Hemophilia is a rare, inherited bleeding disorder, most commonly affecting males, that is characterized by a deficiency in blood clotting. The two most common severe forms are hemophilia A, caused by a deficiency of clotting factor VIII (FVIII), and hemophilia B, caused by a deficiency of clotting factor IX (FIX).

Until the early 20th century, effective treatments were unavailable. Life expectancy was often limited to 10–15 years, and survivors frequently developed severe joint and muscle damage due to repeated bleeding. Scientific breakthroughs later in the century transformed disease management, beginning with clotting factor replacement and the adoption of preventive therapy. More recently, innovation has expanded to long-acting factor products, non-factor therapies and emerging gene and mRNA-based approaches. This article highlights the key milestones that have shaped the evolution of hemophilia treatment.

A Century of Progress in Hemophilia Treatment

Hemophilia treatment began with transfusions of whole blood or fresh frozen plasma to replace missing clotting factors. This early approach had limited effect, and patients with severe hemophilia often lived less than 20 years.

The 1960s brought cryoprecipitate and plasma-derived factor concentrates, which allowed more effective and home-based treatment, greatly improving survival and quality of life. Early products, however, were pooled from multiple donors and lacked virus inactivation, leading to HIV and hepatitis C infections in the 1970s and 1980s.

By the late 20th century, safer production methods—donor screening, pasteurization, heat treatment, and solvent/detergent processing—became standard, paving the way for recombinant and long-acting factor therapies and a new era of safer, more effective hemophilia care.

Factor Replacement Therapies

In the 1990s, recombinant DNA technology led to the development of the first recombinant factor VIII (FVIII) and factor IX (FIX) products, effectively eliminating the risk of blood-borne infections such as HIV and hepatitis associated with plasma-derived therapies. This milestone established the safety foundation of modern hemophilia treatment.

In 1995, prophylactic therapy became the standard of care. Regular infusions, typically two to three times per week, were shown to maintain clotting factor levels and significantly reduce joint bleeding and long-term damage compared with on-demand treatment, resulting in marked improvements in quality of life. However, standard half-life products required more than 100 intravenous infusions per year, placing a substantial burden on patients.

In the early 2000s, long-acting clotting factor technologies emerged. Through approaches such as PEGylation and protein fusion, factor half-life was extended, reducing annual infusion frequency to approximately 30–50 doses. At the same time, next-generation recombinant products eliminated animal- and human-derived proteins from the manufacturing process, lowering the risk of inhibitor development, which affects up to 30% of patients with hemophilia A. For patients who develop inhibitors, immune tolerance induction (ITI) and bypassing agents, including recombinant factor VIIa and activated prothrombin complex concentrates, have provided effective treatment options.

Non-factor Therapies

Although long-acting clotting factors have significantly reduced treatment burden, challenges such as intravenous administration and inhibitor development remain. In 2017, the approval of the bispecific antibody Hemlibra (emicizumab) marked the first new treatment mechanism for hemophilia in more than two decades. By mimicking the cofactor function of activated factor VIII (FVIIIa) and simultaneously binding FIXa and FX, Hemlibra restores coagulation balance. Clinical studies showed an 87% reduction in annualized bleeding rates. With a half-life of approximately 30 days, it supports flexible subcutaneous dosing (weekly, biweekly, or monthly) and is effective in hemophilia A patients with or without inhibitors.

In 2024, two new classes of “rebalancing” therapies were approved. Anti-TFPI (tissue factor pathway inhibitor) monoclonal antibodies (Hympavzi and Alhemo) target tissue factor pathway inhibitor, promoting FXa generation through subcutaneous administration. In parallel, Qfitlia, the first anti-antithrombin siRNA therapy, uses GalNAc conjugation to selectively reduce antithrombin production in the liver. Monthly or less frequent dosing led to a 90% reduction in bleeding rates, with an initial regimen of one subcutaneous injection every two months.

It is worth noting that in December 2025, Pfizer reported a serious adverse event associated with Hympavzi, involving cerebellar infarction followed by intracranial hemorrhage. This case highlights the importance of continued safety monitoring as novel treatment mechanisms enter broader clinical use.

Gene Therapy

Gene therapy is designed as a one-time treatment with the goal of eliminating the need for ongoing therapy. In hemophilia A and B, gene therapy delivers a functional copy of the defective gene to liver cells, enabling the body to produce the missing clotting factor on its own. This is achieved using a viral vector, most commonly derived from adeno-associated viruses. The viral genetic material is removed, leaving only the therapeutic gene to be safely delivered into target cells.

The liver plays a central role in producing blood components, including clotting factors VIII and IX. Once the therapeutic gene is introduced, liver cells receive the instructions needed to produce stable levels of clotting factor, helping to prevent bleeding episodes. Clinical studies have shown that gene therapy can significantly reduce annual bleeding rates, offering the potential for long-term disease control and meaningful improvements in quality of life.

Conclusion

From plasma-derived clotting factors to recombinant therapies, long-acting formulations, non-factor alternatives, and now gene therapy, hemophilia treatment has undergone a remarkable transformation. Each innovation has moved care closer to the shared goal of safer, more effective, and less burdensome disease management.

Huateng Pharma provides PEG derivatives to support research and development across these emerging therapeutic platforms, helping accelerate progress from early discovery to clinical application.

References:

[1] Dushimova, Z., Pashimov, M., Kaibullayeva, J., Danyarova, L., Kultanova, E., Abdilova, G., & Mustapayeva, N. (2025). Therapeutic advances in hemophilia: From molecular innovation to patient-centered global care. Frontiers in Medicine, 12, 1618464. https://doi.org/10.3389/fmed.2025.1618464

[2] Pang, X., Fu, J., Zhou, Z., Tang, N., Lau, H., Wen, Y., Chen, P., Zhao, J., & Xue, H. (2025). Recent Advances in Gene Therapy for Hemophilia. Clinical and Applied Thrombosis/Hemostasis, 31, 10760296251378455. https://doi.org/10.1177/10760296251378455