Publications by authors named "Robert Klamroth"

55 Publications

Consensus Recommendations for Intramuscular COVID-19 Vaccination in Patients with Hemophilia.

Hamostaseologie 2021 Apr 15. Epub 2021 Apr 15.

Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Background:  Currently available coronavirus disease 2019 (COVID-19) vaccines are approved for intramuscular injection and efficacy may not be ensured when given subcutaneously. For years, subcutaneous vaccination was recommended in patients with hemophilia to avoid intramuscular bleeds. Therefore, recommendations for the application of COVID-19 vaccines are needed.

Methods:  The Delphi methodology was used to develop consensus recommendations. An initial list of recommendations was prepared by a steering committee and evaluated by 39 hemophilia experts. Consensus was defined as ≥75% agreement and strong consensus as ≥95% agreement, and agreement as a score ≥7 on a scale of 1 to 9. After four rounds, a final list of statements was compiled.

Recommendations:  Consensus was achieved that COVID-19 vaccines licensed only for intramuscular injection should be administered intramuscularly in hemophilia patients. Prophylactic factor replacement, given on the day of vaccination with a maximum interval between prophylaxis and vaccination of 24 hours (factor VIII and conventional factor IX concentrates) or 48 hours (half-life extended factor IX), should be provided in patients with moderate or severe hemophilia. Strong consensus was achieved that patients with mild hemophilia and residual factor activity greater than 10% with mild bleeding phenotype or patients on emicizumab usually do not need factor replacement before vaccination. Swelling, erythema, and hyperthermia after vaccination are not always signs of bleeding but should prompt consultation of a hemophilia care center. In case of injection-site hematoma, patients should receive replacement therapy until symptoms disappear.

Conclusions:  Consensus was achieved on recommendations for intramuscular COVID-19 vaccination after replacement therapy for hemophilia patients depending on disease severity.
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http://dx.doi.org/10.1055/a-1401-2691DOI Listing
April 2021

Diagnosis and Management of Vaccine-Related Thrombosis following AstraZeneca COVID-19 Vaccination: Guidance Statement from the GTH.

Hamostaseologie 2021 Apr 1. Epub 2021 Apr 1.

Institut für Immunologie und Transfusionsmedizin, Universitätsmedizin Greifswald, Greifswald, Germany.

The COVID-19 pandemic is an ongoing global healthcare crisis. Based on reports of atypically located thromboses following vaccination with the AstraZeneca COVID-19 vaccine, the Society of Thrombosis and Haemostasis Research (GTH) has issued guidance statements on the recognition, diagnosis, and treatment of this rare complication. It shares pathophysiological features with heparin-induced thrombocytopenia (HIT) and is referred to as vaccine-induced prothrombotic immune thrombocytopenia (VIPIT).
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http://dx.doi.org/10.1055/a-1469-7481DOI Listing
April 2021

Efficacy of rFVIIIFc versus Emicizumab for the Treatment of Patients with Hemophilia A without Inhibitors: Matching-Adjusted Indirect Comparison of A-LONG and HAVEN Trials.

J Blood Med 2021 25;12:115-122. Epub 2021 Feb 25.

The Bleeding and Clotting Disorders Institute, University of Illinois College of Medicine-Peoria, Peoria, IL, USA.

Purpose: Primary prophylaxis, using factor VIII replacement, is the recognized standard of care for severe hemophilia A. Recombinant factor VIII-Fc fusion protein (rFVIIIFc) and emicizumab, a humanized, bispecific antibody, are approved for routine prophylaxis of bleeding episodes in severe hemophilia A. These products have different mechanisms of action, methods of administration and treatment schedules. In the absence of head-to-head trials, indirect treatment comparisons can provide informative evidence on the relative efficacy of the two treatments. The aim of the study was to compare the approved dosing regimens for each product, rFVIIIFc individualized prophylaxis and emicizumab administered once every week (Q1W), every 2 weeks (Q2W) or every 4 weeks (Q4W), based on clinical trial evidence.

Patients And Methods: The comparison was conducted using matching-adjusted indirect comparison since clinical evidence did not form a connected network. Individual patient data for rFVIIIFc (A-LONG) were compared with data for emicizumab (HAVEN trial program) for mean annualized bleeding rate (ABR) and proportion of patients with zero bleeds. Safety data reported across the analyzed treatment arms were tabularized but not formally compared.

Results: After matching, no significant differences were observed between mean ABR for rFVIIIFc and emicizumab administered Q1W, Q2W or Q4W. The proportion of patients with zero bleeds was significantly higher with rFVIIIFc compared with emicizumab administered Q4W (51.2% versus 29.3%, respectively; odds ratio 2.53; 95% confidence interval 1.09-5.89); no significant differences noted when rFVIIIFc was compared with emicizumab administered Q1W or Q2W. The mean number of adverse events expressed per participant was 1.9 for individualized prophylaxis with rFVIIIFc and 3.7-4.0, 4.1 and 3.6 for emicizumab administered Q1W, Q2W or Q4W, respectively.

Conclusion: This indirect treatment comparison suggests that rFVIIIFc individualized prophylaxis is more efficacious than emicizumab Q4W, and at least as effective as more frequent emicizumab regimens, for the management of hemophilia A.
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http://dx.doi.org/10.2147/JBM.S288283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921628PMC
February 2021

Rurioctocog alfa pegol PK-guided prophylaxis in hemophilia A: results from the phase 3 PROPEL study.

Blood 2021 Apr;137(13):1818-1827

Baxalta US Inc, a Takeda company, Cambridge, MA.

Rurioctocog alfa pegol prophylaxis targeting factor VIII (FVIII) troughs ≥1% has shown to be efficacious with an acceptable safety profile in people with hemophilia A (PwHA). The PROPEL trial compared safety and efficacy of 2 target FVIII troughs in PwHA aged 12 to 65 years, with severe disease, annualized bleeding rate ≥2, and previous FVIII treatment. PwHA were randomized to 12 months' pharmacokinetic (PK)-guided rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1% to 3% (reference arm) or 8% to 12% (elevated arm); first 6 months was treatment-adjustment period. The primary endpoint was absence of bleeds during the second 6 months, analyzed using multiple imputations (full analysis set [FAS]). In the 1% to 3% and 8% to 12% arms, respectively, point estimates (95% confidence interval) of proportions of PwHA with zero total bleeds were 42% (29% to 55%) and 62% (49% to 75%) in FAS (N = 115; P = .055) and 40% (27% to 55%) and 67% (52% to 81%) in per-protocol analysis set (N = 95; P = .015). Dosing frequency and consumption varied in each arm. Adverse events (AEs) occurred in 70/115 (60.9%) PwHA; serious AEs in 7/115 (6%) PwHA, including 1 treatment-related in 8% to 12% arm (transient anti-FVIII inhibitor). There were no deaths, serious thrombotic events, or AE-related discontinuations. PK-guided prophylaxis was achievable and efficacious in both arms. No new safety signals were observed in the 8% to 12% arm. These results demonstrate elevated FVIII troughs can increase the proportion of PwHA with zero bleeds and emphasize the importance of personalized treatment. This trial was registered at www.clinicaltrials.gov as #NCT02585960.
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http://dx.doi.org/10.1182/blood.2020005673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039905PMC
April 2021

Optimizing the management of patients with haemophilia A and inhibitors in the era of emicizumab: Recommendations from a German expert panel.

Haemophilia 2020 Sep 16. Epub 2020 Sep 16.

Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany.

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100 U/kg/d for ≥24 hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring.
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http://dx.doi.org/10.1111/hae.14010DOI Listing
September 2020

Practical Guidance of the GTH Haemophilia Board on the Use of Emicizumab in Patients with Haemophilia A.

Hamostaseologie 2020 Dec 25;40(5):561-571. Epub 2020 Jun 25.

Haemophilia Center Rhine Main, HZRM, Mörfelden-Walldorf, Germany.

Emicizumab has been approved for bleeding prophylaxis in patients with haemophilia A (PWHAs) with or without inhibitors. Because of substantial differences between factor VIII (FVIII) and Emicizumab, the 'Ständige Kommission Hämophilie' of the German, Austrian, Swiss Society for Thrombosis and Haemostasis Research (GTH) established a practical guidance for the use of Emicizumab in PWHAs. A systematic literature research was conducted in PubMed. Based on this and on personal experience, this practical guidance has been developed. Each single statement has been discussed among members of the 'Ständige Kommission Hämophilie' and revised accordingly. The final set of recommendations has been approved by all authors analogous to the Delphi method. This practical guidance is provided for physicians treating PWHAs with regard to general aspects, patient education, bleeding treatment, surgery, use of Emicizumab in previously untreated patients (PUPs), patients with newly diagnosed inhibitors and elderly patients. Patients should be treated in expert centres and adequate laboratory tests to monitor Emicizumab levels, FVIII replacement and inhibitors should be available. Early experience of immune tolerance induction protocols integrating Emicizumab is reviewed, and the limited experience in PUPs and very young children is described. So far, no thromboembolic complications have been reported with the concomitant use of FVIII or recombinant activated FVII for bleeding treatment or surgery. Activated prothrombin complex concentrate doses of >100 U/kg for >24 hours should be avoided whenever possible because of the high risk of thrombosis and/or thrombotic microangiopathy. In conclusion, this study is designed to support haemophilia physicians using Emicizumab in physicians treating hemophilia and using (PWHAs). With further post-marketing experience and trials, regular updates are necessary.
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http://dx.doi.org/10.1055/a-1127-6476DOI Listing
December 2020

Venous thromboembolism in patients with COVID-19 (SARS-CoV-2 infection) - a position paper of the German Society of Angiology (DGA).

Vasa 2020 Jun 5;49(4):259-263. Epub 2020 Jun 5.

Venous Centre, Klinikum Arnsberg GmbH, Arnsberg, Germany.

As observed in other infections with a systemic inflammatory response, severe COVID-19 is associated with hypercoagulability and a prothrombotic state. Currently, there is growing evidence that pulmonary embolism and thrombosis contribute to adverse outcomes and increased mortality in critically ill patients with COVID-19. The optimal thromboprophylactic regimen for patients with COVID-19 is not known. Whereas pharmacologic thromboprophylaxis is generally recommended for all hospitalized COVID-19 patients, adequate dosing of anticoagulants remains a controversial issue. Therefore, we summarize current evidence from the available literature and, on behalf of the German Society of Angiology (DGA), we aim to provide advice to establish an improved and more uniform strategy for thromboprophylaxis in patients with COVID-19.
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http://dx.doi.org/10.1024/0301-1526/a000885DOI Listing
June 2020

Coagulopathy in COVID-19 and Its Implication for Safe and Efficacious Thromboprophylaxis.

Hamostaseologie 2020 Aug 4;40(3):264-269. Epub 2020 Jun 4.

Institut für Experimentelle Hämatologie und Transfusionsmedizin, Universitätsklinik Bonn, Bonn, Germany.

The novel coronavirus, SARS-CoV-2, is causing a global pandemic of life-threatening multiorgan disease, called COVID-19. Accumulating evidence indicates that patients with COVID-19 are at significant risk of thromboembolic complications, mainly affecting the venous, but also the arterial vascular system. While the risk of venous thromboembolism (VTE) appears to be higher in patients requiring intensive care unit support compared to those admitted to general wards, recent autopsy findings and data on the timing of VTE diagnosis relative to hospitalization clearly suggest that thromboembolic events also contribute to morbidity and mortality in the ambulatory setting. In addition to a severe hypercoagulable state caused by systemic inflammation and viral endotheliitis, some patients with advanced COVID-19 may develop a coagulopathy, which meets established laboratory criteria for disseminated intravascular coagulation, but is not typically associated with relevant bleeding. Similar to other medical societies, the Society of Thrombosis and Haemostasis Research has issued empirical recommendations on initiation, dosing, and duration of pharmacological VTE prophylaxis in COVID-19 patients.
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http://dx.doi.org/10.1055/a-1178-3551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416221PMC
August 2020

Redefining prophylaxis in the modern era.

Haemophilia 2021 Feb 29;27 Suppl 3:21-27. Epub 2020 May 29.

Department of Internal Medicine, Hemophilia Treatment Centre, Vivantes Klinikum im Friedrichshain, Berlin, Germany.

Prophylaxis is the globally accepted standard of care for persons with haemophilia and presents many advantages over episodic treatment. The prophylaxis benefits include bleed reduction, reduction in musculoskeletal complications and improvement in the quality of life. The currently evolving novel therapies for the management of haemophilia has ushered a new era characterized by improved prophylaxis targets and outcomes. These redefined targets and outcomes have necessitated the need to also redefine prophylaxis. In this state-of-the-art review, we redefine prophylaxis in the modern era by revisiting its definition, presenting data to support higher trough levels to achieve with prophylaxis and introducing steady-state haemostasis as a possible new target for prophylaxis.
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http://dx.doi.org/10.1111/hae.14035DOI Listing
February 2021

The Patient Experience of Gene Therapy for Hemophilia: Qualitative Interviews with Trial Patients.

Patient Prefer Adherence 2020 22;14:767-770. Epub 2020 Apr 22.

Department for Internal Medicine, Vascular Medicine and Coagulation Disorders, Vivantes Klinikum im Friedrichshain, Berlin D - 10249, Germany.

Background: The phase ½ hemophilia B clinical trial (AMT-060) demonstrated stable endogenous FIX levels after 3.5 years (mean FIX activity between 5.1% and 7.5%) with continued reductions in annualized bleeds to near zero with the higher dose, and a 78-96% reduction by year in exogenous FIX use.

Objective: The views of all the three participants from Germany participating in the AMT-060 study have been investigated about their experiences with conventional and gene therapy and the effects of the forms of therapy on everyday life.

Patients/methods: The patients (aged 33-35 years) performed regular prophylactic replacement with factor IX concentrate prior to the gene therapy, reported 0-7 bleeds in the year prior to the treatment, with Hemophilia Joint Health Scores of 0-8. Following topics have been investigated "dealing with illness", "participation in studies", "perception of conventional therapy", "perception of gene therapy", "significance of participation in gene therapy studies", "therapy of haemophilia after the end of the study".

Results: All three participants have started to become more active and do more sports. However, they expressed anxiety about not knowing how long the effect would last and they felt that psychological support would be needed if the factor IX level fell back in the future. No patient expressed concern about any long-term potential negative consequences of gene therapy.

Conclusion: Gene therapy has the potential to change the life of patients with haemophilia not only by the reduction of bleeding events but also by the increase of active and sportive activities.
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http://dx.doi.org/10.2147/PPA.S239810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184858PMC
April 2020

Factor VIII activity and bleeding risk during prophylaxis for severe hemophilia A: a population pharmacokinetic model.

Haematologica 2020 04 23. Epub 2020 Apr 23.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Cà Granda Foundation, Maggiore Hospital Policlinic, Milan, Italy.

During factor VIII prophylaxis for severe hemophilia A, bleeding risk increases with time when factor VIII activity is below 1%. Maintaining trough activity above 1% does not protect all patients from bleeding. The relationship between factor VIII activity during prophylaxis and bleeding risk has not been thoroughly studied. We investigated factor VIII activity and annualized bleeding rate for spontaneous bleeds during prophylaxis. A population pharmacokinetic model derived from three clinical trials was combined with dosing data and bleed information from patient diaries. Each patients' time on prophylaxis was divided into five categories of predicted activity (0-1%, >1-5%, >5-15%, >15-50%, and >50%). Exposure time, mean factor VIII activity, and bleed number (from patient diaries) were calculated for each activity category, and annualized bleeding rates estimated using negative binomial regression and a parametric model. Relationships between these bleeding rates and factor VIII activity were evaluated by trial phase (pivotal vs. extension) and age (adults/adolescents [≥12 years] vs. children [0-<12 years]). In total (N=187; 815 patient-years' exposure), factor VIII activity was predicted to reach >1% for 85.64% of the time. Annualized bleeding rate decreased as factor VIII activity increased in each trial phase and age group. However, for a given activity level, bleeding rate differed substantially by trial phase, and age. This suggests that bleeding risk can change over time and is influenced by factors independent of factor VIII pharmacokinetics and trough levels. Target trough and prophylactic regimen should consider patient age, joint disease activity, and other bleeding risk determinants.
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http://dx.doi.org/10.3324/haematol.2019.241554DOI Listing
April 2020

Bleeding and response to hemostatic therapy in acquired hemophilia A: results from the GTH-AH 01/2010 study.

Blood 2020 07;136(3):279-287

Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient's residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds were recorded in 102 patients. There were 141 new bleeds observed starting after day 1 in 59% of the patients, with a mean rate of 0.13 bleed per patient-week in weeks 1 to 12, or 0.27 bleed per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII activity ≥50% abolished the risk of bleeding. A good World Health Organization performance status assessed at baseline (score 0 vs higher) was associated with a lower bleeding rate. Hemostatic treatment was reportedly effective in 96% of bleeds. Thus, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may aid in assessing the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA.
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http://dx.doi.org/10.1182/blood.2019003639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392842PMC
July 2020

Barriers and challenges for the fast treatment of bleeds in the non-haemophilia treatment centre hospital setting.

Haemophilia 2020 May 9;26(3):422-430. Epub 2020 Mar 9.

Haemophiliezentrum, Klinik für Innere Medizin, Vivantes Klinikum im Friedrichshain, Berlin, Germany.

Introduction: Early treatment for acute bleeds in patients with haemophilia and inhibitors is feasible when patients are managed in haemophilia treatment centres (HTCs). Patients may need to attend non-HTCs for out-of-hours emergency care, especially if HTCs are not local and/or transport is difficult.

Aim: We evaluated the barriers to the fast treatment of bleeds in patients with haemophilia and inhibitors presenting at non-HTCs.

Methods: Healthcare professionals (HCPs) from non-HTCs in the United States (n = 218) and Germany (n = 98) were selected from validated online panels and invited to participate in a survey (October-November 2017).

Results: A mean of 6 (US) and 5 (German) patients with haemophilia and inhibitors were managed for bleeds by these HCPs over 12 months; patient characteristics were similar in both countries. The main HCPs involved in treating bleeds were emergency room specialists (94%) and haematologists (91%) (US); haematologists (79%) and anaesthesiologists (59%) (Germany). Only 26% (US) and 28% (Germany) of HCPs had access to treatment guidelines for these patients; access to bypassing agents was similarly limited: 44% (US) and 38% (Germany) of HCPs reported their institution did not stock these agents. In both countries, key reasons for delaying treatment were lack of bypassing agent availability, HCP experience/education of bleed disorders and internal process time.

Conclusion: Barriers to fast treatment of bleeds in patients with haemophilia and inhibitors were identified in non-HTCs in the United States and Germany. These could be reduced by improving the availability of treatment guidelines, bypassing agents and HCP education/training.
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http://dx.doi.org/10.1111/hae.13956DOI Listing
May 2020

Population Pharmacokinetic Modeling Of On-Demand And Surgical Use Of Nonacog Beta Pegol (N9-GP) And rFIXFc Based Upon The paradigm 7 Comparative Pharmacokinetic Study.

J Blood Med 2019 13;10:391-398. Epub 2019 Nov 13.

Department for Internal Medicine, Vascular Medicine and Haemostaseology, Vivantes Klinikum, Berlin, Germany.

Aim/objective: Understanding pharmacokinetic (PK) differences between standard and extended half-life (EHL) products is important, particularly for factor IX (FIX), where differences are more significant than for factor VIII. Two single-dose PK trials showed N9-GP achieves higher FIX levels and greater area-under-the-curve than pdFIX, rFIX, and rFIXFc through higher recovery and longer terminal half-life. In paradigm 7, N9-GP demonstrated consistently favorable PK characteristics compared with rFIXFc. Collins et al explored population PK differences between N9-GP and pdFIX/rFIX based upon paradigm 1 data. This analysis uses population PK models based upon the paradigm 7 trial.

Methods: 15 patients (21-65 years) with hemophilia B received single 50-IU/kg doses of N9-GP and rFIXFc ≥21 days apart. A population PK model developed from single-dose PK profiles simulated plasma FIX activity following dosing for surgery and on-demand treatment of bleeds. Simulations explored doses and frequencies required to sustain target World Federation of Hemophilia (WFH) factor activity levels.

Results: PK profiles of N9-GP and rFIXFc were described by one- and three-compartment models, respectively. Simulations predicted significantly reduced dosing frequency and consumption for N9-GP than rFIXFc. For severe bleeds, a single N9-GP dose (80 IU/kg) is sufficient to maintain WFH-recommended FIX levels, whereas multiple rFIXFc doses are required. For surgery, redosing in the first week with N9-GP is modeled at day 6 vs rFIXFc dosing at 6, 30, 54, 78, and 126 hrs. For life-threatening bleeds, N9-GP is required at days 0, 3, 6, 13, and 18 vs rFIXFc redosing after 6 hrs with 10 additional doses at 24-, 48-, and 72 hr intervals.

Conclusion: PK modeling approaches based upon direct comparative studies offer insights into PK differences between EHL FIX products. Model simulations show N9-GP may allow on-demand treatment and perioperative management with 55-75% fewer injections and 65-74% lower overall factor concentrate consumption than rFIXFc.
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http://dx.doi.org/10.2147/JBM.S217539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859083PMC
November 2019

Development of Haemophilia Treatment in the Eastern Part of Germany over the Last Decade in the Kompetenznetz Hämorrhagische Diathese Ost (KHDO).

Hamostaseologie 2020 Feb 11;40(1):119-127. Epub 2019 Nov 11.

Medical Department I, Division of Haemostaseology, University Hospital Leipzig, Leipzig, Germany.

Introduction:  In 2005 the Kompetenznetz Hämorrhagische Diathese Ost published epidemiologic data about patients with haemophilia A (HA) and haemophilia B (HB) in the eastern part of Germany. This study provides data about the development of treatment in these patients over the past 10 years.

Methods:  Data from 12 haemophilia centres in eastern Germany were retrospectively collected for the year 2015 from patients' records.

Results:  We evaluated 413 patients (115 children, 298 adults) with HA or HB. A total of 286 patients (69.2%) had severe haemophilia (patients with severe haemophilia, PWSH). Compared with 2005, the proportion PWSH on prophylaxis increased from 90% to 98.8% in children and from 64% to 80.2% in adults. The use of plasma-derived factor concentrates decreased from >70% to 55.3% in children and to 55.1% in adults. Mean annual factor consumption in PWSH without inhibitor was higher in 2015 compared with 2005 (children with HA: 151,489 vs. 98,894; adults with HA: 217,151 vs. 151,394; children with HB: 105,200 vs. 64,256; adults with HB: 159,185 vs. 85,295). Median annualized bleeding (annualized bleeding rate, ABR) and joint bleeding rates (annualized joint bleeding rate, AJBR) in 2015 were 2 and 0 in children and 3 and 0 in adults, respectively. In 2015 only one child (1.2%) but 101 (53.2%) adults with severe haemophilia were anti-hepatitis C virus (anti-HCV) positive. The rate of anti-HCV positive patients with active hepatitis C dropped from 63.8% to 12.9%.

Conclusions:  Within the last decade more patients with severe haemophilia were switched to a prophylactic regimen going along with a moderate increase in factor consumption achieving a low ABR and AJBR.
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http://dx.doi.org/10.1055/s-0039-3399493DOI Listing
February 2020

Treatment of the antiphospholipid syndrome with direct oral anticoagulantsPosition statement of German societies.

Vasa 2019 Nov 20;48(6):483-486. Epub 2019 Aug 20.

CardioAngiology Center Bethanien Hospital, Frankfurt, Germany.

The antiphospholipid-syndrome (APS) is one of the most severe forms of thrombophilia, which may not only lead to recurrent venous but also to arterial thromboembolic events (TE), and to severe pregnancy complications, respectively. APS is defined by clinical symptoms and specific laboratory findings: 1. Lupus anticoagulant (LA), 2. anticardiolipin-antibodies (ACA), and 3. β2-Glycoprotein I-antibodies (β2GPI-Ab). All test results have to be confirmed after at least 12 weeks. The thrombotic risk is highest, if all 3 test groups are positive. It must be pointed out that the presence of UFH, VKA or DOACs may lead to false positive LA-test results; the addition of a specific absorber after blood sampling may provide reliable results in the presence of DOACs. A prospective randomized controlled trial comparing warfarin and rivaroxaban (TRAPS-trial) including only high-risk patients with triple positive APS was terminated early because of an increased rate of TE in patients treated with rivaroxaban [19 %, mostly arterial, compared to 3 % with warfarin (HR 7.4;1.7-32.9)]. Subsequently, a warning letter was issued by the pharmaceutical manufacturers of DOACs, including a warning of DOAC use in APS-patients, particularly in triple-positive high-risk patients. Conclusions: 1. Clinical suspicion of APS requires careful diagnostic testing. Because of inadequate diagnostic workup, many patients may not even have an APS, and these patients could be adequately treated with a DOAC. 2. Patients with single or double positive antiphospholipid antibodies but without positive LA may have a comparably low thrombotic risk and may also be treated with a DOAC in venous TE - sufficient evidence for that conclusion is not yet available but is suggested by the results of meta-analyses. 3. Triple positive patients or those with APS who suffered from arterial thromboembolism have a very high recurrence risk of thrombosis; the TRAPS-Study shows that these patients should be treated with VKA instead of a DOAC.
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http://dx.doi.org/10.1024/0301-1526/a000815DOI Listing
November 2019

Pharmacokinetics, immunogenicity, safety, and preliminary efficacy of subcutaneous turoctocog alfa pegol in previously treated patients with severe hemophilia A (alleviate 1).

J Thromb Haemost 2020 02 15;18(2):341-351. Epub 2019 Nov 15.

KD Haemophilia and Thrombosis Centre, Royal Free London NHS Foundation Trust, London, UK.

Background: The current standard of care for patients with hemophilia A is regular prophylaxis with factor VIII (FVIII) administered intravenously. Interest in subcutaneous (s.c.) administration, to potentially increase convenience, reduce the treatment burden and improve compliance, is increasing.

Objectives: Evaluate the pharmacokinetics (PK), immunogenicity, safety, and preliminary efficacy of s.c. administration of turoctocog alfa pegol (s.c. N8-GP) in adult or adolescent previously treated patients (PTPs) with severe hemophilia A (alleviate 1; NCT02994407).

Patients/methods: In part A, 24 PTPs received a single dose of s.c. N8-GP (12.5, 25, 50, or 100 IU/kg) with 6 patients per cohort. PK modelling of data from part A supported a suitable dose for part B. Part B comprised a multiple dose trial in 26 PTPs; patients <60 kg received 2000 IU and patients ≥60 kg received 4000 IU s.c. N8-GP daily for 3 months.

Results: Single-dose s.c. N8-GP supported dose linearity. Daily prophylaxis with s.c. N8-GP appeared well tolerated and efficacious, achieving a mean trough FVIII activity close to 10% at steady state. Five patients developed anti-N8-GP binding antibodies after 42 to 91 exposure days, one of whom developed an inhibitor to FVIII. Anti-N8-GP antibody appearance was associated with a decline in FVIII plasma activity in four of the five patients. Five patients reported a total of nine treatment-requiring bleeding episodes during prophylaxis.

Conclusions: Subcutaneous administration of N8-GP is associated with a high incidence of antibodies in PTPs with severe hemophilia A. Further clinical development of s.c. N8-GP has been suspended.
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http://dx.doi.org/10.1111/jth.14660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027501PMC
February 2020

Cross-reacting inhibitors against recombinant porcine factor VIII in acquired hemophilia A: Data from the GTH-AH 01/2010 Study.

J Thromb Haemost 2020 01 12;18(1):36-43. Epub 2019 Sep 12.

Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.

Background: Recombinant porcine factor VIII (rpFVIII, OBI-1, susoctocog alfa) is used for the treatment of acute bleeds in patients with acquired hemophilia A (AHA). Inhibitors in AHA can sometimes cross-react with rpFVIII.

Objectives: To assess the frequency, strength, and determinants of cross-reactivity.

Patients/methods: Baseline samples from 70 patients of the prospective, observational cohort study GTH-AH 01/2010 were assessed for anti-human FVIII and anti-rpFVIII inhibitors using modified Nijmegen-Bethesda assays, as well as anti-human FVIII domain reactivity using enzyme-linked immunoassay (ELISA).

Results: Anti-human FVIII inhibitors were present in all samples ranging between 0.7 and 3891 Bethesda Units (BU)/mL. Inhibitors from 31 of 70 patients (44%) partially inhibited rpFVIII with anti-rpFVIII titers ranging between 0.5 and 471 BU/mL. Anti-rpFVIII titers were ≤5 BU in most patients. Patients with cross-reacting inhibitors, as compared to patients without, had significantly higher anti-human FVIII titers (27.8 versus 5.4 BU/mL) and lower baseline FVIII activity (<1 versus 2.6 IU/dL). The ratio between anti-rpFVIII to anti-human titers was highest for inhibitors involving the C1 domain. Cross-reactivity was very rare, if inhibitors reacted only with the C2 domain of FVIII (6%). An anti-human FVIII titer of >100 BU/mL predicted cross-reactivity with 97% likelihood, whereas an anti-human FVIII titer of <3.8 BU/mL predicted absent cross-reactivity with 90% likelihood.

Conclusion: Cross-reacting inhibitors should be considered when choosing a treatment for bleeding patients with AHA. Cross-reactivity is frequent in patients with anti-human FVIII titers of >100 BU/mL.
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http://dx.doi.org/10.1111/jth.14618DOI Listing
January 2020

Matching-adjusted indirect comparisons of annualized bleeding rate and utilization of BAY 94-9027 versus three recombinant factor VIII agents for prophylaxis in patients with severe hemophilia A.

J Blood Med 2019 20;10:147-159. Epub 2019 Jun 20.

Department for Internal Medicine - Vascular Medicine and Coagulation Disorders, Vivantes Klinikum im Friedrichshain, Berlin, Germany.

BAY 94-9027 is an extended half-life recombinant factor VIII (rFVIII) that prevents bleeding in persons with hemophilia A at twice-weekly, 5-day, and 7-day dosing intervals. In rare diseases such as hemophilia, where small populations preclude head-to-head comparisons in randomized controlled trials, outcomes from different studies can be compared by matching-adjusted indirect treatment comparisons (MAICs) via matched summary statistics of individual patient data. This study compared MAIC-adjusted outcomes of BAY 94-9027 with other FVIII agents for prophylaxis of hemophilia. Weighted patient data from the BAY 94-9027 PROTECT VIII trial were used to compare annualized bleeding rates (ABRs), percentage of patients with zero bleeds, and factor utilization against published data on rFVIII-Fc fusion protein (rFVIIIFc), BAX 855, and recombinant antihemophilic factor/plasma/albumin-free method (rAHF-PFM). After matching BAY 94-9027 and comparators, the mean BAY 94-9027 utilization was significantly lower than rFVIIIFc pre- and post-matching (66.2 vs 82.2 IU/kg/week; 66.5 vs 82.2 IU/kg/week; both <0.001). Median BAY 94-9027 utilization (IU/kg/week) trended lower than BAX 855 (64.3 vs 87.4) and rAHF-PFM (2004 study: 64.0 vs 107.5; 2012 study: 63.6 vs 109.9). Mean ABRs and percentages of patients with zero bleeds were similar post-matching between BAY 94-9027 and comparators. BAY 94-9027 demonstrated similar MAIC-adjusted ABR with lower utilization than rFVIIIFc, BAX 855, and rAHF-PFM.
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http://dx.doi.org/10.2147/JBM.S206806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592019PMC
June 2019

Efficacy and safety of simoctocog alfa (Nuwiq®) in patients with severe hemophilia A: a review of clinical trial data from the GENA program.

Ther Adv Hematol 2019 26;10:2040620719858471. Epub 2019 Jun 26.

Institute of Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Sigmund-Freud Strasse 25, 53105 Bonn, Germany.

Simoctocog alfa (human-cl rhFVIII, Nuwiq®) is a 4th generation recombinant FVIII (rFVIII), without chemical modification or fusion with any other protein/fragment. Nuwiq® is produced in a human embryonic kidney cell line (HEK293F), which ensures human-specific post-translational protein processing. Nuwiq® was evaluated in seven prospective clinical studies in 201 adult and pediatric previously treated patients (PTPs) with severe hemophilia A. The NuProtect study in 110 previously untreated patients (PUPs) is ongoing. The mean half-life of Nuwiq® was 15.1-17.1 h in PTP studies with adults and adolescents, and 12.5 h in children aged 2-12 years. Clinical trials in PTPs demonstrated the efficacy and safety of Nuwiq® in the prevention and treatment of bleeds and as surgical prophylaxis. In the NuPreviq study of pharmacokinetic (PK)-guided personalized prophylaxis in 66 adult PTPs, 83% of patients had no spontaneous bleeds during 6 months of personalized prophylaxis and 57% were treated ⩽2 per week. No FVIII inhibitors were detected in PTPs after treatment with 43,267 injections and >80 million IU of Nuwiq®. Interim data for 66 PUPs with ⩾20 exposure days to Nuwiq® in NuProtect demonstrated a low cumulative high-titer inhibitor rate of 12.8% [actual incidence 12.1% (8/66)] and convincing efficacy and safety.
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http://dx.doi.org/10.1177/2040620719858471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595650PMC
June 2019

[Leitlinie der Gesellschaft für Thrombose- und Hämostaseforschung (GTH) zur Struktur- und Prozessqualität von Hämophilie-Zentren].

Hamostaseologie 2019 11 24;39(4):311-321. Epub 2019 Apr 24.

Vivantes Klinikum im Friedrichshain, Zentrum für Hämophilie und Hämostaseologie, Landsberger Allee, Berlin, Germany.

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http://dx.doi.org/10.1055/s-0039-1688450DOI Listing
November 2019

Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial.

Res Pract Thromb Haemost 2019 Apr 23;3(2):268-276. Epub 2019 Mar 23.

Department for Internal Medicine Vascular Medicine and Haemostaseology Vivantes Klinikum Berlin Germany.

Background And Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc.

Patients/methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC).

Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC was significantly greater for N9-GP than rFIXFc (ratio: 4.39; <0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound.

Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc.

Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).
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http://dx.doi.org/10.1002/rth2.12192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462750PMC
April 2019

Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis.

Blood Rev 2019 05 3;35:43-50. Epub 2019 Mar 3.

Georgetown University Medical Center, Washington, DC, USA.

Factor VIII protein (FVIII) as a coagulation replacement factor has for decades been used as the standard of care for management of people with haemophilia A. It is effective for treatment of bleeding events, as prophylaxis to prevent bleeding events and preserve joint function, and to support surgery in people with haemophilia A. Despite long experience in treating haemophilia A, we are only beginning to understand the functions of FVIII beyond its established role as a coenzyme to factor IXa to expedite thrombin generation through the intrinsic pathway of coagulation. Here, we review the current role of FVIII coagulant (FVIII:C) in haemophilia A management and emerging evidence for the role of FVIII across multiple systems, including the cardiovascular system, angiogenesis and maintenance of bone health. For instance, supraphysiological FVIII levels are a risk factor for venous thromboembolism. von Willebrand factor (VWF), which forms a non-covalent complex with circulating FVIII, is an established marker and regulator of angiogenesis. In a mouse model of haemophilia, treatment with FVIII decreased expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), a marker for bone turnover. Longitudinal follow-up data in people with haemophilia A are needed to confirm and extend these observations.
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http://dx.doi.org/10.1016/j.blre.2019.03.002DOI Listing
May 2019

Non-vitamin K Antagonist Oral Anticoagulants (NOAC) as an Alternative Treatment Option in Tumor-Related Venous Thromboembolism.

Dtsch Arztebl Int 2019 01;116(3):31-38

Department of Medicine I, Division of Hematology and Hemostaseology, University Hospital "Carl Gustav Carus" Dresden; King's Thrombosis Service, Department of Hematology, King's College London; Department of Internal Medicine, Angiology and Hemostaseology, Vivantes Klinikum im Friedrichshain Berlin; Hematology and Oncology practice, Bad Liebenwerda; II. Medical Clinic and Polyclinic, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg; (UCCH), University Medical Center Hamburg-Eppendorf; Medical Clinic II, Asklepios Klinikum Uckermark, Schwedt; Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin.

Background: The risk of venous thromboembolism (VTE) is 4 to 7 times higher in cancer patients than in the normal population. Moreover, cancer patients who take anticoagulants suffer more frequently from hemorrhagic complications and VTE recurrences. Patients often find low-molecular-weight heparin (LMWH) treatment unpleasant; approximately 20% stop taking LMWH during the first six months of treatment.

Methods: Based on a non-systematic literature search, an interdisciplinary group of specialists (hematology, oncology, hemostaseology, and angiology) developed a set of recommendations concerning the treatment of tumor-related thrombosis with non-vitamin K antagonist oral anticoagulants (NOAC).

Results: Patient-, tumor-, and tumor-treatment-related factors and clinical situations were identified that should be considered in therapeutic decision-making in the indi- vidual case. NOAC may be an alternative that lessens the rate of VTE recurrence (though at the cost of more hemorrhagic complications), without lessening mortality. Moreover, many factors need to be considered that can limit the utility of NOAC treatment or even make it impossible.

Conclusion: It seems likely that, in future, the treatment of tumor-related VTE will often not involve a single decision to use either NOAC or LWMH, but rather a switching of treatment in either of two directions: from LWMH to NOAC in stable phases of the underlying malignant disease, conferring better quality of life to suitable patients; or from NOAC to LWMH, e.g., in patients suffering from emesis or thrombocytopenia, to whom the greater clinical experience with LWMH, parenteral application, or stepwise dose titration can confer benefits.
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http://dx.doi.org/10.3238/arztebl.2019.0031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401514PMC
January 2019

Once-weekly prophylaxis with glycoPEGylated recombinant factor VIII (N8-GP) in severe haemophilia A: Safety and efficacy results from pathfinder 2 (randomized phase III trial).

Haemophilia 2019 May 28;25(3):373-381. Epub 2019 Feb 28.

Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa.

Introduction: Turoctocog alfa pegol (N8-GP) is a site-specific, 40 kDa glycoPEGylated recombinant factor VIII (FVIII) product with an extended half-life. The comprehensive main phase of the pivotal pathfinder 2 trial showed N8-GP dosed every 4 days (Q4D) provided favourable safety and efficacy for preventing bleeds in 175 patients with haemophilia A.

Aim And Methods: We investigated the safety and efficacy of N8-GP prophylaxis when administered weekly (Q7D) for 24 weeks to patients with low bleeding rates in the pathfinder 2 extension trial. Patients (≥12 years) with ≤2 bleeds during the preceding 6 months of the pathfinder 2 main phase were eligible for randomization to receive N8-GP 50 IU/kg Q4D or 75 IU/kg Q7D. Safety and efficacy endpoints were incidence of FVIII inhibitors and annualized bleeding rate (ABR), respectively.

Results: Fifty-five of 143 (38.5%) patients on prophylaxis who continued into the extension phase were randomized to receive 50 IU/kg Q4D (n = 17) or 75 IU/kg Q7D (n = 38). Nine patients in the Q7D cohort reverted to 50 IU/kg Q4D. No inhibitors were detected. In both cohorts, >50% of patients experienced no bleeds. Median ABR for overall, joint, spontaneous, traumatic and muscle was 0.00 for both cohorts. Overall estimated success rate for treating bleeding episodes was 87.5%; 94.7% of bleeds were controlled with ≤2 injections.

Conclusions: Weekly N8-GP was well tolerated and efficacious and may benefit selected "low bleeder" patients with haemophilia A.
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http://dx.doi.org/10.1111/hae.13712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850405PMC
May 2019

Science Meets Clinical Practice.

Hamostaseologie 2019 Feb 18;39(1):4-5. Epub 2019 Feb 18.

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http://dx.doi.org/10.1055/s-0039-1677839DOI Listing
February 2019

Smart Medication ™, an Electronic Diary for Surveillance of Haemophilia Home Care and Optimization of Resource Distribution.

Hamostaseologie 2019 Nov 8;39(4):339-346. Epub 2019 Jan 8.

Praxis für Hämatologie und Onkologie, Köln, Germany.

This report describes the technical features and potential advantages of the application of electronic haemophilia treatment diary and an evaluation of real-life electronic treatment data collected from haemophilia patients. Since 2012, a total of 663 patients from 30 German haemophilia treatment centres (HTCs) have used the device. Data of nine HTCs were merged for real-life data analysis. Patients were divided into four subgroups according to above versus below mean values for annual factor consumption (AFC) and annual joint bleeds (AJB), respectively. The largest subgroup comprised patients with low mean AFC and AJB less than 2.25 (group A: 42%). Second largest was the group with low mean AJB but high AFC (group B: 32%), suggesting that resources could be saved in some patients. The group with low AFC but high AJB may need increased factor dosing (group D: 13%). Patients who showed a high mean AJB despite high AFC (group C: 13%) may require special medical attention, such as pharmacokinetic-adapted treatment modification or orthopaedic measures. enables the HTC to quickly identify patients in need of treatment changes and, thus, to plan individualized therapy modifications prior to patient visits. The growing pool of real-life data facilitates data analysis and may play an important role in the optimization of resource distribution.
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http://dx.doi.org/10.1055/s-0038-1675575DOI Listing
November 2019

Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B.

Blood 2018 03 15;131(9):1022-1031. Epub 2017 Dec 15.

Erasmus University Medical Centre, Rotterdam, The Netherlands.

Gene therapy for hemophilia B aims to ameliorate bleeding risk and provide endogenous factor IX (FIX) activity/synthesis through a single treatment, eliminating the requirement for FIX concentrate. AMT-060 combines an adeno-associated virus-5 (AAV5) vector with a liver-specific promoter driving expression of a codon-optimized wild-type human FIX gene. This multinational, open-label study included 10 adults with hemophilia B (FIX ≤2% of normal) and severe-bleeding phenotype. No participants tested positive for AAV5-neutralizing antibodies using a green-fluorescent protein-based assay, and all 10 were enrolled. A single dose of 5 × 10 or 2 × 10 genome copies of AMT-060/kilogram was administered to 5 participants each. In the low-dose cohort, mean endogenous FIX activity increased to 4.4 IU/dL. Annualized FIX use was reduced by 81%, and mean annualized spontaneous bleeding rate (ASBR) decreased from 9.8% to 4.6% (53%). In the higher-dose cohort, mean FIX activity increased to 6.9 IU/dL. Annualized FIX use decreased by 73%, and mean ASBR declined from 3.0 to 0.9 (70%). There was no reduction in traumatic bleeds. FIX activity was stable in both cohorts, and 8 of 9 participants receiving FIX at study entry stopped prophylaxis. Limited, asymptomatic, and transient alanine aminotransferase elevations in the low-dose (n = 1) and higher-dose (n = 2) cohorts were treated with prednisolone. No decrease in FIX activity or capsid-specific T-cell responses were detected during transaminase elevations. A single infusion of AMT-060 had a positive safety profile and resulted in stable and clinically important increases in FIX activity, a marked reduction in spontaneous bleeds and FIX concentrate use, without detectable cellular immune responses against capsids. This trial was registered at www.clinicaltrials.gov as #NCT02396342; EudraCT #2013-005579-42.
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http://dx.doi.org/10.1182/blood-2017-09-804419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833265PMC
March 2018