An Investigational Dosing Algorithm of Emicizumab for Prophylaxis in Acquired Hemophilia a
Authors: Shima Midori , Nagami Sayaka , Yoneyama Koichiro , Nomura Akira , Ogawa Yoshiyuki , Amano Kagehiro , Nogami Keiji 
Published: November 2020

INTRODUCTION:
Emicizumab is a bispecific antibody that mimics the cofactor function of activated factor VIII and is currently indicated for routine prophylaxis of bleeds in patients with congenital hemophilia A (CHA) regardless of factor VIII (FVIII) inhibitor status. Nonclinical investigations suggest that emicizumab would be efficacious for preventing bleeds also in patients with acquired hemophilia A (AHA) (J Thromb Haemost 2020;18:825-33). However, no dedicated investigations have been performed to explore the optimal dosing algorithm of emicizumab for AHA. We present herein a proposed dosing algorithm of emicizumab potentially appropriate for AHA.
METHODS:
The dose selection for AHA aimed to achieve trough levels of plasma emicizumab concentration (Ctrough) of &gt;30 μg/mL in most patients, at which the effect of emicizumab for preventing bleeds is expected to be almost maximized as in patients with CHA (Res Pract Thromb Haemost 2019;3[Suppl 1]:315). Because the time spent with a high risk of bleeding in AHA is much shorter than in CHA due to the immunosuppressive therapy (IST) given to eradicate FVIII inhibitors (a reported median is 31 days [Blood 2015;125:1091-7]), and because bleeding symptoms in AHA can be severer than in CHA, the loading dose duration of 4 weeks for the current approved subcutaneous dosing regimens of emicizumab for CHA (i.e., 3 mg/kg once weekly [QW] for first 4 weeks [loading dose] followed by 1.5 mg/kg QW, 3 mg/kg every 2 weeks, or 6 mg/kg every 4 weeks from the 5th week onwards [maintenance dose]) was considered too long to maximize the effect of emicizumab in AHA. In addition, the potential risk of hypercoagulation associated with coexistence of emicizumab and FVIII restored as a consequence of successful IST was concerning. Modification of the loading dose together with definition of an appropriate timing for the dosing completion of emicizumab were therefore considered necessary.
Exploration of a modified dosing regimen was performed by pharmacokinetic (PK) simulations using a population PK model developed in patients with CHA (Clin Pharmacokinet 2020 Jun 5) with the covariates adjusted for patients with AHA. The given dose per administration was capped at the maximum one approved for CHA. The dosing frequency of the maintenance dose was set to QW, aiming to keep the maximum plasma emicizumab concentration at steady state low for minimizing the potential risk of hypercoagulation after FVIII activity is restored. Development of the dosing completion criteria for emicizumab was addressed by a literature review.
RESULTS:
A modified subcutaneous dosing regimen of 6 mg/kg and 3 mg/kg on the 1st and 2nd days of the 1st week, respectively (loading dose), followed by 1.5 mg/kg QW from the 2nd week onwards (maintenance dose) was found to meet the defined requirements for AHA. With the modified dosing regimen, the median Ctrough was predicted to achieve &gt;30 μg/mL by the 2nd week and to reach steady state by the 3rd week, which would allow for rapider maximization and stabilization of the effect of emicizumab than with the current approved QW dosing regimen (Figure). However, there remained uncertainty in the PK predictions in association with the older age and severer disease conditions in AHA than in CHA, which may require further adaptation of the dosing regimen in case of insufficient exposure or efficacy.
In reference to the lower limit of the normal range of FVIII activity and the definitions of partial remission employed in previous researches, an endogenous FVIII activity of &gt;50 IU/dL measured in the absence of interference by emicizumab was selected for a criterion for guiding the dosing completion of emicizumab. In addition, taking into account a standardized definition of a bleeding event (J Thromb Haemost 2014;12:1935-9) together with the bleeds in AHA possibly occurring even if FVIII is restored, absence of using coagulation factor products for &gt;72 hours after the last episodic use of coagulation factor products was considered as another dosing completion criterion to be met.
CONCLUSIONS:
A dosing algorithm of emicizumab potentially appropriate for prophylaxis in AHA was proposed leveraging literature information and PK simulations. The appropriateness of the selected dosing regimen together with the developed dosing completion criteria is currently under investigation with possibility of data-driven adaptations in a clinical study (AGEHA; JapicCTI-205151).

Disclosures
Shima: Patents related to anti-FIXa/FX bispecific antibodies: Patents & Royalties; Chugai Pharmaceutical Co. , Sanofi, Bayer, Sysmex: Speakers Bureau; Chugai Pharmaceutical Co., F. Hoffmann-La Roche Ltd, BioMarin, Bayer, Sanofi: Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co.: Consultancy; Chugai Pharmaceutical Co. , F. Hoffmann-La Roche Ltd, Sanofi, CSL Behring, KM Biologics, Novo Nordisk, Shire/Takeda: Research Funding; Chugai Pharmaceutical Co.: Honoraria. Nagami:Chugai Pharmaceutical Co., Ltd.: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Yoneyama:Chugai Pharmaceutical Co., Ltd.: Current Employment, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies. Nomura:Chugai Pharmaceutical Co., Ltd.: Current Employment. Ogawa:Chugai Pharmaceutical Co., Ltd.: Consultancy; Bayer AG: Research Funding. Amano:Pfizer Inc.: Speakers Bureau; Novo Nordisk A/S: Speakers Bureau; F. Hoffmann-La Roche Ltd.: Research Funding; CSL Behring: Speakers Bureau; Japan Blood Products Organization: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; KM Biologics Co., Ltd.: Research Funding, Speakers Bureau; Sanofi S.A.: Speakers Bureau; Bayer AG: Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Speakers Bureau. Nogami:Chugai Pharmaceutical Co., Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of patents related to anti-FIXa/FX bispecific antibodies, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire Plc: Research Funding, Speakers Bureau; Bioverativ Inc.: Research Funding, Speakers Bureau; Novo Nordisk A/S: Research Funding, Speakers Bureau; Bayer AG: Research Funding, Speakers Bureau.

OffLabel Disclosure:
Emicizumab for acquired hemophilia A