Impact of novel hemophilia therapies around the world

Abstract

Hemophilia A and B are hereditary bleeding disorders, characterized by factor VIII or IX deficiencies, respectively. For many decades, prophylaxis with coagulation factor concentrates (replacement therapy) was the standard-of-care approach in hemophilia. Since the 1950s, when prophylaxis started, factor concentrates have been improved with virus inactivation and molecule modification to extend its half-life. The past years have brought an intense revolution in hemophilia care, with the development of nonfactor therapy and gene therapy. Emicizumab is the first and only nonreplacement agent to be licensed for prophylaxis in people with hemophilia A, and real-world data show similar efficacy and safety from the pivotal studies. Other nonreplacement agents and gene therapy have ongoing studies with promising results. Innovative approaches, like subcutaneous factor VIII and lipid nanoparticles, are in the preclinical phase. These novel agents, such as extended half-life concentrates and emicizumab, have been available in resource-constrained countries through the constant efforts of the World Federation of Haemophilia Humanitarian Aid Program. Despite the wide range of new approaches and therapies, the main challenge remains the same: to guarantee treatment for all. In this article, we discuss the evolution of hemophilia care, global access to hemophilia treatment, and the current and future strategies that are now under development. Finally, we summarize relevant new data on this topic presented at the ISTH 2021 virtual congress.

Keywords: blood coagulation factors; emicizumab; factor IX; factor VIII; genetic therapy; hemophilia.

FIGURE 1

Hemophilia care evolution. (A) Evolution of hemostatic agents. (B) Improvement in hemophilia care. Abbreviations: anti‐APC, anti‐activated protein C; anti‐TFPI, anti‐tissue factor pathway inhibitor; aPCC, activated prothrombin complex concentrate; AT siRNA, small interfering RNA targeting antithrombin; DDAVP, desmopressin; EHL rFVIII, extended half‐life recombinant factor VIII concentrate; EHL rFIX, extended half‐life recombinant factor IX concentrate; Emi, emicizumab; HA GT, hemophilia A gene therapy; HB GT, hemophilia B gene therapy; PCC, prothrombin complex concentrate; pdFIX, plasma‐derived factor IX concentrate; pdFVIII, plasma‐derived factor VIII concentrate; RCT, randomized controlled trial; rFIX, recombinant factor IX concentrate; rFVIII, recombinant factor VIII concentrate

FIGURE 2

Gene therapy for hemophilia. (A) Adeno‐associated virus (AAV) vector‐mediated gene therapy: factor VIII (FVIII) or factor IX (FIX) transgene is delivered to hepatocytes by an AAV vector. After efficient transduction, liver cells will express factor VIII or IX. (B) Worldwide distribution of participants in gene therapy trials. Abbreviations: GT, gene therapy; ITR, inverted terminal repeats