Towards achieving a haemophilia‐free mind

Abstract

Never in history has haemophilia research generated so many therapeutic innovations. Beyond the prevention of bleeding complications, these new treatment options should fundamentally change the lives of those who face this disease. Haemophilia is defined as a partial or complete deficiency of coagulation factor VIII (FVIII) or IX (FIX). These deficiencies are responsible for haemorrhagic manifestations with predilection for muscles and joints. In patients with complete or near-complete deficiency, these haemorrhages occur spontaneously. Intra-articular bleeding episodes result in painful and disabling joint destruction. With minimal or no treatment, morbidity and mortality are high.1 The classic treatment for haemophilia is the provision of intravenous FVIII or FIX replacement therapy. The aim is to permanently maintain a minimum amount of FVIII or FIX in the blood, thus preventing spontaneous bleeding complications.2, 3 The standard half-life of these clotting factors, the need to administer them intravenously on a recurrent basis and their immunogenicity are all obstacles and constraints associated with replacement therapy. Subclinical bleeding at low trough levels has been underappreciated despite conclusive evidence published in the Joint Outcome Study in 2007.4 It is, therefore, not surprising that initiatives to facilitate this treatment initially focused on various technologies that could prolong the half-life and persistence of FVIII and FIX after administration.5 These include pegylation or fusion to well-known proteins that are prototypes for longevity in the bloodstream, namely albumin and immunoglobulins. These strategies have proved successful for haemophilia B but less encouraging for haemophilia A.2 The fate of FVIII in the blood is intimately linked and coupled to that of von Willebrand Factor (VWF), leaving no option to extend the half-life of FVIII beyond that of VWF.6 In addition to FVIII and FIX with a prolonged half-life, the last few years have seen a real therapeutic revolution. The development of a bispecific antibody mimicking the action of FVIII, administered subcutaneously on a weekly basis or every 2 or 4 weeksmakes it possible to maintain a constant haemostatic activity equivalent to approximately 15% of FVIII.7 In clinical trials are various therapeutic agents which, by reducing antithrombin or inhibiting Tissue Factor Pathway Inhibitor or Activated Protein C, increase thrombin production independently of the supply of exogenous FVIII or FIX or their neutralization by allo-antibodies.8, 9 These clotting cascade rebalancing agents, designed to decrease anti-coagulant activity in persons with bleeding disorders, will need to be used judiciously since there have been reports of excess coagulation (thrombotic events).10 They may be of benefit to selected patients since they can also be administered subcutaneously and some require infrequent injections.11 The successes of gene therapy, particularly for haemophilia B usher in a potential once and done therapy. Uniquely, the licensed gene therapy is also available to patients with severe haemophilia B who have lower levels of pre-existing antibodies to the adeno-associated viral vector used to deliver the FIX gene. Haemophilia B patients can expect to achieve mean endogenous FIX concentrations of approximately 35%, with a limited risk of needing immunosuppressive therapy to control a secondary hepatic reaction12 and with a prolonged durability of FIX expression of at least 10 years if not more, as recently predicted.13 The long-term risks for haemophilia A and B are unclear and durability of haemophilia A gene therapy is currently of concern.14, 15 Finally, replacement therapy for haemophilia A has just made a giant leap forward with the development and validation of a FVIII that can be described as ultra-long (UL). This factor is decoupled from endogenous VWF and has a prolonged half-life through a triple modification resulting in a unique fusion protein consisting of a VWF-D'D3 domain fused to one immunoglobulin-G1 Fc domain, B-domain deleted FVIII fused to the second Fc domain, and 2 XTEN polypeptides to slow degradation.16 With weekly injections, this UL-FVIII provides 40% activity through the end of 4 days and is at an average of 15% at the end of 7 days, a formidable therapeutic advance.17, 18 The number of haemorrhagic events rigorously recorded and categorized over several months (Annual Bleeding Rate considering all bleeds, treated bleeds, spontaneous bleeds, joint bleeds), the percentage of patients without bleed (% of patients with zero (treated) bleeds), multiple quality of life questionnaires and assessments, the number of injections and quantities of clotting factors for breakthrough bleeds administered are all parameters that have been used to describe, demonstrate and compare the effectiveness and undeniable benefits of these treatments. However, it is first and foremost the freedom for our patients that these innovations allow or aim for that best sums up their enormous potential. It is a freedom in all its dimensions that gives hope to many patients to live a normal life, free of their haemophilia, a “hemophilia-free” mind (Figure 1). It is about freedom from joint and muscle bleeding (bleed-free), whether provoked or spontaneous, clinically evident or sub-clinical. This is the goal of all haemophilia treatments, although the benefits and effects vary according to the treatment strategy used. It is the freedom from joint damage and disabling arthropathy (arthropathy-free). This requires the ability of treatments to abolish all spontaneous and induced bleeding episodes, clinical and subclinical. It is the freedom from having to experience or develop pain (pain-free). This is what should be possible with bleeding abolishing treatments. A reduction in pain complaints is now increasingly being observed among patients with established arthropathy benefiting from the new treatments.19 This is the freedom from the constraint of repeated, invasive, painful and sometimes poorly tolerated treatments (treatment burden-free). This is certainly the objective of new treatments administered less frequently, by subcutaneous route or by a single potentially curative injection such as gene therapy. It is also and ultimately about the freedom to partially or ideally totally free the brain, mind and consciousness from the constraints, fears and restrictions of a serious disease and its treatment (hemophilia mind-free).20 An increasing number of patients can claim this new mental state several days a week or months or even continuously depending on the treatment modality, its effects and constraints. Not having to constantly think about haemophilia, to wonder if something as simple as going up and downs stairs could precipitate a bleed in an arthritically damaged joint, are important distinctions that people with haemophilia have had to live with. Newer treatments offering higher troughs levels, or once and done haemophilia B gene therapy offer relief from this 24/7 burden. By analogy, this freedom represents the culmination of a multi-step process, described by Skinner et al., aiming at a functional cure and heath equity by normalizing haemostasis and providing patients with physical and mental well-being.21 This freedom will be even more important if the treatments are effective and introduced early in life before irreversible joint destruction occurs. This freedom can be partially regained by patients with the sequelae of haemophilia but whose physical and mental effects can be improved by innovative treatments. More research efforts are required to enable gene therapy in small children, who cannot be successfully treated with current technologies. The new treatments of haemophilia, including gene therapy, despite their advantages, do not dissipate the musculoskeletal sequelae and the multiple, possibly irreversible, social, family, professional and educational frustrations or deprivations attributable to haemophilia, as well as the burden of transmitting genetically a disease with serious consequences. More than ever, we can hope to offer more freedom to a growing number of haemophilia patients and their families. This is an ambitious goal that should motivate and inspire all those (health professionals, patient organizations, researchers, pharmaceutical partners, regulatory agencies, health authorities) who are working to improve the treatment of haemophilia patients and to offer them more freedom. We are reminded that health equity exists for only 17% of the world's persons with bleeding disorders, an unacceptably low number.22 Refocusing efforts, including advocating for more differential pricing of these newer agents to permit access in low and low middle income countries, is essential to achieving the World Federation of Haemophilia's vision of “Treatment for All.”23 Both authors contributed to the writing and approved the final version of the manuscript. This manuscript reflects the positions of Glenn F. Pierce, Medical Vice-President, and Cedric Hermans, member of the Board of the World Federation of Hemophilia. The authors have no other relevant conflicts of interest. No funding to declare.

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