Hemophilia A: Why Emicizumab’s Inventors Chose to Mimic Factor VIII

The Albert and Mary Lasker Foundation presents the Lasker Awards to recognize research excellence, with a mission of improving health by accelerating support for medical research.¹ The 2026 Lasker-DeBakey Clinical Medical Research Award went to Kunihiro Hattori, Takehisa Kitazawa, DVM, PhD, and Tomoyuki Igawa, PhD, for the discovery of emicizumab, a bispecific antibody which mimics the cofactor function of factor VIII (FVIII) in hemophilia A.² The 3 scientists developed the drug at Chugai Pharmaceutical and described its development in a Perspective published in JAMA.³

Since its US Food and Drug Administration (FDA) approval in 2017, emicizumab has become a first-line prophylactic option for patients with or without FVIII inhibitors, according to a JCI Viewpoint on the award.² “Emicizumab has been a disruptive force in hemophilia A treatment,” Robert Flaumenhaft, MD, PhD, of Beth Israel Deaconess Medical Center, wrote in the Viewpoint.²

The clinical problem was well defined. Inhibitors develop in approximately 30% of previously untreated patients with severe hemophilia A, and standard half-life FVIII products require frequent intravenous infusions, often through central venous access devices in young children.² Emicizumab remains active in the presence of FVIII inhibitors and can be dosed subcutaneously as infrequently as every 4 weeks.²

Hattori conceived the idea in 2000 of an antibody able to take over the cofactor role of FVIII.² In the following written interview, Hattori explains why the team set out to replace the function of FVIII rather than the factor itself, Kitazawa describes the assay problem behind an early failed candidate, and Igawa discusses the optimization behind more than 2,400 antibody variants.

Q&A: Designing a Factor VIII Mimetic Bispecific Antibody

HCPLive: What led your team to pursue a bispecific antibody mimicking factor VIII activity rather than replacing the missing factor?

Kunihiro Hattori: When considering the limitations of existing therapies for hemophilia A, including the poor quality of life (QOL) that remained in persons with FVIII inhibitors and the challenges in adhering to prophylactic treatment regimens due to the need for venous access, I believed that fundamentally improving treatment by modifying factor VIII itself would be difficult. Instead, I concluded that the optimal solution would be to replace the function of factor VIII with an entirely different molecule. Given my understanding of both blood coagulation mechanisms and antibody biology, I believed antibodies had the potential to achieve this.

HCPLive: What were the main challenges in designing an antibody to bridge activated factors IX and X while retaining therapeutic properties?

Takehisa Kitazawa, DVM, PhD: At the time we started this project, it had not been elucidated precisely how FVIIIa interacts with FIXa and FX, or how it structurally promotes FIXa-catalyzed activation of FX. The precise mechanism remains unresolved even today. Consequently, there was not even a clue as to how to define the molecular properties required for effective treatment. Dr. Hattori’s concept was fairly high-level with regard to very specific antibody profiles.

Under these circumstances, we had to select and develop an in vitro assay capable of “accurately” and “quantitatively” evaluating bispecific antibody activity, to use as a guide for identifying and optimizing the bispecific antibody. In other words, our first key challenge was to determine which type of assay to use in the course of creating a clinical candidate bispecific antibody.

Initially, we applied the standard plasma assay that was widely used to quantitatively predict the hemostatic activity of FVIII agents in persons with hemophilia. Using the plasma assay as a guide, we designed and improved bispecific antibodies and eventually identified a clinical candidate that demonstrated strong activity in the assay in 2005. However, this candidate did not demonstrate a clear hemostatic effect in our non-human primate bleeding model of acquired hemophilia A, indicating that this plasma assay was not useful for designing effective bispecific antibodies. In addition, we observed that this candidate induced bleeding symptoms in non-hemophilic animals. We subsequently found that it competed with FVIII.

We therefore re-explored and developed a series of different assays (reconstituted enzymatic assays) suitable for bispecific antibodies in terms of both efficacy and safety. We validated these assays by assessing the in vivo efficacy of bispecific antibody variants.

In summary, the first challenge in designing the desired bispecific antibody was to select and develop in vitro assays that could accurately evaluate its functional activity. This challenge was ultimately overcome through the process described above.

HCPLive: Your JAMA article describes approximately 2,400 antibody variants. What mattered most in balancing activity, stability, and suitability for subcutaneous administration?

Tomoyuki Igawa, PhD: After screening about 40,000 bispecific antibodies, we identified a lead bispecific antibody. It exhibited quite weak or insufficient factor VIII–mimetic activity, only comparable to that of the previously failed candidate, although it caused substantially less interference with coagulation.

Therefore, our first and most important priority was to substantially improve its biological activity while maintaining its safety profile.

Once this requirement had been met after examining about 700 variants, however, we found that other properties required for long-term, infrequent subcutaneous therapy had been substantially compromised. These included securing appropriate pharmacokinetics and subcutaneous bioavailability, achieving high solubility with low viscosity, and ensuring high physicochemical stability. The next key challenge was to improve these properties while maintaining the biological activity we had achieved. In addition, we had to address immunogenicity risk and establish technologies that would enable robust manufacturing of bispecific antibodies at an industrial scale. All of these attributes were essential for a viable pharmaceutical product.

The greatest challenge we faced during antibody engineering at this stage was that these properties were interdependent. A variant that enhanced activity often impaired other properties, such as pharmacokinetics, stability or solubility, and immunogenicity.

I believe the most important key to the success of emicizumab was that we tried to improve “all” the properties required to create a transformative medicine. Our persistent efforts conducting rigorous, multidimensional evaluations, carefully analyzing the resulting data from multiple perspectives, and identifying useful mutations and combinations of mutations one by one finally enabled the discovery of emicizumab after evaluating more than 2,400 variants.

Editor’s Note: This transcript has been edited for grammar and clarity using artificial intelligence tools.

Editors’ Note: Disclosures for Kunihiro Hattori, Takehisa Kitazawa, DVM, PhD, and Tomoyuki Igawa, PhD, include Chugai Pharmaceutical.

References

1. Albert and Mary Lasker Foundation. Mission. Accessed October 9, 2026. https://laskerfoundation.org/

2. Flaumenhaft R. Kunihiro Hattori, Tomoyuki Igawa, and Takehisa Kitazawa share Lasker Award honors for revolutionary hemophilia A therapy. J Clin Invest. 2026;136(18):e212215. doi:10.1172/JCI212215

3. Hattori K, Kitazawa T, Igawa T. From biological insight to a new class of medicines for hemophilia A: the 2026 Lasker-DeBakey Clinical Medical Research Award. JAMA. Published online September 9, 2026. doi:10.1001/jama.2026.15612