Hemophilia Natural History Study (ATHN 7): Safety of Current Therapies for People with Hemophilia A or B

Abstract INTRODUCTION: The recent introduction of new therapies for people with hemophilia A and B (HA and HB) mandates careful monitoring of the safety of these treatments. The primary aim of ATHN 7: A Natural History Study of the Safety, Effectiveness, and Practice of Treatment for People with Hemophilia (NCT03619863) is to monitor the safety of current hemophilia therapies. METHODS: ATHN 7 is a longitudinal, prospective cohort study being conducted at 26 American Thrombosis and Hemostasis Network (ATHN)-affiliated sites. The study is approved by central and local institutional review boards. Any person with a diagnosis of congenital hemophilia A or B (factor VIII or IX activity < 50%) who receives care at a participating site is eligible for inclusion. Participants and/or a parent/guardian sign informed consent and assent prior to participation. Adverse events, including those events designated by the European Haemophilia Safety Surveillance group as well as other adverse events of special interest, are recorded and monitored. Demographic and clinical information are collected at baseline and at least quarterly through participant interview and medical record review. Descriptive statistics of medical history and demographic data as well as longitudinal data are used to characterize the study population. RESULTS: As of June 2021, a total of 391 participants had enrolled in ATHN 7. The median age of participants was 22.5 ± 17.8 years. Males represented 97.7% (382/391) of participants. Eighty-five percent (333/391) were not Hispanic. White participants comprised 82.6% (323/391) of the study population, while 7.9% (31/391) were Black/African American, 3.8% (15/391) were Asian, 1.8% (7/391) were of mixed race, and 3.8% (15/391) were of other or unknown race. The primary diagnosis of participants included 70.1% (274/391) with severe HA, 15.3% (60/391) with moderate HA, 7.2% (28/391) with mild HA, 4.1% (16/391) with severe HB, 2.0% (8/391) with moderate HB, and 1.0% (4/391) with mild HB. Nineteen percent (71/391) of participants had a documented history of an inhibitor at the time of enrollment with a mean peak inhibitor titer of 96.7 ± 214.3 Bethesda Units. Substitution therapy with a non-factor molecule was the primary medication for 43.4% (162/391) participants, while 4.3% (16/391) utilized a plasma-derived clotting factor concentrate, 28.4% (196/391) utilized a standard half-life, recombinant factor concentrate, 18.3% (126/391) utilized an extended half-life recombinant factor concentrate, 4.1% (28/391) utilized a bypassing agent, and 19.3% (133/391) utilized some other hemostatic agent. Continuous prophylaxis was the primary regimen for 79.1% (295/391) participants. The remaining 19.6% (73/391) of participants were on episodic therapy. Within the cohort of 391 participants, a total of 14 adverse events have been reported in 8 participants. No adverse events of special interest were reported. Redness or rash at injection site accounted for 64.2% (9/14) of the reported adverse events, all in participants receiving emicizumab. Two participants experienced bruising or bleeding while on emicizumab. Two participants on emicizumab were diagnosed with malignancy, neither found to be attributed to their therapy. One participant developed an allergic reaction to their standard half-life recombinant factor concentrate. DISCUSSION: Open to enrollment in January 2019, ATHN 7 has now collected 18 months of longitudinal safety data for therapies used to treat HA and HB in 391 participants, an addition of 12 months and 24 participants since our last report. As the study was designed to enhance representation of those utilizing substitution therapy, almost half of the participants were on emicizumab for prophylaxis of bleeding. Adverse events attributable to hemophilia therapy was limited to minor skin reactions. As previously reported, a single participant experienced delayed bleeding after closed head trauma (despite factor replacement and normal intracranial imaging at the time of the event), providing potentially important information on the risk of delayed bleeding from significant trauma in those receiving emicizumab. Over the coming year, participants in ATHN 7 will be transitioned to ATHN's new longitudinal natural history study, ATHN TRANSCENDS (NCT04398628). Disclosures Buckner: Pfizer: Honoraria; Takeda: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Spark: Honoraria; Genetech: Honoraria; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; uniQure: Consultancy, Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees. Carpenter: Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; Kedrion Pharmaceuticals: Honoraria; Genentech: Honoraria; Novo Nordisk: Honoraria. Raffini: Genentech: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; XaTek: Consultancy; Bayer: Consultancy. Zia: Takeda: Consultancy; Hemophilia and Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees. Recht: Hema Biologics: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; uniQure: Consultancy; Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy.

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Hemophilia Natural History Study (ATHN 7): Baseline Characteristics, Adverse Events, and Self-Reported Health Status of Individuals with Hemophilia a and B

Blood ◽

10.1182/blood-2020-137696 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 2-3

Author(s):

Tyler W. Buckner ◽

Shannon L Carpenter ◽

Stacy E. Croteau ◽

Adam Cuker ◽

Nabil Daoud ◽

...

Keyword(s):

Cohort Study ◽

Health Status ◽

Natural History ◽

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Advisory Board ◽

Advisory Committees ◽

Skin Reactions

INTRODUCTION The recent introduction of new therapies for hemophilia A and B (HA and HB) mandates careful monitoring of the safety of these treatments as their use becomes more widespread. The American Thrombosis and Hemostasis Network (ATHN) collects information about the use of all HA and HB therapies through the more than 140 ATHN-affiliated hemophilia treatment centers (HTCs) in the United States (US). The primary aim of ATHN 7: A Natural History Cohort Study of the Safety, Effectiveness, and Practice of Treatment for People with Hemophilia is to monitor the safety of current hemophilia therapies. Secondary aims include assessment over time of real-world effectiveness and patient experience of current therapies. METHODS ATHN 7 is being sponsored by ATHN. It is a longitudinal, prospective cohort study being conducted at over 20 ATHN-affiliated sites in the US. The study is approved by central and local institutional review boards. Any person with a diagnosis of congenital hemophilia A or B (factor VIII or IX activity < 50%) who receives care at a participating site is eligible for inclusion. All participants and parents/guardians sign informed consents and assents prior to participation. Patients are excluded if they have any other known bleeding disorder. Adverse events, including those events designated by the European Haemophilia Safety Surveillance (EUHASS) group as well as other adverse events of special interest, are recorded and monitored. Demographic and clinical information are collected at baseline and at least quarterly through patient interview and medical record review. Health status is measured using the 5-level EuroQoL-5D questionnaire (EQ-5D-5L). Descriptive statistics of the baseline medical history and demographic data are used to characterize the study population. RESULTS The first participant consented to ATHN 7 in February 2019. As of 06/30/2020, a total of 367 subjects were enrolled in the study from 24 sites. Baseline demographics, clinical characteristics, and treatments are shown in Table 1. Most participants (69.9%) had severe HA. Approximately half of the participants were being treated with clotting factor as their primary therapy and half with a bispecific antibody. Adverse events reported to date include allergic reactions/redness at the injection site, rash unrelated to treatment, and a severe subdural hematoma due to a fall, all in patients receiving emicizumab (Table 2). At baseline, problems with mobility, self-care, and completing usual activities were reported by 32.9%, 13.0%, and 33.7% of participants, respectively. Problems with pain and anxiety were reported by 52.4% and 34.1% of participants (Figure 1). The average health status rating was 83.4 out of 100 (Figure 2). DISCUSSION These results demonstrate the capability of ATHN 7 to enroll a large cohort of subjects from multiple sites, monitor safety events, and assess outcomes related to living with and being treated for HA and HB. Adverse events attributed to any hemophilia therapy have been limited to minor skin reactions and have not led to product discontinuation. One subject experienced a trauma-related subdural hemorrhage, which provides important information on the risk of bleeding from severe/significant trauma in those receiving emicizumab. We provide a sobering picture of the high prevalence of difficulties with activities of daily living, pain, and mental health concerns. Despite many advances in therapy, hemophilia continues to have a real, everyday impact on the lives of our patients. CONCLUSIONS During the first 16 months of enrollment in the ATHN 7 study, we observed skin reactions, as well as one severe, unanticipated bleeding event due to trauma. At baseline, pain, anxiety/depression, and impaired physical function were concerns for a significant proportion of the individuals in the study. Disclosures Buckner: Tremeau Pharmaceuticals: Consultancy; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Takeda: Consultancy; Bayer: Consultancy; uniQure: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Spark: Consultancy; Genentech: Consultancy; Biomarin: Consultancy. Carpenter:Hemostasis & Thrombosis Research Society: Membership on an entity's Board of Directors or advisory committees; American Academy of Pediatrics: Other: PREP Heme/Onc editorial board; Shire: Research Funding; CSL Behring: Research Funding; American Thrombosis and Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Honoraria; Kedrion: Honoraria; Novo Nordisk: Honoraria. Croteau:ATHN: Research Funding; National Hemophilia Foundation: Honoraria; Spark Therapeutics: Research Funding; Novo Nordisk: Research Funding; Bayer: Consultancy; Hemophilia Federation of America: Honoraria; CSL-Behring: Consultancy; Pfizer: Consultancy; Genentech: Consultancy; Sigilon Therapeutics: Consultancy. Cuker:Synergy CRO: Consultancy; Alexion: Research Funding; Bayer: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Spark Therapeutics: Research Funding; Takeda: Research Funding; Novartis: Research Funding. Kempton:Spark Therapeutics: Honoraria; Octapharma: Honoraria; Pfizer: Honoraria; Genentech: Honoraria; Novo Nordisk: Research Funding. Malec:SOBI: Consultancy; Bayer: Consultancy; Takeda: Consultancy; CSL: Consultancy; Sanofi Genzyme: Consultancy, Research Funding, Speakers Bureau. Raffini:XaTek: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board; HemaBiologics: Other: Advisory Board; Roche: Other: Advisory Board. Staber:Spark Therapeutics: Consultancy; Genentech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Bayer: Consultancy. Wang:CSL Behring: Honoraria; Biomarin: Honoraria; Genentech: Honoraria; Bioverativ Inc: Honoraria; Bayer: Honoraria; Takeda: Honoraria. Recht:Novo Nordisk: Consultancy, Other: personal fees, Research Funding; Spark: Research Funding; uniQure: Consultancy, Other: personal fees, Research Funding; Takeda: Consultancy, Other: personal fees, Research Funding; BioMarin: Research Funding; Pfizer: Consultancy, Other: personal fees; Genentech: Consultancy, Other: personal fees, Research Funding; CSL Behring: Consultancy, Other: personal fees.

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An Integrated Analysis of Long Term Safety of an Extended Half-Life, Pegylated, Full-Length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia a

Blood ◽

10.1182/blood.v126.23.3522.3522 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3522-3522

Author(s):

Pratima Chowdary ◽

Barbara Konkle ◽

Tadashi Matsushita ◽

Werner Engl ◽

Lisa Patrone ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Vital Signs ◽

Integrated Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract BAX 855 is a pegylated, full-length, recombinant factor VIII (PEG rFVIII) built on ADVATE with an extended half-life that is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. This safety evaluation was derived from an integrated analysis of 5 clinical studies in previously treated patients (PTPs) who were treated with BAX 855 for prophylaxis, bleeding episodes, or perioperative management, or who received a single-dose for a pharmakokinetic (PK) evaluation. Two studies have been completed (pivotal phase 2/3 and phase 1) and 3 are ongoing (continuation, surgery, and pediatric). In all studies, adverse events (AEs) (including hematology and clinical chemistry laboratory values deemed AEs by the investigator) and immunogenicity (inhibitory and binding antibodies) were assessed. Shifts in laboratory values to clinically abnormal over the course of the study and changes in pre- and post-infusion vital signs were also assessed. Of the 169 unique patients (most participated in more than 1 study), 3 were <6 years of age, 1 was 6 to <12, 25 were 12 to <18, and 140 were ≥18. The mean (SD) age was 30.1 (13.0) years and all were male. Overall, 133 (78.7%) patients were White, 34 (20.1%) were Asian, 1 (0.6%) was Black, and 1 (0.6%) was "other". These 169 patients received nearly 46 million IUs of BAX 855; 117 patients started treatment in the pivotal study and transitioned to the continuation study, for an overall median (Q1;Q3) exposure of 96 (48.0;110) days. A total of 300 AEs were reported in 96 of 169 patients during or after treatment with at least 1 infusion of BAX 855. The overall rate of AEs by infusion was 2.2% (300 AEs/13,579 infusions), the rate of nonserious AEs by infusion was 2.1% (283 AEs/13,579 infusions), and the rate of SAEs by infusion was 0.1% (16 SAEs/13,579 infusions). Common AEs considered related to BAX 855 (in ≥1% of patients) were headache and nausea; diarrhea, flushing, and blood pressure increase occurred once in 1 patient each. None of the 16 SAEs reported were considered related to the use of BAX 855. No treated patient has discontinued from a study due to a treatment related AE (or SAE). None of the patients exposed to BAX 855 developed an inhibitory antibody to FVIII of ≥0.6 BU/mL by the Bethesda assay, including 120 patients with ≥50 EDs (95% CI: 0.000 to 0.030) and 48 with ≥100 EDs (95% CI: 0.000 to 0.074). None of the 169 treated patients developed a persistent binding antibody against FVIII, PEG-FVIII, PEG, or CHO protein. Pre-existing and transient binding antibodies were detected in 21 patients; however, these were not detectable at subsequent visits or at completion of the study and appeared to have no apparent impact on efficacy or temporal association with an AE. No remarkable trends were observed in changes in laboratory parameters from baseline to last study visit or in vital signs evaluated pre- and post-infusions given at the study site (eg, PK assessments). From this integrated analysis, BAX 855 was safe and well tolerated in 169 PTPs with severe hemophilia A. The common adverse events considered related to BAX 855 treatment were consistent with the safety profile of ADVATE. Disclosures Chowdary: Sobi: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding. Konkle:Baxalta: Consultancy, Research Funding; CSL Behring: Consultancy; Pfizer: Consultancy; Novo Nordisk: Consultancy; Octapharma: Research Funding; Biogen: Consultancy, Research Funding. Matsushita:Baxalta: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Patrone:Baxalta: Employment, Equity Ownership. Abbuehl:Baxalta: Employment, Equity Ownership.

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Target Joint Bleeding in Pediatric Patients with Hemophilia Α Receiving Twice Weekly Prophylaxis with a Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life

Blood ◽

10.1182/blood.v128.22.3778.3778 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3778-3778

Author(s):

Amy L. Dunn ◽

Alexis A. Thompson ◽

Werner Engl ◽

Marlies Sharkhawy ◽

Brigitt E. Abbuehl

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Point Estimate ◽

Severe Hemophilia ◽

Advisory Committees ◽

The Mean

Abstract Introduction: Patients with hemophilia A are at risk for acute bleeding which may affect muscles and other soft tissues but characteristically involves joints. Prophylaxis with factor VIII (FVIII) is the optimal treatment to prevent bleeding into joints and, when begun at a young age, may prevent arthropathy. BAX 8551, a polyethylene glycol (peg)ylated, full-length, recombinant FVIII built on ADVATE2, demonstrated extended half-life, efficacy, and safety for prophylaxis and treatment of bleeding in patients with severe hemophilia A. Methods: A phase 3, prospective, uncontrolled, multicenter study was performed in pediatric patients with severe hemophilia A without history of inhibitors. To be eligible, patients aged <6 years had to have ≥50, those aged 6 to <12 years ≥150 previous exposure days (EDs) to FVIII. Patients received twice weekly infusions of 50 ±10 IU/kg of BAX 855 over a period of 6 months or ≥50 EDs. The prevalence of target joints, defined as a single joint with ≥3 spontaneous bleeding episodes in any consecutive 6-month period, was assessed at baseline. Annualized rates of target joint bleeds and the course of target joints were evaluated by age (<6 and 6 to <12 years). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results:Sixty-six patients were treated with a mean (SD) BAX 855 dose of 51.1 (5.5) IU/kg at a mean (SD) frequency of 1.8 (0.2) infusions/week. Fourteen of 66 patients (21.2%), 3/32 (9.4%) in the younger and 11/34 (32.4%) in the older cohort, had a total of 23 target joints at screening. The number of target joint bleeds decreased during a mean (SD) of 48.5 (7.7; median: 49.0) prophylactic EDs/patient. Five of 66 (7.6%) patients had at least 1 target joint bleed, 1/32 (3.1%) in the younger and 4/34 (11.8%) in the older cohort. The point estimate for the mean (95% CI) annualized rate of target joint bleeds was 0 (0 - infinity; median: 0) compared to an annualized rate of all joint bleeds of 1.1 (0.6 - 1.9; median: 0) and an annualized rate of all bleeds of 3.0 (2.2 - 4.2; median: 2.0) (Table 1). The point estimate for the mean (95% CI) annualized bleeding rate (ABR) in 52 patients without target joints was 2.9 (2.0 - 4.2; median: 2.0) and was similar in 14 patients with target joints at screening at 3.5 (1.9 - 6.6; median: 2.1). In the younger cohort, the ABR was lower in patients with than those without target joints. However, the number of patients <6 years with target joints (N = 3) was too small to draw any conclusions (Table 1). During BAX 855 prophylaxis, no new target joints developed in any patient. Ten of 14 patients had at least 1 target joint revert to a non-target joint. In 8 of these 10 patients, 4 with 1 and 4 with 2 target joints, all target joints resolved. Conclusions:These results suggest that twice weekly infusion of BAX 855 is effective in the prevention of bleeding into target joints and may revert target to non-target joints in pediatric patients with severe hemophilia A. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trade mark of Baxalta US Inc., now part of Shire. Disclosures Dunn: NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Research Funding; Pfizer: Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta (now part of Shire): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Thompson:Eli Lily: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

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BIVV001: The First Investigational Factor VIII Therapy to Break Through the VWF Ceiling in Hemophilia A, with Potential for Extended Protection for One Week or Longer

Blood ◽

10.1182/blood-2018-99-113575 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 636-636 ◽

Cited By ~ 7

Author(s):

Barbara A Konkle ◽

Amy Shapiro ◽

Doris Quon ◽

Janice Staber ◽

Takashi Suzuki ◽

...

Keyword(s):

Single Dose ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Low Dose ◽

Hemophilia A ◽

High Dose ◽

Severe Hemophilia ◽

Advisory Committees ◽

Dose Cohort

Abstract Introduction: The standard of care for patients with severe hemophilia A is prophylactic factor VIII (FVIII) replacement. Conventional recombinant FVIII products are efficacious but require frequent administration because of their short half-life, which reflects the dependence of FVIII on von Willebrand factor (VWF). Recombinant FVIII Fc fusion protein (rFVIIIFc) provides an extended dosing interval, as well as joint protection and improved quality of life (Oldenburg et al, Haemophilia, 2018; Wang et al, Blood, 2016), with a well-characterized safety profile. While rFVIIIFc reduces the required administration frequency, longer prophylactic dosing intervals that also offer maximum overall protection are still an unmet need for patients with severe hemophilia A. Increasing the half-life of rFVIII is ultimately dependent upon decoupling FVIII and endogenous VWF. BIVV001 (rFVIII-VWF-XTEN) is a novel investigational rFVIII therapy with single-chain FVIII, the Fc domain of human immunoglobulin G1, 2 XTEN polypeptides, and the FVIII-binding D′D3 domain of VWF, designed to circulate in plasma independently of VWF, thereby breaking the VWF half-life ceiling. Here, we present the low-dose cohort results of EXTEN-A, a Phase 1/2a study assessing the safety and tolerability of a single dose of BIVV001, and the pharmacokinetic (PK) characteristics of a single dose of BIVV001 compared with rFVIII. Methods: EXTEN-A (NCT03205163) is an open-label, dose-escalation, multicenter study. Previously treated adult males with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII activity) with ≥150 exposure days to FVIII products were included. Patients were assigned to either the low-dose cohort (25 IU/kg of rFVIII and 25 IU/kg of BIVV001; n≥6) or the high-dose cohort (65 IU/kg of rFVIII and 65 IU/kg of BIVV001; n≥8). Escalation from the low-dose cohort, and enrolment of patients to the high-dose cohort was undertaken after assessment of available data from the low-dose cohort. After a screening and washout period of up to 28 days, patients received a single dose (25 or 65 IU/kg) of rFVIII. After a 3- to 4-day washout period, patients received a single dose of BIVV001 at the same dose level as rFVIII. Blood samples for PK analysis were collected for 3 days after dosing of rFVIII and up to 14 days after dosing of BIVV001. Inhibitor testing was performed 14 and 28 days following BIVV001 administration. Adverse events, clinical abnormalities in laboratory tests (including inhibitor development), and PK parameters were assessed. An interim analysis is planned, including the first 2 patients of the high-dose cohort. Results: Out of 7 patients enrolled in the low-dose cohort (25 IU/kg), 6 patients were dosed with BIVV001. Patients in this group were primarily white, with 1 patient of Asian descent, and 1 of Hispanic/Latino ethnicity. Patient ages ranged from 19 to 60 years. Low-dose BIVV001 was well tolerated and no inhibitors were detected through 28 days after BIVV001 dosing. Low-dose BIVV001 demonstrated an extended half-life of 37.6 hours, compared with a 12.1-hour half-life for rFVIII. Average FVIII activity post-infusion of BIVV001 was 12.2% at 5 days and 5.3% at 7 days. At least 8 patients will be enrolled in the high-dose cohort (65 IU/kg); preliminary data for the first 2 patients will be reported. Conclusions: BIVV001 was well tolerated in 6 patients with severe hemophilia A who were treated with a single low dose (25 IU/kg). No patient developed an inhibitor to FVIII. Low-dose cohort data demonstrated a breakthrough in the half-life of rFVIII therapy, with BIVV001 providing sustained FVIII levels that could potentially allow for more optimal, extended protection for patients. Disclosures Konkle: Genentech: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding; Gilead: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Sangamo: Research Funding; Shire: Research Funding. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin: Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; OPKO: Research Funding; Octapharma: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Daiichi Sankyo: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; Octapharma: Consultancy; Genetech: Consultancy, Speakers Bureau; Bayer: Consultancy; NovoNordisk: Consultancy, Speakers Bureau; Shire: Speakers Bureau. Staber:uniQure: Honoraria; NovoNordisk: Consultancy; Bayer: Honoraria. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Poloskey:Bioverativ: Employment. Rice:Bioverativ: Employment. Katragadda:Bioverativ: Employment. Rudin:Bioverativ: Employment, Equity Ownership. Fruebis:Bioverativ: Employment, Other: Clinical Development.

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Pharmacokinetics Of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Pediatric Subjects With Hemophilia A: An Interim Analysis Of The Kids A-LONG Study

Blood ◽

10.1182/blood.v122.21.3609.3609 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3609-3609

Author(s):

Guy Young ◽

Johnny Mahlangu ◽

Beatrice Nolan ◽

Simon Brown ◽

Leonard A. Valentino ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Interim Analysis ◽

Research Funding ◽

Hemophilia A ◽

Additional Time ◽

Employment Equity ◽

Advisory Committees ◽

Age Cohorts ◽

Equity Ownership

Abstract Introduction Prophylactic factor VIII (FVIII) administration is the standard of care for patients with severe hemophilia A; however, frequent injections are required to maintain protective factor levels. To reduce injection frequency, we developed a long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) consisting of one rFVIII molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1). rFVIIIFc had a 1.53-fold higher half-life and a 36% reduction in clearance (CL) versus FVIII (Advate®) in a phase 3 study of adults and adolescents (J Thromb Haemost. 2013;11[2]:169). The Kids A-LONG study (NCT01458106) was designed to investigate the pharmacokinetics (PK), safety, and efficacy of rFVIIIFc in pediatric subjects with hemophilia A who were previously treated with FVIII products. The objective of this planned interim analysis was to determine the PK parameters of rFVIIIFc in pediatric subjects and compare these parameters to those of the subjects' prescribed FVIII products. Methods This multi-center, open-label, phase 3 study is currently enrolling previously-treated subjects aged<12 years with severe hemophilia A (≤1 IU/dL endogenous FVIII), at least 50 exposure days (EDs) to FVIII products, and no history of or current inhibitors to FVIII. Subjects are stratified into two age cohorts (<6 years and 6 to<12 years). All subjects are started on a twice-weekly rFVIIIFc prophylactic regimen 25 IU/kg on day 1 and 50 IU/kg on day 4 with subsequent dosing adjustment based on PK data and bleeding frequency. The primary endpoint is the incidence of inhibitor development. A sequential PK analysis is performed to compare the PK parameters of rFVIIIFc with that of the prescribed FVIII product. Subjects undergo a washout period of at least 72 hours before receiving the first dose of either FVIII or rFVIIIFc. For FVIII PK analysis, subjects receive 50 IU/kg of their currently prescribed FVIII product with sampling at baseline and at 4 additional time points after for up to 48 hours. For rFVIIIFc PK assessment, subjects receive 50 IU/kg rFVIIIFc, with sampling prior to rFVIIIFc administration and at 5 additional time points after for up to 72 hours. PK parameters were derived from FVIII activity-over-time profiles estimated by the non-compartmental analysis using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. FVIII activity was measured by the one-stage clotting assay calibrated against a commercially available FVIII plasma standard. A data cut-off date of 8 February 2013 was used to report PK data in this interim analysis. Results At the time of this analysis, 52 subjects were enrolled and received at least one dose of FVIII and/or rFVIIIFc. Of 37 subjects with evaluable PK profiles, 30 received both FVIII and rFVIIIFc. For PK assessment of FVIII, 7 different FVIII products were used, of which Advate ®, Haemosolvate®, and Kogenate FS® were the most common. A comparison of PK parameters for rFVIIIFc versus FVIII for both age cohorts demonstrated that rFVIIIFc had a longer half-life (∼1.5 fold increase) and a lower CL (30% to 50% reduction) than FVIII (Table 1). Conclusion In comparison to currently available FVIII products, rFVIIIFc had an extended half-life and reduced CL in children. These results are in agreement with those previously observed in adults and adolescents. The final analysis of the Kids A-LONG study will provide additional PK information and evaluate the safety and efficacy of rFVIIIFc in children. Disclosures: Young: Novo Nordisk: Consultancy, Honoraria; Biogen Idec, Baxter, Kedrion: Consultancy. Mahlangu:Bayer, Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Research Funding. Brown:Novo Nordisk, Biogen Idec, Baxter: Membership on an entity’s Board of Directors or advisory committees. Valentino:Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Liesner:Bayer, Baxter, Novo Nordisk, Pfizer: Consultancy, Sponsorship Other; Octapharma: Consultancy, Research Funding, Sponsorship, Sponsorship Other; Inspiration Biopharmaceuticals: Research Funding. Dong:Biogen Idec: Employment, Equity Ownership. Diao:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

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Patient-Reported Outcomes and Frailty Among Participants in the NHLBI MDS Natural History Study

Blood ◽

10.1182/blood-2020-136992 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 15-16

Author(s):

Gregory A. Abel ◽

Donnie Hebert ◽

Cecilia Lee ◽

James M. Foran ◽

Steven D. Gore ◽

...

Keyword(s):

Physical Activity ◽

At Risk ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Patient Reported Outcomes ◽

Advisory Committees ◽

Natural History Study ◽

Diagnostic Categories ◽

Patient Reported

Introduction: Patient-reported outcomes (PROs) such as quality of life (QOL) are variably affected in patients with myelodysplastic syndromes (MDS), but the heterogeneous composition of disease states grouped together as "MDS" increases the difficulty of assessing and understanding these outcomes. Moreover, little is known about the potential relationship between QOL and frailty in this population. Methods: The NHLBI MDS Natural History Study (NCT02775383) is a prospective cohort enrolling patients undergoing diagnostic work up for suspected MDS or MDS/myeloproliferative neoplasms (MPNs) in the setting of cytopenias. Untreated participants undergo bone marrow assessment with centralized histopathology review at enrollment for assignment into subcategories for longitudinal follow-up: MDS, MDS/MPN, ICUS, AML (<30% blasts), and "At-Risk" (cases with sub-threshold dysplasia or select karyotypic or genetic mutations). PRO and frailty data are collected at enrollment and every six months thereafter. PRO instruments include MDS-specific (QUALMS) and general (FACT-G, PROMIS Fatigue Short Form 7a, EQ-5D-5L) instruments, and a measure of frailty (VES-13). While no frailty instrument alone has been shown to be a substitute for comprehensive geriatric assessment, VES-13 has been successfully used in cancer-related studies for basic screening, where a score of 3 or more is considered frail (vulnerable). An analysis of variance (ANOVA) was used for the overall comparisons of mean baseline scores between diagnostic categories. Pairwise comparisons of scores between diagnostic categories and vulnerability subgroups were performed via two-sample t-tests. Results : Of 835 participants assessed for eligibility, 369 (44%) were classified as MDS, MDS/MPN, AML, ICUS or At-Risk, and further evaluated. Mean age was 72 years (standard deviation (SD)=10.7) and 68% were male. Mean baseline scores on the PRO measures are compared between diagnostic categories in the Table; scores did not differ significantly across categories. In particular, no significant differences were found between MDS and the other diagnostic categories. ICUS had similar QOL scores to MDS and MDS/MPN (e.g., means (SD) on EQ-5D-5L of 74.1 (17.8) in ICUS and 70.8 (19.4) in MDS, p=0.348) but had significantly higher scores than those for AML on EQ-5D-5L (60.7 (28.4), p=0.031). For the 216 participants with diagnostically-confirmed MDS, QOL impairment was similar to that routinely seen in other cancers; for example, the mean total FACT-G was 81.8 (SD=15.9), similar to localized breast cancer (82.4, SD=16.2), localized colorectal cancer (79.6, SD=16.1), and lung cancer with no current evidence of disease (82.6, SD=15.5; comparison means from Pearlman, Cancer, 2014). For frail/vulnerable participants with MDS or MDS/MPN (N=87), the most common reasons for vulnerability were age ≥75 years (68%), overall rating of health as poor or fair (62%), and difficulty with prolonged physical activity (90%) such as walking a quarter mile (75%) or doing heavy housework (70%). A minority also were vulnerable due to requiring help with instrumental activities of daily living (iADLS) such as shopping (28%) or managing money (16%). Mean QOL scores were compared between vulnerability subgroups (Figure). Vulnerable participants pooled over all diagnostic categories had significantly worse PROs than non-vulnerable participants for all measures (p<0.001). In particular, vulnerable MDS participants scored significantly worse on the QUALMS (mean 64.4, SD=13.4) vs. non-vulnerable MDS participants (mean 72.7, SD=13.3), p<0.001. Conclusions: Participants in our cohort with histologically-confirmed MDS-even low-grade MDS-had similar impairments in PROs as those with other cancers. Among those with histologically-confirmed MDS, vulnerable participants had significantly worse QOL on many measures compared to non-vulnerable participants, suggesting that this domain of function be specifically assessed in clinic. Moreover, while a "gestalt" of frailty may be inferred by observing how patients present and move in the office, these data suggest that other contributing domains, such as difficulty with prolonged physical activity and iADLs, should be evaluated explicitly. Disclosures Foran: H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Xencor: Research Funding; Agios: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Revolution Medicine: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Padron:Incyte: Research Funding; Kura: Research Funding; Novartis: Honoraria; BMS: Research Funding. Sekeres:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda/Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Lack of Inhibitor Development in the American Thrombosis and Hemostasis Network (ATHN)-2 Factor Switching Study: Preliminary Report of Primary Outcome

Blood ◽

10.1182/blood-2019-128612 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1114-1114

Author(s):

Robert F. Sidonio ◽

Dunlei Cheng ◽

Christine Guelcher ◽

Janna M. Journeycake ◽

Susan U Lattimore ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Primary Outcome ◽

Hemophilia A ◽

Advisory Board ◽

Severe Hemophilia ◽

Advisory Committees ◽

Inhibitor Development

Introduction: With many standard half-life (SHL) and extended half-life (EHL) recombinant factor VIII and factor IX products licensed in the US over the last 6 years, it is likely that previously treated patients (PTPs) will consider switching to a new EHL FVIII or FIX product. Although past product switching surveillance suggests no increased inhibitor development risk, there is the need for a real-world data on the incidence of inhibitor development following switching from SHL to EHL rFVIII or rFIX in PTPs with hemophilia A and B. Methods: A longitudinal, observational study of participants with Hemophilia A or B who switched to a rFVIII or rFIX concentrate licensed after Jan 1, 2013. The study included retrospective (switched within 50 exposure days (EDs) and prospective arms. Participants were recruited from ATHN-affiliated Hemophilia Treatment Centers (HTCs). The primary outcome measure was the development of a new inhibitor (i.e. neutralizing antibodies to factor VIII or IX) a 1 year or during the 50 EDs following the product switch. Plasma samples were collected at baseline, 10 EDs and 50 EDs. Inclusion criteria include moderate or severe hemophilia A/B currently on a plasma-derived or recombinant FVIII or FIX concentrate with planned or recent switch to an EHL FVIII or FIX concentrate approved after Jan 1, 2013. Participants with an active inhibitor at time of enrollment or undergoing ITI or switched to a non-factor product were excluded. Results: 303 hemophilia participants from 27 treatment centers were enrolled from 2015 to June 2019. The median age at enrollment was 17 years (IQR 10-32 years). 300 of 303 participants were male, Caucasian (72.6%) and had private insurance (44.9%). 74.3% were FVIII deficient and 25.7% were FIX deficient. Most had severe hemophilia A or B, 82.3% (n=237) and 12.8% (n=37) had a prior history of inhibitor but were negative at the time of enrollment. Prior to the switching, 92.1% (n=197) and 7.9% (n=17) of hemophilia A participants took standard rFVIII or pdFVIII respectively, while 87.8% (n=65) and 12.2% (n=9) of hemophilia B participants took standard rFIX or pdFIX, respectively. The three most frequent switching reasons were extended half-life consideration (n=192; 66.7%), a desire for a longer acting version (n=55; 19.1%) and less than expected clinical response to the current product (n=15; 5.2%). Among 214 participants with hemophilia A, 182 (85.0%) switched to FVIII EHL products while 23 (10.7%) switched to new SHL FVIII. For nine patients (4.2%) switching product information was not available. 72 out of 74 (97.3%) participants with hemophilia B that switched products, switched to an EHL rFIX. Eleven hemophilia participants (six A and five B) entered a second cycle of switching after the completion of the first switching cycle. Following that, four switched to FVIII EHL products, two to new SHL rFVIII and five to rFIX EHL products. A total of 193 (63.7%; 148 FVIII, 45 FIX) participants completed the clinical trial while 36 (11.9%; 26 FVIII, 10 FIX) did not complete the trial and 74 (24.4%) are ongoing in the trial. None of 303 (0%) enrolled participants developed an inhibitor, the primary outcome for this study, through data updated 6/2019. Variability was noted in per-site enrollment. The median enrollment per Hemophilia Treatment Center (HTC) was 10, the IQR was 7-16 with a range of 1-31. The types of factors associated with patients switches are summarized in the figure. Conclusion: No new inhibitors were noted among 303 moderate/severe hemophilia A/B PTPs without active inhibitors at entry, who switched factor VIII or IX products over 50 exposure days or 12 months. This result provides real-world evidence of the rarity of inhibitor development after a product switch in PTPs. The study also achieved a key logistical objective: to demonstrate feasibility of a prospective observational study across ATHN sites. Figure Legend: Factor types to which ATHN-2 patients switched during the study. Disclosures Sidonio: Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding. Guelcher:Takeda: Other: Advisory Board; Genetech: Other: Advisory Board; NovoNordisk: Other: Advisory Board; Octapharma: Other: Advisory Board. Takemoto:genentech: Membership on an entity's Board of Directors or advisory committees; novartis: Other: DSMB membership. Tarantino:Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Michael Tarantino, MD SC: Other: President, Owner- Private Practice ; Magellan Healthcare: Consultancy; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial PI, Speakers Bureau; Roche: Consultancy; Grifols: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bleeding and Clotting Disorders Institute: Employment; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Other: Grant Reviewer , Research Funding; Octapharma: Consultancy, Speakers Bureau. Neufeld:Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored).

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An Ongoing Global, Longitudinal, Observational Study of Patients with Pyruvate Kinase Deficiency: The PEAK Registry

Blood ◽

10.1182/blood-2019-123059 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2223-2223

Author(s):

Rachael F. Grace ◽

Paola Bianchi ◽

Bertil Glader ◽

Andreas Glenthøj ◽

Bryan Jones ◽

...

Keyword(s):

Natural History ◽

Blood Cell ◽

Longitudinal Data ◽

Board Of Directors ◽

Pyruvate Kinase ◽

Red Blood Cell ◽

Research Funding ◽

Advisory Committees ◽

Natural History Study ◽

Equity Ownership

Pyruvate kinase (PK) deficiency is an autosomal recessive disease caused by mutations in the PKLR gene that lead to reduced red blood cell PK (PK-R) enzyme activity. This rare hereditary glycolytic enzymopathy, with over 300 causative PKLR mutations identified to date, results in defective red blood cell glycolysis and hemolytic anemia. While the clinical presentation is variable, patients with PK deficiency may experience symptoms of hemolytic anemia, most commonly fatigue (sometimes extreme), jaundice, and dyspnea. No disease-specific therapy currently exists and treatment is limited to supportive care, including red blood cell transfusions, splenectomy/cholecystectomy, and iron chelation. Affected neonates may need phototherapy or exchange transfusions for severe hyperbilirubinemia. Allogeneic stem cell transplantation may cure the disease but experience is limited and the outcome is variable. Due the rarity of PK deficiency, its prevalence, clinical burden, and long-term clinical course are not well defined. To address this gap, Boston Children's Hospital is nearing completion of the observational PK deficiency Natural History Study (ClinicalTrials.gov NCT02053480; N=254) to better understand the natural history and clinical burden of the disease. This longitudinal analysis (2-year follow-up) will report on PK deficiency-related signs, symptoms, and treatment outcomes. In order to continue and expand upon the collection of longitudinal data for PK deficiency, the Pyruvate Kinase Deficiency Global Longitudinal Registry (the PEAK Registry; NCT03481738) was developed. This registry study is a global, longitudinal, observational study for adult and pediatric patients with PK deficiency. Its primary objective is to record the natural history, treatment, outcomes, variability in clinical manifestations, and disease burden of patients with PK deficiency. Secondary objectives include data collection to assess the prevalence, incidence, and complications associated with PK deficiency; evaluate pregnancy outcomes; and investigate possible phenotype-genotype correlations. The study also aims to provide longitudinal data to assist physicians with the clinical management of individual patients. In order to maximize the amount of longitudinal data available, a novel data management system is being employed to harmonize Natural History Study and PEAK Registry data. Approximately 500 patients will be enrolled over 7 years at an estimated 60 study centers in up to 20 countries in the 9-year study. All enrolled patients will be followed prospectively for at least 2 years and up to 9 years. Site and patient recruitment began in 2018. As of July 2019, 43 sites in 11 countries are active (Figure) and site recruitment has begun in Thailand, South Korea, and Australia. An update on patient enrollment will be provided. Disclosures Grace: Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Bianchi:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glenthøj:Celgene: Consultancy; Novo Nordisk: Honoraria; Alexion: Research Funding; Novartis: Consultancy; Agios Pharmaceuticals, Inc.: Consultancy. Jones:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Kanno:Agios Pharmaceuticals, Inc.: Honoraria. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Bluebird Bio: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy. Layton:Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Cerus Corporation: Membership on an entity's Board of Directors or advisory committees. van Beers:Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding. Xu:Agios: Employment, Equity Ownership.

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Adoption of Prophylaxis in the United States in the Era of Extended Half-Life Factor Concentrates

Blood ◽

10.1182/blood-2018-99-115231 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2467-2467

Author(s):

Lynn M. Malec ◽

Gilbert C. White ◽

Stacy E. Croteau ◽

Dunlei Cheng ◽

Margaret V. Ragni

Keyword(s):

United States ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

The United States ◽

Hemophilia B ◽

Severe Hemophilia ◽

Advisory Committees ◽

Number Of Patients

Abstract Background: Use of prophylaxis is the evidence-based strategy to prevent joint bleeds and reduce arthropathy for patients with severe hemophilia however, prophylaxis has not been universally adopted in the United States. Amongst patients with severe hemophilia enrolled in the ATHNdataset, the largest database of patients with disorders of hemostasis and thrombosis in the United States, as of 2015, 37% of patients with hemophilia A, and 45% of patients with hemophilia B do not receive prophylaxis. With the approval of extended half-life (EHL) factor products, patients and providers have options for less treatment-intense and burdensome prophylaxis. With the changing landscape of available hemophilia products, we aimed to quantify the number of patients treated at U.S. HTCs on prophylaxis utilizing the ATHNdataset with the objective determining the impact of EHL products on the proportion of patients with severe hemophilia receiving prophylaxis and to characterize use of prophylaxis according to age, race and ethnicity, geographic region, and payer. Methods: The ATHNdataset, a HIPAA compliant limited dataset sponsored by the American Thrombosis and Hemostasis Network (ATHN), was accessed as of June 30, 2018. The proportion of subjects with severe hemophilia on prophylaxis were compared to those on demand by age cohort. The proportion of subjects on prophylaxis was analyzed by race, ethnicity, insurance status, and hemophilia treatment center region. For each group receiving prophylaxis, the product (EHL versus standard half-life (SHL)), dose and frequency of treatment was analyzed. Results: ATHNdataset included 6,160 severe hemophilia patients using factor replacements, 5,234 individuals with hemophilia A and 926 individuals with hemophilia B. Overall, 76.0% (n=4,864) of patients with severe hemophilia are on prophylaxis whereas 24.0% (n=1426) are on demand; this included a total of 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B on prophylaxis. Treatment type (prophylaxis or not) had significant associations with age (p-value <0.001), ethnicity (p<0.001), race (p=0.005), hemophilia treatment center (HTC) region (p<0.001), and hemophilia type (p=0.015) (Table 1). Prophylaxis was not significantly correlated with payer (p=0.847) with a similar number of patients with Medicare/Medicaid or private insurance receiving prophylaxis. Among patients on prophylaxis, 30.8% (n=1,462) are prescribed EHL products including 27.4% of patients with hemophilia A and 50.4% with hemophilia B. In terms of dosing frequency (n=758), 73.8% of hemophilia A patients on prophylaxis receive EHL two times per week while 73.7% (n=1,906) receive SHL every other day (Table 2). Of hemophilia B patients using EHL products, 63.3% of patients receive prophylaxis once weekly, 12.7% every 10 days, and 15.0% every 2 weeks (Table 2). Discussion: The ATHNdataset highlights increased use of prophylaxis over the past 3 years in the U.S. with 76.6% of patients with severe hemophilia A and 72.9% of patients with severe hemophilia B currently receiving prophylactic therapy as compared to 63% and 55% of patients, respectively, in 2015. Further, the majority (83.7%) of patients are beginning prophylaxis according to the World Federation of Haemophilia recommendation to initiate prophylaxis by three years of age. There has been an uptake of the use of EHL factor products including a majority of patients (50.4%) with severe hemophilia B. Although not captured in the ATHNdataset, a plausible reason for the increased uptake of EHL in the hemophilia B population includes the data that 91% of patients are able to dose between weekly or less frequently. As the hemophilia treatment landscape continues to evolve, it is important to continue to understand the adoption of these new products into practice and to examine their real-world impact. Disclosures Malec: Shire: Consultancy; Bioverativ: Consultancy; Bayer: Consultancy; Bioverativ: Research Funding. White:Biomarin: Other: DSMB; Bioverativ: Other: DSMB; Bayer: Other: GRAC; Shire: Other: Physician Leadership Group; Novo Nordisk: Consultancy; Asklepios: Other: Scientific Advisory Board; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Croteau:Biomarin: Consultancy; Bioveritiv: Consultancy; Catalyst Biosciences: Consultancy; CSL-Behring: Consultancy; Genetech: Consultancy, Research Funding; Novo Nordisk: Consultancy; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Tremeau Pharmaceuticals: Consultancy; Bayer: Consultancy; Baxalta/Shire: Consultancy, Research Funding. Ragni:Sangamo: Research Funding; CSL Behring: Research Funding; Bioverativ: Consultancy, Research Funding; SPARK: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Shire: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

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A Practical, One Clinic Visit, Population Pharmacokinetic (PK) Protocol for Generation of PK Profiles in Subjects with Severe Hemophilia a

Blood ◽

10.1182/blood-2018-99-111024 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2480-2480 ◽

Cited By ~ 1

Author(s):

Victor S. Blanchette ◽

Laura Tiseo ◽

David Lillicrap ◽

Shannon Jackson ◽

Massimo Morfini ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Clinic Visit ◽

Fixed Dose ◽

Severe Hemophilia ◽

Advisory Committees ◽

Perfect Agreement ◽

Post Infusion

Abstract Introduction Clearance of infused factor VIII (FVIII) varies approximately 2-fold between persons with severe hemophilia A. This results in significant interpatient differences in factor levels following an infusion of FVIII and contributes to potentially significant differences in protection against spontaneous musculoskeletal bleeding in patients on fixed dose prophylaxis regimens. Aim The aim of this study is to compare two PK protocols: 1) a 6-point PK protocol with a 72 hour washout; and 2) a 2-point, one clinic visit PK protocol with no washout using the following pharmacokinetic (PK) parameters: clearance (Cl) and time to FVIII:C of 1% above baseline (tt1%) in persons with severe hemophilia A. Methods Inhibitor negative males with severe hemophilia A (FVIII<2%) receiving a standard half-life recombinant FVIII (rFVIII) concentrate (ADVATE®) were consented into a research ethics board approved study. In the 6-point PK protocol, participants were infused with approximately 50 IU/kg rFVIII after a minimum washout of 72 hours and FVIII levels were measured pre-infusion and at 1, 3, 9, 24 and 48 hours post-infusion. The 2-point PK protocol consisted of a blood sample taken in clinic approximately 24 hours after the participant infused their prophylactic dose at home (15-50 IU/kg), followed by a 25 IU/kg dose given in clinic and a 3 hour post-infusion sample. Frozen plasma samples were sent to a central laboratory in Kingston, Ontario where one-stage and chromogenic FVIII assays were performed. PK parameters (Cl and tt1%) were estimated using the 2 compartmental models of PK programs Phoenix WinNonlin 7.0 (Certara USA Inc.) and myPKFiT version 3.0 (Baxalta US Inc). Intra-class correlations (ICCs) were used to compare the PK parameters derived from the two PK protocols using WinNonlin and myPKFiT. Results 28 males (median age: 12 years, range: 2-69 years) participated. The frequency distribution of clearance and the median half-life (t1/2) generated using myPKFiT is presented in Figure 1. There was a substantial to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout using the two PK programs (Table 1). There was a moderate to almost perfect agreement observed when comparing the PK parameters derived from the 6-point PK protocol with washout to the 2-point PK protocol with no washout using the myPKFiT program (Table 2). Conclusion The 2-point, one clinic visit, PK protocol (24 and 3 hrs) with no washout offers a convenient and practical approach to generating clinically relevant PK parameters in persons with severe hemophilia A. It can provide information relevant to selection of personalized prophylaxis regimens that aim to reduce to a minimum/eliminate spontaneous joint bleeding. Disclosures Blanchette: Shire: Other: Investigator-initiated research funding; Novo Nordisk: Other: Speaker's fees; Shire: Other: Speaker's fees; Bayer: Other: speaker's fees; Bioverativ: Other: Investigator-initiated research funding; Pfizer: Other: Speaker's fees. Jackson:Pfizer: Honoraria; Roche: Honoraria; Bayer: Honoraria; Novo Nordisk: Honoraria; Shire: Honoraria; Bioverativ: Other: Investigator initiated grant funding. Carcao:Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: 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, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Khoo:Shire: Research Funding; Biogen Idec: Research Funding. Blatny:Shire, Pfizer, Roche: Consultancy, Speakers Bureau.

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