Haemophilia care: the only constant is change

Abstract

Prior to modern medical care, haemophilia was a lethal paediatric disease indeed, limitations in haemophilia care affected the political activity of the royal houses of Europe leading up to World War I in which multiple of Queen Victoria’s descendants inherited haemophilia B and publicly succumbed to complications at a young age. Fortunately, the advances in blood banking following World War II provided the first haemostatic treatments for people with haemophilia. As is comprehensively reviewed in this issue by Doctors Fassel and McGuinn, haemophilia treatment has subsequently evolved from this early use of whole blood and large volume plasma transfusions to increasingly sophisticated biotechnologies with two new therapeutic categories of extended half-life (EHL) factor products and non-factor therapies (NFTs), both receiving regulatory approval within the last decade. As they outline, innovation in haemophilia continues unabated with several new (and hopefully improved) EHL factor products and NFTs advancing rapidly through clinical development. The authors also discuss the multiple ongoing haemophilia gene therapy trials in various phases of clinical development, ranging from proof-of-concept studies to pivotal licensing trials for both haemophilia A and B. With this expanding and diverse therapeutic armamentarium, both clinicians and patients have begun contemplating what a functional cure of haemophilia might look like. The pace of progress of novel drug development for haemophilia combines two strengths of the field: 1) a depth of understanding in the molecular basis of the disease including the biochemistry of coagulation that permits rational design of new therapies, and 2) an organised patient advocacy and physician provider network that fosters both basic research and clinical trials. These attributes are further amplified by advances in molecular therapeutics, especially gene therapy, in which haemophilia has long been a targeted disease. The rapidity of innovation may be fuelled, in part, by the high cost of current therapies that likely incentivise pharmaceutical interest and research. Early data suggest that some new therapies for haemophilia may modestly reduce the cost of therapy. However to date, these novel therapies do not appear to have meaningfully decreased the treatment gap between patients in developed and developing countries, with most haemophilia patients worldwide continuing to have only limited or no access to haemostatic agents. Nonetheless, there is hope that new haemophilia therapeutics may decrease the market shares of some established drugs driving down pricing and expanding target markets and, consequently, treatment options for those patients that do not currently routinely have access to therapy. As the authors review, how these new drugs will reshape haemophilia care and how best to implement them into clinical practice remain open questions, but there is considerable optimism. For example, the success of emicizumab, a bispecific antibody that indiscriminately binds factor IX (FIX)/activated coagulation FIX (FIXa) and FX/FXa mimicking FVIII’s function to co-localise the protein components of the intrinsic tenase, for prophylaxis of severe haemophilia A with and without inhibitors has substantially ‘de-medicalised’ severe haemophilia A care. In turn, the success of emicizumab has challenged the role of immune tolerance induction as a stalwart, standard of care for patients with haemophilia A with inhibitors and reduced care demands of haemophilia treatment centres. The long-term success of the expansive repertoire of novel EHL factor products and NFTs recently licensed or in clinical Correspondence: Benjamin J. Samelson-Jones, University of Pennsylvania School of Medicine, Hematology, The Children’s Hospital of Philadelphia, Colket Translational Research Building, Room 5028, 3501 Civic Center Boulevard, Philadelphia, PA 19104 USA. E-mail: [email protected] Lindsey A. George, University of Pennsylvania School of Medicine, Director of Clinical In Vivo Gene Therapy, The Children’s Hospital of Philadelphia Hematology, The Children’s Hospital of Philadelphia, Colket Translational Research Building, Room 5016, 3501 Civic Center Boulevard, Philadelphia, PA 19104 USA. E-mail: [email protected] commentary