Physical activity and factor VIII levels in patients with haemophilia: A real-world prospective observational study.

INTRODUCTION: Regular physical activity (PA) is recommended for patients with haemophilia (PwH). For PwH it is crucial to ensure a sufficient factor level to prevent PA-induced bleedings. However, there is a gap in the literature dealing with specific factor levels, which are needed when performing specific types of PA. AIM: To provide data on factor VIII (FVIII) levels at the start of PA performed by PwH. METHODS: In this prospective 12-month real-world observational study, 23 PwH recorded every PA they performed and the FVIII levels at the start of the PA using a pharmacokinetic application. PA types were clustered according to the collision and injury risk into three categories (Cat I = low, Cat II = medium, Cat III = high risk). Haemophilia Joint Health Scores (HJHS) were performed at baseline, after 6 and 12 months. RESULTS: 795 PA sessions of Cat I, 193 of Cat II, and 23 of Cat III were documented. FVIII levels at the start of PA were different between categories (Cat I: 29.8 ± 32.1%, Cat II: 38.3 ± 33.4%, Cat III: 86.6 ± 29.2%). Out of all PA sessions, 145 (14%) were performed at a factor level of ≤3%. Three PA-induced bleeding occurred. Baseline HJHS was 14.5 ± 13.6 points and did not change throughout the study. CONCLUSION: This study provides real-life data on FVIII levels at the start of 1011 PA sessions. PwH are mainly active in low-risk sports with higher FVIII levels observed in Cat II and III, respectively. Only three PA-induced bleeding occurred, even though several PA were started with low FVIII levels.

Exploring the relationship between condition severity and health-related quality of life in people with haemophilia A across Europe: a multivariable analysis of data from the CHESS II study.

BACKGROUND: Haemophilia A (HA; Factor VIII deficiency) is a congenital X-linked bleeding disorder characterized by trauma-related or spontaneous bleeding events, most notably arising within the intraarticular space and resulting in chronic inflammation and degeneration of affected joints. Endogenous clotting factor activity relative to normal levels determines the severity of HA symptoms, as mild (> 5-40%), moderate (1-5%), or severe (< 1%). Within the current environment of rapid evolution in HA management, we seek to understand the interplay of condition severity and health-related quality of life (HRQoL) to characterise and differentiate unmet needs among people with HA (PwHA). METHODS: A generalised linear regression model (GLM) was developed to explore the relationship between HA severity and EQ-5D-5 L index score from adult HA patients sampled in the "Cost of Haemophilia across Europe - a Socioeconomic Survey II" (CHESS II) cross-sectional, retrospective burden of illness study among adults with hereditary haemophilia A or B from eight European countries. HA patients of any severity with no active inhibitors during the 12 months prior to data capture and a completeEQ-5D-5 L response were included. A base GLM model was specified with covariates for demographic and clinical characteristics (age, body mass index, country, employment, HA severity, annual bleeding rate, problem joints, and chronic pain). RESULTS: Of 381 evaluable patients, 221 (58.0%) had severe HA, 96 (25.2%) had moderate HA, and 64 (16.8%) had mild HA. Among the covariates included in the GLM model and after controlling for haemophilia-related outcomes, a significant association was observed between mild HA and higher EQ-5D-5 L index score (average marginal effects, 0.084; p = 0.016) relative to severe HA. Patient country of residence and magnitude of HA-related chronic pain were also associated with significant differences in index scores, with the latter showing a negative relationship with HRQoL outcomes. CONCLUSIONS: Condition severity and chronic pain are significant predictors of HRQoL in PwHA. Durable bleeding protection and effective management of chronic pain have the potential to address unmet treatment needs in this population.

Association of factor expression levels with annual bleeding rate in people with haemophilia B.

INTRODUCTION: Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. AIM: We evaluated the association between FEL and ABR in PwHB. METHODS: This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. RESULTS: The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05). CONCLUSION: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.

Endothelial specific isoform of type XVIII collagen (COL-18N): A marker of vascular integrity in haemophilic arthropathy.

BACKGROUND: Haemophilic arthropathy (HA) is a major complication in haemophilia. Collagens IV, XV and XVIII are responsible for maintaining the integrity of the vessel wall in the joint. Following joint remodelling and damage, the short isoform of collagen type XVIII (COL-18N) is degraded, releasing measurable fragments. Our goal was to quantify the specific isoform COL-18N in haemophilia A patients and to assess its relation to the clinical and radiological data as well as haemophilia joint health score (HJHS), functional independence score for haemophilia (FISH), and haemophilia quality of life (Haemo-Qol). METHODS: This cross-sectional study included 50 haemophilia A patients recruited from the Paediatric Haematology and Oncology unit, Ain Shams University, Cairo, Egypt. Quantification of COL-18N was done by ELISA. Assessment of joint state clinically using FISH and HJH scores and radiologically by X-rays and ultrasound. RESULTS: Haemophilia A patients had significantly higher median COL-18N levels compared to the control group. Inhibitor positive and negative haemophilia A patients as well as those on non-steroidal anti-inflammatory drug and those not had comparable COL-18N levels. Patients with ≥2 target joints had significantly higher COL-18N level compared to those with one or those without target joints. There were significant positive correlations between COL-18N level and the total HJHS, Haemo-Qol, the HEAD-US score and annual bleeding rate. CONCLUSION: Our results demonstrated a high level of COL-18N in haemophilia A patients and argued its benefit as a potential marker for monitoring the development of haemophilic arthropathy and tailoring the optimal treatment to prevent further joint damage.

Clinical application of extended half-life factor VIII in children with severe haemophilia A.

INTRODUCTION: Only few studies have presented results from real-world clinical use of Extended Half-Life (EHL) products in children with haemophilia (CWH). AIM: To retrospectively examine real-life experience with EHL factor VIII products use in CWH A, comparing with clinical experience from standard half-life products (SHL). METHODS: A retrospective review of medical records of CWH A who have been prescribed EHL factor concentrates was conducted. All before/after comparisons were performed with the Wilcoxon matched-pairs signed-ranks test. RESULTS: Twenty-three children with severe haemophilia A were enrolled in the study (3-6 years old: n = 4, 7-12 years old: n = 7 and 13-18 years old: n = 12). Median length of time that patients were treated with EHL products was 78 weeks. Median dosing interval was significantly lengthened from 2.3 to 3.5 days after switching from SHL to EHL concentrates. Mean trough FVIII levels were significantly increased from 2.3% to 4.1% after treatment with EHL products. Also, CWH A had a reduction of mean annual bleeding rate (ABR) and mean annual joint bleeding rate (AJBR) from 1 and .8 to .3 and .2, respectively, following treatment with EHL concentrates (ABR: p = .02, AJBR: p = .05). However, after switching to factor EHL, actual FVIII consumption, including bleeds, was significantly increased from 94 IU/kg/week to 118 IU/kg/week in CWH A. There was no inhibitor development. CONCLUSION: This study demonstrates the successful transition of 23 CWH A from SHL to EHL factor concentrates.

Emicizumab in children: bleeding episodes and outcome before and after transition to Emicizumab.

PURPOSE: Real-world data and study data regarding therapy with Emicizumab in pediatric cohorts with haemophilia A is scarce. Especially, data on previously untreated pediatric patients (PUPs) and minimally treated patients (MTPs) are missing. METHODS: Thirteen pediatric patients with haemophilia A and treatment with Emicizumab were retrospectively evaluated for Annual Bleeding Rates (ABR) pre-and post-Emicizumab treatment. Safety data and data on management of minor surgery as well as laboratory results were collected. Additionally, we describe the clinical features of two PUPs and one MTP that are included in our cohort. RESULTS: Median age at initiation of Emicizumab was 5.3 (range: 0.26-17.5) years, three patients were younger than one year at initiation of treatment with Emicizumab. Median follow-up time on Emicizumab was 23.8 (range: 0.7-40) months. Total ABR (p = 0.009) as well as spontaneous (p = 0.018), traumatic (p = 0.018), and joint (p = 0.027) ABR reduced significantly post-Emicizumab transition. Safety profile was favourable as only one local site reaction occurred; no cessation of treatment was necessary. Surgery was successfully performed in three patients receiving rFVlla pre- and post-surgery. Emicizumab trough levels showed a median of 43.2 µg/ml (range: 23.9-56.8) after three doses of 3 mg/kg and 51.9 µg/ml (range: 30.4-75) at first follow-up with 1.5 mg/kg. CONCLUSION: Emicizumab is safe and efficient in pediatric patients with and without inhibitors. More data on larger multicenter cohorts and especially on PUPs/MTPs are still needed.

A single centre retrospective study of low dose prophylaxis with extended half-life factor IX for severe haemophilia B.

INTRODUCTION: Extended half-life factor IX concentrates (EHL-FIX) can be administered weekly to prevent bleeding for persons with severe haemophilia B. We report the experience of a large UK haemophilia comprehensive care centre using low dose EHL-FIX for persons with severe haemophilia B. AIM: The low doses used in real world are approximately half of the doses used in clinical trials. We aim to assess the efficacy and safety of low dose EHL-FIX. METHODS: Data from a cohort of 13 patients who were switched from standard half-life factor IX (SHL-FIX) to Alprolix® (mean dose 31.5 IU/kg) and seven patients who switched from standard half-life factor IX to Idelvion® (mean dose 20.2 IU/kg) were included. RESULTS: The median annualized bleeding rate was similar for SHL-FIX (median 3, interquartile range [IQR] 1-5) and EHL-FIX (median 3, IQR 1-5.25). Quality of life scores, measured using the European Quality of Life 5 Dimensions assessment were similar for SHL-FIX (median 0.76, IQR: 0.63-0.84) and EHL-FIX (median 0.79, IQR: 0.58-0.88). CONCLUSION: This study shows that EHL-FIX given at low doses can be effective for prevention of bleeding for persons with severe haemophilia B.

Long-term analysis of the benefit of prophylaxis for adult patients with severe or moderate haemophilia A.

INTRODUCTION: Prophylaxis with factor VIII (FVIII) concentrates in children with haemophilia A (HA) is current standard of care. The benefit of prophylactic treatment for adult HA patients is not commonly accepted. AIM: To investigate the benefit of prophylaxis over on-demand treatment in adult and elderly patients with severe or non-severe HA in a real-life setting. METHODS: Data from 163 patients comprising 1202 patient-years were evaluated for 7.5 (±5.3) years. The effects on the annual bleeding rate (ABR, including spontaneous and traumatic bleeds) of treatment with a plasma-derived FVIII concentrate, the patient's age and disease severity were investigated. The effect of changing the treatment from on demand to continuous prophylaxis on the patients' ABRs was further analysed. RESULTS: Prophylaxis had the greatest effect on the ABRs of patients of any age with severe or non-severe HA. The difference in ABR of all patients treated on demand (median 31.4; interquartile range (IQR) 27.6; N = 83) compared with those treated prophylactically (median 1.3; IQR 3.6; N = 122) was statistically significant (P < .05), even for patients with non-severe HA (median 8.4; IQR 15.5; N = 11) vs median 1.5; IQR 4.2 (N = 17), P < .05). Patients, aged up to 88 years, switching from on demand to continuous prophylaxis showed the lowest median ABR (1.1; N = 51) after their regimen change. CONCLUSION: Any (even low-frequency) prophylaxis results in lower ABR than on-demand treatment. Patients switching to prophylaxis benefitted the most, irrespective of age or HA severity. Prophylactic treatment-even tertiary-is the regimen of choice for patients of any age, including elderly patients, with severe or non-severe HA.

Improvement in clinical outcomes and replacement factor VIII use in patients with haemophilia A after factor VIII pharmacokinetic-guided prophylaxis based on Bayesian models with myPKFiT®.

OBJECTIVES: Patients with severe haemophilia A (HA) receive factor VIII (FVIII) replacement therapy as prophylaxis. myPKFiT® is an online medical application that allows authorized users to simulate dosing regimens with patient pharmacokinetic (PK) profiles based on only 2 blood samples. Our aim was to assess the impact of using this medical device in routine practice in terms of FVIII consumption and clinical outcomes. METHODS: Thirty-six patients with severe HA on prophylaxis with Advate® were recruited in 3 centres in Spain. Annual bleeding rate (ABR), annual joint bleeding rate (AJBR) and annual FVIII consumption before and after adjustment were obtained using the patient's clinical history (12 months before) and prospectively recorded data (12 months after), respectively. Adjustment was based on PK parameters provided by myPKFiT® , joint status and relative risk associated with physical activity and bleeding phenotype. RESULTS: ABR and AJBR were significantly reduced after adjustment in the overall sample (-2.2 ± 1.3, P = .018 and -1.9 ± 1.2, P = .012, respectively) and in patients aged >15 years (-2.6 ± 1.4, P = .011 and -2.0 ± 1.2, P = .005, respectively). Adjustment had an effect on the individual FVIII consumption of most patients: annual amount was reduced in 18 cases and increased in 14. There was no significant effect on the mean amount (198 784 ± 110 387) compared to that used the year prior to myPKFiT® -adjusted prophylaxis (199 466 ± 103 670; P = .737). DISCUSSION: Our results suggest that PK-guided prophylaxis using myPKFiT® improved clinical outcomes and optimized FVIII consumption in the study population. This personalized approach may reduce bleeding rates without significantly increasing the overall cost of FVIII therapy.

Clinical and Humanistic Burden of Non-inhibitor Haemophilia A in Five European Countries: Insights from the CHESS II Study.

INTRODUCTION: Haemophilia A (HA) is a congenital bleeding disorder caused by a deficiency/absence of factor VIII (FVIII) and characterised by frequent, acute and prolonged spontaneous or traumatic bleeding events, often leading to haemophilic arthropathy and progressive joint deterioration. HA severity is characterized by endogenous FVIII activity: mild (> 5-40%), moderate (1-5%), or severe (< 1%). HA poses a substantial clinical and socioeconomic burden on people with HA (PWHA), their caregivers, and society. This analysis evaluates clinical and patient-centric outcomes of a cohort of individuals with non-inhibitor HA sampled from France, Germany, Italy, Spain, and the UK in the 'Cost of Haemophilia in Europe: A Socioeconomic Survey II' (CHESS II) study. METHODS: CHESS II was a cross-sectional burden-of-illness study collecting clinical and socioeconomic data on adult (≥ 18 years) individuals with haemophilia A or B of any severity with or without inhibitors from eight European countries. Descriptive analyses were conducted examining physician-reported demographics, clinical and health resource utilisation information. PWHA-reported health-related quality of life (HRQoL) using the EQ-5D-5L and Work Productivity and Activity Impairment (WPAI) were also examined. Outcomes were stratified by HA severity and reported at country level. RESULTS: Demographics and clinical characteristics of the cohort (N = 880) were generally consistent across countries. Individuals with severe HA experienced more frequent bleeding events and joint disease despite broad use of factor replacement therapy long-term prophylaxis. A minority of those with mild or moderate HA also experienced such challenges. HRQoL and workforce participation diminished, and chronic pain increased, with increasing HA severity. CONCLUSION: This analysis provides up-to-date insights on the impact of HA across five European countries. Increasing HA severity was generally associated with worse clinical outcomes, HRQoL and workforce participation. These findings suggest a place for continued evidence-based tailored treatment and clinical management approaches in addressing the residual burden of HA.

Etranacogene dezaparvovec-drlb gene therapy for patients with hemophilia B (congenital factor IX deficiency).

INTRODUCTION: Congenital hemophilia B (HB) is an X-linked bleeding disorder resulting in Factor IX (FIX) deficiency and bleeding of variable severity. There is no cure for HB. Typical management consists of prophylactic intravenous (IV) recombinant or plasma-derived FIX infusions. Etranacogene dezaparvovec-drlb (Hemgenix, AMT-061) is an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant of the human F9 gene with a liver-specific promoter. Etranacogene dezaparvovec-drlb received FDA approval on 22 November 2022 for the treatment of HB in adult patients who use FIX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have experienced repeated, serious spontaneous bleeding episodes. AREAS COVERED: This drug profile discusses the safety and efficacy of etranacogene dezaparvovec-drlb in patients with HB. EXPERT OPINION: Etranacogene dezaparvovec-drlb therapy results in stable and sustained expression of near-normal to normal FIX levels in patients with HB regardless of neutralizing antibodies to AAV5 up to a titer of 678. Its use has led to significant reduction in bleeding and FIX prophylaxis. Etranacogene dezaparvovec-drlb was well tolerated; however, 17% of patients required corticosteroid therapy for alanine aminotransferase (ALT) elevation. Etranacogene dezaparvovec-drlb therapy marks the beginning of an exciting era in HB treatment and opens questions regarding treatment longevity and long-term safety.

Impact of pharmacokinetics to reduce bleeding in a cohort of patients with severe hemophilia A in a personalized comprehensive management program.

In recent decades, hemophilia A treatment has been focused on body weight, without taking pharmacokinetic parameters into account. Previous research has shown that the individual pharmacokinetic response is more effective in predicting the required dose of clotting factor. We want to evaluate the impact on reducing the frequency of bleeding in patients treated with recombinant factor VIII, based on a personalized comprehensive management program. Our aim was to compare the results of a standard comprehensive treatment program (stage I) vs. a personalized pharmacokinetic - based treatment program (stage II) in a cohort of 60 patients with severe hemophilia without inhibitors. The median age was 15.5 years (3-68). The annual bleeding rate (ABR) was 1.03 (62 episodes) in the first stage and 0.58 (35 episodes) in the second one, (p=0.004). By type of bleeding, the impact of the intervention differs significantly in spontaneous bleeding (p=0.007) and a 73% reduction in the first stage. There were no significant differences in traumatic bleeding. The use of pharmacokinetics (PK) for personalized dosing of patients with severe hemophilia A, significantly reduces ABR and spontaneous bleeding, improving the patient's quality of life and costs for the health system.

Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis.

Emicizumab is a bispecific antibody to factor (F) IX/IXa and FX/FXa, which mimics FVIIIa cofactor function. Emicizumab prophylaxis significantly decreases bleeding events for patients with hemophilia A (PwHA). However, global hemostatic monitoring in emicizumab-treated PwHA remains poorly investigated. Using rotational thromboelastometry (ROTEM), we evaluated coagulation potentials of whole blood samples from seven emicizumab-treated PwHA who participated in ACE001JP/ACE002JP studies. Dose-dependent coagulation-enhancing effects of emicizumab to whole blood from PwHA mixed with an anti-FVIII C2 antibody in vitro were evident by non-activated ROTEM analysis (NATEM). The relationship between FVIII levels and NATEM parameters in PwHA not participating in the clinical trials demonstrated that CT + CFT inversely correlated with FVIII levels. These parameters were defined as NATEM-based grading of coagulation potential; 'T1' (FVIII < 1 IU/dL), 'T2' (1 ≤ , < 12 IU/dL) and 'T3' (12 ≤ , < 60 IU/dL). Coagulation function in emicizumab-treated PwHA was determined to be 'T2' or 'T3,' and was dependent on plasma emicizumab concentration. Improvement of NATEM-based grades corresponded with significant reduction of bleeding episodes, except for target joints, and differences were due to the time to reach the coagulation-steady state in individual patients. The NATEM analysis may be useful for intra- and inter-individual evaluation of coagulation function in emicizumab-treated PwHA.

The Efficacy of Recombinant FVIII Low-Dose Prophylaxis in Chinese Pediatric Patients With Severe Hemophilia A: A Retrospective Analysis From the ReCARE Study.

OBJECTIVE: This study explores the efficacy of recombinant factor VIII (rFVIII) low-dose prophylaxis in Chinese pediatric patients with severe hemophilia A from the Retrospective Study in Chinese Pediatric Hemophilia A Patients With rFVIII Contained Regular Prophylaxis (ReCARE) population. METHODS: This is additional analysis of the multicenter, retrospective ReCARE study, in which the annual bleeding rate (ABR), annual joint bleeding rate (AJBR), and safety of >12-week, low dose (10-30 IU/kg/wk) rFVIII prophylaxis divided into primary, secondary, and tertiary groups based on the joint status and joint bleeding history were analyzed. RESULTS: A total of 57 patients (median age: 8.2 [0.4-17.3] years) from the ReCARE study receiving primary (n = 3), secondary (n = 21), and tertiary (n = 33) prophylaxes were included. Low-dose prophylaxis had significant bleeding reduction in all 3 groups compared to the baseline ( S = 408.5, P < .001), with median ABR rates of -4.0 (-8.0 to -3.1), -4.0 (-24.0 to 8.0), and -13.9 (-110.6 to 20.6) in the primary, secondary, and tertiary groups, respectively, with a significant difference between the secondary and tertiary groups ( P = .008). Median AJBR reduction rates were -2.3 (-6.3 to 8.4) and -14.9 (-61.5 to 19.1) in the secondary and tertiary groups, respectively. But there was no significant difference in AJBRs between the secondary and tertiary groups ( P = .061), which was related to damaged joint status. Hence, longer prophylaxis was associated with better prevention of joint bleeding ( P = .024). CONCLUSION: Despite significant ABR/AJBR reduction in all 3 groups, the efficacy of the primary prophylaxis was better than the secondary and tertiary prophylaxes.

Efficacy, safety and pharmacokinetic profiles of a plasma-derived VWF/FVIII concentrate (VONCENTO®) in subjects with haemophilia A (SWIFT-HA study).

INTRODUCTION: VONCENTO® (CSL Behring) is a plasma-derived, high-concentration, low-volume, high-purity concentrate,which contains a high level of von Willebrand factor (VWF) high-molecular-weight multimers and aVWF/factor VIII (FVIII) ratio of ~2.4:1, similar to Haemate® P (CSL Behring). METHODS: The pharmacokinetic, efficacy and safety profiles of VONCENTO® were investigated in this multicentre,double-blind, randomised study. Subjects aged ≥ 12 years with haemophilia A who required treatment of nonsurgical bleeds, treatment during surgical events or who were receiving prophylaxis were included. Pharmacokinetics were investigated with a single dose of 50 IU FVIII/kg body weight of either VONCENTO® or BIOSTATE® reference product (Biostate-RP) (Day 1; Day 8 [n= 16], repeated on Day 180 [VONCENTO® only; n=15]). Efficacy and safety analyses were performed either during on-demand treatment (n=52) or prophylaxis (n=29)for ≥ 6 months and ≥ 50 exposure days, respectively. RESULTS: Besides the confirmation of bioequivalence between VONCENTO® and Biostate-RP, which displayed comparable PK profiles, haemostatic efficacy was rated by the investigators as either 'excellent' or 'good' in 96.4% of all bleeding events (96.5% spontaneous, 96.6% traumatic, 96.9% joint bleeds) as well as in 80% of major and 100% of minor surgical procedures at discharge. The median number of annualised bleeding events per subject [range] was significantly lower in the prophylaxis group (2.0 [0.0-34.6]) than in the on-demand group (14.0 [0.0-87.8], p = 0.0013).VONCENTO® was well tolerated and no inhibitory antibodies were identified during the study period. CONCLUSIONS: This study demonstrated the bioequivalence of VONCENTO® to Biostate-RP, and its excellent efficacy and safety profile in haemophilia A subjects.