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. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on-demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose-related manner, with steady-state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment-related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).

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. Injection frequency, dosing, blood loss, transfusions, and hemostatic response were assessed. Results: Forty-five major (n = 31 subjects) and 90 minor (n = 70 subjects) procedures were performed in hemophilia A; 35 major (n = 22) and 62 minor (n = 37) procedures were performed in hemophilia B. Unilateral knee arthroplasty was the most common major orthopedic procedure (hemophilia A: n = 15/34; hemophilia B: n = 8/24). On the day of surgery, median total dose in adults/adolescents was 81 IU/kg for rFVIIIFc and 144 IU/kg for rFIXFc; most major procedures required ≤2 injections (including loading dose). Through days 1-14, most major procedures had ≤1 injection/day. Hemostasis was rated excellent (rFVIIIFc: n = 39/42; rFIXFc: n = 29/33) or good (n = 3/42; n = 4/33) in evaluable major surgeries, with blood loss comparable with subjects without hemophilia. Most minor procedures in adults/adolescents required one injection on the day of surgery, including median loading dose of 51 IU/kg (rFVIIIFc) and 80 IU/kg (rFIXFc). No major treatment-related safety concerns were identified. No subjects developed inhibitors or serious vascular thromboembolic events. Conclusions: rFVIIIFc and rFIXFc were efficacious and well tolerated for the management of perioperative hemostasis across a wide spectrum of major and minor surgeries in hemophilia.

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH.

Hemophilia A and B predominantly attracts clinical attention in males due to X-linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01-0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research.

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. Phase 1 data from the three anti-TFPI studies showed acceptable safety profiles, and currently, available phase 2 data are encouraging. While these data support these molecules' further development progression, there is uncertainty on several aspects of their evolution. Two of the three anti-TFPIs have shown drug-related thrombosis, with one study consequently terminated. None of the thrombotic events is predictable with current monitoring tools, and none correlate with known coagulation parameters. All three anti-TFPIs undergo target mediated drug disposition, which impacts the formulation of dosing regimen fo these therapies. They would require more frequent dosing than some of the extended half-life clotting factor products and antithrombin RNAi therapy. There is no assay to measure the TFPI as the physiological levels are very low, which makes monitoring the impact of the anti-TFPI a challenge. The anti-TFPIs have several advantages, including their bioavailability when administered subcutaneously, their stable pharmacokinetics and their ability to prevent bleeds in haemophilia A or B patients with and without inhibitors. Whether these advantages can be realized will depend on the outcome of the currently ongoing studies.

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. METHODS: Participants were PwHA without FVIII inhibitors age ≥12 years; they remained on existing episodic treatment or prophylaxis. HRQoL was assessed by Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) or Haemophilia-Specific Quality of Life Assessment for Children and Adolescents Short Form (Haemo-QoL-SF II). Health status was assessed through EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score and visual analogue scale (EQ-VAS). RESULTS: Ninety-four participants enrolled; median age was 34.0 years (range 12-76). Forty-five received episodic treatment and 49 received prophylaxis for a median time of 27.7 weeks and 30.4 weeks, respectively. Mean (standard deviation) baseline Haem-A-QoL total scores were 40.1 (17.0) for the episodic group and 26.6 (14.6) for the prophylaxis group, indicating impairments in HRQoL, which remained consistent over time. Mean EQ-5D-5L IUS scores were similar between treatment regimens (0.8 episodic; 0.9 prophylaxis) and consistent over time. The mean EQ-VAS scores were similar between treatment regimens, and lower on days when bleeding occurred (79.0 vs 85.0 for episodic treatment; 77.0 vs 82.0 for prophylaxis, respectively). CONCLUSIONS: Adult and adolescent PwHA without FVIII inhibitors had HRQoL impairments regardless of whether they were treated with episodic or prophylactic standard care with FVIII.

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. METHODS: To develop the SQ-ISHI, we conducted four rounds of in-person interviews at five qualitative research facilities. Participants aged ≥12 years with moderate or severe haemophilia A, receiving intravenous factor VIII (FVIII) prophylaxis, provided feedback to optimize content understanding, ease of completion and item relevance. The final SQ-ISHI was completed by HAVEN 3 participants who previously received FVIII prophylaxis; baseline scores were compared with those at Week 21 or 25 of emicizumab prophylaxis. RESULTS: Sixty-three HAVEN 3 participants were eligible to complete the questionnaire and rate their satisfaction on a scale of 0 ('not at all satisfied') to 10 ('extremely satisfied'). Mean 'overall satisfaction' with previous FVIII prophylaxis at baseline was 6.9 (95% confidence interval [CI]: 6.2 to 7.7) increasing to 8.8 (95% CI: 8.4 to 9.3) at follow-up (Week 21/25 of treatment with emicizumab). The greatest improvement was observed in satisfaction with treatment half-life (mean score at baseline: 5.8 [95% CI: 4.9 to 6.6] vs 8.6 [95% CI: 8.0 to 9.2] at follow-up). CONCLUSION: These results demonstrate that emicizumab prophylaxis leads to greater treatment satisfaction compared with FVIII prophylaxis, reflecting in part the low treatment burden of emicizumab associated with its infrequent, SC administration.

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. Bioengineered clotting factors with enhanced pharmacokinetic profiles can reduce the burden of treatment. However, replacement therapy is associated with a risk for inhibitor development that adversely affects bleeding prevention and outcomes. Novel molecules that are subcutaneously delivered provide effective prophylaxis in the presence or absence of inhibitors, either substituting for the procoagulant function of clotting factors (eg, emicizumab) or targeting the natural inhibitors of coagulation (ie, antithrombin, tissue factor pathway inhibitor, or activated protein C). The ultimate goal of haemophilia treatment would be a phenotypical cure achievable with gene therapy, currently under late phase clinical investigation.

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. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state-of-the-art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady-state haemostasis as a possible new target for prophylaxis.

Application of a hemophilia mortality framework to the Emicizumab Global Safety Database.

BACKGROUND: As the first non-factor replacement therapy for persons with congenital hemophilia A (PwcHA), emicizumab's safety profile is of particular interest to the community. OBJECTIVES: We applied an algorithm for categorization of fatal events contemporaneous to emicizumab using reporter-assessed causality documented in the Roche Emicizumab Global Safety Database. PATIENTS/METHODS: All fatalities in PwcHA reported to the database (from clinical trials, pre-market access, and spontaneous post-marketing reports) were categorized into: associated with hemophilia A-hemorrhagic, thrombotic, human immunodeficiency virus (HIV)/hepatitis C virus (HCV), hepatic (non-HCV); associated with general population-trauma/suicide, non-HA-associated conditions; or, unspecified. Reported cause of death was not reassessed. RESULTS: As of cut-off May 15, 2020, 31 fatalities in PwcHA taking emicizumab were reported. Median age at death was 58 years; 51% had factor VIII inhibitors. Fifteen fatalities were considered associated with HA; overall, the most frequent category was hemorrhage (11/31). Of these, six had a history of life-threatening bleeds, and four had a history of intracranial hemorrhage. The remaining HA-associated fatalities were related to HIV/HCV (3/31) and other hepatic causes (1/31). No cases were categorized as thrombotic. Of 10 cases considered not associated with HA, two were categorized as cardiovascular (non-thrombotic), five as infection/sepsis, and one each of trauma/suicide, pulmonary, and malignancy. Six cases were unspecified. CONCLUSIONS: No unique risk of death was associated with emicizumab prophylaxis in PwcHA. The data reveal that mortality in PwcHA receiving emicizumab was primarily associated with hemorrhage or non-HA-associated conditions, and was not reported by treaters to be related to emicizumab treatment.

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. PATIENTS/METHODS: We identified known causes of mortality in PwcHA through literature review, analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, and expert insights. Leading causes of death in general populations are those recognized by the Centers for Disease Control and Prevention and the World Health Organization. We developed an algorithm for assessing fatalities in PwcHA and used this to categorize FAERS data as a proof of concept. RESULTS: PwcHA share mortality causes with the non-HA population including cardiovascular disease, malignancy, infections, pulmonary disease, dementias, and trauma/suicide. Causes associated with HA include hemorrhage, thrombosis, human immunodeficiency virus, hepatitis C virus, and liver dysfunction. We propose an algorithm employing these classes to categorize fatalities and use it to classify FAERS fatality data between 01/01/2000 and 03/31/2020; the most common causes were hemorrhage (22.2%) and thrombosis (10.4%). CONCLUSIONS: A conceptual framework for examining mortality in PwcHA receiving any hemophilia therapy is proposed to analyze and interpret fatalities, enabling consistent and objective assessment. Application of the framework using FAERS data suggests a generally consistent pattern of reported mortality across HA treatments, supporting the utility of this unified approach.

Requirements to participate in haemophilia clinical trials.

INTRODUCTION: 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. When these elements are in place, it is possible to conduct haemophilia clinical trials anywhere in the world.

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. Accuracy was evaluated on 32 samples by comparing results using the Siemens® Innovance® reagent. An intra-run reproducibility study was performed on controls. Linearity and lower limit of detection was studied on external-quality-assurance (EQA) material with a known VWF-Ac level. RESULTS: STA-VWF:RCo® reagent results were within clinical interpretation agreement with Siemens® Innovance®. The reproducibility study yielded % CVs of 8.41 for normal and 11.46 for abnormal controls and the assay was linear between 73 and 14.6% and remained linear to 2% with extrapolation. CONCLUSIONS: The STAGO® STA-VWF:RCo® reagent showed clinically meaningful accuracy and acceptable precision.

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. Sociodemographic and clinical characteristics were obtained using a proforma. Blood samples were collected for serum electrolytes and hematological parameters. Predictors of low hemoglobin and iron deficiency anemia (IDA) were evaluated using multivariable binary logistic regression. RESULTS: The mean age and prevalence of anemia among the CKD participants were 55.3±15.0 years and 43.18% (95% CI: 38.1%-48.4%), respectively. Blacks had the highest prevalence of anemia (46.9%), while Indians/Asians had the lowest (18.2%). Although the odds of anemia was 3.8-fold higher (odds ratio =3.8, P-value =0.059) among CKD stage V participants as compared to CKD stage I, the relationship between anemia and stages of CKD was non-linear. Diabetes mellitus (odds ratio =2.31, P-value =0.005) had a strong association with anemia among the CKD participants. CONCLUSION: Almost half of the CKD participants were anemic, and the odds of anemia did not increase linearly with increasing severity of CKD. There was a marked ethnic disparity in anemia prevalence. Our study highlights the need for risk-based management of anemia among CKD patients.

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. RESULTS: The overall prevalence of anaemia in the CKD and control population was 46.9% and 19.6% respectively. Twenty-six per cent of CKD participants were iron deficient. The prevalence of rs855791 C homozygosity was similar among iron deficient and non-iron deficient anaemia groups (86.1% vs 84.2%, P=0.723). When the analysis was confined to subjects with or without functional iron deficiency anaemia, C homozygote (88.3% vs 84.4%, P=0.425) was similar for both groups. CONCLUSIONS: Our study suggests that homozygosity for TMPRSS6 rs855791 C genotype does not influence IDA in non-dialysis CKD patients in our population.

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. METHODS: PwHA with inhibitors aged ≥12 years previously on episodic bypassing agents (BPAs) were randomized to emicizumab prophylaxis (Arm A; n = 35) or no prophylaxis (Arm B; n = 18); participants previously on BPA prophylaxis received emicizumab prophylaxis (Arm C; n = 49). Health-related outcomes assessed at baseline and monthly thereafter: Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL), Haemophilia-specific Quality of Life Questionnaire for Children Short Form (Haemo-QoL SF), EuroQol 5-Dimensions 5-Levels (EQ-5D-5L) index utility score (IUS) and visual analogue scale (EQ-VAS) and work/school days. Days hospitalized also recorded. RESULTS: At week 25, differences (ANCOVA) in adjusted mean scores (95% confidence interval) favoured Arm A versus B for Haem-A-QoL "Total" score (14.0 [5.6, 22.5]; P = 0.002) and "Physical Health" (21.6 [7.9, 35.2]; P = 0.003); EQ-VAS (-9.7 [-17.6, -1.82]; P = 0.017); and IUS (-0.16 [-0.25, -0.07]; P = 0.001); mean scores are comparable in Arms A and C. Throughout the study, a greater proportion of participants on emicizumab prophylaxis than no prophylaxis exceeded questionnaire-specific responder thresholds. Mean proportion of missed work days and number of days hospitalized were lower with emicizumab prophylaxis than no prophylaxis. CONCLUSIONS: In PwHA with inhibitors, emicizumab prophylaxis was associated with substantial and meaningful improvements in health-related outcomes.

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. METHODS: The present study describes the clinical presentation, treatment, therapeutic endpoints, and outcome of TTP patients at the Charlotte Maxeke Johannesburg Academic Hospital, South Africa. The inpatient and outpatient records of 41 consecutive adults with TTP were reviewed between 2012 and 2016. Patients were classified according to aetiology and treatment response. RESULTS: TTP was the initial presenting feature of HIV infection in 78.0%, and 12.5% were noncompliant with antiretroviral therapy (ART). Most study patients were of black ethnicity (95%) and female gender (78.1%). Treatment included initial TPE (87.8%), plasma infusion (78.1%), antiretroviral therapy (78.3%), corticosteroids (61.0%) intensive care admission (41.5%), renal dialysis (12.2%), and other immunosuppressive agents (4.9%). The median (range) number of TPEs was 10.0 (7.0-15.0). A high rate of refractory disease (63.4%) was reported. Haemoglobin, platelet count, lactate dehydrogenase, red cell distribution width, and creatinine were reliable therapeutic end-points (P < .05). The relapse rate was 9.8% and the mortality rate was 29.3%. CONCLUSION: The high mortality rate emphasises the importance of early diagnosis, referral, and appropriate management of TTP. Anti-retroviral therapy and adherence monitoring are essential to TTP management associated with HIV. Future studies to identify patients at risk for refractory disease are indicated.

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. In HAVEN 2, there was a 63% reduction in all bleeds, 94.7% reduction in treated bleeds, 94.7% reduction in treated spontaneous bleeds, 100% reduction in treated joint bleeds, and 100% reduction in treated target joint bleeds on emicizumab prophylaxis when compared with no prophylaxis. For patients on bypassing agent prophylaxis, emicizumab resulted in a 68% reduction in bleeds in HAVEN 1 and a 100% reduction in bleed rates in HAVEN 2. In HAVEN 1, three patients developed thrombotic microangiopathy (TMA) and two developed thrombosis when emicizumab was used together with an activated prothrombin complex concentrate (aPCC) at high or frequent doses. When the combination was avoided in HAVEN 2, no patient developed TMA or thrombosis. In both studies, no anti-emicizumab antibodies developed and the pharmacokinetic profile of emicizumab was similar. Emicizumab use is currently being explored in haemophilia A patients without inhibitors as well as in combination with other haemophilia A replacement therapies. The role of emicizumab in combination with current factor VIII replacement therapies and evolving non-replacement therapies remains to be established.

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. Current data from the three EHL rFIX clinical studies indicate that these products have acceptable safety profiles with no allergic reactions, thromboembolic phenomena or neutralizing antibodies when given to previously treated adolescent and adults for the prevention of bleeds, for the treatment of bleeds and in the perisurgical haemostasis use. Studies in previously untreated paediatric participants are currently ongoing. The EHL rFIX products have the potential impact to reduce the treatment burden associated with prophylactic infusion of replacement FIX, to treat and prevent bleeds in participants with haemophilia B and to improve the participant's health-related quality of life. The impact of EHL rFIX is likely to be modified by current development of other haemophilia B therapy such as antitissue factor pathway inhibitors and haemophilia B gene therapy. In this review, we aim to provide an update on the safety and efficacy data from the three EHL rFIX clinical studies and to consider their roles in the face of novel haemophilia B therapy currently evolving.

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. Serum iron, serum ferritin and transferrin were measured using standard laboratory methods, while the haematology analyser was employed to measure CHr and %HYPO. The validity of CHr and %HYPO as markers of IDA were evaluated. Multivariable binary logistic regression was conducted to determine predictors of the relationship between IDA, CHr and %HYPO. The area under the receiver operator characteristics (ROC) curve (AUC) of the final models were utilised to evaluate the discriminatory value of CHr and %HYPO respectively. RESULTS: About one-quarter (26.1%) of the participants had IDA which was more than three times more frequent among CKD patients, compared to controls (35.3% vs 9.2%); 32.3% (95%CI: 27.90%- 37.10%) of the study population had iron deficiency without anaemia and the prevalence of iron deficiency without anaemia was lower in CKD patients compared to controls (29.5% vs 37.6%). The mean age of CKD patients was higher than in controls (52.7 ±14.3 vs 40.4 ±12.6 years, P-value<0.001). The sensitivity and specificity for diagnosing IDA among CKD participants was 62.6% and 80.2% respectively for CHr (at a cut-off value of <28pg) and 63.3% and 79.8% respectively for %HYPO. CKD participants with CHr levels >28pg were 82% less likely to be diagnosed as having IDA as compared to those with CHr levels ≤ 28pg) (adj odds ratio = 0.18, 95% CI: 0.09-0.37). The AUC of CHr (0.81, 95% CI: 0.76-0.87) was higher than the AUC of %HYPO (0.76, 95%CI: 0.70-0.82). CONCLUSION: The diagnostic usefulness of CHr and the screening performance of %HYPO in predicting IDA among CKD patients are high. Their lower cost compared to conventional markers of ID recommend their use in clinical practice. Further cost effectiveness studies of these parameters are warranted.