Which Level of Emicizumab Is Necessary for a Good Hemostasis?

Introduction

Emicizumab is a recombinant, humanized, bispecific antibody restoring the function of missing activated factor VIII (FVIII) by bridging activated FIX (FIXa) and zymogen factor X (FX), medicating the activation of FX. Emicizumab is approved in several countries, at the doses of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks, for the prophylaxis of bleeding episodes in patients with hemophilia A with and without inhibitors. The drug has shown a good efficacy either during registration studies as well as in real-world experiences and was well tolerated without significant side effects. The development of neutralizing anti-emicizumab antibodies has been reported in very few cases which frequently required the switch to other products due to inefficacy of the prophylaxis. Patients maintaining a plasma concentration range of the drug within 30-80 ug/ml did not show significant bleeds. However, real life experiences bring the need of personalization of the drug dose. A recent case series presented at ISTH 2021 from Malaysian authors evaluated the efficacy of a dose of emicizumab between 1.7 and 1.9 mg/kg every 4 weeks, showing that even at a lower dose than that approved could be effective for the prevention of bleeding events. Here we report the case of an adult patient with moderate hemophilia A with inhibitor who developed an anti-emicizumab antibody which reduced the concentration of the drug by 50%. Despite that the patient did not report bleeding events in a follow-up period of 18 weeks. Treatment with emicizumab requires further evaluation to understand the best dose for the prevention of bleeding.

Case report

A 74 years old patient with moderate hemophilia A (FVIII 1-3%) followed at our Center had history of high-titer inhibitor (maximum titer 20 BU). The patient was treated on-demand with plasma-derived FVIII concentrates, when, in Jul 2000, he developed a neutralizing anti-FVIII antibody requiring treatment with activated prothrombin complex concentrates (Feiba). In Nov 2020 the patient was hospitalized for traumatic brain hemorrhage treated with plasma-derived FVIII (inhibitor titer < 5 BU) and subsequently, for the recurrence of inhibitor, with activated prothrombin complex concentrates. In Feb 2021 the patient started prophylaxis with emicizumab at the initial dose of 3 mg/kg once weekly (loading dose), followed by a maintenance dose of 1.5 mg/kg. The patient underwent periodic blood withdrawal for monitoring drug plasma concentration. In Apr 2021 (week 10) drug concentration showed a slight decrease from initial levels, from 39.1 ug/ml (week 5) to 28.3 (week 10) and a weak positivity for an anti-emicizumab antibody was detected. At the following test (week 15) positivity for the anti-emicizumab antibody was confirmed, witnessed by the consistent reduction in drug plasma concentration up to 20.9 ug/ml. During the following weeks, until week 22, drug plasma concentrations were stable (range 17.0-19.4 ug/ml) and positivity for anti-emicizumab antibody remained, as shown in the table. The results of partial Thromboplastin Time (PTT) were consistent with the drug plasma concentrations during the observation period, in which the patient did not developed any bleeding event.

Conclusion

This case report may corroborate the hypothesis of the efficacy of a reduced dose of emicizumab in patients with hemophilia A. Close laboratory monitoring in patients in prophylaxis with emicizumab is warranted for the evaluation of drug plasma concentration and the prompt detection of anti-drug antibodies, particularly if patient show a reduced therapeutic efficacy. However, in the absence of bleeding events, positivity for anti-emicizumab antibodies should not bring to sudden drug discontinuation. Indeed, in the view of the above, a lower drug plasma concentration than standard might be effective in the prevention of bleeding.

1. Tang ASO et al. July 2021. Efficacy of Reduced-dose Emicizumab in Haemophilia A with Inhibitors: Real World Experience in East Malaysia. ISTH 2021.

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