Abstract
AbstractProphylaxis with emicizumab, a subcutaneously administered bispecific humanized monoclonal antibody, promotes effective hemostasis in persons with hemophilia A (PwHAs). The primary efficacy, safety, and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHAs with/without factor VIII (FVIII) inhibitors who were enrolled in the phase 3 HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies (NCT02622321, NCT02795767, NCT02847637, NCT03020160) have been pooled to establish a long-term efficacy, safety, and pharmacokinetics profile. Across a median efficacy period of 120.4 weeks (interquartile range, 89.0-164.4) (data cutoff 15 May 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval [CI], 1.1-1.7). ABRs declined and then stabilized at <1 in an analysis of 24-week treatment intervals; at weeks 121 to 144 (n = 170), the mean treated ABR was 0.7 (95% CI, 0-5.0). During weeks 121 to 144, 82.4% of participants had 0 treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported no treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participant discontinued because of adverse events beyond the 5 previously described. This data cutoff includes the previously reported 3 thrombotic microangiopathies (one in the PwHA with fatal rectal hemorrhage) and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use, as well as a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHAs of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified.
Highlights
Persons with hemophilia A (PwHAs) have a deficiency in coagulation factor VIII (FVIII), resulting in spontaneous and traumatic bleeding, most commonly into joints, muscles, and soft tissues; intracranial bleeding can be life-threatening.[1,2] Without adequate prophylaxis, recurrent joint bleeding results in hemophilic arthropathy, which is the most serious long-term complication.[3]
400 participants were included in the efficacy analyses; 1 participant in HAVEN 3, who was randomized to the no prophylaxis arm, was lost to follow-up, received no emicizumab treatment, and is not included
In the primary analyses of the HAVEN studies, emicizumab prophylaxis resulted in statistically significant and clinically meaningful reductions in annualized bleed rate (ABR) across bleed-related end points, regardless of age, FVIII inhibitor status, or dosing regimen.[8,9,10]. In this pooled analysis of HAVEN 1-4, ABRs continued to decrease with ongoing emicizumab treatment and were maintained at,1 after 24 weeks of prophylaxis
Summary
Persons with hemophilia A (PwHAs) have a deficiency in coagulation factor VIII (FVIII), resulting in spontaneous and traumatic bleeding, most commonly into joints, muscles, and soft tissues; intracranial bleeding can be life-threatening.[1,2] Without adequate prophylaxis, recurrent joint bleeding results in hemophilic arthropathy, which is the most serious long-term complication.[3]. Emicizumab improves hemostasis by bridging activated FIX and FX to substitute for the function of missing activated FVIII.[6,7] It has been demonstrated to be effective for the prevention of bleeds in PwHAs with or without FVIII inhibitors when administered subcutaneously once weekly, once every 2 weeks, or once every 4 weeks.[8,9,10,11] The efficacy and safety of emicizumab across a broad population of children and adults with hemophilia A, with or without FVIII inhibitors, have been demonstrated in the HAVEN clinical trials (HAVEN 1 [NCT02622321], HAVEN 2 [NCT02795767], HAVEN 3 [NCT02847637], HAVEN 4 [NCT03020160]).[8,9,10,11] During the primary analyses of HAVEN 1-4 (supplemental Table 1, available on the Blood Web site), emicizumab prophylaxis resulted in marked reductions in annualized bleeding rates (ABRs) of treated bleeds, irrespective of FVIII inhibitor status, and the majority of participants (54% to 90%) receiving emicizumab in each study did not report any treated bleeds.[8,9,10,11]
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