This trial will enroll patients with severe hemophilia A. Experiments will be run in vitro by spiking patients\' blood with different molecules (currently used and theoretically proposed as adjunctive therapy to emicizumab), therefore no more than minimal direct risk to patients is expected. This is a pilot preclinical study.

Introduction: The phase 3 XTEND-1 trial (NCT04161495) demonstrated that efanesoctocog alfa prophylaxis provided superior bleed protection compared with pre-trial factor VIII (FVIII) prophylaxis in patients with severe haemophilia A. The aim of this study was to indirectly compare the efficacy of efanesoctocog alfa with non-factor replacement therapy emicizumab in adolescent and adult patients with severe haemophilia A without inhibitors. Methods: A systematic literature review was conducted to identify phase 3 trials of emicizumab. Matching-adjusted indirect comparisons were used to compare annualised bleeding rates (ABRs) for any, treated, joint, and spontaneous bleeds, and joint health (measured using Hemophilia Joint Health Score [HJHS]), between efanesoctocog alfa and emicizumab. Estimated effects for different emicizumab regimens were pooled using random-effect meta-analysis to evaluate the overall difference in bleed outcomes between efanesoctocog alfa and emicizumab. Results: One emicizumab trial was included (HAVEN 3), which investigated three dosing regimens. In meta-analyses, efanesoctocog alfa once-weekly (Q1W) was associated with significantly lower ABRs for any (incidence rate ratio [95% CI] 0.33 [0.20; 0.53]), any treated (0.49 [0.30; 0.80]) and treated joint (0.51 [0.28; 0.91]) bleeds compared with emicizumab Q1W in non-inhibitor patients with prior prophylaxis or on-demand treatment. Efanesoctocog alfa Q1W was also associated with a significantly better improvement from baseline in HJHS Joint Score (mean difference [95% CI] −2.06 [−3.97; −0.14]) and Total Score (−2.37 [−4.36; −0.39]) versus emicizumab Q1W or every 2 weeks. Conclusion: Efanesoctocog alfa prophylaxis was associated with significantly lower rates of any, treated, and joint bleeds and improved joint health compared with emicizumab in patients with severe haemophilia A.

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This open-label, multicenter expanded access program (EAP) is designed to provide emicizumab to eligible participants with hemophilia A with factor VIII (FVIII) inhibitors before it is commercially available in the United States for the indication of hemophilia A with FVIII inhibitors. Discontinuation may occur earlier if participant or physician decides to discontinue treatment or the sponsor discontinues emicizumab clinical development.

Acquired haemophilia is a rare coagulopathy characterized by acquired inhibitors directed against clotting factors resulting in bleeding episodes. A middle-aged woman with HIV developed refractory haemophilia with bleeding episodes resulting in recurrent hospitalizations despite several rounds of bypassing agents and several lines of immunosuppressive agents. She was eventually successfully treated with Emicizumab and has not had any major bleeding episodes for 3 years since initiation of this treatment. Emicizumab, which is a bispecific, FVIII-mimetic therapeutic antibody, has considerably reduced the annualized bleeding rates in congenital haemophiliacs with and without inhibitors and should be considered as an agent for acquired haemophilia to reduce recurrent bleeding episodes and even decrease inhibitor titer.

Clot stability is an important hemostatic aspect in treating patients with hemophilia A (HA). Effects of factor VIII (FVIII), recombinant activated FVII (rFVIIa), FXIII and tranexamic acid on clot stability in hemophilia had been reported . Emicizumab (Emi), FVIIIa-mimicking bispecific antibody, is a recently approved novel therapeutics for HA with inhibitor. Although hemostatic activity of Emi was confirmed by preclinical and clinical studies, whether Emi-driven clot stability is similar to that of FVIII or not remains unknown. Furthermore, in clinical trial of Emi, thrombotic events were reported when high doses of activated prothrombin complex concentrates (aPCC) were used concurrently with Emi. Effect of aPCC on clot stability and its possible association with the thrombotic events should be also clarified. In this study, we investigated the effect of Emi on clot stability with a thromboelastometry (ROTEM) -based assay using tissue plasminogen activator (tPA) as a fibrinolysis trigger, and compared it with that of FVIII or bypassing agents (BPAs). Furthermore, we assessed the effect of BPAs on Emi-driven clot stability. Normal blood from healthy volunteer (n=22) was incubated with anti-FVIII antibody (

FVIII:

C <1 IU/dL), which was regarded as HA model blood. HA model blood was spiked with Emi (50 μg/ml), rFVIIa (22 nM), and aPCC (1 U/ml). ROTEM was performed with/without tPA (2 nM). We used ellagic acid (Elg, x300 INTEM ) as a trigger in addition to tissue factor (TF, 0.5 pM) since TF-trigger was not sensitive to Emi. Residual area under the curve in 30 min (%AR30) was used as a clot stability parameter. Median values (25-75%tile) of %AR30 were compared among the groups with Dunn's multiple comparison test [∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001]. In Elg-trigger ROTEM, %AR30 of HA model blood had no values since coagulation did not occur within test time. However, coagulation was improved in HA model spiked with Emi and its clot stability showed slightly weak value with no statistical significance [50% (30-76), p>0.05] compared to normal blood [75% (56-90)]. Whilst, HA model + rFVIIa [13%∗∗∗ (7-22)] and HA model + aPCC [41%∗∗∗ (20-71)] showed significantly weak values, indicating that effect of Emi on clot stability was comparable to normal blood and better than BPAs in Elg trigger. Concomitant effect of Emi and BPAs were evaluated. Compared to HA model + Emi [50% (30-76)], clot stability increased in the co-presence of Emi and aPCC [99%∗∗∗ (96-101)] but not in that of Emi and rFVIIa [53% (29-78)]. TF trigger, which was sensitive to BPAs but not to Emi, was also used in order to evaluate concomitant effect of Emi and BPAs. In TF trigger, clot stability of HA model blood + Emi [31% (19-47)] was similar to that of HA mode blood [27% (20-44)] or normal blood [32% (22-55)], but increased in HA model + rFVIIa [43%∗∗ (30-62)] and HA model + aPCC [41%∗∗ (29-68)]. rFVIIa increased clot stability of HA model blood in the presence of Emi [56%∗∗ (28-65)] more than its absence. Effect of the aPCC in the presence of Emi [87%∗∗∗ (78-91)] was much more remarkable than that of rFVIIa. In conclusion, effect of Emi on clot stability in HA model blood was comparable to that of normal blood, indicating that clot formation under Emi had no qualitative difference with FVIII. Clot stability remarkably increased in Emi in the presence of aPCC, suggesting that hyper clot stability might be one of the reasons of thrombotic events in the concomitant use of Emi and aPCC.

The purpose of the aPCC-emicizumab safety study is to prospectively investigate the safety and hemostatic efficacy of a personalized dose of aPCC in children and adults with hemophilia A and inhibitors on emicizumab prophylaxis during acute bleeding events or prior to procedures.

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BACKGROUND:

Emicizumab is a monoclonal antibody approved for prophylaxis against bleeds for people with hemophilia A (PwHA). A systematic review was conducted evaluating the efficacy/effectiveness and the safety of emicizumab as prophylaxis for PwHA compared to prophylaxis with factor VIII (FVIII) or bypassing agents (BPA), respectively in patients without and with inhibitors.

RESEARCH DESIGN AND METHODS:

Database-directed search strategies were performed in Aug/26/2022 and updated in Mar/16/2023. Studies evaluating the prophylaxis with emicizumab versus prophylaxis with FVIII or BPA in PwHA without or with inhibitors, respectively, were selected by two independent reviewers. Data were extracted by two independent reviewers. Annualized bleeding rates for total treated bleeding events (ABR-all) were evaluated by meta-analysis. The quality of studies and certainty of evidence were assessed.

RESULTS:

A total of 11 studies were included. The standard mean differences for ABR-all were -0.6 (95%CI -1.0 to -0.2, p-value = 0.0002), among PwHA without inhibitors, and -1.7 (95%CI -2.4 to -0.9, p-value <0.00001), among PwHA with inhibitors. However, there was moderate heterogeneity in both meta-analyses. The most frequent adverse event was injection site reaction.

CONCLUSIONS:

Emicizumab prophylaxis was superior in reducing the ABR-all when compared with prophylaxis with FVIII or BPA.