INTRODUCTION:

Emicizumab-kywh (ACE910) is a recombinant, humanized, asymmetric bispecific antibody that functions to bring activated FIX (FIXa) and zymogen FX into an appropriate steric conformation to medicate the activation of FX to FXa thereby mimicking the cofactor function of FVIIIa.

AIM:

The objective of this manuscript was to review the development and potential role for emicizumab in the treatment of patients with haemophilia A with and without inhibitors.

METHODS:

A Cochrane Library and PubMed (MEDLINE) search focusing on emicizumab in haemophilia was conducted.

RESULTS:

In total, 37 citations were retrieved and serve as the database for the literature reviewed herein. Once-weekly subcutaneous injection of emicizumab at three dose levels has been shown to be effective as prophylaxis to prevent bleeding in a majority haemophilia A patients with inhibitors to FVIII. Likewise, prevention of bleeding was also observed in more than two thirds of patients without inhibitors to FVIII. One antidrug antibody to emicizumab has been reported in over 600 treated patients, two have developed thromboembolic events and three thrombotic microangiopathy. These thrombotic complications have occurred in conjunction with FVIII-bypassing agents, and none have been observed following recommendations from the manufacturer regarding concomitant use of bypassing agents. The median annual treated bleeding rates were decreased in patients with as well as those without an inhibitor to FVIII.

CONCLUSION:

The principal advantage of emicizumab is subcutaneous administration and effectiveness irrespective of the presence of inhibitors. Emicizumab could conceivably represent a new epoch in the treatment of people with haemophilia A.

Background Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies that inhibit coagulation factor VIII (FVIII). The disorder is understudied given its rarity and there are no randomized prospective trials to guide therapy. In practice, treatment involves attaining hemostasis and eliminating the FVIII inhibitor, typically with high-dose steroids (1 mg/kg daily) and either cyclophosphamide or rituximab. However, current approaches carry risk of significant adverse events and delayed or inadequate responses. Emicizumab is a bispecific antibody that targets coagulation factors IXa and X to recapitulate the function of endogenous FVIII. We present a case series of patients with acquired hemophilia A who were successfully treated with a regimen consisting of rituximab and emicizumab. Methods We identified patients >18 years who were diagnosed with acquired hemophilia A and received treatment with rituximab and emicizumab at Brigham and Women's Hospital between 2019 and 2020. We performed a retrospective chart review. Data collected included the patients’ clinical presentation, laboratory studies (including coagulation testing, FVIII activity, and FVIII inhibitor titer), and treatments received (including systemic therapies, recombinant factor VIIa [rFVIIa], red blood cell [RBC] transfusions, and vascular embolization). We recorded the time to normalization of the activated partial thromboplastin time (aPTT) and chromogenic FVIII activity following emicizumab and rituximab initiation, respectively. Activated prothrombin complex concentrate was avoided given the use of emicizumab. Results We identified 8 patients with acquired hemophilia A who received treatment with emicizumab and rituximab. The median patient age was 81 (range 47-93). All patients sought medical attention for extensive ecchymoses or bleeding and were found to have prolonged aPTT leading to FVIII inhibitor identification (Table 1). The median inhibitor titer was 18 Bethesda units (range 9.2-107.5). Patients concurrently received 4 weekly doses of rituximab 375mg/m2 and 4 weekly loading doses of emicizumab 3mg/kg. Patient (Pt) #1 continued emicizumab 3mg/kg every two weeks to complete three months of treatment. Pts #2, #3, and #8 received high-dose prednisone (1mg/kg) at the start of treatment for a range of 10-14 days. Pt #8 received 7 additional days of prednisone for an initial aPTT of 60.7 seconds before starting emicizumab and rituximab; she had no clinical response when treated with prednisone alone. Pts #2, #5, and #7 required vascular embolization. 7 patients (Pts #2 through #8) had aPTT retested within 1 week of starting emicizumab, and the aPTT for these patients normalized within 10 days of starting emicizumab (i.e. after only 1-2 doses; Figure 1). Except for Pt #5 who had recurrent hematuria from a persistent anatomic bladder defect that eventually required prostatic artery embolization, patients did not require rFVIIa or RBC transfusions for more than 7 days after starting emicizumab. Except for Pt #5 who required 28 doses of rFVIIa and 3 units of RBC transfusions after starting emicizumab, the median number of rFVIIa doses and RBC units given to the remaining 7 patients was zero (range 0-6 doses) and zero (range 0-4 units), respectively. Pts #2 and #3 had chromogenic FVIII levels obtained >30 days after starting rituximab with improvement in FVIII activity to 29% (day 71) and 86% (day 91), respectively. During a median follow-up of 102 days, no patients experienced recurrent bleeding. However, Pt #3 exhibited a slowly increasing aPTT that reached 46.3 seconds on day 233 of follow-up without symptoms; further diagnostic testing is pending. Conclusion Our case series demonstrates that the combination of rituximab and emicizumab can be an effective and safe regimen for the treatment of acquired hemophilia A. No thrombotic events or thrombotic microangiopathy occurred. Treatment with weekly emicizumab led to aPTT normalization after 1-2 doses and facilitated hemostasis, as reflected by a median usage of zero rFVIIA doses and zero RBC transfusions after starting emicizumab when excluding one patient with hematuria from an anatomic defect. This compares favorably to historical reports. While no patient has had recurrent bleeding, additional chromogenic FVIII activity testing for patients is needed to confirm long-term normalization of FVIII activity. [Formula presented] Disclosures: Gibson: Ampressa therapeutics: Current equity holder in private company; nference: Consultancy, Current equity holder in private company; ImmPACT-Bio: Consultancy; Boston Clinical Research Institute: Consultancy. Parnes: Bayer: Consultancy; I-Mab: Consultancy; Sunovion: Consultancy; UniQure: Consultancy; Sigilon: Consultancy; Shire/Takeda: Consultancy, Research Funding; Genentech: Research Funding; Geron: Current equity holder in publicly-traded company. OffLabel Disclosure: Emicizumab is used off-label in our case series for the treatment of acquired hemophilia A.

One of the most serious complications of the treatment of severe haemophilia A is the development of alloantibodies against exogenous factor VIII (FVIII). Inhibitors render factor replacement therapy ineffective, exposing patients to a remarkably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in newer haemostatic therapies that are not based on the replacement of the deficient FVIII. This review will focus on the most interesting among these innovative therapies, emicizumab, and will provide an update on its current stage of clinical development.

This study is an international, multicenter, open-label, single arm, prospective clinical trial and will evaluate the efficacy of prophylactic emicizumab administered on a scheduled basis to prevent bleeds in patients with acquired hemophilia A (AHA).

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INTRODUCTION:

Emicizumab is an effective new treatment option for people with hemophilia A (PwHA). The approved dosing regimens are based on body weight, without the necessity for laboratory monitoring. This assumes a clear dose-concentration-response relationship, with acceptable variability due to factors other than body weight. To investigate this assumption, a systematic review on the pharmacokinetics (PK) and associated efficacy of emicizumab in humans was conducted.

METHODS:

The EMBASE, Pubmed and CENTRAL databases were systematically searched to November 2020 to identify studies on the PK data of emicizumab in humans. Data on the study, population, PK and efficacy (annualized bleeding rate of treated [joint] bleeds) were extracted and synthesized, and exposure effects modeling was performed using non-linear least squares regression in a maximum effect (Emax) model.

RESULTS:

The 15 included studies reported on data for 140 volunteers and 467 PwHA, including children (0 to <12 years) and adolescents and adults (≥12 years), both with and without factor VIII (FVIII) inhibitors. Emicizumab demonstrated dose-linear PK. The interindividual variability of trough concentrations was moderate (32%) and was similar across various subgroups, such as FVIII inhibitor status, age group and dosing interval. The control of bleeds did not further improve above emicizumab concentrations of 30 µg/mL, potentially enabling lower dosing in a substantial proportion of PwHA.

CONCLUSION:

This review supports body weight-based dosing, although individualized monitoring of emicizumab concentrations may allow for more cost-effective dosing.

<b>

BACKGROUND:

</b>Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.<b>

METHODS:

</b>We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C.<b>

RESULTS:

</b>A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected.<b>

CONCLUSIONS:

</b>Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

The goal of this multicentre, prospective, open-label, cross-over clinical study is to determine whether individualized PK-guided dosing of emicizumab is non-inferior to conventional dosing of emicizumab in the prevention of bleeding in congenital haemophilia A patients.

This is a phase II multicenter open-label, single-arm prospective study to evaluate the efficacy of prophylactic emicizumab administered on a scheduled basis to prevent bleeds in patients with acquired hemophilia A (AHA).

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