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

Abstract

BackgroundEmicizumab (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.MethodsUsing 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.ResultsThe 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.ConclusionsA 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.Electronic supplementary materialThe online version of this article (10.1007/s40262-017-0616-3) contains supplementary material, which is available to authorized users.

Emicizumab: Review of the literature and critical appraisal

“…Utilizing the phase 1‐1/2 study data, population pharmacokinetic and repeated time‐to‐event (RTTE) modelling were carried out by Yoneyama et al to quantitatively delineate the interrelation between the pharmacometrics of emicizumab and the decrease in bleeding incidence. Simulations were then carried out to examine the minimal exposure anticipated to accomplish zero bleeding episodes for 1 year in at least 50% of patients and to decide the dosing regimens to be examined in phase 3 studies.…”

“…Phase 3 investigations with the selected dosing regimens are currently under way. Yoneyama further suggested that a pharmacometric method can substitute for a habitual dose‐finding research in rare illnesses and will consolidate the medication development process …”

Rotational thromboelastometry can predict the probability of bleeding events in a translational rat model of haemophilia A following gene‐based FVIIa prophylaxis

“…18 Large variation was observed in the mean total plasma FVII/ FVIIa levels among rats receiving the same dose of vector genomes/ kg ( Figure 2). However, this does not affect our conclusions as our modelling approach is not limited to prophylactic gene therapy.…”

“…In contrast, Young et al 10 were able to detect a concentration-response relationship of rhFVIIa in only one out of fourteen patients in a multicentre trial evaluating TEG/ROTEM for monitoring efficacy of rhFVIIa. 18 Key benefits of quantifying the relationship between TEG/ROTEM parameters and the probability of having bleeding events may include better monitoring of bleeding risk for patients using a simple laboratory assay and more efficient dose titration of bypassing agents and non-factor products, which ultimately would be of high economic and clinical value. 11,12 The primary efficacy end point in clinical trials of haemophilia is the occurrence of spontaneous bleeding events (event-type data), summarized as annualized bleeding rate (ABR) for statistical evaluation.…”

Miracle of haemophilia drugs: Personal views about a few main players

“…Subsequently, they published in 2017 the long‐term extension data of the phase 1/2 study . Satisfied with these early results, Chugai started a novel collaboration with the Big Pharma Roche and Genentech, and developed together a new pharmacometric approach to estimate the optimal dose of emicizumab, thereby avoiding a conventional dose‐finding study and accelerating clinical development. Using the dosing regimen so identified, Genentech, Roche and Chugai decided to perform multinational phase 3 studies (HAVEN 1‐4) that started in 2015.…”