Clinical characteristic and management of haemophilia patients in Malaysia: A single centre experience.

INTRODUCTION: Haemophilia is one of the commonest inherited bleeding disorders which may lead to long term disabilities if not treated properly. Our aim of study is to understand the clinical characteristic, treatment and complications of adult haemophilia patients in our centre. MATERIALS AND METHODS: A retrospective cross-sectional review of all adult haemophilia A (HA) or haemophilia B (HB) patients who received treatment in Hospital Pulau Pinang from January 2021 to December 2022 was conducted. Data was retrieved from patients' medical records. RESULTS: A total of 75 haemophilia patients (64 HA and 11 HB) were included in this study with median age of 37 years (range 19 70). 42 of them had severe haemophilia (50% of HA, 91% of HB). All HB and 93.8% of severe HA patients were on prophylaxis. Six severe and one mild HA patients developed inhibitor with four of them currently on non-factor prophylaxis. 24 patients (32%) had prior hepatitis C infection and all of them have been successfully treated. The mean annual bleeding rate for severe haemophilia patients were 1.77 (SD ±3.6). Target joints were observed in 9.3% of patients with ankle joint (71.4%) being the most affected joint. More than one quarter (26.7%) of our patients have comorbidities with majority of them having hypertension (17/20), followed by diabetes mellitus (5/20) and ischemic heart disease (5/20). CONCLUSION: Our study showed that a significant number of adult patients with haemophilia have comorbidities. Apart from optimising factor replacement therapy, future planning should include improvement in screening, risk modification and prevention of cardiovascular disease.

Matching-Adjusted Indirect Comparison of Recombinant Factor IX Albumin Fusion Protein Versus Recombinant Factor IX Fc Fusion Protein for Weekly Prophylactic Treatment of Hemophilia B.

INTRODUCTION: Prophylactic treatment of hemophilia B with recombinant factor IX (rFIX) molecules with enhanced pharmacokinetics including rIX-FP (albutrepenonacog alfa; Idelvion©) and rFIXFc (eftrenonacog alfa; Alprolix©) have commonly been used in the clinic. In the absence of head-to-head comparative trials, the aim of this study was to estimate the efficacy of rIX-FP versus rFIXFc using matching-adjusted indirect comparisons (MAICs). METHODS: MAIC analyses leveraged individual patient data from the PROLONG-9FP trial and published summary-level data from the B-LONG trial for subjects who received weekly prophylaxis regimens. Individual patient data were used to assign weights and balance subjects from PROLONG-9FP with subjects from B-LONG on baseline disease severity, age, prior FIX regimen, and body mass index (BMI). Six efficacy outcomes were analyzed including annualized bleeding rate (ABR), annualized spontaneous bleeding rate (AsBR), annualized joint bleeding rate (AjBR), and the proportion of subjects without bleeding events (for total, spontaneous, and joint bleeding events). RESULTS: After adjustment for baseline disease severity, age, prior FIX regimen, and BMI, rIX-FP was associated with a statistically significant decrease in AsBR (rate ratio [RR] 0.42; 95% confidence interval [CI] 0.22, 0.82; P = 0.0107), and the proportion of patients without bleeding events (odds ratio [OR] 3.24; 95% CI 1.41, 7.45; P = 0.0057), spontaneous bleeding events (OR 3.47; 95% CI 1.56, 7.73; P = 0.0023), and joint bleeding events (OR 2.41; 95% CI 1.10, 5.26; P = 0.0274) compared with rFIXFc. Prophylactic treatment with rIX-FP was also associated with a numerically lower ABR (RR 0.75; 95% CI 0.32, 1.75; P = 0.5095) and AjBR (RR 0.82; 95% CI 0.37, 1.82; P = 0.6178). CONCLUSION: The MAICs demonstrated that weekly prophylaxis treatment of severe hemophilia B with rIX-FP resulted in favorable efficacy outcomes as compared to rFIXFc. These findings suggest rIX-FP may offer improved clinical benefits over rFIXFc.

The frequency of complications in a cohort of patients diagnosed with hemophilia A and hemophilia B receiving prophylactic treatment in Colombia: A retrospective noninterventional study.

INTRODUCTION: Hemophilia A and B are disorders associated with the deficit of coagulation factors VIII and IX. OBJECTIVE: Was to determine the incidence of complications in a cohort of patients diagnosed with moderate and severe hemophilia A or B under treatment in a specialized institution. METHODS: A retrospective study of a cohort of patients with replacement therapy for hemophilia A or B, evaluating treatment and complications between January/2012 and July/2019. Sociodemographic, clinical and disease management-related variables were extracted from the medical records. Time to inhibitor development and rate associated with bleeding and hospitalizations were evaluated. RESULTS: A total of 159 male patients were identified with hemophilia A (n = 140; 88.1%) and B (n = 19; 11.9%) with a mean follow-up of 5.9±2.3 years. The mean age was 23.6±16.1 years, hemophilia was reported as severe in 125 patients in hemophilia A (89.3%) and 13 patients in hemophilia B (68.4%). Primary prophylaxis was registered in 17.0% of patients, 44.7% secondary, and 38.3% tertiary, with recombinant factors (n = 84; 52.8%) followed by plasma derived factors (n = 75; 47.2%). The incidence of inhibitor development was 0.3 per 100 patients/year, with mean time to event of 509 days. The incidence of bleeding was 192 per 100 patients/year, especially at the joint (n = 99; 62.3%) and muscle (n = 25; 15.7%) level. The incidence of hospitalization was 3.7 per 100 patients/year. CONCLUSIONS: The most common complication was joint bleeding which was expected in this type of patients. Low proportion of patients developed factor inhibitors during the follow up.

Skeletal complications in patients with hemophilia: a single-center experience.

BACKGROUND: Arthropathy is a common complication in patients with hemophilia. We examined the prevalence of this skeletal complication in patients with hemophilia who were registered at a Comprehensive Hemophilia Center in Shiraz, Southern Iran. MATERIALS AND METHODS: In this cross-sectional study, an orthopedic specialist visited 448 patients and conducted screenings for skeletal complications. The assessment included evaluating the type of hemophilia, disease severity, treatment modality, the presence of inhibitors, and the identification of skeletal complications. RESULTS: Ninety patients with hemophilia A, with a mean age (SD) of 31.6 (14.4) years, and 10 patients with hemophilia B, with a mean age of 30.5 (20.6) years, were assessed. The most frequently affected joints were the knee and ankle joints. In the univariate analysis, patients with severe disease were more likely to exhibit synovitis, a target joint, and bone disease compared to patients with non-severe disease. Additionally, a history of treated or active hepatitis and an annual bleeding rate showed significant associations with the target joint. In the multivariable logistic regression analysis, disease severity (OR 14.43, 95% CI 1.6-129.6) and a higher age at diagnosis (OR 1.06, 95% CI 1.00-1.13) increased the likelihood of developing osteoporosis. A history of hepatitis (OR 3.67, 95% CI 1.28-10.48) was identified as an independent risk factor for the target joint. CONCLUSION: Skeletal complications are a common occurrence in hemophilia. Regular consultations with orthopedic specialists, focusing on bleeding control and hepatitis prevention, are essential for reducing the impact of this debilitating complication.

Perioperative management of a patient with haemophilia B and PSVT undergoing radiofrequency ablation: A case report.

Haemophilia B is a rare inherited bleeding disorder in which patients have impaired coagulation. This study describes a patient with Haemophilia B and paroxysmal supraventricular tachycardia (PSVT) who underwent radio frequency catheter ablation (RFCA). The perioperative replacement therapy with coagulation factor IX (FIX) was agreed upon after an interdisciplinary consultation involving a team of specialists in haematology, cardiovascular medicine and cardiothoracic surgery. There were no obvious bleeding points or complications during the perioperative period following the treatment, nor recurrence of PSVT within a three-year follow-up period. In summary, RFCA can be performed safely in patients with haemophilia B on the premise of developing an individualized perioperative exogenous coagulation factor supplementation regimen based upon an adequate preoperative evaluation and clinical monitoring and management by an interdisciplinary team.

Benefits of rIX-FP prophylaxis in patients with Haemophilia B: real-world evidence from a Spanish reference centre.

Standard FIX prophylaxis for PWHB require frequent injections, which has led to the development of extended half-life products like rIX-FP (albutrepenonacog alfa) that has shown good efficacy in clinical studies. This ambispective study aims to report a real-world experience with rIX-FP in a Spanish centre with PWHB who switched from SHL-FIX or began prophylaxis with rIX-FP. Five PWHB were included in this study, Four PTP switched to rIX-FP with prophylaxis every 7 days whilst one PUP started with an every-14-days regimen. 3 PTPs extended their dosing intervals to every 14 days or every 21 days. In all PTPs, median annualized spontaneous and joint bleeding rates were maintained at 0.00 and median (range) of ABR was 0.92 (0.00-2.77) after switch to rIX-FP. Mean trough level with previous product was 3.68% (SD = 2.06), while it was 7.08% (SD = 3) with all rIX-FP dosing intervals. After switching to rIX-FP, all PTP reduced their annual infusion rate between 50 and 84% and their annual FIX consumption by 61% (59-67%). This is the first reported real-world experience with albutrepenonacog alfa in a small cohort in Spain and demonstrates good bleeding control together with a reduction of the infusion rate, factor consumption and higher through factor level than previous treatment.

Efficacy and safety evaluation of eptacog beta (coagulation factor VIIa [recombinant]-jncw) for the treatment of hemophilia A and B with inhibitors.

INTRODUCTION: Bypassing agents (BPAs) are used to treat acute bleeding episodes, manage bleeding during perioperative care, and prophylactically minimize bleed occurrence in persons with hemophilia A or B with inhibitors (PwHABI). However, the effectiveness of BPAs that have been prescribed for the last several decades can be variable, motivating the development of a new recombinant activated factor VII, eptacog beta. AREAS COVERED: This review covers key eptacog beta findings from phase 1b and phase 3 (PERSEPT) clinical trials, which formed the basis for its regulatory approval to treat PwHABI ages 12 and older. Descriptions of eptacog beta structure and glycosylation profile, mechanism of action, preclinical study results, and cost analyses are also presented. EXPERT OPINION: PwHABI have had only two options for bleed treatment for the past several decades. With its distinct glycosylation profile, eptacog beta offers a novel therapy aiming to improve upon BPAs currently in use, providing an option with more than one dosing regimen and a rapid response that allows most bleeds to be treated with just one dose. This has become particularly important given the use of subcutaneous medications (e.g., emicizumab) for prophylaxis of bleeding. Clinicians should consider eptacog beta as a BPA for all PwHABI.

Evaluation of treatment and outcome for patients with haemophilia A and haemophilia B on extended half-life (EHL) factor products: A 12-month data analysis.

INTRODUCTION: Extended half-life (EHL) factor VIII and IX concentrates as prophylaxis against bleeds have been available to selected persons with haemophilia (PWH) in Australia since March 2018. Preliminary analysis of switching to EHL demonstrated increased treatment adherence, fewer injections and improved bleeding outcomes. AIMS: To characterise clinical practices regarding the use of EHL in Australia, to further evaluate treatment regimens and bleeding outcomes, and to analyse the influence of EHL product pharmacokinetics on clinical decision-making. METHODS: A national, retrospective study was conducted using the Australian Bleeding Disorders Registry (ABDR). Patients on EHL products during the entire 2019 calendar year were included for analysis. RESULTS: A complete and validated dataset of 174 PWH was analysed, 115 Haemophilia A (HA) and 59 Haemophilia B (HB). Adherence to EHL therapy was 85.7% in HA and 87.2% in HB. About 63.5% of HA and 64.4% of HB PWH reported zero spontaneous bleeds over 12months. Ankles were the most frequent spontaneous bleed site. Approximately one-third patients underwent dose adjustments, with most frequent reasons being pharmacokinetics, body weight change and breakthrough bleeds. About 19.5% of PWH had target joint history, with spontaneous bleeds reported in 58% of that cohort on EHL. Multivariate regression showed significant impact of non-adherence, target joint history and short half-life on spontaneous bleeds in the HA cohort; however only short half-life had significant impact in the HB cohort. CONCLUSION: EHL usage in Australia shows excellent treatment adherence and bleeding outcomes. This study affirms the use and value of widely available population-based pharmacokinetics as a clinical tool.

Haemophilia and Fragility Fractures: From Pathogenesis to Multidisciplinary Approach.

Haemophilia A (HA) and haemophilia B (HB) are X-linked inherited bleeding disorders caused by the absence or deficiency of coagulation factors VIII (FVIII) and IX (FIX), respectively. Recent advances in the development of effective treatments for haemophilia have led to a significant increase in life expectancy. As a result, the incidence of some comorbidities, including fragility fractures, has increased in people with haemophilia (PWH). The aim of our research was to perform a review of the literature investigating the pathogenesis and multidisciplinary management of fractures in PWH. The PubMed, Scopus and Cochrane Library databases were searched to identify original research articles, meta-analyses, and scientific reviews on fragility fractures in PWH. The mechanism underlying bone loss in PWH is multifactorial and includes recurrent joint bleeding, reduced physical activity with consequent reduction in mechanical load, nutritional deficiencies (particularly vitamin D), and FVIII and FIX deficiency. Pharmacological treatment of fractures in PWH includes antiresorptive, anabolic and dual action drugs. When conservative management is not possible, surgery is the preferred option, particularly in severe arthropathy, and rehabilitation is a key component in restoring function and maintaining mobility. Appropriate multidisciplinary fracture management and an adapted and tailored rehabilitation pathway are essential to improve the quality of life of PWH and prevent long-term complications. Further clinical trials are needed to improve the management of fractures in PWH.

Haemophilia joint health score (HJHS) usage, patterns and outcome data in patients with haemophilia A and haemophilia B in Australia: A descriptive study using the Australian Bleeding Disorders Registry (ABDR).

INTRODUCTION: Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors. AIMS: To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage. METHODS: A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS. RESULTS: 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs. CONCLUSION: This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed.

Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.

BACKGROUND: Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. OBJECTIVES: To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. METHODS: We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. RESULTS: Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). CONCLUSION: A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.

Assessment of joint bleeding and target joints in patients with severe or moderately severe hemophilia B (factor IX ≤2%) receiving prophylaxis with rIX-FP in the PROLONG-9FP clinical trial program.

OBJECTIVE: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes. METHODS: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period. RESULTS: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study. CONCLUSION: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis.

Individualizing primary prophylaxis in patients with hemophilia A and B, adherence and new products.

The purpose of prophylaxis in hemophilic patients is to prevent bleeding. The latest guidelines of the World Hemophilia Federation recommend that all patients with a severe hemorrhagic phenotype should receive prophylactic treatment, defined as the regular administration of therapeutic products (either factor concentrates or nonfactor replacement treatments). These products are aimed at preserving hemostasis and preventing bleeding, especially into joints. The guidelines also stipulate that prophylaxis should allow patients with hemophilia to lead healthy and active lives, participating in most physical and social activities, similar to the nonhemophilic population.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance haemostasis in people with haemophilia A or haemophilia B, irrespective of inhibitor status. We evaluated the efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors. METHODS: This multicentre, randomised, open-label phase 3 study was done at 26 sites (primarily secondary or tertiary centres) in 12 countries. Men, boys, and young adults aged 12 years or older with severe haemophilia A or haemophilia B with inhibitors previously treated with on-demand bypassing agents were randomly assigned (2:1) to receive once-a-month 80 mg subcutaneous fitusiran prophylaxis (fitusiran prophylaxis group) or to continue with bypassing agents on-demand (bypassing agents on-demand group) for 9 months. The primary endpoint was mean annualised bleeding rate during the efficacy period in the intention-to-treat population estimated by negative binomial model. Safety was assessed as a secondary endpoint in the safety population. This trial is complete and is registered with ClinicalTrials.gov, NCT03417102. FINDINGS: Between Feb 14, 2018, and June 23, 2021, 85 participants were screened for inclusion, of whom 57 (67%; 57 [100%] men; median age 27·0 years [IQR 19·5-33·5]) were randomly assigned: 19 (33%) participants to the bypassing agent on-demand group and 38 (67%) participants to the fitusiran prophylaxis. Negative binomial model-based mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (1·7 [95% CI 1·0-2·7]) than in the bypassing agents on-demand group (18·1 [10·6-30·8]), corresponding to a 90·8% (95% CI 80·8-95·6) reduction in annualised bleeding rate in favour of fitusiran prophylaxis (p<0·0001). 25 (66%) participants had zero treated bleeds in the fitusiran prophylaxis group versus one (5%) in the bypassing agents on-demand group. The most frequent treatment-emergent adverse event in the fitusiran prophylaxis group was increased alanine aminotransferase in 13 (32%) of 41 participants in the safety population; there were no increased alanine aminotransferase treatment-emergent adverse events in the bypassing agents on-demand group. Suspected or confirmed thromboembolic events were reported in two (5%) participants in the fitusiran prophylaxis group. No deaths were reported. INTERPRETATION: Subcutaneous fitusiran prophylaxis resulted in statistically significant reductions in annualised bleeding rate in participants with haemophilia A or haemophilia B with inhibitors, with two-thirds of participants having zero bleeds. Fitusiran prophylaxis might show haemostatic efficacy in participants with haemophilia A or haemophilia B with inhibitors; therefore, the therapeutic might have the potential to improve the management of people with haemophilia. FUNDING: Sanofi.

Structural changes after ankle joint distraction in haemophilic arthropathy: an explorative study investigating biochemical markers and 3D joint space width.

INTRODUCTION: Ankle joint distraction (AJD) is a promising treatment for patients with severe haemophilic ankle arthropathy (HAA). However, some patients showed no clinical improvement after AJD and these differences may be related to structural differences. AIM: Primarily to quantify the structural changes after AJD in patients with HAA by the use of 3D joint space width (JSW) measurements and biochemical markers and secondarily to correlate these findings with clinical pain/function. METHODS: Patients with haemophilia A/B who underwent AJD were included for this study. Bone contours on MRI (performed before and 12 and 36 months after AJD) were drawn manually and percentage change in JSW was calculated. Blood/urine (before and 6, 12, 24 and 36 months after AJD) was collected for biomarker measurement (COMP, CS846, C10C, CALC2, PRO-C2, CTX-II) and combined indexes of markers were calculated. Mixed effects models were used for analyses on group level. Structural changes were compared with clinical parameters. RESULTS: Eight patients were evaluated. On group level, percentage changes in JSW showed a slight decrease after 12 months followed by a non-statistically significant increase in JSW after 36 months compared to baseline. Biochemical marker collagen/cartilage formation also showed an initial decrease, followed by a trend towards net formation 12, 24 and 36 months after AJD. On individual patient level, no clear correlations between structural changes and clinical parameters were observed. CONCLUSION: Cartilage restoration activity on group level in patients with HAA after AJD was in concordance with clinical improvements. Correlating structural modifications with clinical parameters in the individual patient remains difficult.

Functional decline in persons with haemophilia and factors associated with deterioration.

INTRODUCTION: The World Haemophilia Federation advises regular musculoskeletal assessment covering all International Classification of Functioning and Health (ICF) domains, including limitations in activities and participation in persons with haemophilia (PWH). This enables clinicians to detect changes early and enable adjustments in personalized healthcare when needed. However, data on the course of physical functioning and occurrence of decline is lacking. The aim of this study is to describe changes in perceived limitations in activities of PWH and to identify factors associated with a change. METHODS: Data were collected from medical health records of regular check-up visits of adults with moderate and severe haemophilia in two time periods. Perceived limitations in activities was measured with the Haemophilia Activities List (HAL). Association between variables (e.g., age, body mass index, bleeding rate and synovitis) and change in perceived limitations was assessed using a generalized linear model. RESULTS: A total of 104 PWH were included. At T0, the median HAL sum score was 79.5 (IQR 62.1-93.6) and at T1 the median HAL sum score was 74.2 (IQR 57.5-88.3). A functional decline was found in 35.6% of PWH, 55.8% remained stable and 8.7% improved. Among other variables, a BMI > 30 kg/m2 appeared to be an important factor that negatively influenced the change in perceived functioning in adult PWH. With the included factors we could only explain a small part of this decline (R2 adj : .12). CONCLUSION: The majority of PWH remained stable in their perceived functional ability over mid-long term (median 3.5 years). However, about a third showed a clinical relevant decline in their functional ability.

No difference in quality of life between persons with severe haemophilia A and B.

INTRODUCTION: Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient. AIM: To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care. METHODS: The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS). RESULTS: The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R2 .22) and EQ VAS score (B -.37, R2 .17). CONCLUSION: Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.

Gene Therapy with Etranacogene Dezaparvovec for Hemophilia B.

BACKGROUND: Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS: In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS: The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS: Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. (Funded by uniQure and CSL Behring; HOPE-B ClinicalTrials.gov number, NCT03569891.).