Health-related quality of life and physical activity in Nordic patients with moderate haemophilia A and B (the MoHem study).

INTRODUCTION: The impact of moderate haemophilia on health-related quality of life (HRQoL) and physical activity (PA) is not well known. In previous studies, persons with factor VIII/factor IX activity (FVIII/FIX:C) below 3 IU/dL were associated with a more severe bleeding phenotype than predicted. AIM: To explore HRQoL and PA in patients with moderate haemophilia A (MHA) and B (MHB). METHODS: A cross-sectional, multicentre study covering patients with MHA and MHB in Sweden, Finland, and Norway. HRQoL was assessed with the EuroQoL 5-Dimensions (EQ-5D) form and PA with the International Physical Activity Questionnaire among participants aged ≥15 years. RESULTS: We report on 104 patients aged 15-84 years from the MoHem study. Overall, EQ-5D utility was .85 (median) (Q1-Q3 0.73-1.0) with corresponding visual analogue scale (VAS) 80 (70-90), which were similar regardless of treatment modality, FVIII/FIX:C, and MHA or MHB. Pain and mobility were most frequently affected dimensions. Utility (r = -.54), VAS (r = -.42), and PA (r = -.32) correlated negatively with arthropathy (HJHS). Only patients aged 41-50 years displayed lower utility (p = .02) and VAS (p < .01) than the Norwegian population norm. Patients on prophylaxis aged 35-54 years reported higher PA than those treated on-demand (p = .01). CONCLUSION: Haemophilic arthropathy had negative impact on HRQoL and PA in Nordic patients with moderate haemophilia. Middle-aged patients captured lower utility and VAS than observed in the general population. Tailored prophylaxis and improved joint health may influence positively on HRQoL and PA also in moderate haemophilia.

Area under the curve: Comparing the value of factor VIII replacement therapies in haemophilia A.

INTRODUCTION: In factor VIII (FVIII) prophylaxis for haemophilia A, cost comparisons have used price per international unit (IU) based on the once reasonable assumption of equivalent outcome per IU. Now, with several extended half-life (EHL) products available, new outcome-oriented ways to compare products are needed. Area under the curve (AUC) quantifies FVIII levels over time after infusion providing comparable data. AIM: To develop a decision analytical model for making indirect comparisons of FVIII replacement products based on AUC. METHODS: A literature search identified 11 crossover studies with relevant pharmacokinetic data. A common comparator FVIII level curve was calculated using pooled data from selected studies. Absolute curves for other products were estimated based on relative differences to the common comparator (% difference vs the anchor). Three scenarios were investigated: (1) Kogenate® versus Kovaltry® and Jivi® ; (2) Advate® versus Elocta® , NovoEight® , Kovaltry, Adynovate® , Afstyla® , and ReFacto® ; and (3) Jivi versus Elocta, Adynovate, and Kogenate. Sensitivity analyses investigated effects of assay type and dose. RESULTS: In scenario 1, Jivi (+50%) and Kovaltry (+14%) showed larger AUCs versus Kogenate. In scenario 2, EHL products, Elocta and Adynovate, had the largest AUC (+64% and +58%, respectively) versus Advate. Compared with all other products in scenario 3, Jivi had the largest AUC by +13%-28%. CONCLUSION: This analysis concludes that EHL products differ in relative AUC, have a larger AUC compared with standard half-life, and thus, different FVIII levels over time after infusion. This model may aid decision makers in the absence of head-to-head data.

Clinical, economic, and health-related quality of life burden associated with von Willebrand disease in adults and children: Systematic and targeted literature reviews.

INTRODUCTION: Debilitating clinical complications in von Willebrand disease (VWD) can affect health-related quality of life (HRQoL), increase healthcare costs and cause long-lasting consequences. However, the magnitude of these burdens needs to be more fully explored. AIM: To estimate the prevalence and burden of clinical complications, the impact on HRQoL and the economic burden associated with VWD. METHODS: Embase® , MEDLINE® , the Cochrane Library and conference proceedings were searched for studies on VWD evaluating clinical complications, HRQoL and cost and resource use. RESULTS: Among 16 studies assessing clinical complications in VWD, the most prevalent bleeding symptoms were menorrhagia (2%-95% [n = 7 studies]), epistaxis (12%-80% [n = 6]) and easy bruising (46%-65% [n = 2]). Among 17 studies evaluating HRQoL, the most common assessment scales were the generic SF-36 (n = 8 studies) and the EQ-5D (n = 2). Bleeding symptoms were associated with reduced QoL in six of seven studies, and of six studies evaluating treatment impact, four reported improvements in one or more HRQoL components. Among 25 studies on cost and resource use, key observations included higher post-surgery healthcare costs in VWD versus non-VWD patients (n = 1 study) and higher costs and resource use in VWD patients with bleeding complications versus those without (n = 1). CONCLUSION: Although limited, available evidence suggests that VWD patients experience a high burden of clinical complications, reduced QoL and high healthcare costs. Haemarthrosis is more common in severe VWD than is often assumed, and bleeds (including haemarthrosis) can reduce QoL. Research efforts to improve QoL and other outcomes should be prioritized.

Impact of timing of prophylaxis commencement, F8 genotype and age on factor consumption and health-related quality of life in patients with severe haemophilia A.

INTRODUCTION: The timing of prophylaxis and F8 genotype can impact treatment outcomes in adults with severe haemophilia A (HA). AIM: To investigate how F8 genotype, timing, and type of prophylaxis influence arthropathy, bleeding rates, factor consumption and health-related quality of life (HRQoL). METHODS: Thirty-eight patients with severe HA were enrolled. Bleeding events were recorded retrospectively during median 12.5 months. F8 gene variants were classified as null or non-null. Joint health and HRQoL were assessed with HJHS and EQ-5D-5L, respectively. RESULTS: The median age at prophylaxis start was 1.25 years in the primary prophylaxis group (N = 15, median age 26 years) and 31.5 years in the secondary group (N = 22, 45 years), respectively. There were significant differences in the medians of HJHS (4 vs. 20, p < .001), EQ-5D-5L index (0.9647 vs. 0.904, p = .022), EQ VAS (87 vs. 75, p = .01) and FVIII consumption (3883 vs. 2737 IU/kg/year, p = .02), between the primary and secondary groups, respectively. Median annualized bleeding rate (ABR) was 0 for both groups. Twenty-five null and thirteen non-null F8 gene variants were identified. In the secondary prophylaxis group, lower median FVIII consumption (1926 vs. 3370 IU/kg/year) was shown for non-null compared to null variants, respectively, with similar ABR and HJHS. CONCLUSION: Delayed prophylaxis start with intermediate dose intensity prevents bleeds but at a cost of more arthropathy and reduced HRQoL, compared to higher intensity primary prophylaxis. Non-null F8 genotype may allow lower factor consumption with similar HJHS and bleeding rates, compared to null genotype.

Prophylaxis use of clotting factor replacement products in people with non-severe haemophilia: A review of the literature.

INTRODUCTION: People with non-severe haemophilia appear to be under-treated in many countries, and this may lead to joint damage and worsen quality of life. AIM: To review literature for clotting factor replacement prophylaxis in people with non-severe haemophilia A and B (HA/HB) in relation to long-term outcomes to support clinical decision-making. METHODS: A targeted literature search was performed to identify studies published between 2000 and 2021 that included prophylaxis in people with non-severe HA/HB and long-term outcomes, including annualized bleeding rates, joint health and quality of life. RESULTS: Although eligible articles included 2737 and 2272 people with mild or moderate HA, respectively, only 22% (n = 609) and 29% (n = 668) reported treatment regimens. A total of 549 people with moderate HA were treated with factor replacement prophylaxis and were from high-income countries. On the contrary, nearly all people with mild HA received desmopressin (n = 599). Details of treatment regimens for women with haemophilia and people with HB were sparse. Three studies provided long-term outcomes for people with moderate haemophilia who received prophylaxis with factor concentrate, supporting early prophylaxis in people with a frequent bleeding phenotype regardless of their endogenous clotting factor level to preserve joint health. CONCLUSION: There remain large knowledge gaps when considering how to provide optimal treatment for people with non-severe haemophilia. Nonetheless, there is a strong rationale that prophylaxis should be considered early in life according to similar strategies as for severe haemophilia for those with a frequent severe bleeding phenotype.

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.

Applicability of the European Society of Cardiology Guidelines on the management of acute coronary syndromes to older people with haemophilia A - A modified Delphi consensus by the ADVANCE Working Group.

INTRODUCTION: As people with haemophilia (PWH) receive better treatment and live longer they are more likely to encounter cardiovascular disease (CVD) and other comorbidities. ESC guidelines for the acute management of patients presenting with acute coronary syndrome (ACS) are based on the non-haemophilia population. AIM: To review the guidelines and propose relevant adaptations for PWHA without inhibitors who are treated with prophylaxis and present with ACS. METHODS: As part of the ADVANCE Group, 20 European haemophilia experts used a modified Delphi approach to develop and gain consensus on proposed adaptations of the ESC guidelines for PWHA without inhibitors. RESULTS: Of the 32 Class I recommendations across both guidelines, adaptions were considered necessary and proposed for 15. The adaptions highlight the need to provide sufficient FVIII trough levels at the time of antithrombotic treatment in people with haemophilia A (HA) without inhibitors. Patients receiving emicizumab prophylaxis and requiring oral anticoagulation therapy or combined single antiplatelet plus oral anticoagulation therapy will require additional FVIII replacement therapy. CONCLUSION: In the absence of high-quality clinical evidence, the combined expert opinion used to develop these adaptions to the current ESC guidelines may help to guide clinicians in their treatment decisions when a PWHA presents with ACS.

Alternative payment models for durable and potentially curative therapies: The case of gene therapy for haemophilia A.

INTRODUCTION: The emergence of durable and potentially curative cell and gene therapies (also known as advanced therapy medicinal products) with high price tags is challenging conventional health care payment systems. Among these are gene therapies in various phases of development for haemophilia A and B. The emergence of these therapies comes with clinical and economic uncertainties for payers, providers, patients, and manufacturers. These include uncertainties about expression of the intended physiological response, patient outcomes, and duration of treatment effect, along with potentially high upfront costs, variable additional costs, and uncertainties about uptake of the therapy among indicated patient populations. These clinical and economic uncertainties raise interest among payers, providers, and manufacturers in risk-sharing arrangements, including alternative payment models (APMs). SUMMARY: APMs differ from traditional fee-for-service payment for health care. For example, some APMs are designed to reward clinicians and provider organizations for delivering high-quality and cost-effective care. The APMs described here, outcomes-based models (or value- or performance-based models) and finance-based models, are designed to mitigate or otherwise manage financial risks associated with health care payment, including instances in which patient outcomes for costly therapies are uncertain. We examine how such APMs may be applicable in the context of emerging gene therapies for haemophilia A, including considerations in determining whether any particular APM may be most suitable. KEY POINTS OF CONSIDERATION: Gene therapies for haemophilia are among the emerging durable and potentially curative cell and gene therapies with high price tags that are challenging conventional payment systems. These therapies present clinical and economic uncertainties for payers, providers, patients, and manufacturers, including regarding expression of the intended physiological response, duration of treatment effect, patient outcomes, potentially high upfront costs and variable additional costs, and uptake among potentially indicated, diverse patient subgroups. These uncertainties raise interest among payers, manufacturers, and providers in risk-sharing arrangements, including alternative payment models (APMs) such as various outcomes-based and finance-based models. This paper describes a taxonomy of APMs. Then, for the particular context of gene therapy for haemophilia A, we present a set of factors to be considered when determining whether an APM risk-sharing arrangement may be appropriate for a given gene therapy, and, if so, which APM may be most suitable. [Correction added on 21 February 2022, after first online publication: the 'Key Points of Consideration' have been added in this version.].

Clinical outcome and adherence rate in Scandinavian patients with intermediate-intensity prophylaxis before and after the switch of standard half-life FVIII products to BAY 81-8973.

INTRODUCTION: Treatment optimization in haemophilia A can be achieved by choice of FVIII product and knowledge of pharmacokinetics (PK), phenotype and adherence. A favourable PK profile of BAY 81-8973 (octocog alfa) (Kovaltry, Bayer AB) compared to other standard half-life (SHL) FVIII products has been suggested. AIM: To evaluate whether the switch to BAY 81-8973, using the same dosing schedule, impact factor consumption and bleed rates, taking arthropathy and adherence into account METHODS: Forty patients on prophylaxis with SHL (median age 40.5 years) attending the haemophilia treatment centres in Malmö and Oslo were enrolled. The annualised bleeding rate (ABR) and joint bleeding rate (AJBR) before and after the switch to BAY 81-8973 was calculated. PK analyses were performed with WAPPS-Hemo. Joint health status and treatment adherence were assessed. RESULTS: The median ABR and AJBR was 0 before and after the switch, at both centres. The median yearly factor consumption was 3,345 IU/Kg/year in the entire study group corresponding to intermediate-intensity prophylaxis in most patients and with significantly more used in Malmö (3,862 IU/Kg/year), compared to Oslo (2,337 IU/Kg/year) (P .006). There was no correlation between arthropathy and bleeding. The median BAY 81-8973 t½ was 15.15 h (range 7.5-29 h), with significant correlation to VWF levels, and 13.4 h after exclusion of VWF outliers. Adherence to treatment was 97%. CONCLUSIONS: Concentrate switch, using mainly intermediate-intensity regimens with high adherence rates, preserves excellent prophylaxis outcome using standard half-life FVIII products, indicating the value of individualized prophylaxis and close follow-up.

Sixth Åland Island Conference on von Willebrand disease.

INTRODUCTION: The sixth Åland Islands Conference on von Willebrand disease (VWD) on the Åland Islands, Finland, was held from 20 to 22 September 2018. AIM: The meeting brought together experts in the field of VWD from around the world to share the latest advances and knowledge in VWD. RESULTS AND DISCUSSION: The topics covered both clinical aspects of disease management, and biochemical and laboratory insights into the disease. The clinical topics discussed included epidemiology, diagnosis and treatment of VWD in different countries, management of children with VWD, bleeding control during surgery, specific considerations for the management of type 3 VWD and bleeding control in women with VWD. Current approaches to the management of acquired von Willebrand syndrome were also discussed. Despite significant advances in the understanding and therapeutic options for VWD, there remain many challenges to be overcome in order to optimise patient care. In comparison with haemophilia A, there are very few registries of VWD patients, which would be a valuable source of data on the condition and its management. VWD is still underdiagnosed, and many patients suffer recurrent or severe bleeding that could be prevented. Awareness of VWD among healthcare practitioners, including non-haematologists, should be improved to allow timely diagnosis and intervention. Diagnosis remains challenging, and the development of fast, simple assays may help to facilitate accurate and rapid diagnosis of VWD.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

A comparison of MyPKFiT and WAPPS-Hemo as dosing tools for optimizing prophylaxis in patients with severe haemophilia A treated with Octocog alfa.

INTRODUCTION: MyPKFiT and the Web-Accessible Population Pharmacokinetic service-Hemophilia (WAPPS-Hemo) are web-based population-based applications developed for helping physicians individualize and optimize replacement therapy. Although MyPKFiT is intended for Octocog alfa and Rurioctocog alfa pegol use only, the WAPPS-Hemo is applicable to all factor VIII concentrates. AIM: To compare MyPKFiT and WAPPS-Hemo as dosing tools for optimizing treatment of patients with severe haemophilia A on regular prophylaxis with Octocog alfa in a real-world setting. METHODS: Fourteen patients with severe haemophilia A (median age 30.8 years; range 20-71) were enrolled. The FVIII activity was measured twice after a regular dose of Octocog alfa by the chromogenic and the one-stage assays. PK analyses were performed using each tool and dosing estimations to reach trough levels of 1%, 3% or 5% after 48 h. Findings were calculated and compared. RESULTS: The two PK algorithms yielded similar t½ independent of the type of FVIII assay used. However, there were significant differences in the time to reach 1%, 3% and 5%. The WAPPS-Hemo generated 10-12 h longer time to a trough of 1% and up to 4 h for the troughs of 3% and 5%. Accordingly, the doses estimated by WAPPS-Hemo for a daily regimen were between 28% and 100% of those proposed by MyPKFiT. CONCLUSIONS: MyPKFiT and WAPPS-Hemo provided similar half-life estimations for Octocog alfa independent of the FVIII assay used. The doses suggested by WAPPS-Hemo to reach specific troughs were overall lower, which may have implications for treatment optimization.

Bleeding phenotype of patients with moderate haemophilia A and B assessed by thromboelastometry and thrombin generation.

INTRODUCTION: Predicting the bleeding phenotype is crucial for the management of patients with moderate haemophilia. Global coagulation assays evaluate haemostasis more comprehensively than conventional methods. AIM: To explore global coagulation assays and the bleeding phenotype of patients with moderate haemophilia A (MHA) and B (MHB). METHODS: The MoHem study is a cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Thromboelastometry in whole blood and thrombin generation (TG) in platelet-poor plasma (1, 2.5 and 5 pM tissue factor (TF)) were compared with joint health (Haemophilia Joint Health Score (HJHS)) and treatment modality. RESULTS: We report on 61 patients from Oslo and Helsinki: 24 MHA and 37 MHB. By TG (2.5 pM TF), patients who had been without replacement therapy during the previous 12 months depicted higher endogenous thrombin potential (P = .03). In contrast, those who had low ETP (< median) captured higher HJHS (P = .02). Patients who had undergone orthopaedic surgery generated least thrombin (P = .02). By thromboelastometry, those without the need of factor consumption had short clotting times, and quick times to maximum velocity (< median values) (P = .03). Factor VIII/factor IX activity (FVIII/FIX:C) did not align with the bleeding phenotype, but FIX:C ≤ 3 IU/dL was associated with lower peak thrombin (P = .03). CONCLUSION: TG differentiated patients with moderate haemophilia according to HJHS, annual factor consumption, and whether orthopaedic surgery had been performed. Thromboelastometry differentiated according to factor consumption only. Global coagulation assays may assist predicting the bleeding phenotype in moderate haemophilia.

Treatment outcomes in persons with severe haemophilia B in the Nordic region: The B-NORD study.

INTRODUCTION: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). AIM: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. METHODS: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). RESULTS: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. CONCLUSION: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Haemophilia early arthropathy detection with ultrasound and haemophilia joint health score in the moderate haemophilia (MoHem) study.

INTRODUCTION: Detection of early arthropathy is crucial for the management of haemophilia, but data on moderate haemophilia are limited. Therefore, we evaluated joint health and treatment modalities in Nordic patients with moderate haemophilia A (MHA) and B (MHB). AIM: To explore and compare the Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) and Haemophilia Joint Health Score (HJHS) to detect early arthropathy in moderate haemophilia. METHODS: A cross-sectional, multicentre study covering Nordic patients with MHA and MHB. Arthropathy was evaluated by HEAD-US and HJHS 2.1. RESULTS: We assessed 693 joints in 118 patients. HEAD-US scores (medians [interquartile ranges]) were as follows: elbows 0 points (0-0), knees 0 (0-0) and ankles 0 (0-1). Respectively, by HJHS: elbows 0 (0-1), knees 0 (0-1) and ankles 0 (0-1). Cartilage (14%) and bone (13%) were most commonly affected by HEAD-US. Frequent HJHS findings were crepitus on motion in knees (39%), and loss of flexion (23%) and extension (13%) in ankles. HEAD-US correlated strongly with HJHS (elbows r = .70, knees r = .60 and ankles r = .65), but 24% had discordant scores. Joints with HJHS zero points, 5% captured HEAD-US ≥1 point. Moreover, 26% had HJHS findings without HEAD-US pathology. Notably, 31% of knees had crepitus on motion and normal HEAD-US. CONCLUSION: Overall, the joints attained low scores implying good joint health. HEAD-US correlated strongly with HJHS. In 5%, HEAD-US detected subclinical pathology. Crepitus on motion was frequently reported despite normal HEAD-US, thus not necessarily reflecting arthropathy. HEAD-US therefore improves the joint assessment in moderate haemophilia.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Direct comparison of two extended half-life PEGylated recombinant FVIII products: a randomized, crossover pharmacokinetic study in patients with severe hemophilia A.

An open-label, crossover randomized study was performed to compare the pharmacokinetics (PK) of damoctocog alfa pegol and rurioctocog alfa pegol, two recombinant factor VIII (FVIII) products indicated in patients with hemophilia A, both conjugated to polyethylene glycol to reduce clearance and extend time in circulation. Adult patients (N = 18) with severe hemophilia A (FVIII < 1 IU/dL), previously treated with any FVIII product for ≥ 150 exposure days, were randomized to receive a single 50 IU/kg infusion of damoctocog alfa pegol followed by rurioctocog alfa pegol, or vice versa, with ≥ 7-day washout between doses. FVIII activity was measured using the one-stage clotting assay. PK parameters, including area under the curve from time 0 to the last data point (AUC0-tlast, primary parameter), dose-normalized AUC (AUCnorm), and time to threshold, were calculated based on 11 time points between 0.25 and 120 h post-dose and evaluated using a noncompartmental model. Due to differences in batch-specific vial content used for the study, actual administered median doses were 54.3 IU/kg for damoctocog alfa pegol and 61.4 IU/kg for rurioctocog alfa pegol. Based on actual dosing, a significantly higher geometric mean (coefficient of variation [%CV]) AUCnorm was observed for damoctocog alfa pegol (43.8 h kg/dL [44.0]) versus rurioctocog alfa pegol (36.0 h kg/dL [40.1, P < 0.001]). Based on population PK modeling, median time to reach 1 IU/dL was 16 h longer for damoctocog alfa pegol compared with rurioctocog alfa pegol. No adverse events or any immunogenicity signals were observed. Overall, damoctocog alfa pegol had a superior PK profile versus rurioctocog alfa pegol. Trial registration number: NCT04015492 ( ClinicalTrials.gov identifier). Date of registration: July 9, 2019.

Achieving the unimaginable: Health equity in haemophilia.

Historically, treatment based on the availability of clotting factor replacement has resulted in an arcane guideline for the correction of factor deficiencies in people with haemophilia (PwH). While all other disease entities seek to restore function to a normal level, PwH are restricted to factor nadirs still equivalent to mild or moderate disease, resulting in continued risk of bleeding. A new treatment paradigm is needed based on the defined needs of PwH. A treatment model was developed by a panel of haemophilia providers, patient advocates and health economists to establish specific treatment milestones and targeted outcomes. The panel defined a series of treatment milestones to characterize the activity and outcomes linked to level of factor deficiency correction. All agreed that the ultimate goal should be 'functional cure' and 'health equity'. Seven levels to achieving a functional cure were identified, (a) Sustain life; (b) Minimal joint impairment; (c) Freedom from any spontaneous bleeds; (d) Attainment of 'normal' mobility; (e) Able to sustain minor trauma without additional intervention; (f) Ability to sustain major surgery or trauma; and (g) Normal haemostasis. A parallel set of patient-reported outcomes to achieve health equity was identified. These guidelines are now comparable with other disorders where the goal is to replace missing proteins to attain normal activity levels. As we are no longer limited by plasma supply due to the manufacture of recombinant factors, mimetics, and the early success of gene therapy, health equity is now achievable.