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].