Can German Health Insurance Claims Data Fill Information Gaps in Rare Chronic Diseases: Use Case of Haemophilia A.

Claims data are increasingly discussed to evaluate health care for rare diseases (resource consumption, outcomes and costs). Using haemophilia A (HA) as a use case, this analysis aimed to generate evidence for the aforementioned information using German Statutory Health Insurance (SHI) claims data. Claims data (2017-2019) from the German SHI 'AOK Bayern - Die Gesundheitskasse' were used. Patients with ICD-10-GM codes D66 and HA medication were included in descriptive analyses. Severity levels were categorized according to HA medication consumption. In total, 257 patients were identified: mild HA, 104 patients (mean age: 40.0 years; SD: 22.9); moderate HA, 17 patients, (51.2 years; SD: 24.5); severe HA, 128 patients, (34.2 years; SD: 18.5). There were eight patients categorized with inhibitors (37.8 years; SD: 29.6). Psychotherapy was reported among 28.8% (mild) to 32.8% (severe) of patients. Joint disease was documented for 46.2% (mild) to 61.7% (severe) of patients. Mean direct costs per patient per year were 1.34× for mild, 11× for moderate, 81× higher for severe HA patients and 223× higher for inhibitor patients than the mean annual expenditure per AOK Bayern insurant (2019). German SHI data provide comprehensive information. The patient burden in HA is significant with respect to joint disease and psychological stress regardless of the HA severity level. The cost of HA care for patients is high. Large cost ranges suggest that the individual situation of a patient must be considered when interpreting costs. The main limitation of SHI data analysis for HA was the lack of granularity of ICD codes.

Emicizumab versus immunosuppressive therapy for the management of acquired hemophilia A.

BACKGROUND: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII (FVIII). Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST. OBJECTIVE: To compare outcomes of two studies that used either IST (GTH-AH 01/2010; n=101) or prophylaxis with emicizumab (GHT-AHA-EMI; n=47) early after diagnosis of AHA. METHODS: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival. RESULTS: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio 0.325, 95% confidence interval (CI) 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab treated patients (0%) compared with IST treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than IST (7%). Overall survival after 24 weeks was better with emicizumab (90% versus 76%, HR 0.44; 95% CI 0.24-0.81). CONCLUSION: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections, and improved overall survival.

Management of Deep Vein Thrombosis: An Update Based on the Revised AWMF S2k Guideline.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of venous thromboembolism (VTE). Most DVTs affect the lower-extremity veins. Since the symptoms of DVT are non-specific, a prompt and standardised diagnostic work-up is essential to minimise the risk of PE in the acute phase and to prevent thrombosis progression, post-thrombotic syndrome and VTE recurrence in the long-term. Only recently, the AWMF S2k guidelines on Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism have been revised. In the present article, we summarize current evidence and guideline recommendations focusing on lower-extremity DVT (LEDVT). Depending on whether the diagnostic work-up is performed by a specialist in vascular medicine or by a primary care physician, different diagnostic algorithms are presented that combine clinical probability, D-dimer testing and diagnostic imaging. The diagnosis of ipsilateral recurrent DVT poses a particular challenge and is presented in a separate algorithm. Anticoagulant therapy is an essential part of therapy, with current guidelines clearly favouring regimens based on direct oral anticoagulants over the traditional sequential therapy of parenteral anticoagulants and vitamin K antagonists. For most DVTs, a duration of therapeutic-dose anticoagulation of at least 3 to 6 months is considered sufficient, and this raises the question of the risk of VTE recurrence after discontinuation of anticoagulation and the need for secondary prophylaxis in the long-term. Depending on the circumstances and trigger factors that have contributed to the occurrence of DVT, management strategies are presented that allow decision-making taking into account the individual bleeding risk and patient's preferences.

Recurrent Venous Thromboembolism in Patients on Anticoagulation: An Update Based on the Revised AWMF S2k Guideline.

In the recently updated German S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," a new chapter was incorporated about recurrent venous thromboembolism (VTE) in patients on anticoagulation treatment. Despite the high efficacy of anticoagulation in most patients, approximately 2% experience a recurrent VTE event while receiving anticoagulant drugs. The proper diagnosis of the recurrent VTE is important and possible only with the knowledge of localization and thrombus burden of the primary VTE event. Possible reasons for recurrent VTE events in patients on anticoagulation are non-adherence to medication, sub-therapeutic drug levels due to resorption disorders or drug interactions, or concomitant disease with high thrombogenicity. Cancer is the most common underlying disease, but it is important to investigate and understand possible other causes whenever a breakthrough VTE event occurs. This results in the recommendation that in patients with VTE recurrence on therapeutic anticoagulation, in particular, the presence of malignant disease, antiphospholipid syndrome, and rare diseases like paroxysmal nocturnal hemoglobinuria or Behçet's disease should be considered. For VTE recurrence during heparin therapy, heparin-induced thrombocytopenia type II needs to be ruled out, even if platelet counts are within the normal range. Although the mechanisms of recurrence on anticoagulation can be evaluated in a certain degree, clinical evidence for the management of recurrent VTE in anticoagulated patients is minimal and mainly based on expert opinion. Switching anticoagulant medication and intensifying anticoagulant treatment are possible options.

Current Topics from the Revised German S2k Guideline on Diagnosis and Treatment of Venous Thromboembolism.

It is an honor and a great pleasure for us to be guest editors for this special issue of Hämostaseologie - Progress in Haemostasis, which addresses important issues surrounding the complex of venous thromboembolism (VTE). In February 2023, the revised guideline on "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism" has been published on the website of the Association of the Scientific Medical Societies in Germany (AWMF)1. This guideline was drawn up under the leadership of the German Society of Angiology (DGA), and representatives of 17 scientific societies contributed to its content. As an S2k guideline, its recommendations are consensus based and are the result of a systematic review and evaluation of current evidence and consideration of the benefits and harms of diagnostic and therapeutic options. In this special issue, guideline authors provide a comprehensive overview of selected guideline topics which might be of clinical relevance to our readers and our community of haemostaseologists.

Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec transfers a human factor (F)VIII coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. OBJECTIVES: To present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. METHODS: GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate, annualized FVIII utilization, FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults. Safety was assessed by adverse events (AEs). RESULTS: At week 156, 131 of 134 participants remained in the study; overall, 17 of 134 resumed prophylaxis. Mean annualized bleeding rate for treated bleeds decreased from 4.8 (SD, 6.5) bleeds/y at baseline to 0.8 (SD, 2.3; P < .0001) bleeds/y after prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/y during year 3. Annualized FVIII utilization decreased 96.8% from baseline after prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2 and 3 than between years 1 and 2. At the end of year 3, clinically meaningful improvements in the Haemophilia-Specific Quality of Life Questionnaire for Adults Total Score were observed (mean change from baseline, 6.6; 95% CI, 4.24-8.87; P < .0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. CONCLUSION: Hemostatic efficacy was maintained, and safety remained unchanged from previous years.

Benefits and risks of non-factor therapies: Redefining haemophilia treatment goals in the era of new technologies.

INTRODUCTION: Over the last decades progress in haemophilia treatment has been remarkable and prophylaxis with clotting factor concentrates in haemophilia A and B has been established as the standard of care in individuals with haemophilia and a severe bleeding phenotype. Besides clotting factor products with prolonged half-life non-factor therapies were developed which enable prophylaxis via subcutaneous administration. Factor VIIIa mimetics like emicizumab facilitate the coagulation pathway and are used in routine clinical practice for indivdiduals with haemophilia A. Rebalancing therapeutic agents like fitusiran, concizumab, marstacimab and serpin PC block the anticoagulant pathway and clinical trials using these products in individuals with haemophilia A and B are ongoing. AIM AND METHODS: A narrative review to asess the benefits and risks of non-factor therapies taking in to account re-defined haemophilia treatment goals. RESULTS: Prophylaxis for prevention of bleeds using non-factor products by subcutaneous administration is effective and results in reductions of bleeding episodes in individuals with haemophilia A or B with and without inhibitors. The treatment with emicizumab showed tolerable safety both in clinical trials and long-term real-world observations with few thrombotic events. In some clinical trials with rebalancing therapies (fitusiran and concizumab) thrombotic events occurred. Monitoring of the haemostatic function of novel therapies especially with concomitant haemostatic treatment is not yet established. CONCLUSION: With the advent of novel therapeutic agents including factor concentrates with ultra-long half-life and improved FVIIIa mimetics aimed at raising the bar of protection into the non-hemophilic range redefinition of haemophilia treatment goals is eagerly needed.

Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper.

BACKGROUND: With the widespread use of direct oral anticoagulants (DOACs), there is an urgent need for a rapid assay to exclude clinically relevant plasma levels. Accurate and rapid determination of DOAC levels would guide medical decision-making to (1) determine the potential contribution of the DOAC to spontaneous or trauma-induced hemorrhage; (2) identify appropriate candidates for reversal, or (3) optimize the timing of urgent surgery or intervention. METHODS AND RESULTS: The DOAC Dipstick test uses a disposable strip to identify factor Xa- or thrombin inhibitors in a urine sample. Based on the results of a systematic literature search followed by an analysis of a simple pooling of five retrieved clinical studies, the test strip has a high sensitivity and an acceptably high negative predictive value when compared with levels measured with liquid chromatography tandem mass spectrometry or calibrated chromogenic assays to reliably exclude plasma DOAC concentrations ≥30 ng/mL. CONCLUSION: Based on these data, a simple algorithm is proposed to enhance medical decision-making in acute care indications useful primarily in hospitals not having readily available quantitative tests and 24/7. This algorithm not only determines DOAC exposure but also differentiates between factor Xa and thrombin inhibitors to better guide clinical management.

Measurement of recombinant porcine factor VIII in patients with congenital haemophilia A and inhibitors in the presence of emicizumab.

INTRODUCTION: Recombinant porcine factor VIII (rpFVIII) is a treatment option for break-through bleeds in patients with congenital haemophilia A with inhibitors (CHAwI) on emicizumab. However, there are limited data about the measurement of rpFVIII in the presence of emicizumab. AIM: To analyse whether rpFVIII can be measured with a chromogenic assay with bovine component (bCSA) in plasma from CHAwI on emicizumab treatment. METHODS: In the first part of the study, FVIII deficient plasma was spiked with rpFVIII, in the second part, commercial plasma from CHAwI was spiked with emicizumab and rpFVIII, and in the third part, plasma from CHAwI on emicizumab treatment was spiked with rpFVIII. FVIII was then measured with bCSA and a chromogenic assay with human component (hCSA). Thrombin generation (TG) and clot-waveform analysis (CWA) were also carried out. RESULTS: The recovery of rpFVIII measured with bCSA is approximately 80% and is further influenced by the presence of an anti-porcine inhibitor. rpFVIII assessed with hCSA was influenced by emicizumab. CWA and TG showed a weak correlation with baseline emicizumab concentration, but peak thrombin and CWA correlated well with increasing emicizumab concentrations and rpFVIII activities. CONCLUSION: This study indicates that rpFVIII can be measured in the presence of emicizumab with a bCSA. A calibration curve for the measurement of rpFVIII with bCSA should be established.

[Venous thromboembolism - was is new in the revised AWMF guideline?] / Venöse Thromboembolie ­ was ist neu in der aktualisierten AWMF-Leitlinie?

For the diagnosis of a lower-extremity deep vein thrombosis (LEDVT), venous duplex ultrasound is the method of first choice. If a qualified ultrasonography is not timely available, D-dimer testing, and limited ultrasound protocols (point-of-care ultrasound, POCUS) can contribute to therapeutic decision-making when clinical probability is low. A DOAC-based treatment regimen is preferable to a vitamin K antagonist for both acute therapy and secondary prophylaxis of venous thromboembolism (VTE). Treatment with DOACs is unproblematic up to a body weight (BW) of 120 kg or a body mass index (BMI) of 40 kg/m². Weight restrictions are no longer recommended for apixaban and rivaroxaban, but determination of DOAC trough and peak levels is recommended in the extremely obese and patients after bariatric surgery. In cancer-associated VTE, the direct factor Xa inhibitors are a good and safe alternative to low-molecular weight heparins (LMWH) for many patients; the adherence to oral therapy is also higher. Meaningful initial documentation and structured follow-up after LEDVT and pulmonary embolism (PE) are important in order to make an individualized risk-benefit assessment at the end of the therapy phase with regard to continued pharmacological secondary prophylaxis and to reassess patients' symptoms indicating post-thrombotic syndrome (PTS) or chronic thromboembolic pulmonary hypertension (CTEPH).

Evaluation of collagen turnover biomarkers as an objective measure for efficacy of treatment with rurioctocog alfa pegol in patients with hemophilia A: a secondary analysis of a randomized controlled trial.

BACKGROUND: Patients with hemophilia who have recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor (F) VIII (FVIII) can reduce HA, but there is a need for objective outcome measures to evaluate treatment efficacy. OBJECTIVES: Evaluate and assess collagen turnover biomarkers in patients with hemophilia A to determine the efficacy of rurioctocog alfa pegol treatment and understand their potential as tools for guiding treatment decisions and monitoring outcomes. METHODS: Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1 to 3 International Units (IU)/dL or 8 to 12 IU/dL (PROPEL study, NCT0285960). RESULTS: Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1 to 3 IU/dL (P = .049, P < .0001) and 8 to 12 IU/dL FVIII trough levels (P = .0002, P < .0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1 to 3 IU/dL FVIII trough level (P = .0001, P = .009) and 23% at 8 to 12 IU/dL FVIII trough level (P = .0002, P = .001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (P = .01, P = .005). When stratified by prior treatment, changes in C3M (P = .03) and C4M (P = .02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry. CONCLUSION: Joint improvement measured by collagen remodeling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA.

Indirect treatment comparisons of the gene therapy etranacogene dezaparvovec versus extended half-life factor IX therapies for severe or moderately severe haemophilia B.

INTRODUCTION: Etranacogene dezaparvovec gene therapy for haemophilia B demonstrated superior efficacy at 24 months in reducing bleeds versus a ≥6-month lead-in period of prophylaxis with FIX products in the phase 3 trial, HOPE-B. In the absence of head-to-head comparisons of etranacogene dezaparvovec versus FIX products, indirect treatment comparisons (ITC) can be used. AIM: To compare the efficacy of etranacogene dezaparvovec versus rIX-FP, rFIXFc and N9-GP using ITC, and support HOPE-B results. METHODS: Data were leveraged from Phase 3 pivotal trials: HOPE-B, PROLONG-9FP, B-LONG and Paradigm 2. Annualised bleeding rates (ABR), spontaneous (AsBR) and joint (AjBR) bleeding rates, percentage of patients with no bleeds, and FIX consumption were assessed using inverse probability of treatment weighting and matching adjusted indirect comparisons. RESULTS: Etranacogene dezaparvovec demonstrated statistically significantly lower bleeding rates versus all comparators. Rate ratios for ABR, AsBR and AjBR versus rIX-FP were 0.19 (p < .0001), 0.08 (p < .0001) and 0.09 (p < .0001), respectively. Rate ratios for ABR, AsBR and AjBR versus rFIXFc were 0.14 (p < .0001), 0.13 (p = .0083) and 0.15 (p = .0111), respectively. Rate ratios for ABR and AsBR, versus N9-GP were 0.24 (p = .0231) and 0.13 (p = .0071), respectively. Etranacogene dezaparvovec demonstrated significantly higher percentage of patients with no bleeds versus rIX-FP and rFIXFc; odds ratios: 17.60 (p < .0001) and 5.65 (p = .0037), respectively. Etranacogene dezaparvovec resulted in significantly lower FIX consumption than all comparators. CONCLUSIONS: ITC suggests that etranacogene dezaparvovec offers patients with haemophilia B (≤2% of normal FIX expression) a single dose treatment that can significantly reduce bleeding rates and eliminate routine infusions associated with FIX therapies.

Emicizumab for the Treatment of Acquired Hemophilia A: Consensus Recommendations from the GTH-AHA Working Group.

BACKGROUND: Acquired hemophilia A (AHA) is a severe bleeding disorder caused by autoantibodies against coagulation factor VIII (FVIII). Standard treatment consists of bleeding control with bypassing agents and immunosuppressive therapy. Emicizumab is a bispecific antibody that mimics the function of activated FVIII irrespective of the presence of neutralizing antibodies. Recently, the GTH-AHA-EMI study demonstrated that emicizumab prevents bleeds and allows to postpone immunosuppression, which may influence future treatment strategies. AIM: To provide clinical practice recommendations on the use of emicizumab in AHA. METHODS: A Delphi procedure was conducted among 33 experts from 16 German and Austrian hemophilia care centers. Statements were scored on a scale of 1 to 9, and agreement was defined as a score of ≥7. Consensus was defined as ≥75% agreement among participants, and strong consensus as ≥95% agreement. RESULTS: Strong consensus was reached that emicizumab is effective for bleed prophylaxis and should be considered from the time of diagnosis (100% consensus). A fast-loading regimen of 6 mg/kg on day 1 and 3 mg/kg on day 2 should be used if rapid bleeding prophylaxis is required (94%). Maintenance doses of 1.5 mg/kg once weekly should be given (91%). Immunosuppression should be offered to patients on emicizumab if they are eligible based on physical status (97%). Emicizumab should be discontinued when remission of AHA is achieved (97%). CONCLUSION: These GTH consensus recommendations provide guidance to physicians on the use of emicizumab in AHA and follow the results of clinical trials that have shown emicizumab is effective in preventing bleeding in AHA.

Cancer-Associated Venous Thromboembolism-Diagnostic and Therapeutic Considerations: An Update Based on the Revised AWMF S2k Guideline.

Patients with cancer are prone to develop venous thromboembolism (VTE) with negative impact on quality of life, morbidity, and mortality. Treatment of established VTE is often complex in patients with cancer. Treatment of cancer-associated VTE (CAT) basically comprises initial and maintenance treatment, for 3 to 6 months, secondary preventions, and treatment in special situations. Therapeutic anticoagulation is the treatment of choice in CAT. In addition to the efficacy and safety of low-molecular-weight heparin (LMWH) that had been recommended for decades, direct oral anti-factor Xa inhibitors, a subgroup of direct oral anticoagulants (DOACs), demonstrated their advantages along with the accompanying concerns in several randomized controlled treatment trials of CAT. The latest guidelines, such as the German AWMF-S2k Guideline "Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism," agree with each other on most aspects with respect to the treatment of CAT. Encompassing recent clinical studies, and meta-analyses, as well as the focus on some special management aspects of CAT, the objective of this review is to present a current overview and recommendations for the treatment of CAT.

Emicizumab prophylaxis in patients with acquired haemophilia A (GTH-AHA-EMI): an open-label, single-arm, multicentre, phase 2 study.

BACKGROUND: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis. METHODS: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete. FINDINGS: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab). INTERPRETATION: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising. FUNDING: This study was supported by funding from Hoffman-La Roche.

Accreditation model of European Haemophilia Centres in the era of novel treatments and gene therapy.

INTRODUCTION: The international certification of haemophilia centres in Europe is run by the European Association of Haemophilia and Allied Disorders (EAHAD) and European Haemophilia Consortium (EHC) since 2013. The centres are designated as European Haemophilia Comprehensive Care Centres (EHCCC) or European Haemophilia Treatment Centres (EHTC), based on the specific requirements which evaluate centres' ability to provide care for patients with haemophilia and allied disorders. AIM: To establish the new protocol for accreditation of European Haemophilia Centres. METHODS: EAHAD, in collaboration with EHC, established Accreditation Working Group with the aim to define necessary measures to safeguard quality and improvement of bleeding disorders care throughout Europe and to build a novel model for accreditation of European Haemophilia Centres. RESULTS: The European guidelines for certification of haemophilia centres have been updated to guidelines for the accreditation and include all the requirements regarding facilities, laboratory and personnel needed for optimal management of novel treatment options, including the introduction of the hub-and-spoke model for delivery of gene therapy. A pilot project for the accreditation of haemophilia centres including on-site audit has been designed. CONCLUSION: Implementation of the novel accreditation protocol of the haemophilia treatment and haemophilia gene therapy centres has been made to further improve the quality of care for patients with haemophilia and other inherited bleeding disorders.

Health-related quality of life following valoctocogene roxaparvovec gene therapy for severe hemophilia A in the phase 3 trial GENEr8-1.

BACKGROUND: Severe hemophilia A (HA) negatively impacts health-related quality of life (HRQOL). OBJECTIVES: We aimed to analyze HRQOL in adult men with severe HA without inhibitors after valoctocogene roxaparvovec gene transfer in the phase 3 trial GENEr8-1. METHODS: Participant-reported outcomes were the hemophilia-specific quality of life questionnaire for adults (Haemo-QOL-A), the EQ-5D-5L instrument, the Hemophilia Activities List (HAL), and the Work Productivity and Activity Impairment Questionnaire: Hemophilia Specific (WPAI+CIQ:HS). Participants completed the questionnaires at baseline and through 104 weeks postinfusion with 6 × 1013 vg/kg of valoctocogene roxaparvovec. Scores were analyzed per participant characteristics and outcomes. RESULTS: For 132 HIV-negative participants, mean change from baseline in Haemo-QOL-A Total Score met the anchor-based clinically important difference (CID: 5.5) by week 12; the mean (SD) increase was 7.0 (12.6) at week 104. At week 104, improvement in Consequences of Bleeding, Treatment Concern, Worry, and Role Functioning domain scores exceeded the CID (6). EQ-5D-5L Utility Index scores improved above the CID at week 52, but not at week 104. EQ-5D-5L visual analog scale and HAL scores increased from baseline to week 104. Participants reported less activity and work impairment at week 104 than baseline. Participants with problem joints had lower mean baseline Haemo-QOL-A Total and domain scores than those without them, but improved over 104 weeks, except for 11 participants with ≥3 problem joints. Participants with 0 bleeds during the baseline prophylaxis period reported Haemo-QOL-A score improvements above the CID, including in the Consequences of Bleeding domain. CONCLUSION: Valoctocogene roxaparvovec provided clinically meaningful HRQOL improvement for men with severe HA.

Efficacy of rFIXFc versus N9-GP Prophylaxis in Patients with Hemophilia B: Matching-Adjusted Indirect Comparison of B-LONG and PARADIGM 2 Trials.

Purpose: For patients with hemophilia B, extended half-life factor IX (FIX) products are available for prophylaxis and for treating bleeds. Different methods are used to extend the half-lives of recombinant FIX Fc fusion protein (rFIXFc) and nonacog beta pegol (N9-GP). This affects their biodistribution and plasma FIX levels, although differences do not always correlate with clinical outcomes. A matching-adjusted indirect comparison (MAIC) of prophylaxis with rFIXFc and N9-GP was performed, based on licensed dosing in the European Union. Patients and Methods: Combined rFIXFc data from the weekly and individualized interval prophylaxis arms of the B-LONG clinical trial, and N9-GP data from the 40 IU/kg once-weekly prophylaxis arm of PARADIGM 2 were used in a MAIC. Individual patient data for rFIXFc (n=87) were matched to aggregated data for N9-GP (n=29). Estimated annualized bleeding rates (ABRs) for rFIXFc were recalculated using a Poisson regression model with adjustment for over-dispersion, and compared with ABRs reported for N9-GP, using incidence rate ratios (IRRs) with 95% confidence interval (CI). Results: There was no evidence of significant differences in estimated ABRs between prophylaxis with rFIXFc and N9-GP. Analysis of pooled rFIXFc weekly and interval-adjusted dosing compared with N9-GP 40 IU/kg once weekly produced estimated ABRs of 2.59 versus 2.51 (IRR 1.03; 95% CI 0.56-1.89), as well as 1.34 versus 1.22 (IRR 1.10; 95% CI 0.42-2.91) and 1.13 versus 1.29 (IRR 0.88; 95% CI 0.47-1.63) for overall, spontaneous, and traumatic bleeding events, respectively. Conclusion: The study did not reveal any significant differences in the efficacy of rFIXFc and N9-GP prophylaxis. Given differences in trough levels (rFIXFc dosing was targeted to achieve a trough 1-3 IU/dL above baseline versus a reported estimated N9-GP mean trough of 27.3 IU/dL), interpreting plasma FIX levels as potential surrogate efficacy markers requires consideration of compound-specific pharmacokinetic profiles.