A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia.

A phase 1b/2, three-month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300-mg loading dose with subsequent 150-mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment-emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes.

Managing surgery in hemophilia with recombinant factor VIII Fc and factor IX Fc: Data on safety and effectiveness from phase 3 pivotal studies.

Background: Surgical procedures impose hemostatic risk to people with hemophilia, which may be minimized by optimal factor (F) replacement therapy.

Methods: This analysis evaluates the efficacy and safety of extended half-life factor replacement recombinant FVIII and FIX Fc fusion proteins (rFVIIIFc and rFIXFc) during surgery in phase 3 pivotal (A-LONG/Kids A-LONG and B-LONG/Kids B-LONG) and extension (ASPIRE and B-YOND) studies. Dosing regimens were determined by investigators.

Progress in the Development of Anti-tissue Factor Pathway Inhibitors for Haemophilia Management.

The unprecedented progress in addressing unmet needs in haemophilia care to date includes developing several novel therapies that rebalance haemostasis by restoring thrombin generation in patients with haemophilia A or B with and without inhibitors. These novel therapies are FVIII mimetics, antithrombin interference RNA therapy and several monoclonal antibodies directed against the tissue factor pathway inhibitor (anti-TFPI). In this review, we provide an update on the progress made in developing anti-TFPI therapie.

Health-related quality of life and health status in adolescent and adult people with haemophilia A without factor VIII inhibitors-A non-interventional study.

Introduction: Real-world data on health-related outcomes in persons with haemophilia A (PwHA) can provide useful information for improving patient care. The global, non-interventional study (NIS; NCT02476942) prospectively collected high-quality data in PwHA, including those without factor VIII (FVIII) inhibitors treated according to local routine clinical practice.

Aim: To report health-related quality of life (HRQoL) and health status of adult/adolescent PwHA without FVIII inhibitors.

Development and testing of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection and results from the Phase 3 HAVEN 3 study of emicizumab prophylaxis in persons with haemophilia A without FVIII inhibitors.

Introduction: Emicizumab is a subcutaneously (SC) administered prophylactic agent for persons with haemophilia A (PwHA). As part of its clinical development, a new instrument was required to measure treatment satisfaction.

Aim: Describe development of the Satisfaction Questionnaire with Intravenous or Subcutaneous Hemophilia Injection (SQ-ISHI) and its subsequent testing with HAVEN 3 study participants to measure patient satisfaction with emicizumab.

The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing.

Congenital haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked bleeding disorders. Replacement therapy has been the cornerstone of the management of haemophilia, aiming to reduce the mortality and morbidity of chronic crippling arthropathy. Frequent intravenous injections are burdensome and costly for patients, consequently with poor adherence and restricted access to therapy for many patients worldwide.

Establishment of a framework for assessing mortality in persons with congenital hemophilia A and its application to an adverse event reporting database.

Background: Despite recent therapeutic advances, life expectancy in persons with congenital hemophilia A (PwcHA) remains below that of the non-HA population. As new therapies are introduced, a uniform approach to the assessment of mortality is required for comprehensive evaluation of risk-benefit profiles, timely identification of emerging safety signals, and comparisons between treatments.

Objectives: Develop and test a framework for consistent reporting and analysis of mortality across past, current, and future therapies.

Redefining prophylaxis in the modern era.

Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes.

Requirements to participate in haemophilia clinical trials.

Clinical trials in haemophilia product development are expanding rapidly however, the number of sites and expertise in the clinical trial conduct is limited. Guidance on the requirement for conducting clinical trials is required AIM: The aim of this paper is to outline generic requirements to participate in clinical trials in haemophilia MATERIALS: This paper describes three elements which are the requirements for success conduct of haemophilia clinical trials. These are the study product, study participant, and the global regulatory and ethics framework RESULTS AND CONCLUSION: In haemophilia clinical trials, requirements for participate in studies are many and include considerations of study product, study participant and ethical and regulatory framework.

Analytical Performance of a New Immunoturbidimetric Assay for von Willebrand Factor (VWF) Activity Testing.

Background: Von Willebrand disease requires laboratory confirmation with quantitative and qualitative measurements of von Willebrand factor (VWF). Qualitative VWF-activity (VWF-Ac) tests have poor inter- and intra-laboratory reproducibility with coefficients of variation (CVs) as high as 64%, often lacking accuracy at low VWF-Ac levels.

Methods: This study evaluated the recently launched immunoturbidometric STAGO® STA-VWF:RCo® reagent for VWF-Ac.

TMPRSS6 rs855791 polymorphism and susceptibility to iron deficiency anaemia in non-dialysis chronic kidney disease patients in South Africa.

Background: In genome-wide studies, there is a strong association between the TMPRSS6 allele A736V (rs855791) and significantly lower levels of serum iron, transferrin saturation, haemoglobin, and mean corpuscular volumes. The influence of this genetic variant on susceptibility to iron deficiency anaemia (IDA) in chronic kidney disease (CKD) patients is unknown.

Methods: In this cross-sectional study, we measured the full blood count and TMPRSS6 T>C polymorphism in black adult participants (n=260) with CKD and healthy controls (n=146) at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa.

Ethnic prevalence of anemia and predictors of anemia among chronic kidney disease patients at a tertiary hospital in Johannesburg, South Africa.

Introduction: Anemia is a complication of chronic kidney disease (CKD) that can greatly impact on its prognosis. However, the risk factors for anemia, including the influence of ethnicity, are not well established among the CKD population in Johannesburg.

Methods: This was a cross-sectional study of 353 adult CKD patients attending the renal outpatient clinic of the Charlotte Maxeke Johannesburg Academic Hospital (Johannesburg, South Africa) from June 1, 2016 to December 30, 2016.

Thrombotic thrombocytopenic purpura: A 5-year tertiary care centre experience.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is associated with high mortality if not managed timeously with therapeutic plasma exchange (TPE). TTP secondary to human immunodeficiency virus (HIV) infection is unique to sub-Saharan Africa. The management and outcome of TTP in the era of improved access to therapy has not been described.

Bispecific Antibody Emicizumab for Haemophilia A: A Breakthrough for Patients with Inhibitors.

Current unmet needs in haemophilia A patients with inhibitors include the need for intravenous infusion of replacement therapy and the high burden of treatment associated with prophylaxis. Emicizumab is a humanised bispecific monoclonal antibody designed to address these unmet needs and has completed phase III clinical trials in adolescents/adults (HAVEN 1) and paediatric (HAVEN 2) inhibitor populations. In HAVEN 1, there was an 80% bleed reduction across all bleeds, 89% reduction in treated joint bleeds, 92% reduction in treated spontaneous bleeds, and 95% reduction in treated target joint bleeds on emicizumab compared with no prophylaxis.

The effect of emicizumab prophylaxis on health-related outcomes in persons with haemophilia A with inhibitors: HAVEN 1 Study.

Introduction: Persons with haemophilia A (PwHA) with inhibitors to factor VIII often experience decreased health-related outcomes. In HAVEN 1 (NCT02622321), there was a statistically significant reduction in bleeding with emicizumab prophylaxis versus no prophylaxis.

Aim: Describe health-related outcomes in PwHA with inhibitors in HAVEN 1.

Updates in clinical trial data of extended half-life recombinant factor IX products for the treatment of haemophilia B.

Whilst the global prevalence of haemophilia B is less than that of haemophilia A, rapid and remarkable innovations have been made in the development of haemophilia B therapies in the last decade. The most recent developments are the evolution of extended half-life haemophilia B replacement therapies which are designed to reduce the treatment burden associated with prophylactic infusion of factor IX (FIX) to prevent bleeding in haemophilia B participants. Clinical development programmes have culminated in the completion of three phase III studies on extended half-life (EHL) recombinant FIX (rFIX) products and subsequent approval and registration of these in many countries around the world.

Utility of reticulocyte haemoglobin content and percentage hypochromic red cells as markers of iron deficiency anaemia among black CKD patients in South Africa.

Introduction: Iron deficiency anaemia (IDA) worsens the prognosis and outcomes of chronic kidney disease (CKD). However, while the haemoglobin level is unreliable for early detection of IDA, reticulocyte haemoglobin content (CHr) and hypochromic red cells (%HYPO) are early markers of IDA.

Methods: This was a cross sectional study of black adult participants (n = 258) with CKD and apparently healthy members of staff and patients' relatives (n = 141) at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa, between 1 June 2016 and 31 December 2016.

BAY 81-8973, a full-length recombinant factor VIII for the treatment of hemophilia A: product review.

BAY 81-8973 (Kovaltry) is an unmodified, full-length recombinant factor VIII (rFVIII) approved for the prevention and treatment of bleeding episodes in patients with hemophilia A. The amino acid sequence for BAY 81-8973 is identical to that of sucrose-formulated rFVIII (rFVIII-FS; Kogenate FS/KOGENATE, Bayer), but the two products differ in their manufacturing approaches. The manufacture of BAY 81-8973 includes several modifications and enhancements, such as the introduction of the gene for human heat shock protein 70, a molecular chaperone protein that facilitates folding of proteins; no addition of human- or animal-derived proteins in the cell culture, purification process, or final formulation; and use of a 20-nm filter to remove any potential aggregates and pathogens.

Emicizumab Prophylaxis in Hemophilia A with Inhibitors.

Background: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors.

Methods: We enrolled participants who were 12 years of age or older.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

Background: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy.

Methods: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites.

Long-acting recombinant factor VIII Fc fusion protein (rFVIIIFc) for perioperative haemostatic management in severe haemophilia A.

The Phase 3 A-LONG and Kids A-LONG studies demonstrated the prolonged half-life of rFVIIIFc compared with rFVIII, and the safety and efficacy of rFVIIIFc in subjects with severe haemophilia A. Eligible subjects from A-LONG and Kids A-LONG continued rFVIIIFc treatment by enrolling in ASPIRE, an ongoing extension study. Based on combined data from the primary studies and ASPIRE interim data, the safety and efficacy of rFVIIIFc in subjects requiring surgery were evaluated.

Diagnosis of iron deficiency anaemia in hospital patients: Use of the reticulocyte haemoglobin content to differentiate iron deficiency anaemia from anaemia of chronic disease.

The diagnosis of iron deficiency anaemia in hospital patients with chronic infections and inflammation presents a challenge. Recently laboratory tests such as the reticulocyte haemoglobin content, which are independent of infection and inflammation, have become available for routine diagnostic use.