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ABSTRACT
Introduction
Hemophilia A is a severe bleeding disorder affecting about 1 in 5,000 males. The gold standard for prophylaxis and treatment of acute bleeding has been factor (F) VIII concentrate. A multitude of treatment modalities are now available and under clinical investigation.
Areas covered
This review discusses ongoing/recently completed early-phase clinical trials registered on ClinicalTrials.gov in patients with hemophilia A through April 2022. These new pipeline therapies are focused on addressing the safety and efficacy of new factor-related products, non-factor related products, and gene therapy options for hemophilia.
Expert opinion
Current standard of care effectively prevents and treats acute bleeding and has significantly improved the quality of life in hemophilia. The biggest challenges in the improvement of care are treatment-related burden and the burden of cost in developing countries. New drugs under development are likely to enter practice by the end of this decade and address many of the unmet needs particularly of those with severe disease. Data is limited in unique populations (e.g. congenital/inherited FVIII inhibitors, non-severe hemophilia A, women/girls with hemophilia and children) which are important areas for future research; additional clinical trials and long-term outcome data are necessary prior to incorporating these new therapies in our treatment arsenal.
Article highlights
Therapy-related barriers that contribute to high disease burden in hemophilia include frequent need for prophylactic treatment, difficulty administering intravenous formulations, as well as expanding treatment options for those who have developed inhibitors.
Current trials investigating factor therapies are focusing on increasing their half-life and developing subcutaneous formulations. These novel drugs include the use of factor (F) FVII, FVIII + Von Willebrand factor (VWF), FX and inhibition of activated protein C.
The most promising factor-related therapies are the class of fusion proteins that focus on eliminating the chaperone effect of VWF on FVIII half-life; its use has been shown to increase the circulating half-life of FVIII up to 42.5 hours.
Non-factor therapy trials are looking into different mechanisms to treat those with hemophilia such as monoclonal antibodies, anti-tissue factor pathway inhibitors, reduction in antithrombin production, and immune mediated therapies.
Gene therapy trials suggest the possibility of a curative option for hemophilia A with various types of adeno-associated viral vectors and lentivirus vectors with and without hematopoietic stem cell transplant.
The ability of gene therapy to allow for natural production of FVIII from the liver may provide years of sustained normal FVIII levels that may eliminate the need for prophylactic and on-demand treatment and over time reduce overall healthcare costs related to hemophilia.
Abbreviations
| AAV | = | Adeno-associated viral |
| ABR | = | Annualized bleeding rate |
| AHA | = | Acquired hemophilia A |
| APC | = | Activated protein C |
| aPCC | = | Activated prothrombin complex concentrate |
| BPAs | = | Bypassing agents |
| BU | = | Bethesda units |
| EHL | = | Extended half-life |
| F | = | Factor |
| HA | = | Hemophilia A |
| HSCT | = | Hematopoietic stem cell transplant |
| ISTH | = | International Society on Thrombosis and Haemostasis |
| IV | = | Intravenous |
| LA-rFVIIa | = | Long-acting recombinant factor VII |
| LVs | = | Lentiviruses |
| PD | = | Pharmacodynamics |
| PEG | = | Polyethylene glycol |
| PK | = | Pharmacokinetics |
| rFVIIa | = | Recombinant Factor VIIa |
| rh | = | Recombinant human |
| TEG | = | Thromboelastography |
| TFPI | = | Tissue factor pathway inhibitor |
| vg | = | Vector genome |
| VWF | = | Von Willebrand factor |
Declaration of interest
K Regling received a 2020 HTRS/ Novo Nordisk Clinical Fellowship Award in Hemophilia and Rare Bleeding Disorders from the Homeostasis and Thrombosis Research Society (HTRS), which was supported by an educational grant from Novo Nordisk Inc. K Regling has also received grant funding through the Hemophilia of Georgia Clinical Scientist Development grant and has received honoraria from Sanofi Genzyme. RF Sidonio Jr. has investigator initiated grant funding from Takeda (ATHN 9 and SAFE study), Genentech/ Octapharma (Emi PUPs and Nuwiq ITI) and Octapharma (MOTIVATE study); they have also received honoraria from Sobi/Sanofi, Genentech/Roche, Grifols, Sigilon, Hema Biologics, Takeda, Pfizer, Bayer, Novo Nordisk and Octapharma. MU Callaghan has received honoraria from Sanofi, Genentech/ Roche, Hema Biologics, Takeda, Pfizer, Bayer, Novo Nordisk, Octapharma, Spark, Biomarin, Uniqure, Global Blood Therapeutics, Cheisi. MU Callaghan is also an employee of Agios Pharmaceuticals.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.