OC 66.2 - Characterizing the Relationship between Milvexian Exposure, Efficacy, and Safety in Total Knee Replacement Patients to Support Milvexian Phase 3 Dose Selection.

Tuesday, June 25, 2024

15:00 – 15:15 ICT

Room: 111 A-C

Presenting Author(s)

Wangda Zhou, PHD

Associate Director Pharmacometrics
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine
Spring House, Pennsylvania, United States

Co-Author(s)

EB

Emily Bozenhardt

Sr. Scientist Pharmacometrics
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine
Spring House, Pennsylvania, United States
SM

Samira Merali

Sr. Director
Clinical Pharmacology and Pharmacometrics, Bristol Myers Squibb
Princeton, New Jersey, United States
PZ

Peter Zannikos

Scientific Director
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine
Spring House, Pennsylvania, United States
HB

Hyunmoon Back

Associate Director
Clinical Pharmacology and Pharmacometrics, Bristol Myers Squibb
Princeton, New Jersey, United States
AA

Antoinette Ajavon-Hartmann

Director
Clinical Pharmacology and Pharmacometrics, Bristol Myers Squibb
Princeton, New Jersey, United States
JS

John Strony

Sr. Director
Global Clinical Development of CVM, Johnson and Johnson Innovative Medicine
Raritan, New Jersey, United States
AP

Alexei Plotnikov

Sr. Clinical Program Head
Global Clinical Development of CVM, Johnson and Johnson Innovative Medicine
Raritan, New Jersey, United States
AL

Alistair Lindsay

VP Portfolio Development Lead Milvexian
Global Clinical Development of CVM, Johnson and Johnson Innovative Medicine
Raritan, New Jersey, United States
NG

Navin Goyal

Sr. Director CVM PA
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine
Raritan, New Jersey, United States
MS

Mahesh N. Samtani

Sr. Director
Clinical Pharmacology and Pharmacometrics, Johnson and Johnson Innovative Medicine
Spring House, Pennsylvania, United States

Background: Factor XI is a promising target for the development of anticoagulants with reduced bleeding and similar if not better efficacy compared to other available antithrombotic agents. Milvexian, an oral factor XIa inhibitor, is currently being evaluated for the prevention and treatment of major thrombotic conditions.

Aims: The relationship between milvexian exposure in subjects undergoing total knee replacement (TKR) and the primary clinical efficacy (prevention of venous thromboembolism [VTE]) and safety (bleeding) endpoints was characterized.

Methods: A population pharmacokinetic model (PopPK) was developed with milvexian PK data from a Phase 2 TKR study and multiple Phase 1 healthy volunteer studies utilizing a non-linear mixed-effects modeling approach. The model allowed characterization of milvexian disposition and estimating exposures at the individual patient level. Subsequently, the relationship between clinical efficacy (e.g. total VTE) as well as safety (e.g. total bleeding or clinically relevant non-major [CRNM] bleeding) and milvexian exposure was evaluated by logistic regression analysis.

Results: The PK of milvexian in TKR patients was well characterized with a 2-compartment PK model with linear elimination. The exposure-response analysis suggests that an increase in milvexian exposure is associated with lower probability of total VTE (Figure 1). There was no meaningful relationship between any (or CRNM) bleeding and milvexian exposure over the range of doses evaluated in the TKR study (25mg QD to 200mg BID).

Conclusion(s): The unique exposure-response relationship of clinical efficacy and safety endpoints favorably distinguishes milvexian from previously studied direct oral anticoagulants. These analyses play a critical role in support of the dose selection for the milvexian Phase 3 program.