduced ability to form clots in response to bleeds. Marstacimab, an inhibitor of the Tissue Factor Pathway Inhibitor (TFPI, a protein in the extrinsic coagulation pathway) is under clinical development and recently completed a pivotal Phase 3 study in severe Hemophilia A and B patients. A dosing regimen of 150 mg subcutaneous (SC) once-weekly (QW) with a loading dose of 300 mg SC was used in the Phase 3 study (NCT03938792) study.

Methods: A modified Target Mediated Drug Disposition (TMDD) model with non-linear clearance for the drug was developed using single and multiple dose drug and total TFPI data from patient and healthy volunteer populations over a range of doses (NONMEM 7.4). In addition, an Emax PK/PD model was developed to link population PK model-predicted free target (TFPI) concentrations to a key biomarker, peak thrombin and provide dose-justification for an adolescent hemophilic population.

Results: The TMDD was able to describe the marstacimab PK and total TFPI results from both healthy volunteers and hemophilia participants. Weight was identified as the key structural covariate affecting marstacimab PK. No clinically relevant effect of race (Asian vs. non-Asian), anti-drug antibodies (ADA), site of injection, mild renal and mild hepatic impairment was seen on marstacimab PK. No clinically significant difference in adolescent CL compared to adults was observed after adjusting for body weight. Good agreement was seen between observed and model-predicted peak thrombin in adults and adolescents, with no clinically relevant differences between the populations (Figure 1). Although a trend is seen for increase in concentrations with decrease in body weight, similar trends were not seen in peak thrombin or clinical endpoint (Annualized Bleeding Rate); as such no dose modifications are needed based on weight.

Conclusion: A TMDD model with first-order absorption and quasi-steady state approximation characterized marstacimab and total TFPI concentrations well. An Emax model described the relationship between model predicted free TFPI and peak thrombin. The model was used to support the same dosing regimen in the adolescent population as well as a weight-independent (flat) dosing regimen for marstacimab.