Redefining prophylaxis in the modern era Mahlangu, Johnny N.; Blanchette, Victor; Klamroth, Robert
Haemophilia : the official journal of the World Federation of Hemophilia,
February 2021, 2021-Feb, 2021-02-00, 20210201, Letnik:
27, Številka:
S3
Journal Article
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Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in ...musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state‐of‐the‐art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady‐state haemostasis as a possible new target for prophylaxis.
A recombinant fusion protein linking coagulation factor IX (FIX) with human albumin (rIX-FP) has been developed to facilitate hemophilia B treatment by less frequent FIX dosing. This first-in-human ...dose-escalation trial in 25 previously treated subjects with hemophilia B (FIX ≤ 2 IU/dL) examined the safety and pharmacokinetics of 25, 50, and 75 IU/kg rIX-FP. Patients in the 50-IU/kg cohort underwent a comparative pharmacokinetics assessment with their previous FIX product (plasma-derived or recombinant). No allergic reactions or inhibitors were observed. Four mild, possibly treatment-related adverse events were reported. In the 50-IU/kg cohort (13 subjects), the mean half-life of rIX-FP was 92 hours, more than 5 times longer than the subjects' previous FIX product. After 25 or 50 IU/kg rIX-FP administration, the baseline-corrected mean FIX activity remained elevated at day 7 (7.4 IU/dL and 13.4 IU/dL, respectively) and day 14 (2.5 IU/dL and 5.5 IU/dL, respectively). The incremental recovery of rIX-FP was higher than both recombinant and plasma-derived FIX (1.4 vs 0.95 and 1.1 IU/dL per IU/kg, respectively). These results demonstrated both the safety and improved pharmacokinetics of rIX-FP, thus indicating this new product with extended half-life as possibly able to control and prevent bleeding with less frequent injection. The trial was registered at www.clinicaltrials.gov as no. NCT01233440.
In the recently updated German S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," a new chapter was incorporated about recurrent venous thromboembolism (VTE) in ...patients on anticoagulation treatment. Despite the high efficacy of anticoagulation in most patients, approximately 2% experience a recurrent VTE event while receiving anticoagulant drugs. The proper diagnosis of the recurrent VTE is important and possible only with the knowledge of localization and thrombus burden of the primary VTE event. Possible reasons for recurrent VTE events in patients on anticoagulation are non-adherence to medication, sub-therapeutic drug levels due to resorption disorders or drug interactions, or concomitant disease with high thrombogenicity. Cancer is the most common underlying disease, but it is important to investigate and understand possible other causes whenever a breakthrough VTE event occurs. This results in the recommendation that in patients with VTE recurrence on therapeutic anticoagulation, in particular, the presence of malignant disease, antiphospholipid syndrome, and rare diseases like paroxysmal nocturnal hemoglobinuria or Behçet's disease should be considered. For VTE recurrence during heparin therapy, heparin-induced thrombocytopenia type II needs to be ruled out, even if platelet counts are within the normal range. Although the mechanisms of recurrence on anticoagulation can be evaluated in a certain degree, clinical evidence for the management of recurrent VTE in anticoagulated patients is minimal and mainly based on expert opinion. Switching anticoagulant medication and intensifying anticoagulant treatment are possible options.
This review compares the methodology of published clinical studies investigating the extended-half-life (EHL) factor VIII (FVIII) products, rFVIIIFc (efmoroctocog alfa, Elocta®/Eloctate®), BAY ...94‐9027 (damoctocog alfa pegol, Jivi®), BAX 855 (rurioctocog alfa pegol, Adynovate®) and N8-GP (turoctocog alfa pegol, Esperoct®) including the phase 2/3 studies, A-LONG (NCT01181128), PROTECT VIII (NCT01580293), PROLONG-ATE (NCT01736475) and pathfinder2 (NCT01480180), respectively, and their corresponding pediatric studies and extensions. Study results are interpreted from a treating physician’s perspective, translating into evidence-based, real-life use of the different EHL recombinant FVIII products for personalized prophylaxis. The similarities between the studies include methodology, objectives, study design and cohort size. The differences include duration, prophylactic dosing intervals, number of patient arms, use of control group and randomization, and treatment allocation. Comparing these studies broadens physicians’ understanding of each treatment’s applicability. Further evaluation of study data and future real-world studies should help physicians to confidently individualize and select treatment for each patient.
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•Comparison of extended-half-life FVIII registration studies from the HCP’s view.•Studies differ in length, prophylaxis intervals and method of treatment allocation.•Similarities include methodology, objectives, study design and cohort size.•Extension studies demonstrate prophylaxis efficacy at various infusion intervals.•This review may help physicians to individualize treatments for hemophilia A.
Introduction
Over the last decades progress in haemophilia treatment has been remarkable and prophylaxis with clotting factor concentrates in haemophilia A and B has been established as the standard ...of care in individuals with haemophilia and a severe bleeding phenotype. Besides clotting factor products with prolonged half‐life non‐factor therapies were developed which enable prophylaxis via subcutaneous administration. Factor VIIIa mimetics like emicizumab facilitate the coagulation pathway and are used in routine clinical practice for indivdiduals with haemophilia A. Rebalancing therapeutic agents like fitusiran, concizumab, marstacimab and serpin PC block the anticoagulant pathway and clinical trials using these products in individuals with haemophilia A and B are ongoing.
Aim and Methods
A narrative review to asess the benefits and risks of non‐factor therapies taking in to account re‐defined haemophilia treatment goals.
Results
Prophylaxis for prevention of bleeds using non‐factor products by subcutaneous administration is effective and results in reductions of bleeding episodes in individuals with haemophilia A or B with and without inhibitors. The treatment with emicizumab showed tolerable safety both in clinical trials and long‐term real‐world observations with few thrombotic events. In some clinical trials with rebalancing therapies (fitusiran and concizumab) thrombotic events occurred. Monitoring of the haemostatic function of novel therapies especially with concomitant haemostatic treatment is not yet established.
Conclusion
With the advent of novel therapeutic agents including factor concentrates with ultra‐long half‐life and improved FVIIIa mimetics aimed at raising the bar of protection into the non‐hemophilic range redefinition of haemophilia treatment goals is eagerly needed.
Introduction
Recombinant porcine factor VIII (rpFVIII) is a treatment option for break‐through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there ...are limited data about the measurement of rpFVIII in the presence of emicizumab.
Aim
To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment.
Methods
In the first part of the study, FVIII deficient plasma was spiked with rpFVIII, in the second part, commercial plasma from CHAwI was spiked with emicizumab and rpFVIII, and in the third part, plasma from CHAwI on emicizumab treatment was spiked with rpFVIII. FVIII was then measured with bCSA and a chromogenic assay with human component (hCSA). Thrombin generation (TG) and clot‐waveform analysis (CWA) were also carried out.
Results
The recovery of rpFVIII measured with bCSA is approximately 80% and is further influenced by the presence of an anti‐porcine inhibitor. rpFVIII assessed with hCSA was influenced by emicizumab. CWA and TG showed a weak correlation with baseline emicizumab concentration, but peak thrombin and CWA correlated well with increasing emicizumab concentrations and rpFVIII activities.
Conclusion
This study indicates that rpFVIII can be measured in the presence of emicizumab with a bCSA. A calibration curve for the measurement of rpFVIII with bCSA should be established.
Efanesoctocog alfa is a factor VIII fusion agent that permits weekly treatment to prevent bleeding. In this study, two thirds of treated patients had no bleeding episodes, and the annualized bleeding ...rate fell by 77%.
AAV (adeno-associated virus)-based gene therapy is a new treatment for hemophilia and has recently received approval for the treatment of severe hemophilia A. It does not suffer from the limitations ...of the current standard treatment (regular prophylactic intravenous injections of the missing clotting factor; subcutaneous injection of a bispecific antibody in hemophilia A) and can, it is hoped, raise the concentration of the missing clotting factor over the long term. AAV-based gene therapy can only be performed once, however, because of the generation of antibodies to AAV.
This review is based on publications retrieved by a selective search in the MEDLINE/PubMed database employing the relevant key words, supplemented by expert opinions and the recommendations of the relevant medical societies.
Data from non-randomized phase 1 to phase 3 trials reveal an adequate expression of factors VIII and IX in patients with mostly severe hemophilia A or B. Even though they were no longer receiving prophylactic treatment, most patients experienced a considerable reduction, by 53% to 96%, in the number of bleedings compared to previous therapy. Persistently elevated factor levels have been described for up to six years in hemophilia A and up to eight years in hemophilia B. The most common side effect of gene therapy is an inflammatory response with elevated alanine aminotransferase levels (17% to 89%, depending on the study), which may be associated with a reduced clotting factor level and requires treatment with transient immunosuppression.
Gene therapy for hemophilia holds out the prospect of freedom from hemorrhage without the need for regular treatment with drugs. The various steps that need to be carried out in gene therapy should be coordinated in a graded and partly overlapping integrated care model (a so-called hub-and-spoke model). Electronic platforms should be used for data acquisition and transmission.
Summary
During surgery and childbirth, patients with hereditary antithrombin (AT) deficiency are at high risk for thrombosis,and heparin prophylaxis may not be sufficiently efficacious. In these ...patients, exogenous AT may be used in association with heparin. A recombinant human AT (generic name: antithrombin alfa) has been developed. This multi-center study assessed the efficacy and safety of prophylactic intravenous administration of antithrombin alfa to hereditaryAT deficient patients in high risk situations, including elective surgery, childbirth, or cesarean section. Antithrombin alfa was administered prior to and during the high risk period for restoration and maintenance of AT activity at 100% of normal. Heparin, low-molecular-weight heparin, and/or vitamin K antagonists were used according to standard of care. The primary efficacy endpoint was the incidence of acute deep vein thrombosis (DVT) from baseline up to day 30 post dosing as assessed by independent central review of duplex ultrasonograms and/or venograms. Safety was assessed based on adverse events (AEs) and laboratory evaluations. Five surgical and nine obstetrical hereditary AT deficiency patients received antithrombin alfa for a mean period of seven days.No clinically overt DVT occurred. Central review of ultrasonograms identified signs of acute DVT in two out of 13 evaluable patients. No antithrombin alfa-related AEs were reported. No patient developed anti-antithrombin alfa antibodies. In conclusion, this study suggests that antithrombin alfa is a safe and effective alternative to human plasma-derived AT for treating hereditary AT deficiency patients at high risk for thromboembolic events.
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