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

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.

Download Full-text

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).

Download Full-text

Pegylated Full-Length Recombinant Factor VIII with Extended Half-Life in Previously Treated Pediatric Patients with Hemophilia Α: Efficacy of Prophylaxis and Treatment By Time (of Day/of Week) of Occurrence of Bleeding

Blood ◽

10.1182/blood.v128.22.1409.1409 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1409-1409

Author(s):

Eric S. Mullins ◽

Christine M. Knoll ◽

Amy L. Dunn ◽

Werner Engl ◽

Marlies Sharkhawy ◽

...

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Pediatric Patients ◽

Bleeding Event ◽

Time Of Day ◽

Advisory Committees ◽

Previously Treated ◽

The Mean

Abstract Introduction: Hemophilia A (HA) is an X linked recessive bleeding disorder characterized by frequent bleeding predominantly in joints. To avoid the sequelae of hemarthroses (e.g., target joints and arthropathy), timing of factor VIII (FVIII) infusions to cover periods of physical activity and adherence to a prophylactic schedule are particularly important in children with HA. BAX 8551, a polyethylene glycol (peg)ylated, extended half-life, full-length, recombinant FVIII built on ADVATE2, was developed to reduce infusion frequency while maintaining or improving therapeutic efficacy. Methods: Efficacy of twice-weekly prophylaxis with BAX 855 was evaluated in a phase 3, prospective, uncontrolled, multicenter study in pediatric previously treated patients with severe HA (FVIII level <1%) without inhibitors (<0.6 BU using the Nijmegen modification). Annualized bleeding rates (ABRs) and efficacy of bleed treatment were analyzed by time of day (morning [04:00 - 11:59], afternoon [12:00 - 17:59], evening [18:00 - 03:59]) and period of the week (weekday [Monday - Friday], weekend [Saturday, Sunday]). The study was performed in accordance with the principles of the Declaration of Helsinki of the World Medical Association. Results: Sixty-six patients, 32 aged <6 and 34 aged 6 to <12 years, were treated with a mean (SD) prophylactic BAX 855 dose of 51.1 (5.5) IU/kg at a frequency of 1.8 (0.2) infusions per week for 48.5 (7.7) exposure days. ABRs were highest in the evening with point estimates (95% CIs) of the mean of 1.0 (0.7 - 1.5) compared to 0.6 (0.4 - 1.0) in the afternoon and 0.5 (0.3 - 1.1) in the morning. On weekdays, the point estimate (95% CI) of the mean ABR was 2.4 (1.7 - 3.5), on weekends it was 0.9 (0.6 - 1.2). For all periods assessed except for mornings, ABRs were higher in the older than in the younger cohort (Table 1). Seventy minor or moderate bleeding events in 34/66 (51.5%) patients were treated with a mean (SD) dose of 57.9 (31.0) IU/kg of BAX 855. Most treated bleeds occurred in the evening (34.3%; 24/70), fewer in the afternoon (22.9%; 16/70) and in the morning (14.3%; 10/70). The proportion of moderate bleeds increased during the day from 20.0% (2/10) in the morning to 31.3% (5/16) in the afternoon and 70.8% (17/24) in the evening. For 28.6% (20/70) of treated bleeds, the time of day of occurrence was unknown. The mean interval between the preceding prophylactic infusion and the bleeding event was similar for all times of day, ranging from 51.0 h to 54.6 h (median 51.4 h to 57.8 h). On weekends, the mean interval between prophylactic dose and bleeding event was lower (38.8 h; median 35.7 h) than on weekdays (54.6 h; median 52.9 h), suggesting that the time of infusion was chosen to cover for weekend activities. Bleeding severity was similar on weekdays and on weekends. Efficacy of bleed treatment with BAX 855 was rated excellent or good for ≥85% of bleeds and ≥85% were treated with 1 or 2 infusions, irrespective of the time of day/period of the week the bleeds occurred. Conclusions: In this study in pediatric patients with severe HA, bleeding was observed more frequently in the evening than during other times of day and more frequently on weekdays than on weekends. BAX 855 was shown to be effective for the prevention and treatment of bleeding in this patient population. 1BAX 855 (Baxalta US Inc., now part of Shire) is licensed in the US and Japan under the trade name ADYNOVATE. 2ADVATE is a trademark of Baxalta US Inc., now part of Shire. Disclosures Mullins: Baxalta (now part of Shire): Honoraria; US WorldMeds: Membership on an entity's Board of Directors or advisory committees. Dunn:Bayer: 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; Biogen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Kedrion: Research Funding; NovoNordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Research Funding. Engl:Shire: Employment, Equity Ownership. Sharkhawy:Baxalta (now part of Shire): Employment. Abbuehl:Baxalta (now part of Shire): Employment.

Download Full-text

Early Prophylaxis Provides Continued Joint Protection in Severe Hemophilia A: Results of the Joint Outcome Continuation Study

Blood ◽

10.1182/blood-2018-99-117413 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 382-382 ◽

Cited By ~ 3

Author(s):

Beth Boulden Warren ◽

Dianne Thornhill ◽

Jill Stein ◽

Michael Fadell ◽

Sharon Funk ◽

...

Keyword(s):

Soft Tissue ◽

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Joint Damage ◽

Severe Hemophilia ◽

Advisory Committees ◽

Episodic Treatment ◽

Bayer Healthcare

Abstract Background: The Joint Outcome Study (JOS) was a randomized controlled trial showing that, in severe hemophilia A, prophylactic factor VIII every other day starting prior to age 30 months leads to better joint outcomes at age 6 years than enhanced episodic treatment with factor VIII for bleeding1. After conclusion of the JOS, all participants were encouraged to continue on, or to transition to, prophylaxis. Here we describe the results of the Joint Outcome Continuation Study (JOS-C), which followed the participants of the JOS to age 18 years. Methods: All participants of the JOS were eligible for the JOS-C. MRIs of 6 index joints (right and left ankles, knees, and elbows), index joint physical exam scores using the Colorado Haemophilia Paediatric Joint Physical Examination Scale2 , estimates of joint bleeding episodes, and surgery information were collected. The primary endpoint, as in the initial JOS analysis, was evidence of hemophilia-related osteochondral joint damage on MRI, scored using the extended MRI scale3. Results: Of the 65 previous participants of the JOS, 37 gave informed consent for the JOS-C study, including 18 initially randomized to prophylaxis prior to age 30 months ("early prophylaxis"), and 19 initially randomized to enhanced episodic treatment who started prophylaxis at a mean age of 7.5 years (median 6.1, range 2.7-17.1, "delayed prophylaxis"). All initially on prophylaxis in the JOS continued on prophylaxis through the JOS-C. One participant (early prophylaxis arm) failed to complete an MRI, and four others (2 early and 2 delayed prophylaxis) had their MRIs excluded for technical reasons. Four participants (3 early prophylaxis and 1 delayed prophylaxis) developed high titer inhibitors during or shortly after the JOS and were analyzed separately. Osteochondral joint damage was defined as evidence of osteochondral damage on MRI or a need for joint surgery. The relative risk of osteochondral damage in those on delayed prophylaxis as compared to those on early prophylaxis was 6.5 (95% CI 1.3, 33.6; p=0.029). At age 18, 67% of those on early prophylaxis, and only 24% of those on delayed prophylaxis had zero index joints with osteochondral damage (Figure 1). Twenty-five percent of early prophylaxis and 47% of delayed prophylaxis participants had osteochondral damage to more than one joint. Most participants had some soft tissue changes on MRI, defined as effusion, synovial hypertrophy, or hemosiderin deposition. There was no difference in risk of soft tissue damage between initial treatment groups (p=0.48). Osteochondral damage scores were available for 3 patients with inhibitors: two with refractory inhibitors had osteochondral changes on at least one joint, and one with an inhibitor that tolerized within 3 months had no osteochondral damage. Total physical exam scores were also higher in the delayed prophylaxis arm (mean 22.6, standard deviation (SD) 15.5) than in the early prophylaxis arm (mean 16.2, SD 10.5), but this difference was not statistically significant (p=0.19). Conclusion: The JOS-C demonstrates that, in severe hemophilia A, initiation of prophylaxis prior to age 30 months provides continued protection against joint damage throughout childhood. Those who started on prophylaxis later in childhood had higher risk of joint damage at age 18. Initiation of factor VIII prophylaxis in the toddler years is critical to preventing osteochondral joint damage and should not be delayed. ReferencesManco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-544.Hacker MR, Funk SM, Manco-Johnson MJ. The Colorado Haemophilia Paediatric Joint Physical Examination Scale: normal values and interrater reliability. Haemophilia. 2007;13(1):71-78.Hong W, Raunig D, Lundin B. SPINART study: validation of the extended magnetic resonance imaging scale for evaluation of joint status in adult patients with severe haemophilia A using baseline data. Haemophilia. 2016;22(6):e519-e526. Figure 1: Percentage of participants with zero joints with osteochondral damage at JOS exit (age 6 years) and JOS-C exit (age 18 years), excluding participants with inhibitors. Disclosures Warren: Bayer Healthcare: Research Funding; HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program Fellowship Project Award: Research Funding; CSL Behring Heimburger Award: Research Funding. Shapiro:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Prometic Life Sciences: Consultancy, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; Sangamo Biosciences: Consultancy; Octapharma: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; OPKO: Research Funding; BioMarin: Research Funding. Recht:Shire: Research Funding; Biogen: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Bayer AG: Honoraria, Research Funding; Novo Nordisk: Honoraria; Biogentek: Honoraria; CSL Behring: Honoraria; Baxalta, now part of Shire: Honoraria.

Download Full-text

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.

Download Full-text

Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study)

Blood ◽

10.1182/blood-2018-99-115792 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1186-1186 ◽

Cited By ~ 5

Author(s):

Midori Shima ◽

Keiji Nogami ◽

Sayaka Nagami ◽

Seitaro Yoshida ◽

Koichiro Yoneyama ◽

...

Keyword(s):

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Pediatric Patients ◽

Hemophilia A ◽

Bispecific Antibodies ◽

Severe Hemophilia ◽

Advisory Committees ◽

Favorable Safety ◽

Cutoff Date

Abstract Introduction: Emicizumab is a novel, subcutaneously injectable, recombinant humanized bispecific monoclonal antibody which mimics the function of activated coagulation factor VIII. Due to its mechanism of action and lack of sequence homology, emicizumab is not expected to induce or be affected by anti-factor VIII (FVIII) antibodies (inhibitors). Emicizumab once-weekly dosing has been approved for hemophilia A patients with inhibitors of all ages in several countries. A clinically meaningful prophylactic effect and favorable safety of emicizumab given every 2 weeks (Q2W) and every 4 weeks (Q4W) in adult/adolescent patients has been demonstrate in HAVEN3 study (NCT02847637) and HAVEN4 study (NCT03020160). This is the first report to assess emicizumab prophylaxis in pediatric patients without inhibitors including a patient previously untreated with FVIII. Methods: The present study (JapicCTI-173710) enrolled Japanese patients aged <12 years with hemophilia A without inhibitors. Patients received a loading dose of 3 mg/kg weekly for the first 4 doses, followed by a maintenance dose of 3 mg/kg Q2W or 6 mg/kg Q4W. This interim analysis was performed after at least 6 patients in each dosing cohort had completed at least 12 weeks of treatment with emicizumab prophylaxis. Results: A total of 13 male patients were enrolled in 2 cohorts. The numbers of patients aged 0 - < 2, 2 - < 6, and 6 - < 12 years were 1, 2, and 3 in the Q2W cohort and 2, 2, and 3 in the Q4W cohort. All patients had been previously treated with FVIII prophylaxis except for 1 patient aged 4 months in the Q4W cohort who was previously untreated. As of the data cutoff date of March 14, 2018, the medians (range) of treatment duration were 21 (18.3 - 22.1) and 16 (4.3 - 16.6) weeks in the Q2W and Q4W cohorts, respectively. The interim analysis results showed a clinically meaningful effect of emicizumab prophylaxis with the Q2W and Q4W regimens. As of the data cutoff date, 3/6 patients in the Q2W cohort and 5/7 patients including 1 patient previously untreated with FVIII in the Q4W cohort experienced no treated bleeds. There were no treated spontaneous bleeds and a total of 6 treated bleeds were traumatic. Two out of them were treated joint bleeds. Model-based annualized bleeding rates for treated bleeds with FVIII products under emicizumab prophylaxis were 1.6 (95% CI, 0.60 to 4.25) and 1.0 (95% CI, 0.25 to 4.06) in the Q2W and Q4W cohorts, respectively. All 13 patients experienced at least 1 adverse event (AE) and a total of 78 AEs were reported. There were no AEs that were grade 3 or higher, serious, led to withdrawal from treatment, or resulted in dose modification or interruption. None of the AEs were considered related to emicizumab. Neither thromboembolic events, thrombotic microangiopathy, systemic hypersensitivity reactions, nor local injection site reactions were reported. The most frequent AEs were contusion in 10 (76.9%) patients, excoriation and nasopharyngitis in 4 (30.8%) patients each, and ligament sprain and influenza in 3 (23.1%) patients each. The emicizumab exposures observed in this study were within the observed variability in preceding studies. No effects of age or body weight on emicizumab exposure were evident. Conclusions: This interim analysis results suggested clinically meaningful efficacy and favorable safety of the emicizumab Q2W and Q4W regimens in patients aged <12 years with severe hemophilia A without inhibitors. This suggests that it should be appropriate to apply the same dosing regimens of emicizumab for pediatric patients without inhibitors and other patient populations of hemophilia A. The updated results of primary analysis after completing at least 24 weeks on emicizumab treatment will be presented at the meeting. Disclosures Shima: Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Nagami:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership. Yoshida:Chugai Pharmaceutical Co., Ltd: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd: Employment, Patents & Royalties: Anti-FIXa/X bispecific antibodies . Ishiguro:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Taki:Chugai Pharmaceutical Co., Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Download Full-text

Breakthrough Bleeding in Hemophilia a Patients on Prophylaxis

Blood ◽

10.1182/blood.v128.22.2581.2581 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2581-2581 ◽

Cited By ~ 2

Author(s):

Beth Boulden Warren ◽

Taylor Blades ◽

Natalie L Smith ◽

Michael Wang ◽

Marilyn J. Manco-Johnson

Keyword(s):

Factor Viii ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Advisory Committees ◽

Breakthrough Bleeding ◽

University Of Colorado ◽

The University

Abstract Background: Patients with severe hemophilia A (factor VIII (FVIII)<1%), as well as many patients with moderate hemophilia A (FVIII 1-5%), are treated intravenously with FVIII prophylaxis to prevent bleeding. However, breakthrough bleeding occurs in many patients. Methods: To better understand breakthrough bleeding, we evaluated the effect of hemophilia severity, prophylaxis adherence, and replacement FVIII utilization on bleeding rates in patients with hemophilia A on prophylaxis. Data on hemophilia severity and bleeding rates were collected from subjects with hemophilia A, ages 2-30 years, treated at the University of Colorado for hemophilia A, using the University of Colorado Clinical Research Bleeding Disorders Database (UCBDD). Adherence and FVIII utilization data were collected from a subset of subjects with hemophilia A on prophylaxis without active inhibitors who participated in the Centers for Disease Control/American Thrombosis and Hemostasis Network Community Counts (CDCCC) registry between December 2013 and June 2016, which surveyed participants about their estimated percentage of missed prophylaxis doses. The CDCCC registry was also used to corroborate bleeding rates. The effect of hemophilia severity and missed prophylaxis doses (percentage of prescribed doses) on bleeding rates were analyzed using logistic regression, with bleeding rates dichotomized as high or low relative to study population median bleeding rates. The relationship between weekly factor utilization and annualized bleeding rates was evaluated using Pearson's correlation. Results: Of 89 patients with severe hemophilia A in the UCBDD, 86.5% of patients were on continuous prophylaxis, with an additional 7.9% on immune tolerance induction. The 5.6% of patients with severe hemophilia on episodic treatment had been encouraged to use prophylaxis but had declined. Of 37 patients with moderate hemophilia A, 48.7% were on continuous prophylaxis. Sixty-nine subjects on prophylaxis had data in the UCBDD and the CDCCC registry collected during the defined time period. Bleeding rates are shown in Table 1. Prophylaxis doses in this population had an interquartile range of 74.3 to 120 units/kg/week (mean 96.9 units/kg/week), dosed 2-7 times per week depending on activities and historic bleeding patterns. Eighty-two percent of patients rated their percentage of missed prophylaxis doses at <10%, 11.6% rated their missed doses at 10-20%, 2.9% rated their missed doses at 21-50%, and 2.9% rated missed doses at >50%. There was not a statistically significant relationship between any bleeding rate and percentage of missed doses, hemophilia severity, or factor utilization, as shown graphically in figures 1 and 2. Conclusion: Although prophylaxis usage and adherence were excellent, breakthrough bleeding was common, with breakthrough joint bleeding occurring in 36% of subjects, and was not related to FVIII dose per week. Prospective studies are needed to better determine individually tailored prophylaxis regimen using dose, product class, and timing with activities, in order to achieve more effective prophylaxis. Table 1 Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Table 1. Bleeding Rates on Continuous Prophylaxis. No intracranial or gastrointestinal hemorrhages were recorded in this population. Figure 1 Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 1. Relationship between Bleeding Rates, Hemophilia Severity and Adherence Figure 2 No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Figure 2. No correlation was found between bleeding rates and factor VIII utilization as measured in units per kg per week. Disclosures Warren: HTRS/Novo Nordisk: Research Funding; Bayer Hemophilia Awards Program: Research Funding. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Manco-Johnson:Baxalta: Honoraria; NovoNordisk: Honoraria; BiogenIdec: Honoraria; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria.

Download Full-text

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.

Download Full-text

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.

Download Full-text

Immune Tolerance Induction Using Rfviiifc (Eloctate)

Blood ◽

10.1182/blood.v126.23.3531.3531 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3531-3531 ◽

Cited By ~ 2

Author(s):

Lynn M. Malec ◽

Margaret V Ragni ◽

Janna M. Journeycake ◽

Michelle Alabek

Keyword(s):

Board Of Directors ◽

Immune Tolerance ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Central Venous Access ◽

Tolerance Induction ◽

Severe Hemophilia ◽

Advisory Committees ◽

Immune Tolerance Induction

Abstract Introduction: Inhibitor formation affects approximately 30% of individuals with severe hemophilia A. The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy, although typically requires daily high-dose factor VIII via a port for up to a year. Extended half-life recombinant factor VIII Fc fusion protein (rFVIIIFc, Eloctate¨) has a half-life extension 1.5-fold longer than standard recombinant FVIII (rFVIII), reducing treatment frequency, and also induces regulatory T cell response to FVIII in animal models. We hypothesized that rFVIIIFc would provide more effective ITI, specifically shortening ITI, than rFVIII. We describe ITI with rFVIIIFc in three patients with severe hemophilia A. Methods: Immune tolerance induction was initiated with rFVIIIFc (Eloctate) in three children with severe hemophilia A and an anti-FVIII inhibitor. Dosing was per MD discretion with family agreement, and performed by central venous access device or intravenous infusion via heplock. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U. and half-life, t½ >6 hours. FVIII half-life was determined by one-stage FVIII:C assay on citrate samples drawn pre- and 10 minutes, 1, 2, 4, and 6 hours post-infusion of a single dose of rFVIIIFc. Once a t½ >6 hours was documented, incremental reduction to 50 IU/kg every other day or three times weekly, once there was evidence of maintenance of inhibitor neutralization and a >6 hour FVIII:C half-life. Results: Immune tolerance induction was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc via central venous access device every other day or three times weekly per MD discretion in three children with severe hemophilia A and in anti-FVIII inhibitor > 5 B.U. (Table 1). Two patients had F8 genetic testing. In two patients, Pt 1 and Pt 3, this was the initial ITI course, and in the third child (Pt 2) this was salvage ITI after failing to achieve tolerance due to noncompliance with daily rFVIII ITI taper regimen. In two rFVIIIFc ITI was begun when anti-FVIII was < 10 B.U. Historic peak titers were 16-422 B.U. The time to anti-FVIII tolerance was 4-12 weeks Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. There were no adverse effects. These data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in children with inhibitors. Whether ITI may be accomplished more rapidly with rFVIIIFc, and the optimal dose for ITI will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the H emophilia I nhibitor R esponse to E loctate (HIRE) Study, is underway. Table 1. Immune Tolerance Induction with rFVIIIFc in Hemophilia A Inhibitor Patients Patient (Pt) Hemophilia Severity F8 Gene Mutation Age at Anti-FVIII Detection Peak Anti-FVIII Titer Initial ITI Dose Time toAnti-FVIII = 0 Current Anti-FVIII 1 <0.01 IU/ml Intron 22 inversion 13 months 32 B.U. 200 IU/kg QOD 12 weeks 0 B.U. 2 < 0.01 IU/ml Exon 18 nonsense variant 9 months 422 B.U. 200 IU/kg 3x/week 4 weeks 0 B.U. 3 <0.01 IU/ml Not available 10 years 16 B.U. 100 IU/kg QOD 11 weeks 0 B.U. Disclosures Malec: Baxter: Research Funding; Biogen: Research Funding. Ragni:Pfizer: Research Funding; Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Dimension: Research Funding; Vascular Medicine Institute: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; SPARK: Research Funding; Biomarin: Research Funding; Genentech Roche: Research Funding; Bayer: Research Funding; Biogen: Research Funding; Alnylam: Research Funding. Journeycake:CSL, Baxalta, NovoNordisk: Consultancy; ATHN: Research Funding; Biogen: Speakers Bureau; ATHN: Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Efficacy of an Extended Half-Life GlycoPEGylated rFVIII (N8-GP): Pooled Analysis of ABR (Results from Two Clinical Trials)

Blood ◽

10.1182/blood-2018-99-110308 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1177-1177 ◽

Cited By ~ 1

Author(s):

Pratima Chowdary ◽

Lone Hvitfeldt Poulsen ◽

Miguel A Escobar ◽

Susan Kearney ◽

Meera B. Chitlur ◽

...

Keyword(s):

Health Care ◽

Clinical Trials ◽

Board Of Directors ◽

Half Life ◽

Research Funding ◽

Hemophilia A ◽

Severe Hemophilia ◽

Advisory Committees ◽

Primary Investigator ◽

To Receive

Abstract Introduction The short half-life of standard factor VIII (FVIII) products means that frequent injections (3 to 4 times/week) are needed for effective prophylaxis in patients with hemophilia A. N8-GP (turoctocog alfa pegol), an extended half-life glycoPEGylated recombinant FVIII developed for the prophylaxis and treatment of bleeds in patients with hemophilia A, allows for less frequent dosing. Bleed frequency is an important outcome measure in hemophilia, particularly when choosing a dosing regimen that best suits a broad range of patients. Objectives To summarize annualized bleeding rate (ABR) data from 2 clinical trials of N8-GP in patients with severe hemophilia A. Methods Patients with severe hemophilia A (FVIII <1%) were enrolled into the pathfinder comprehensive clinical trial program:pathfinder 2 main phaseAdults/adolescents ≥12 years, N8-GP 50 IU/kg every 4 days (Q4D) or 20-75 IU/kg on demandpathfinder 2 extension phaseAdults/adolescents ≥12 years, randomized to receive N8-GP 50 IU/kg Q4D or 75 IU/kg once weekly (Q7D)Patients with ≤2 bleeds in the last 6 months were eligible for randomizationpathfinder 5 main phase Children <12 years, N8-GP 60 IU/kg (50-75 IU/kg) twice weekly. ABR was analyzed using a Poisson-regression model on the number of bleeds per patient, allowing for over-dispersion and using log-planned observation duration as an offset to allow for different treatment durations, with age cohort as a factor for pathfinder 5. Median and estimated Poisson mean ABR data from the 2 trials were summarized for overall, spontaneous, traumatic, joint, and muscle bleeds. Results For adults/adolescents receiving N8-GP 50 IU/kg Q4D (pathfinder 2 main phase) and those randomized to receive 50 IU/kg Q4D or 75 IU/kg Q7D (pathfinder 2 extension), median overall ABRs were 1.18, 0.00, and 0.00, respectively (Table). Corresponding median ABRs were:For spontaneous bleeds 0.00, 0.00, and 0.00For traumatic bleeds 0.00, 0.00, and 0.00For joint bleeds 0.85, 0.00, and 0.00For muscle bleeds 0.00, 0.00, and 0.00. For children (aged 0-11 years) receiving 60 IU/kg twice weekly (pathfinder 5), median overall, spontaneous, traumatic, joint, and muscle ABRs were 1.95, 0.00, 0.00, 0.00, and 0.00, respectively. Poisson estimated mean ABR data for all bleed types are also shown in the Table. Conclusion N8-GP provides effective prophylactic protection in adult/adolescent and pediatric patients with severe hemophilia A, as demonstrated by low ABRs in phase 3 clinical trials. For patients of all ages, N8-GP enables simplicity in the choice of prophylaxis dose and dosing frequency with no need for pharmacokinetic-tailored dosing. Disclosures Chowdary: Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI (publ): Research Funding; Baxalta (Shire), Baxter, Biogen Idec, CSL Behring, Freeline, Novo Nordisk, Pfizer, Roche, Shire, and SOBI: Consultancy. Hvitfeldt Poulsen:Lecturer on Nordic meeting on EHL FVIII (SOBI): Other: Lecturer ; Primary investigator and national coordinator on clinical trials from Bayer Health Care: Other: Primary Investigator and national coordinator; Nordic advisory boards (Bayer Health Care, Roche): Membership on an entity's Board of Directors or advisory committees; Chaired an educational haemophilia symposium for nurses: Other: Chair. Escobar:Bayer, CSL Behring, Genentech, Hemabiologics, Kedrion, Novo Nordisk, Octapharma, Pfizer and Shire: Consultancy; Pfizer: Research Funding. Kearney:Bayer, Bioverativ, Daiichi Sankyo, Grifols and Novo Nordisk: Research Funding; Bayer, Bioverativ and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Chitlur:Novo Nordisk Inc: Consultancy; Baxter, Bayer, Biogen Idec, and Pfizer: Honoraria. Klamroth:Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Research Funding; Baxalta (Shire), Bayer, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Shire, and SOBI: Consultancy. Negrier:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Clausen:Novo Nordisk: Employment. Driessler:Novo Nordisk: Employment. Landorph:Novo Nordisk: Employment. Santagostino:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees.

Download Full-text