Current and future therapies for haemophilia—Beyond factor replacement therapies

Abstract

Summary Some non‐factor products that work by facilitating the coagulation pathway (emicizumab) and blocking the anticoagulant pathway (fitusiran, concizumab and marstacimab) for patients with haemophilia (H) have been developed, and clinical trials using these products are currently ongoing. Prophylaxis using non‐factor products by subcutaneous administration provides marked reductions of bleeding episodes in patients with HA or HB, regardless of the presence of inhibitor. Emicizumab has already been approved globally. Emicizumab alters the phenotype of patients with HA from severe to mild by maintaining trough levels of equivalent factor VIII activity (15–20 iu/dl). Phase 3 clinical trials and long‐term observations assessing emicizumab revealed tolerable safety and efficacy. However, thrombotic events have occurred in patients receiving these non‐factor products. Furthermore, monitoring of the haemostatic function of these products with concomitant therapy is also required in clinical practice. These products have promising haemostatic efficiency, but wider clinical experience is needed to provide optimal therapeutic strategies in the future.

Six-Year, Real-World Use of Prophylaxis with Recombinant Factor IX–Albumin Fusion Protein (rIX-FP) in Persons with Hemophilia B: A Single-Center Retrospective–Prospective Study

“…The current minimization of bleeding by prophylaxis regimens, as shown in our cohort, aims to extend the assessment of treatment outcomes and value beyond the ABR and target joints [ 34 ]. Along this line, early signs/markers of joint damage, as well of more reliable functional and patient-reported outcomes (including treatment satisfaction, as reported in our study) should be identified, also considering innovative products recently introduced in or approaching clinical practice in hemophilia, i.e., non-replacement agents and gene therapy [ 2 , 3 ].…”

“…Regular prophylaxis, i.e., the long-term administration of therapeutic products aimed at preventing bleeding, particularly joint hemorrhages, with their deleterious impact on muscle–skeletal status and quality of life, is currently recommended in patients with severe hemophilia A and B (i.e., congenital deficiencies of coagulation factor [F] VIII or IX < 1%) and in moderate patients (FVIII/FIX 1–5%) with a severe bleeding phenotype [ 1 ]. Unlike hemophilia A, for which the first ‘non-replacement’ product, subcutaneously administered, is also available [ 2 ], intravenous injections of replacement factor concentrates are the mainstay of prophylaxis in hemophilia B [ 3 ]. The introduction of extended half-life (EHL) recombinant FIX (rFIX) concentrates, with relevant improvements of pharmacokinetic (PK) properties compared with standard half-life (SHL) concentrates [ 4 ], allowed for prolonged dosing intervals (up to 14–21 days vs. 2–4 days) and factor trough levels higher than those previously achieved, increasingly recognized to be inadequate to prevent all (clinical and subclinical) bleeding and the progression of arthropathy [ 5 ].…”

The effects of emicizumab on in vitro coagulation and fibrinolysis parameters in patients with disseminated intravascular coagulation with and without addition of anti‐FVIII antibody

“…While Emi maintains the coagulability of PwHA at a constant, it seemed unlikely to foster the prothrombotic tendency of PwHA suffering from sepsis‐associated DIC. In phase 3 clinical trials (HAVEN study) and long‐term observations, two and three patients receiving high doses of activated partial complex concentrates (aPCC; > 100 IU/kg daily for ≥24 h) developed TEs and thrombotic microangiopathy (TMA) respectively 6,32 . Therefore, if DIC develops during Emi and aPCC concomitant therapy, thrombotic symptoms should be noted.…”

Perspectives and perception of haemophilia gene therapy by French patients

“…Some of these molecules are already authorized in some countries and others are currently evaluated in clinical trials. All allow for a remarkable reduction of bleeding accidents and are administered subcutaneously 8 . Yet, although symptomatic joint bleeds are significantly reduced, no current therapy is able to suppress the risk of haemophilic arthropathy which persists and appears to be related to sub‐clinical micro‐bleeds 9 …”

“…All allow for a remarkable reduction of bleeding accidents and are administered subcutaneously. 8 Yet, although symptomatic joint bleeds are significantly reduced, no current therapy is able to suppress the risk of haemophilic arthropathy which persists and appears to be related to sub-clinical micro-bleeds. 9 Hemophilia gene therapy (HGT) has been designed with the aim of getting the patient's hepatocytes to produce of the missing clotting factor.…”