Introduction: Scientific evidence increasingly suggests that, for many patients with severe hemophilia A, targeting higher sustained factor VIII (FVIII) levels is required to improve protection from ...bleeds, preserve joint health, and advance closer to the goal of a functional cure and health equity (Skinner MW, et al. Haemophilia. 2020). However, achieving high sustained factor activity levels with once-weekly dosing is not possible with currently approved FVIII therapies due to the FVIII half-life ceiling imposed by endogenous von Willebrand factor (VWF).
Efanesoctocog alfa (rFVIIIFc-VWF-XTEN; BIVV001) is a novel fusion protein designed to decouple recombinant FVIII (rFVIII) from endogenous VWF and thereby overcome the VWF-imposed half-life ceiling (Chhabra ES, et al Blood. 2020). Once-weekly efanesoctocog alfa (50 IU/kg) has a geometric mean half-life of 41 hours and provides high sustained FVIII activity levels in the normal to near-normal range (>40%) for 3-4 days post dose and 10% at Day 7 (Lissitchkov T, et al. Blood. 2019). Therefore, efanesoctocog alfa has the potential to offer extended bleed protection with less frequent dosing in patients with severe hemophilia A (Konkle B, et al. N Engl J Med. 2020). In the Phase 1/2a and Phase 1 studies (EXTEN-A single-dose and repeat-dose, respectively), efanesoctocog alfa was well tolerated in previously treated adults with severe hemophilia A and no safety concerns were identified (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019). The aim of this post hoc analysis is to evaluate the relationship between endogenous VWF antigen levels and efanesoctocog alfa half-life and clearance in patients with severe hemophilia A from the single- and repeat-dosing studies.
Methods: A total of 40 previously treated adult males (N=16 and N=24, respectively) with severe hemophilia A (<1 IU/dL <1% endogenous FVIII at screening) and ≥150 exposure days of prior FVIII treatment enrolled in the EXTEN-A single-dose (NCT03205163) and repeat-dosing (EudraCT No: 2018-001535-51)studies (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019). Subjects received either a single IV dose of 25 IU/kg (n=7) or 65 IU/kg (n=9) efanesoctocog alfa in EXTEN-A (Konkle B, et al. N Engl J Med. 2020) or 4 once-weekly doses of either 50 IU/kg (n=10) or 65 IU/kg (n=14) efanesoctocog alfa in the repeat-dosing study (Lissitchkov T, et al. Blood. 2019). Each study assessed safety and tolerability as its primary objective, with pharmacokinetics (PK) evaluated as a secondary objective (Konkle B, et al. N Engl J Med. 2020; Lissitchkov T, et al. Blood. 2019).
All subjects with evaluable PK profiles were included in this post hoc analysis. The half-life and clearance of efanesoctocog alfa were evaluated as a function of pre-dose endogenous VWF antigen levels. VWF antigen levels were also assessed at various time points after dosing through end of study. Linear correlations were calculated using Pearson's correlation coefficient.
Results : Of 40 enrolled subjects, mean (range) age was 39 (19-63) years. Mean (range) pre-dose VWF antigen levels were 151% (74%-297%; n=14) and 128% (49%-265%; n=24) for the single- and repeat-dose studies, respectively. Individual patient antigen levels of endogenous VWF were relatively stable over time, from screening and pre dose through 336 hours post dose and end of study (Figure 1A). Similar results were observed for VWF:RCo levels.
A total of 37 subjects were eligible for inclusion in the pooled correlation analyses; 3 subjects had missing values and were excluded from analysis. Efanesoctocog alfa half-life showed no correlation with VWF antigen levels (R 2=0.0007; P=0.88) (Figure 1B). A similar result was observed for clearance of efanesoctocog alfa, which showed no correlation with VWF antigen levels (R 2=0.0493; P=0.19).
Conclusions: Endogenous VWF levels are unaffected during and after treatment with single- or repeat-dosing of efanesoctocog alfa in previously treated patients with severe hemophilia A. Furthermore, the half-life and clearance of efanesoctocog alfa are independent of endogenous VWF levels. This is consistent with previous findings from preclinical data and supports the continued evaluation of efanesoctocog alfa as a VWF-independent rFVIII in ongoing Phase 3 clinical trials in hemophilia A (XTEND-1, NCT04161495; XTEND-Kids, NCT04759131; XTEND-ed, NCT04644575).
This analysis was funded by Sanofi and Sobi.
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Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Lissitchkov: Catalist: Other: Principal Investigator of Clinical Trials; Grifols: Other: Principal Investigator of Clinical Trials; Bayer: Other: Principal Investigator of Clinical Trials. Konkle: BioMarin Pharmaceutical Inc.: Other: Data and safety monitoring; Sigilon Therapeutics: Honoraria; CSL Behring: Other: Data and safety monitoring; Genentech USA Inc.: Honoraria. Shapiro: OPKO: Research Funding; Prometric BioTherapeutics: Research Funding; Sangamo: Other: Advisory board fees, Research Funding; Takeda: Research Funding; Sigilon Therapeutics: Other: Advisory board fees, Research Funding; Glover Blood Therapeutics: Research Funding; Genentech: Other: Advisory board fees, Research Funding, Speakers Bureau; Octapharma: Research Funding; Pfizer: Research Funding; Novo Nordisk: Other: Advisory board fees, Research Funding, Speakers Bureau; Novartis: Research Funding; Kedrion Biopharma: Research Funding; BioMarin: Research Funding; Bioverativ (a Sanofi company): Other: Advisory board fees, Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding. Quon: Orthopaedic Institute for Children: Current Employment. Kulkarni: Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamilton: Sobi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chhabra: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Katragadda: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Altincatal: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Willemze: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Ragni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding.
Background: A new recombinant activated factor VII, eptacog beta (SEVENFACT®, rFVIIa-jncw) has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of bleeding events (BEs) ...in individuals >12 years of age with hemophilia A or B (HAB) with inhibitors. In the eptacog beta phase III trial (Wang, Haemophilia, 2017), 87% of BEs were successfully treated using two different dosing regimens within 12 hours of bleeding onset. In two studies looking at the safety of eptacog beta Ducore, Haemophilia, 2017), a total of 11 treatment-emergent adverse events (TEAEs) were reported in 42 participants, all mild and transitory. To date, no studies designed to assess safety of treatment of breakthrough BEs in people on emicizumab with eptacog beta have been performed.
Objective: To evaluate the safety of eptacog beta when used to treat BEs in participants with HAB with inhibitors with or without prophylactic treatment.
Methods: ATHN 16 (NCT04647227) is a phase IV, United States-centric multi-center, open-label safety study enrolling participants with HAB with inhibitors aged 12 to 65 years, inclusive, who are either on long-term prophylactic treatment (e.g., emicizumab) at risk of experiencing a breakthrough BE or who are not on prophylactic treatment who may need to control a BE. Exclusion criteria include any bleeding disorder in addition to HAB, a known hypersensitivity to eptacog beta or rabbit proteins, or the inability to provide informed consent. The maximum study duration for any participant in the study is up to 2 years from the time of enrollment. We plan to enroll between 28 to 55 participants with the goal of collecting data on 100 BEs.
Safety of eptacog beta will be evaluated based on events included in the European Haemophilia Safety Surveillance (EUHASS) protocol, including allergic or other acute events, treatment-emergent side effects, transfusion-transmitted infections, inhibitor development, thrombosis, cardiovascular events, malignancies, neurological events, and death.
After signed informed consent is obtained, demographics, bleeding disorder history, inhibitor history, baseline medical and surgical history for the 6-month period before the baseline visit will be captured. Each participant will receive nine 75 µg/kg doses of eptacog beta supplied by the study funder. Eptacog beta will be administered at the time of a BE by the participant or by study staff; the dose and duration of treatment will be determined at the discretion of the treating physician. BE details such as timing, any treatments associated with the BE (including eptacog beta), and timing of resolution of the BE will be collected as well as surgical procedures and all AEs and serious AEs.
Results: At the time of abstract submission, ATHN 16, having received central IRB approval, is being rolled out across the United States Hemophilia Treatment Center Network. There are a total of 20 sites where the protocol will be conductedalex. We plan to report participant demographics, BE details, as well as all safety data meeting the EUHASS endpoints. In addition, we will report any pregnancies as AEs of special interest. All serious AEs will also be reported.
The ATHN 16 Safety Analysis Set is defined as all participants who received at least a single dose of eptacog beta. Baseline characteristics will be summarized using descriptive statistics for continuous variables, and frequencies and percentages for categorical variables.
The number and percentage of participants with treatment-emergent AEs (TEAEs), serious AEs (SAEs), serious TEAEs, and treatment-related TEAEs (i.e., adverse drug reactions) will be presented for all participants. The number and percentage of participants with TEAEs and/or allergic and anaphylactic reactions will be presented for all participants. There are no pre-specified efficacy endpoints.
Conclusions: ATHN 16 will explore the safety of eptacog beta as therapy for BEs in participants with HAB complicated by inhibitors with or without concurrent prophylactic treatment. As the first interventional study sponsored by ATHN, ATHN 16 represents a crucial step forward in ATHN's clinical research capabilities.
Chrisentery-Singleton: CSL Behring: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; HEMA Biologics: Consultancy, Honoraria; Novo Nordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Spark: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Kedrion: Consultancy; Biomarin: Speakers Bureau; Global Blood Therapeutics: Speakers Bureau; Bayer: Honoraria; BPL Plasma: Honoraria. Alexander: HEMA Biologics: Consultancy, Ended employment in the past 24 months; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company; Roche/Genentech: Current equity holder in publicly-traded company. Al-Sabbagh: LFB: Current Employment. Bonzo: LFB: Current Employment. Callaghan: Kedrion: Consultancy; Biomarin: Consultancy; Spark: Consultancy; uniQure: Consultancy; Global Blood Therapeutics: Consultancy, Speakers Bureau; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Hema Biologics: Consultancy; Forma: Consultancy; Chesei: Consultancy; Agios Pharmaceuticals: Current Employment. Giermasz: Bayer: Consultancy; ATHN: Consultancy; NovoNordisk: Consultancy; UniQure: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Bioverativ/Sanofi: Consultancy, Research Funding, Speakers Bureau; Sangamo Therapeutics,: Research Funding; Pfizer: Consultancy; Genentech/Roche: Consultancy, Research Funding, Speakers Bureau; BioMarin: Consultancy, Research Funding. Journeycake: LFB: Honoraria; HEMA Biologics: Honoraria. Nasr: HEMA Biologics: Consultancy. Quon: Orthopaedic Institute for Children: Current Employment. Recht: uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Oregon Health & Science University: Current Employment.
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Introduction. Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus gene therapy that transfers a B-domain deleted factor VIII (FVIII) cDNA to hepatocytes. The open-label, ...single-arm, multicenter phase 3 GENEr8-1 trial (NCT03370913) evaluated valoctocogene roxaparvovec in 134 men with severe hemophilia A (HA) and demonstrated an 83.8% reduction in annualized treated bleeding rate (ABR) and superiority to FVIII prophylaxis (P <0.001). The relationship between baseline FVIII activity and ABR was estimated in congenital HA (den Uijl, et al. Haemophilia 2011;171:41-4); it is unknown if a similar relationship exists after gene transfer. We present here post-hoc analyses of transgene-derived FVIII activity and bleeds in GENEr8-1.
Methods. Men ≥18 years of age with severe HA previously on FVIII prophylaxis who were negative for FVIII inhibitors and anti-AAV5 antibodies received one 6x10 13 vg/kg infusion of valoctocogene roxaparvovec. FVIII activity was measured by chromogenic substrate (CSA; lower limit of quantitation LLOQ, 3.0 IU/dL) and one stage assays (OSA; LLOQ, 1.0 IU/dL); median FVIII activity in every 4- or 6-week window was assessed. Self-reported treated bleeds were counted after week 4, when routine prophylaxis was scheduled to end. The relationship between number of treated joint bleeds and matched median FVIII activity levels in each 4- or 6-week window was modeled using negative binomial regression.
Results. As of the data cut date, mean follow-up was 71.6 weeks; 1 participant was lost to follow-up at week 66. At weeks 49-52 (latest time with data for all participants; intent-to-treat population), 9% (12/134) had CSA FVIII activity <3 IU/dL, 3% (4/134) had median FVIII activity ≥3-<5 IU/dL, 17% (23/134) had median FVIII activity ≥5-<15 IU/dL, and 71% (95/134) had median FVIII activity ≥15 IU/dL.
While on FVIII prophylaxis prior to gene transfer, 32% of participants (43/134) had an ABR of 0. Following gene transfer, 75% of participants (101/134) were bleed-free through their last follow-up prior to the data cut. The remaining 33 participants reported 149 treated bleeds total, 62% (93/149) as traumatic and 38% (56/149) as spontaneous. By location, 53% (79/149) occurred in joints, 19% (28/149) in muscle, 14% (21/149) in soft tissue, and 14% (21/149) in other or unspecified locations.
Relative to FVIII level, 54% of treated bleeds (80/149) occurred when CSA FVIII was <3 IU/dL (LLOQ), 12% (18/149) when FVIII was ≥3-<5 IU/dL, 23% (35/149) when FVIII was ≥5-<15 IU/dL, and 11% (16/149) when FVIII was ≥15 IU/dL. Of 16 treated bleeds that occurred when FVIII was ≥15 IU/dL, 13 were traumatic.
Treated joint bleeds followed a similar pattern: 51% (40/79) occurred when FVIII was <3 IU/dL, 15% (12/79) when FVIII was ≥3-<5 IU/dL, 27% (21/79) when FVIII was ≥5-<15 IU/dL, and 8% (6/79) when FVIII was ≥15 IU/dL. A negative binomial regression model based on these data and matched FVIII activity levels predicts <1 treated joint bleed in 2 years for individuals treated with valoctocogene roxaparvovec with FVIII activity ≥15 IU/dL (CSA; Figure).
Clinical value of the CSA at low FVIII levels is limited by its LLOQ of 3 IU/dL. Of 12 participants with median FVIII levels below the CSA LLOQ at weeks 49-52, 9 had improved or the same ABR post-gene therapy relative to prophylaxis. The OSA, with its LLOQ of 1 IU/dL, provided important information here. By OSA, 1 had FVIII <1 IU/dL, 5 had FVIII ≥1-<5 IU/dL, and 3 had FVIII ≥5 IU/dL. The remaining 3 participants who had increased ABR after gene transfer had FVIII levels by OSA of 0, 2.1, and 4.8 IU/dL. For participants with OS FVIII <5 IU/dL at week 52 (n = 11), median (IQR) ABR was 1.2 (0-7.9), similar to the median (IQR) ABR of 1.6 (0.6-3.5) reported for people with moderate HA (Abdi, et al. J Throm Haemost 2020;1812:3203-10).
Conclusions. Gene transfer with valoctocogene roxaparvovec led to sustained endogenous FVIII production and reduced ABR in this phase 3 trial. After gene transfer, the majority of bleeds were traumatic. When FVIII was ≥15 IU/dL, reports of treated bleeds, including joint bleeds, were rare. CSA FVIII activity was predictive of bleeding risk post-gene transfer, as for epidemiologic congenital HA results. At FVIII levels below the CSA LLOQ, the OSA provided clinically relevant information; bleeding with OSA FVIII <5 IU/dL was similar to observations in people with moderate HA, though further exploration with more data is needed.
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Pipe: Biomarin: Consultancy, Other: Clinical trial investigator; Regeneron/ Intellia: Consultancy; uniQure: Consultancy, Other; Spark Therapeutics: Consultancy; Takeda: Consultancy; Sanofi: Consultancy, Other; Sangamo Therapeutics: Consultancy; Roche/Genentech: Consultancy, Other; Pfizer: Consultancy; Novo Nordisk: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; HEMA Biologics: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Bayer: Consultancy; ASC Therapeutics: Consultancy; Apcintex: Consultancy; Octapharma: Consultancy; Shire: Consultancy. Ozelo: BioMarin Pharmaceutical Inc.: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Travel support, Speakers Bureau; Pfizer: Consultancy, Other: Clinical trial investigator, Research Funding; Roche: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Sanofi: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator, Travel support, Research Funding, Speakers Bureau; Grifols: Other: Grants review. Kenet: Takeda: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy; Shire: Research Funding; Pfizer: Consultancy, Research Funding; Opko Biologics: Research Funding; Bayer: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding. Reding: Bayer, CSL Behring, Sanofi Genzyme, Takeda: Speakers Bureau; Bayer, Biomarin (institutional research funding): Research Funding; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda: Honoraria; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda (advisory committees): Membership on an entity's Board of Directors or advisory committees. Mason: BioMarin Pharmaceutical Inc.: Other: Participation as a clinical trial investigator; Roche: Other: Participation as a clinical trial investigator, Travel support, Speakers Bureau. Leavitt: Syntimmune: Research Funding; Sangamo Therapeutics: Research Funding; Pfizer: Research Funding; Merck: Consultancy; CSL DOVA: Consultancy; Catalys: Consultancy; BioMarin: Consultancy, Research Funding; BPL: Consultancy; Behring: Consultancy; HEMA Biologics: Consultancy; Rigel: Consultancy. Laffan: Shire: Membership on an entity's Board of Directors or advisory committees; Leo-Pharma: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; AstraZeneca: Consultancy; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Bayer: Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioMarin Pharmaceutical Inc.: Research Funding. Quon: Orthopaedic Institute for Children: Current Employment. von Drygalski: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix, Inc: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Super FVa; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biomarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Chou: Bayer: Other: Clinical trial investigator, Speakers Bureau; Novo Nordisk: Consultancy, Other: Clinical trial investigator, Speakers Bureau; BioMarin: Other: Clinical trial investigator; Sanofi: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Chugai: Consultancy, Other: Clinical trial investigator, Speakers Bureau; Pfizer: Other: Clinical trial investigator, Speakers Bureau; CSL: Consultancy, Other: Clinical trial investigator, Speakers Bureau. Shapiro: Sobi: Consultancy; Shire: Consultancy; Pfizer: Consultancy, Speakers Bureau; Bayer: Other: Travel support, Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; CSL Behring: Other: travel support. Dunn: Genentech/Roche: Consultancy, Speakers Bureau; ATHN: Research Funding; Biomarin: Consultancy, Research Funding; Freeline: Research Funding; Takeda: Research Funding; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Uniqure: Consultancy; Sanofi: Research Funding; Kedrion: Consultancy. Wang: Bioverativ: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy, Other: Clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial
Abstract 4438
Hemophilia B patients often require orthopedic surgical intervention for the improvement of function and quality of life. In these patients, coagulation factor replacement is essential, ...but the safety and efficacy of plasma-derived factor IX in controlling bleeding during surgeries has been little studied. Issues of particular concern for surgical intervention include appropriate dosing of factor concentrate, pharmacokinetics, and safety considerations.
The purpose of this study was to examine outcomes in patients with hemophilia B following surgical intervention and treatment with plasma-derived factor IX.
Following IRB approval, 22 patients who underwent 31 surgical procedures at the Hemophilia Treatment Center at Orthopedic Hospital or its affiliates in Los Angeles, CA, during the period 1996 to present, were identified. Once identified, inpatient charts for these patients were reviewed and abstracted. Outcomes of interest included pre- and post operative dosing of factor IX, perioperative blood loss and use of blood products, pharmacokinetics factors, and hemostatic response.
For identified patients, 9.1% were diagnosed with mild hemophilia B (factor IX levels > 5%), 13.6% had moderate hemophilia B (factor IX levels between 1% - 5%), and 77.3% had severe hemophilia B (factor IX < 1%). The mean age at surgery was 48.0 years old. All but 3 surgical procedures were orthopedic (90.3%) and most frequently involved the knee (38.7%), elbow (16.1%), hip (12.9%), or shoulder (9.6%). All surgeries were completed under general anesthesia and average time in surgery was 3:15 hours. Dose of factor IX averaged 238 IU/kg on the day of surgery and was adjusted over the course of the hospital stay. Selection of replacement factor IX was by patient choice and AlphaNine® SD was the most common factor IX concentrate used (94% of procedures). Mean perioperative blood loss was 283ccs (range 0-1000) and blood replacement was required in only 2 surgeries (6.5%). Pharmacokinetic analysis performed pre-operatively related well to factor IX levels obtained peri- and post-operatively. Average hospital length of stay was 10.7 days and all patients were discharged to home.
The results of this study demonstrated that patients with Hemophilia B undergoing major surgery who were treated with plasma derived factor IX had little unexpected blood loss perioperatively, seldom required blood replacement, and had no bleeding related surgical complications. These results suggest that pre- and postoperative treatment with plasma derived factor IX is both safe and effective for patients with hemophilia B undergoing surgical intervention.
Logan:Grifols, S.A.: Consultancy. Quon:NovoNordisk: Speakers Bureau; Grifols, S.A.: Honoraria.
The Joint
Activity and Damage Exam (JADE) is a point-of-care (POC) musculoskeletal ultrasound (MSKUS) protocol for non-radiologists to evaluate hemophilic arthopathy. Our aim was to determine the ...consistency of cross-sectional analyses of direct tissue measurements (JADE protocol) and clinical Hemophilia Joint Health Score HJHS and functional joint assessments (arc) at three clinic visits.
We prospectively studied adults (n = 44) with hemophilia (A or B) of any severity and arthropathy at 3 North American sites. We assessed HJHS, total arc, and JADE parameters (bilateral elbows, ankles, and knees) at study entry, at ≈12-18 months, and at ≈24-36 months, and used MSKUS to evaluate painful episodes between study visits. JADE measurements included osteochondral alterations, cartilage thickness, and soft tissue expansion at sentinel positions. Associations between joint HJHS and total arc with each JADE variable were examined with random intercept models.
At each visit increasing HJHS and decreasing total arc were associated in the expected direction with increasing length of OAs and soft tissue expansion in all joints, and decreasing cartilage thickness in the knee. However, HJHS associations with cartilage thickness were U-shaped for elbow and ankle (i.e. cartilage thinning and thickening). Associations between total arc and cartilage thickness followed a similar curve. (Near) normal levels of both joint parameters (HJHS and total arc) were associated with normal ranges of cartilage thickness. JADE views were also helpful to detect hemarthrosis in association with joint pains.
POC MSKUS applying direct tissue measurements using the JADE protocol provided reproducible cross-sectional associations with joint health outcomes on three visits. These findings advance protocol validation and enable iterative adaptations resulting in JADE protocol version 2.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Patients with hemophilia (PWH) have a higher prevalence of hypertension and intracranial hemorrhage than the general male population. However, the etiology of the hypertension, and to what extent ...blood pressure and associations with cardiovascular risk factors vary from the general population, is incompletely understood. We therefore investigated the prevalence of hypertension as well as the associations of blood pressure measurements with usual cardiovascular risk factors, in a cross-sectional analysis of a cohort of 486 PWH. The PWH (median age 38 years) came from 3 geographically different areas in the United States. They were compared against males from the contemporary National Health and Nutrition Examination Survey (NHANES), matched for age and race in a 1:5 ratio. Subsequently, at the University of California San Diego, a pilot cohort of PWH (n=28; median age 37 years) was examined prospectively for hypertension and associations with hemophilia-specific risk factors pertaining to joint health.
PWH had a significantly higher prevalence of hypertension compared to subjects from NHANES. The prevalence of hypertension was 53.4% in PWH compared to 28.8 % in NHANES (p<0.01). In untreated (not taking anti-hypertensive medications) and treated subjects median systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in PWH than in NHANES. Differences in prevalence of hypertension and blood pressure measurements were most pronounced in the youngest age group (18-29 years). In untreated PWH median SBP and DBP were 125 and 78 mmHg (118 and 72 mmHg in NHANES), and in treated PWH 134 and 84 (127 and 76 mmHg in NAHES), respectively; all p-values <0.0001. However, despite higher blood pressures the usual cardiovascular risk profile was better in PWH compared to NHANES, in that body mass index (BMI), total cholesterol, smoking and diabetes were lower and renal function was better.
While the usual cardiovascular risk factors were associated with blood pressure in both PWH and NHANES, they did not account for the differences between the two groups. Whether each risk factor was considered by itself, or in combination with the others in multivariate models, the blood pressure differences remained. Therefore, to elucidate to what extent hemophilia-specific factors might play a role in the pathophysiology of hypertension, we assessed hypertension and blood pressures in association with joint health parameters in a pilot cohort of young adult PWH. These patients underwent prospective baseline examination of 6 joints (both elbows, knees and ankles, n=168) for joint pain (Visual Analogue Scale 0-10), radiographic Pettersson score (maximum score 78), clinical Hemophilia Joint Health Score (HJHS, maximum score 120), severity of hemophilia (severe vs mild/moderate), clotting factor usage, and joint vascular perfusion quantified with Power Doppler (PD, maximum score 54) and high resolution musculoskeletal ultrasound. We found that 54% were hypertensive, similar to the larger cohort. In univariate analysis, PD score was the risk factor most strongly associated with hypertension (p = 0.07). After adjustment for confounders, the odds for hypertension increased by 1.29 (95% CI: 1.04, 1.60; p = 0.02) for each unit increase in PD score. Moreover, there was a strong association of PD scores with SBP when adjusted for confounders.
In conclusion, our findings demonstrate that PWH not only have a significantly higher prevalence of hypertension, but also significantly higher blood pressures compared to the general population, even when treated with anti-hypertensive medications. The difference in blood pressures could not be explained by the usual cardiovascular risk factors but appeared to be strongly associated with the degree of vascular changes in the joint. Based on previous findings that vascular remodeling is a prominent feature of hemophilic arthropathy and may be mediated systemically, we postulate that vascular remodeling is associated with the etiology of hypertension in hemophilia. These findings warrant further basic and clinical investigation.
Kruse-Jarres:Octapharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Quon:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. von Drygalski:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Introduction
Musculoskeletal ultrasound (MSKUS) is being used increasingly for point-of-care (POC) assessment of painful hemophilic joints and has proven to be a critical tool in the evaluation of ...the presence of hemarthrosis. To date, MSKUS examinations are exclusively performed in the clinic, which often results in delays to definitive diagnosis since patients and caregivers are not always able to undergo or perform a clinical assessment at the time of the event. The use of pocket handheld ultrasound devices, which have primarily been applied for cardiopulmonary and abdominal POC bedside assessments, offers a promising solution to this problem by enabling patients and remote clinics to acquire images for off-site real-time evaluations via tele-transmission. In this study, we evaluated the extent to which the quality of images generated by the handheld ultrasound devices compared to stationary MSKUS and if the image interpretation was similar between various health care providers. The aim is to establish the dynamic potential of this pocket sized device as a cost effective and comparable alternative to the stationary MSKUS.
Methods
A total of 72 typical joint views (36 of the knee, 20 of the elbow and 16 of the ankle) were acquired from healthy volunteers and hemophilia patients at the same session with the stationary GE LogiqS8 and the handheld GE V2scan. Ten different health care providers (7 physicians, 2 physical therapists and 1 nurse), all trained at least in the CME-accredited MSKUS course at the University of California, San Diego, (UCSD), reviewed these images side by side. Information about view, probe placement and tissue compressibility to identify effusions was provided. Each subject was asked to evaluate the following characteristics on a graded scale: (1) similarity of the handheld image to the GE LogiqS8 image, (2) their confidence in identification of major landmarks on the handheld image compared to the GE LogiqS8 image and if an effusion was present, (3) their ability to identify the effusion on both images. The adjudicators were a board-certified radiologist and a senior hematologist trained and experienced in MSKUS. Study procedures complied with rules set forth by the UCSD Human Research Protection Program.
Results
A total of 720 responses were analyzed from the images of normal and hemophilic joints. Among the responses, 87% of images were rated as at least moderately similar to very similar between the handheld device and the stationary ultrasound. In terms of identification, 88% of the responses were rated as at least moderately confident to very confident in the identification of major landmarks on the handheld image. Among a total of 170 responses for effusions, 87% of effusions were identified with both the handheld device and the stationary MSKUS (Table). These percentages were consistent between the different joints with slightly higher rates of correct identification on the handheld device noted in the knee where 100% of effusions were recognized correctly. Representative images depicting an effusion in the lateral recess of the knee acquired simultaneously with the handheld GE V2scan and stationary MSKUS is provided (Figure). There was no significant discrepancy of answers between the types of providers.
Conclusion
The image quality of the handheld pocket device (GE V2 scan) was sufficient to determine major landmarks in joints and to diagnose effusions, with image interpretation comparable between the various health care providers encompassing physicians, nurses, and physical therapists. These findings highlight the potential in the application of this device as a novel POC modality for both patient-performed tele-ultrasound or tele-ultrasound use in remote, resource limited regions for real-time assessments of hemarthrosis. While encouraging, these observations need to be further validated and extended more broadly in future studies.
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Kruse-Jarres:Baxalta: Consultancy, Honoraria; Grifols: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Quon:Bayer: Consultancy; Biogen: Consultancy, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau. von Drygalski:Pfizer: Consultancy, Honoraria, Speakers Bureau; Hematherix LLC: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; CSL-Behring: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Baxalta/Shire: Consultancy, Honoraria, Speakers Bureau.
Introduction: High collision-risk physical activity can increase bleeding risk in people with hemophilia A, as can increasing the time between factor VIII (FVIII) administration and physical ...activity. FVIII prophylaxis may be tailored to planned activities to prevent activity-related bleeding. Aim: To explore the relationship between physical activity levels, FVIII infusion timing, and occurrence of bleeding in patients with severe/moderately severe hemophilia A without FVIII inhibitors receiving antihemophilic factor (recombinant) (rAHF; ADVATER; Baxalta US Inc., a Takeda company, Lexington, MA, USA). Methods: SPACE was a 6-month, prospective, multicenter, observational outcomes study (NCT02190149). Enrolled patients received an eDiary application and a wearable activity tracker, which recorded physical activity, rAHF infusion, and occurrence of bleeding. Physical activity risks were ranked using National Hemophilia Foundation criteria. Results: Fifty-four patients aged 11-58 years (n = 47 prophylaxis, n = 7 on-demand) were included in the analysis. Patients had a mean (SD) 8.14 (10.94) annualized bleeding rate, and recorded 4980 intervals between an rAHF infusion and physical activity; 1759 (35.3%) of these intervals were less than or equal to 24 hours. Analysis of recorded eDiary data showed that the risk of activity-related bleeding did not significantly increase with time between last infusion and activity, but did increase with higher-risk physical activities. Analysis of activity tracker recorded data showed that the risk of bleeding reported by patients as spontaneous increased with prolonging time (less than or equal to 24 to >24 hours) from last infusion to physical activity start (odds ratio 2.65, p < 0.05). Joint health data collected at baseline were not included in the regression analysis because of small sample size; therefore the study could not assess whether patients with more joint disease at baseline were at higher risk of injury-related and reported spontaneous occurrence of bleeding. Conclusion: These results show that activities with a high risk of collision lead to an increased risk of bleeding. Further investigation is warranted to explore potential benefits of FVIII infusion timing to reduce the risks of activity-related occurrence of bleeding. Keywords: hemophilia A, recombinant factor VIII, physical activity, post-authorization study, prophylaxis, bleeding
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Introduction: Prophylactic treatment with factor VIII (FVIII) replacement therapy reduces the frequency of bleeding and prevents arthropathy in patients with hemophilia A. The phase 3 A-LONG study ...(Mahlangu et al. Blood 2014) demonstrated the prolonged half-life of recombinant FVIII Fc fusion protein (rFVIIIFc) relative to recombinant FVIII, as well as the efficacy and safety of rFVIIIFc for routine prophylaxis and treatment of bleeding in subjects with severe hemophilia A. While the efficacy of rFVIIIFc for the treatment of bleeding was previously evaluated in an aggregate analysis of subjects on prophylaxis and episodic treatment in A-LONG, the efficacy results of rFVIIIFc for treatment of bleeding solely in those receiving prophylaxis have yet to be published. Furthermore, for FVIII therapies, there are limited data describing resultant activity levels when treatment of bleeding doses are given to patients receiving prophylaxis. In this analysis, the efficacy of rFVIIIFc for the treatment of bleeding episodes in those receiving rFVIIIFc prophylaxis was assessed. Additionally, population pharmacokinetic (PK) models were used to predict FVIII activity in patients who use rFVIIIFc to treat bleeding episodes in close proximity to their next scheduled prophylactic dose.
Methods: The efficacy of rFVIIIFc for treatment of bleeding was assessed in previously treated males ≥12 years of age with severe hemophilia A (<1 IU/dL FVIII activity or severe genotype) that received individualized prophylaxis (Arm 1) or weekly prophylaxis (Arm 2) in A-LONG. The number of bleeds, dose per infusion used to treat a bleed, and percent of bleeds resolved with a single infusion were evaluated. A previously validated, two-compartment rFVIIIFc population PK model was used to predict factor activity levels in 1000 hypothetical patients. Activity was modeled assuming a 25 IU/kg dose of rFVIIIFc was used to treat a bleeding episode 24 hours before a scheduled prophylaxis dose for patients at steady-state on regimens of either 50 IU/kg every 4 days (E4D) or 50 IU/kg every 3 days (E3D). The treatment of bleeding dose was selected to approximate the median dose/infusion used to treat bleeds in A-LONG. Twenty-four hours is likely to be the closest proximity for a separate dose to treat a bleeding episode prior to a prophylaxis dose. The regimens of 50 IU/kg E4D and 50 IU/kg E3D represented the length of one interval in the most common dosing regimen in Arm 1 of A-LONG and the shortest dosing interval in Arm 1 of A-LONG, respectively.
Results: There were 209 bleeding episodes reported in 64 of the 117 subjects in Arm 1 of A-LONG (median annualized bleeding rate ABR 1.6, median spontaneous ABR 0.0). The median dose per infusion to treat a bleed in Arm 1 was 29.94 IU/kg (interquartile range IQR 24.49-50.93), and 85.6% of bleeds resolved with one infusion. There were 92 bleeds in 19 of the 23 subjects in Arm 2 (median ABR 3.6, median spontaneous ABR 1.9). Median dose per infusion to treat a bleed in Arm 2 was 21.65 IU/kg (IQR 19.84-32.47), and 80.4% of bleeds resolved with one infusion. rFVIIIFc was generally well-tolerated, and no serious vascular thrombotic events were reported. The population PK model predicted median peak plasma concentrations (Cmax) of 54.8 IU/dL (95% prediction interval PI 34.4-91.9) and 62.6 IU/dL (95% PI 37.3-112) following treatment of a bleed in patients on the E4D and E3D regimens, respectively (Figure 1). The predicted median Cmax values for the two regimens following the subsequent prophylactic dose were 116 IU/dL (95% PI 74.1-186) and 120 IU/dL (95% PI 74.8-196), respectively.
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Conclusions: A validated population PK model showed that even among patients on prophylactic regimens with short intervals, predicted factor activity levels are likely to fall in the normal range for the majority of patients when a bleeding episode is treated in close proximity to a scheduled prophylactic dose. Though bleeding episodes were rare with rFVIIIFc prophylaxis, rFVIIIFc was found to be safe and efficacious when used to treat bleeding episodes in subjects on routine prophylaxis.
Quon:Novo Nordisk: Consultancy, Speakers Bureau; Baxter: Speakers Bureau; Grifols: Speakers Bureau; Baxter: Consultancy; Bayer: Consultancy. Mahlangu:Amgen: Membership on an entity’s Board of Directors or advisory committees; Bayer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Research Funding, Speakers Bureau; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Genentech: Membership on an entity’s Board of Directors or advisory committees; Biotest: Speakers Bureau. Shapiro:Baxter: Consultancy, Global Steering Committee Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Global Steering Committee, Global Steering Committee Other, Research Funding; CSL Behring: Research Funding; Biogen Idec: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Kedrion: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Pasi:Bayer: Membership on an entity’s Board of Directors or advisory committees; BPL: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Educational Support and Travel Grants, Educational Support and Travel Grants Other, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Educational Support and Travel Grants, Educational Support and Travel Grants Other; OctaPharma: Educational Support and Travel Grants Other, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Educational Support and Travel Grants Other, Membership on an entity’s Board of Directors or advisory committees. Zhu:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.
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