1. Introduction
Haemophilia A and B are rare X chromosome-linked monogenic disorders resulting from a deficiency in a coagulation factor in the intrinsic pathway of blood coagulation. These two diseases affect approximately 210,000 persons worldwide [1]. Developing medicines intended for small numbers of patients has little commercial incentive under normal market conditions. Therefore, the EU offers a range of incentives to encourage the development of designated orphan medicines [2]. The scope of this review is to provide an overview of the clinical development of medicinal products currently holding an orphan designation in EU for treatment of haemophilia A and B based on current experience and knowledge.
Haemophilia is caused by mutations in the genes encoding for Factor VIII (haemophilia A, the more prevalent form) and Factor XI (haemophilia B), resulting in decreased production and/or function of factor VIII and factor IX proteins. Both FVIII and FXI are naturally synthesized in the liver: FVIII in the liver sinusoidal endothelial cells (LSEC) and FIX in hepatocytes. Patients with severe haemophilia have an absence of circulating plasma FVIII and FIX activity (<1%), resulting in spontaneous or excessive bleeding into joints and muscles. If left untreated, recurrent bleedings result in the development of chronic arthropathy (knee, ankle and elbow) and early mortality from spontaneous or trauma-induced bleeds.
Haemophilia care has undergone remarkable improvements over the past decades and haemophilia has been transformed from a debilitating disease to a manageable condition. Although the diffused/pervasive availability of safe and effective replacement therapy, haemophilia patients continue to experience enormous burden of treatment, spontaneous bleeding and progressive joint disease, as well as high rates of development of inhibitors to factor products. In the past 20 years, recombinant bioengineering has led to extended half-life (EHL) therapies with increased efficacy and easier modes of administration, as well as decreased immunogenicity. [4]. We are now on a paradigm shift in prophylaxis for haemophilia through the development of the first substitution therapy, as well as innovative rebalancing therapies. Investigational gene therapy holds the promise for a definitive clinical cure [5-6].