Journal Article

A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A

Yoneyama, Koichiro, Iida, Satofumi, Shima, Midori, Kawanishi, Takehiko, Kasai, Ryu, Schmitt, Christophe, Kotani, Naoki, Levy, Gallia G.

2018

Overview

Background Emicizumab (ACE910) is a bispecific antibody mimicking the cofactor function of activated coagulation factor VIII. In phase I–I/II studies, emicizumab reduced the bleeding frequency in patients with severe hemophilia A, regardless of the presence of factor VIII inhibitors, at once-weekly subcutaneous doses of 0.3, 1, and 3 mg/kg. Methods Using the phase I–I/II study data, population pharmacokinetic and repeated time-to-event (RTTE) modeling were performed to quantitatively characterize the relationship between the pharmacokinetics of emicizumab and reduction in bleeding frequency. Simulations were then performed to identify the minimal exposure expected to achieve zero bleeding events for 1 year in at least 50% of patients and to select the dosing regimens to be tested in phase III studies. Results The RTTE model adequately predicted the bleeding onset over time as a function of plasma emicizumab concentration. Simulations suggested that plasma emicizumab concentrations of ≥  45 μg/mL should result in zero bleeding events for 1 year in at least 50% of patients. This efficacious exposure provided the basis for selecting previously untested dosing regimens of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks, and 6 mg/kg every 4 weeks for phase III studies. Conclusions A pharmacometric approach guided the phase III dose selection of emicizumab in hemophilia A, without conducting a conventional dose-finding study. Phase III studies with the selected dosing regimens are currently ongoing. This case study indicates that a pharmacometric approach can substitute for a conventional dose-finding study in rare diseases and will streamline the drug development process.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Adolescent / Adult / Antibodies, Bispecific - administration & dosage / Antibodies, Bispecific - pharmacokinetics / Antibodies, Bispecific - therapeutic use / Antibodies, Monoclonal, Humanized - administration & dosage / Antibodies, Monoclonal, Humanized - pharmacokinetics / Antibodies, Monoclonal, Humanized - therapeutic use / Clinical trials / Coagulation / Disease / Dose-Response Relationship, Drug / Drug development / Drug dosages / Factor VIII - antagonists & inhibitors / Factor VIII - immunology / Hemophilia / Hemophilia A - drug therapy / Hemorrhage - prevention & control / Humans / Internal Medicine / Male / Medicine / Medicine & Public Health / Models, Biological / Monoclonal antibodies / Original / Original Research Article / Pharmacology / Pharmacology/Toxicology / Pharmacotherapy / Plasma / Rare Diseases - drug therapy / Young Adult