Biological Rationale for New Drugs in the Bleeding Disorders Pipeline

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.