The treatment of hemophilia, which has undergone many transformative changes over the past 60 years, is poised for yet another disruptive change: the use of gene therapy to produce functional cures ...in some persons with hemophilia A or B. The path toward achieving subnormal to normal levels of factor VIII and factor IX activity has not been straightforward and is littered with failures over these past 25 years. Through setbacks and iteration, adeno-associated virus (AAV) proved to be a useful vector to carry the factor VIII and IX transgenes; once cassettes were optimized and dose escalation proceeded, therapeutic levels of clotting factors were achieved by several groups. Because these transgenes produce fully active proteins, breakthrough bleeding and the use of exogenous clotting factors have nearly been eliminated for most clinical trial participants when they express a sufficient amount of protein. These first-generation gene therapies, which have initiated regulatory review, will decrease or eliminate the burden of hemophilia for many of the patients who are eligible to receive them. However, many are ineligible, including those who are seropositive or cross-reactive to multiple AAV serotypes, children, those with comorbid conditions, and those who live in countries where even the most basic plasma-derived clotting factors are not reliably available. Thus, although the first-generation gene therapies will have an important impact on the burden of hemophilia, many questions remain to be answered regarding safety, durability, and reliability as this technology advance progresses toward individuals worldwide with hemophilia.
Introduction
The SARS‐CoV‐2 coronavirus‐induced infection (COVID‐19) can be associated with a coagulopathy mainly responsible for pulmonary microvasculature thrombosis and systemic thromboembolic ...manifestations. The pathophysiology and management of the COVID‐19 coagulopathy are likely more complex in patients with inherited bleeding diseases such as haemophilia. These individuals might indeed present with both bleeding and thrombotic complications and require simultaneous antithrombotic and haemostatic treatments.
Objective
We propose practical guidance for the diagnosis and management of COVID‐19 coagulopathy in persons with haemophilia.
Results
Continuation of regular haemostatic treatment is recommended for ambulatory patients. For patients requiring hospital admission and on replacement therapy with factors VIII or IX concentrates, prophylaxis with concentrates should be intensified according to the risk of bleeding complications and associated with prophylactic doses of LMWH. For patients on nonreplacement therapy, emicizumab should be continued and possibly combined with factor VIII and prophylactic doses of LMWH depending on the risk of bleeding and thrombosis. Dose escalation of LMWH tailored to the risk of thrombosis can be employed but not supported by evidence.
Conclusions
These practical recommendations are based on the current literature on COVID‐19 with its impact on haemostasis, indications and modalities for thromboprophylaxis mainly in nonhaemophilic patients and how that is likely to affect persons with haemophilia in different circumstances. They will need to be tailored to each patient's clinical status and validated in future studies.
Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term ...outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement, rFVIIIFc-VWF-XTEN (BIVV001), that is physically decoupled from endogenous VWF and has enhanced pharmacokinetic properties compared with all previous FVIII products. BIVV001 was bioengineered as a unique fusion protein consisting of a VWF-DʹD3 domain fused to rFVIII via immunoglobulin-G1 Fc domains and 2 XTEN polypeptides (Amunix Pharmaceuticals, Inc, Mountain View, CA). Plasma FVIII half-life after BIVV001 administration in mice and monkeys was 25 to 31 hours and 33 to 34 hours, respectively, representing a three- to fourfold increase in FVIII half-life. Our results showed that multifaceted protein engineering, far beyond a few amino acid substitutions, could significantly improve rFVIII pharmacokinetic properties while maintaining hemostatic function. BIVV001 is the first rFVIII with the potential to significantly change the treatment paradigm for severe hemophilia A by providing optimal protection against all bleed types, with less frequent doses. The protein engineering methods described herein can also be applied to other complex proteins.
•BIVV001 is a novel fusion protein that provides fourfold longer hemostatic control than rFVIII in preclinical hemophilia A models.•BIVV001 has the potential to allow for more optimal, extended protection against all bleeding types in patients with severe hemophilia A.
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World Federation of Hemophilia Gene Therapy Registry Konkle, Barbara A.; Coffin, Donna; Pierce, Glenn F. ...
Haemophilia : the official journal of the World Federation of Hemophilia,
July 2020, Volume:
26, Issue:
4
Journal Article
Abstract Introduction Valoctocogene roxaparvovec is an adeno‐associated virus vector serotype 5 (AAV5)‐mediated gene therapy approved for severe haemophilia A (HA). Aim To report the safety and ...efficacy of valoctocogene roxaparvovec 7 years after dosing in a phase 1/2 clinical study (NCT02576795). Methods Males ≥18 years with severe HA (factor VIII FVIII ≤1 international unit IU/dL) who were previously receiving exogenous FVIII and had no history of FVIII inhibitors or anti‐AAV5 antibodies received valoctocogene roxaparvovec treatment and were followed for 7 (6 × 10 13 vg/kg; n = 7) and 6 (4 × 10 13 vg/kg; n = 6) years. Results In the last year, one participant in each cohort reported treatment‐related adverse events (AEs): grade 1 (G1) hepatomegaly (6 × 10 13 ), and G1 splenomegaly and G1 hepatic steatosis (4 × 10 13 ). During all follow‐up, mean annualized treated bleeds and exogenous FVIII infusion rates were ≥88% lower than baseline values. At years 7 and 6, mean (median) FVIII activity (chromogenic assay) was 16.2 (10.3) and 6.7 (7.2) IU/dL in the 6 × 10 13 ( n = 5) and 4 × 10 13 ( n = 4) cohorts, respectively, corresponding to mild haemophilia. Regression analyses of the last year estimated rate of change in FVIII activity was ‐0.001 and ‐0.07 IU/dL/week for the 6 × 10 13 and 4 × 10 13 cohorts, respectively. Two participants (6 × 10 13 ) resumed prophylaxis in year 7: one after a non‐treatment‐related G4 serious AE of spontaneous internal carotid artery bleed, and the other to manage bleeds and FVIII activity. Conclusions The safety and efficacy of valoctocogene roxaparvovec remain generally consistent with previous reports, with good haemostatic control for most participants. Two participants returned to prophylaxis.
Preventive subcutaneous treatment of severe hemophilia A with bispecific antibodies that mimic the action of coagulation factor VIII (FVIII) is emerging as an effective alternative to replacement ...therapy with intravenous administration of FVIII concentrates, either derived from plasma or produced by biotechnology. Access to this innovative therapeutic approach for a growing number of patients worldwide increasingly appears to be a priority public health strategy. Inclusion of FVIII mimetic bispecific antibodies on the World Health Organization essential medicines list would contribute to health equity in lower-income countries.
•New hemophilia agents called bispecific antibodies mimicking factor VIII are important treatments.•The new medicine emicizumab is one and is effective administered under the skin instead of intravenously.•Wider access to these antibodies worldwide appears to be a public health priority.•Granting of WHO essential medicine status would lead to more equity for low-income countries.
Hemophilia gene therapy: first, do no harm Valentino, Leonard A.; Kaczmarek, Radoslaw; Pierce, Glenn F. ...
Journal of thrombosis and haemostasis,
09/2023, Volume:
21, Issue:
9
Journal Article
Peer reviewed
Open access
The introduction of adeno-associated virus–mediated, liver-directed gene therapy into the hemophilia treatment landscape brings not only great promise but also considerable uncertainty to a community ...that has a history punctuated by the devastating effects of HIV and hepatitis C virus. These infections were introduced into people with hemophilia through the innovation of factor concentrates in the 1970s and 1980s. Concentrates, heralded as a major advance in treatment at the time, brought devastation and death to the community already challenged by the complications of bleeding into joints, vital organs, and the brain. Over the past 5 decades, considerable advances in hemophilia treatment have improved the survival, quality of life, and participation of people with hemophilia, although challenges remain and health equity with their unaffected peers has not yet been achieved. The decision to take a gene therapy product is one in which an informed, holistic, and shared decision-making approach must be employed. Bias on the part of health care professionals and people with hemophilia must be addressed and minimized. Here, we review data leading to the regulatory authorization of valoctocogene roxaparvovec, an adeno-associated virus 5 gene therapy, in Europe to treat hemophilia A and etranacogene dezaparvovec-drlb in the United States and Europe to treat hemophilia B. We also provide an overview of the decision-making process and recommend steps that should be taken by the hemophilia community to ensure the safety of and optimal outcomes for people with hemophilia who choose to receive a gene therapy product.
Despite proven benefits, prophylactic treatment for hemophilia A is hampered by the short half-life of factor VIII. A recombinant factor VIII-Fc fusion protein (rFVIIIFc) was constructed to determine ...the potential for reduced frequency of dosing. rFVIIIFc has an ∼ 2-fold longer half-life than rFVIII in hemophilia A (HemA) mice and dogs. The extension of rFVIIIFc half-life requires interaction of Fc with the neonatal Fc receptor (FcRn). In FcRn knockout mice, the extension of rFVIIIFc half-life is abrogated, and is restored in human FcRn transgenic mice. The Fc fusion has no impact on FVIII-specific activity. rFVIIIFc has comparable acute efficacy as rFVIII in treating tail clip injury in HemA mice, and fully corrects whole blood clotting time (WBCT) in HemA dogs immediately after dosing. Furthermore, consistent with prolonged half-life, rFVIIIFc shows 2-fold longer prophylactic efficacy in protecting HemA mice from tail vein transection bleeding induced 24-48 hours after dosing. In HemA dogs, rFVIIIFc also sustains partial correction of WBCT 1.5- to 2-fold longer than rFVIII. rFVIIIFc was well tolerated in both species. Thus, the rescue of FVIII by Fc fusion to provide prolonged protection presents a novel pathway for FVIII catabolism, and warrants further investigation.
Current factor IX (FIX) products display a half-life (t1/2) of ∼ 18 hours, requiring frequent intravenous infusions for prophylaxis and treatment in patients with hemophilia B. This open-label, ...dose-escalation trial in previously treated adult subjects with hemophilia B examined the safety and pharmacokinetics of rFIXFc. rFIXFc is a recombinant fusion protein composed of FIX and the Fc domain of human IgG1, to extend circulating time. Fourteen subjects received a single dose of rFIXFc; 1 subject each received 1, 5, 12.5, or 25 IU/kg, and 5 subjects each received 50 or 100 IU/kg. rFIXFc was well tolerated, and most adverse events were mild or moderate in intensity. No inhibitors were detected in any subject. Dose-proportional increases in rFIXFc activity and Ag exposure were observed. With baseline subtraction, mean activity terminal t1/2 and mean residence time for rFIXFc were 56.7 and 71.8 hours, respectively. This is ∼ 3-fold longer than that reported for current rFIX products. The incremental recovery of rFIXFc was 0.93 IU/dL per IU/kg, similar to plasma-derived FIX. These results show that rFIXFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia B. The trial was registered at www.clinicaltrials.gov as NCT00716716.
Due to variability in the one-stage clotting assay, the performance of new factor IX (FIX) products should be assessed in this assay. The objective of this field study was to evaluate the accuracy of ...measuring recombinant FIX Fc fusion protein (rFIXFc) activity in clinical haemostasis laboratories using the one-stage clotting assay. Human haemophilic donor plasma was spiked with rFIXFc or BeneFIX® at 0.80, 0.20, or 0.05 IU/ml based on label potency. Laboratories tested blinded samples using their routine one-stage assay and in-house FIX plasma standard. The mean spike recoveries for BeneFIX (n=30 laboratories) were 121 %, 144 %, and 168 % of expected at nominal 0.80, 0.20, and 0.05 IU/ml concentrations, respectively. Corresponding rFIXFc spike recoveries were 88 %, 107 %, and 132 % of expected, respectively. All BeneFIX concentrations were consistently overestimated by most laboratories. rFIXFc activity was reagent-dependent; ellagic acid and silica gave higher values than kaolin, which underestimated rFIXFc. BeneFIX demonstrated significantly reduced chromogenic assay activity relative to one-stage assay results and nominal activity, while rFIXFc activity was close to nominal activity at three concentrations with better dilution linearity than the typical one-stage assay. In conclusion, laboratory- and reagent-specific assay variabilities were revealed, with progressively higher variability at lower FIX concentrations. Non-parallelism against the FIX plasma standard was observed in all one-stage assays with rFIXFc and BeneFIX, leading to significant overestimation of FIX activity at lower levels and generally high inter-laboratory variability. Compared to the accuracy currently achieved in clinical laboratories when measuring other rFIX products, most laboratories measured rFIXFc activity with acceptable accuracy and reliability using routine one-stage assay methods and commercially available plasma standards.
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