Concomitant Use of rFVIIa and Emicizumab in People with Hemophilia A with Inhibitors: Current Perspectives and Emerging Clinical Evidence

Figures & data

Table 1 Drugs for Treatment of Patients Affected by Hemophilia A with Inhibitors

	Emicizumab	aPCC	rFVIIa
Mechanism of action	Bispecific antibody mimicking FVIIIa	Increase of prothrombinase complex activity by supplying multiple factor products	Activation of extrinsic coagulation pathway
Dose: on demand	n.a.	50–100 U/kg every 6–12 h until hemostasis	90–120 μg/kg every 2–3 h until hemostasis; used also as a single megadose of 270 μg/kg
Dose: prophylaxis	1.5 mg/kg per week or 3 mg/kg every 2 week or 6 mg/kg once monthly	85 U/kg 3–5 times per week	90 μg/kg or 270 μg/kg daily
Maximum safe dose	n.a.	100 U/kg per dose; 200 U/kg daily	Individual doses rarely greater than 300 μg/kg
Administration	s.c. injection	Up to 30 min i.v. infusion	2–5 min i.v. infusion
Thrombotic or thromboembolic adverse events	Thrombotic microangiopathy and venous thrombotic events when aPCC is used at ≥100 IU/kg/day for ≥24 hours	Thromboembolic events	Arterial and venous thrombotic events
Laboratory monitoring	Emicizumab interferes with aPTT and aPTT-based assays. One-stage FVIII measurement is not reliable. PT-based or chromogenic assays (bovine reagents for FVIII and inhibitor titration by Bethesda method) are not influenced by emicizumab	No assays clinically validated to determine coagulation status	No assays clinically validated to determine coagulation status

Abbreviations: n.a., not applicable; i.v., intravenous; s.c., subcutaneous; aPTT, activated partial thromboplastin time; PT, prothrombin time.

Table 2 Emicizumab Clinical Program of Phase III Trials in Hemophilia A with Inhibitors

	Study Population	Enrolled Patients	Study Design	Efficacy	Safety
HAVEN 1	Hemophilia A with inhibitors ≥12 years of age	N=113	2 randomized arms 2 non-randomized arms	87% reduction in randomized arm between emicizumab prophylaxis vs no prophylaxis 63% with no treated bleeding	2 thrombotic events 3 thrombotic microangiopathy events 2 anti-drug antibodies 0 neutralizing antibodies
HAVEN 2	Hemophilia A with inhibitors <12 years of age	N=88	Single arm, all patients receiving emicizumab prophylaxis	95% of patients with no treated bleeding 99% bleeding reduction in subset of patients in comparison to prior BPA prophylaxis	0 thrombotic events 0 thrombotic microangiopathy events 4 anti-drug antibodies 1 neutralizing antibodies 1 allergy reaction
HAVEN 4	Hemophilia A with or without inhibitors ≥12 years of age	N=48	Pharmacokinetic trial evaluating an every 4 week dosing regimen	Preliminary data shows that this dosing regimen follows the pre-study pharmacokinetic model, suggesting that this may be an effective alternative dosing regimen	0 thrombotic events 0 thrombotic microangiopathy events 2 anti-drug antibodies 0 neutralizing antibodies

Abbreviation: BPA, bypassing agent.