OC 69.4 - Safety, Pharmacokinetics, and Pharmacodynamics of Single Subcutaneous Injection of NXT007, an Emicizumab-Based Next-Generation Bispecific Antibody, in Healthy Volunteers (NXTAGE Study)

Wednesday, June 28, 2023

11:00 – 11:15 ET

Room: 517

Session Available As: Live-Stream and On-Demand

Presenting Author(s)

Midori Shima, MD, PhD

Dean
Thrombosis and Hemostasis Research Center, Nara Medical University, Kashihara, Japan
Kashihara, Nara, Japan

Co-Author(s)

TS

Takehiko Sambe

Clinical Research Center for Clinical Pharmacology & Therapeutics, Tokyo, Japan
Showa University
Tokyo, Tokyo, Japan
TM

Takuya Miwa

Early Clinical Development Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
Koichiro Yoneyama, MSc

Pharmaceutical Science Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
TI

Takaaki Ishida

Pharmaceutical Science Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
RO

Ryoto Ozaki

Biometrics Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
TY

Taigi Yamazaki

Clinical Research Center for Clinical Pharmacology & Therapeutics, Tokyo, Japan
Showa University
Tokyo, Tokyo, Japan
SK

Shinichi Kobayashi

Clinical Research Center for Clinical Pharmacology & Therapeutics, Tokyo, Japan
Showa University
Tokyo, Tokyo, Japan

Background: NXT007 is a bispecific antibody that mimics the cofactor function of activated factor VIII and was engineered and optimized based on emicizumab. Nonclinical investigations suggested its potential to provide non-hemophilic level of coagulation activity to people with hemophilia A (PwHA). A phase I/II clinical study of NXT007 in healthy volunteers (HVs) and PwHA is currently ongoing (NXTAGE; JapicCTI-194919).

Aims: To evaluate safety, pharmacokinetics, and pharmacodynamics of NXT007 in HVs.

Methods: Forty Japanese male HVs were enrolled in Part A of NXTAGE which consisted of five cohorts. In each cohort, eight subjects were randomized to receive a single injection of NXT007 (N=6; 0.0018, 0.0054, 0.018, 0.054, or 0.18 mg/kg) or placebo (N=2) subcutaneously under a blinded condition. Informed consent and ethics committee approval were obtained.

Results: NXT007 exposure increased dose-dependently. Mean elimination half-life was approximately 10 weeks in anti-NXT007 antibody (ADA)-negative subjects. With ex vivo neutralization of endogenous factor VIII in plasma samples, activated partial thromboplastin time was shortened and thrombin generation was promoted in a dose-dependent manner. The incidence of adverse events (AEs) was comparable between the overall NXT007 groups (17 of 30 subjects, 56.7%) and the placebo groups (6 of 10 subjects, 60.0%). There were no dose-dependent increases in the incidence of AEs and no thromboembolic events. One SAE of erythema whose causality to NXT007 could not be ruled out was reported in the 0.0054 mg/kg group. Nine subjects developed ADAs; all of them were considered associated with faster clearance of NXT007 with no impact on safety.

Conclusion(s): Single subcutaneous doses of NXT007 were well tolerated without thromboembolic events. The long half-life, pharmacological effect, and safety supported the study progress to the subsequent parts. Evaluation of safety, efficacy, pharmacokinetics, and immunogenicity on multiple dosing expected to achieve non-hemophilic level of coagulation activity in PwHA is ongoing.

Learning Objectives:

Evaluate the data of NXT007, an Emicizumab-Based Next-Generation Bispecific Antibody, in healthy volunteer.
Recognize the characteristics of NXT007, an Emicizumab-Based Next-Generation Bispecific Antibody, in healthy volunteer.
Discuss the potential of NXT007, an Emicizumab-Based Next-Generation Bispecific Antibody, as a future therapeutic option.