Innovative Pharmacological Therapies for the Hemophilias Not Based on Deficient Factor Replacement

Abstract

).Hemophilias A and B are X-linked, recessive bleeding disorders resulting from the impaired deficiency or dysfunction of coagulation factor (F)VIII and FIX. 1,2 The prevalence of hemophilia A is 1 in 5,000 male live births and that of hemophilia B is 1 in 30,000. 3 Disease classification is based on plasma FVIII and FIX levels, with < 1% factor level of normal defined as severe, 1 to 5% moderately severe, and > 5 to < 40% mild disease. 4 The main clinical signs are the occurrence of bleeding manifestations, which may be spontaneous, especially in severe hemophilia. Hemorrhages most commonly affect large joints (ankles, knees, and elbows), leading to the development of arthropathy, which severely impairs mobility and quality of life. Bleeding may also occur in soft tissues and (more seldom) in the gastrointestinal tract and central nervous system. 5,6 Hemorrhages are treated with coagulation factor concentrates (replacement therapy), plasma-derived or recombinant. 7 Prophylaxis of bleeding, involving the regular infusion of the deficient coagulation factor, is the mainstay of hemophilia care because its early implementation reduces the risk of joint bleeding and the resulting development of arthropathy, allowing patients to lead a life comparable to that of healthy individuals. 8,9The most severe complication associated with FVIII and FIX replacement therapy is the development of inhibitory alloantibodies against FVIII or FIX, affecting at least one-third of patients with severe hemophilia A and approximately 3 to 5% AbstractIn recent years, advances in the pharmacological treatment of hemophilias A and B have mainly focused on the development of long-acting factor (F)VIII and FIX products. Alternative approaches not based on the replacement of the missing factor have also been explored, with the aim of producing therapeutic agents with reduced immunogenicity and yet equally effective in patients with or without inhibitors. These new classes of hemostatic agents act mainly by bypassing the need of FVIII and FIX in tenase formation, quenching anticoagulant pathways, enhancing the activity of some coagulation factors or stabilizing the fibrin clot. Current knowledge on the status of development of these novel molecules is summarized in this narrative review. We also surmise that the main interests for these products not based on the replacement of FVIII or FIX in deficient patients pertain to the potential for bleeding prevention in inhibitor patients, an earlier and easier prophylaxis implementation thanks to subcutaneous administration and prolonged half-life, and a low immunogenicity with the potential for prevention of inhibitor development in high-risk patients.

Inhibitors in haemophilia A and B: Management of bleeds, inhibitor eradication and strategies for difficult‐to‐treat patients

“…A new FVIII agent for replacement therapy, recombinant B‐domain deleted porcine FVIII (OBI‐1), demonstrated efficacy and safety for the treatment of bleeding episodes in patients with acquired haemophilia A in phase II/III studies and in patients with congenital haemophilia A in a phase II study . A recombinant fusion protein linking rFVIIa with albumin (rVIIa‐FP), a new bypassing agent in clinical development with extended half‐life, showed good tolerability in 40 healthy males in a phase I study …”

“…As with emicizumab, potential benefits of these other non‐factor therapies include improved compliance due to more convenient subcutaneous (rather than intravenous) administration. Promising early results have been demonstrated with concizumab, a humanised monoclonal antibody targeting anti‐tissue factor pathway inhibitor (TFPI): there were no serious AEs in concizumab‐treated patients with haemophilia A or B; improved thrombin generation was observed in patients with haemophilia A and B and in plasma samples from patients with haemophilia A and inhibitors . Two other monoclonal antibodies targeting TFPI (BAY 1093884 and PF‐06741086) are in development.…”

“…Two phase III trials investigating efficacy and safety of fitusiran in patients with haemophilia A or B with/without inhibitors (NCT03417102 and NCT03417245, respectively) are currently recruiting patients. Concizumab and fitusiran are being investigated for prophylactic use in patients with inhibitors using subcutaneous administration . This would circumvent the need for venous access, which can be problematic for treatments requiring regular infusions, such as ITI and prophylaxis.…”

“…While eradication of inhibitors will likely remain the first priority in inhibitor patients, the non‐ITI therapies described here offer promising alternatives as they have the ability to improve haemostasis in the presence of inhibitors, despite differing modes of action …”

“…The preferred management strategy for patients with haemophilia A who develop high‐titre inhibitors is antibody eradication via immune tolerance induction (ITI) . Bleeding episodes can be treated with bypassing agents and potentially with novel haemostatic agents currently in development . The majority of patients with haemophilia A and inhibitors will become “immune tolerant” to FVIII following ITI, with international registries reporting success rates of 51%‐79% .…”