Abstract
Background: Emicizumab is a novel therapeutic bispecific antibody for treatment of patients with hemophilia A (PWHA) irrespective of FVIII inhibitors. In the phase 3 clinical study of emicizumab focusing on PWHA with inhibitor (-inh) over 12 years old (NEJM2017), several thromboembolic events were reported among participants after multiple infusions of activated prothrombin complex concentrate (APCC) for breakthrough bleeding. We recently reported that the global hemostatic function evaluated by ROTEM was additively enhanced by infusion of APCC under treatment of emicizumab in the Japanese phase 1/2 study (ISTH2017). There exist three forms of emicizumab in the circulating plasma such as i) monomer, ii) binary complex with either FIX(a) or FX, and iii) ternary complex with FIX(a) and FX. According to in vitro experiments, we recently demonstrated that the percent of the ternary complex would be predicted by KD -based simulation based on concentration of emicizumab, FIX(a) and FX (Thromb Haemost. 2017). The in vivo pharmacodynamics of FIX(a) and FX after infusion of APCC in the presence of emicizumab are to be elucidated for confirmation of safety.
Aim: To clarify the relationship between pharmacodynamics of FIX(a) and FX after infusion(s) of APCC and hemostatic potential in the presence of emicizumab.
Methods: We first examined the hemostatic function by addition of emicizumab (0, 10, 50, 100μg/ml) in the citrated blood samples obtained from seven PWHAs-inh (who do not participate in the clinical study) received APCC (80-100U/kg) by thrombin generation assay (TGA) using tissue factor (0.5pM) and ellagic acid (0.3µM) as trigger reagents. The plasma samples were classified by APCC-dosing at collection as summarized in Table. Class A was defined as single or prophylactic administration while class B was defined as treatment with multiple administrations. For patient 7, intra-individual evaluation was examined before (as class A) and after initiation of treatment by APCC (as class B). We further confirmed the in vivo additional effect by APCC to emicizumab in the samples obtained from one PWHA-inh (patient 8) enrolled in the Japanese phase 1/2 study. This patient received four multiple infusions of APCC (~50U/kg, every 12hr) for a major bleeding.
Results: Spike of emicizumab in vitro exhibited a dose-dependent modest increase of PeakTh maximally by ~1.6-fold of that in the absence of emicizumab (212 ± 22.8 nM) in class A. On the other hand in class B, PeakTh augmented dose-dependently on emicizumab (max. to 1,538 ± 38 nM by ~12.5-fold of that in its absence) far beyond normal control (382 nM). As for the samples from patient 8, PeakTh increased from 80.6 nM to 240 nM after 4th infusion of APCC. This increase of PeakTh was less than that in class B (from 122 ± 9.73 nM to 793 ± 29.3 nM) after spike of emicizumab (10µg/ml) which is equivalent to the target concentration in patient 8. To identify the determinant of these different hemostatic enhancing effects, antigen (Ag) levels of FX and FIX(a) in the plasmas were measured by ELISAs. The median values of FX:Ag and FIX(a):Ag were 424nM (~3.1-fold of normal control) and 124nM (~1.4-fold of normal) in class A, and those in class B were 2,000nM (~15-fold of normal) and 278nM (~3-fold of normal), respectively. In the samples of patient 8 from the Japanese phase 1/2 study, FX:Ag increased up to 3.7-fold of normal after 1st administration of APCC and further increased to 7-fold of normal after 4th administration, while FIX(a):Ag was little affected by administrations of APCC different from class B, which would be attributed to that the lower dose of APCC were infused for patient 8 than that for patients in class B. Taken together, dose and/or frequency of APCC infusion(s) seemed to affect the pharmacodynamics of FIX(a) and FX in the plasma. The elevation of both of them, especially FX, resulting in the increase of ternary complex in the presence of emicizumab, contribute to hemostatic enhancement.
Conclusion: In conclusion, high-dose and frequent infusions of APCC contribute to the predominant accumulation of FX accompanied by the increase of FIX(a) in the plasma enhancing the hemostatic effect in the presence of emicizumab, in addition to the bypassing reactions.
Yada: Chugai Pharmaceutical Co.: Research Funding. Nogami: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai Pharmaceutical Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Matsumoto: Chugai Pharmaceutical Co.: Research Funding. Kitazawa: Chugai Pharmaceutical Co.: Employment, Equity Ownership, Patents & Royalties. Shima: Chugai Pharmaceutical Co.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
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