scholarly journals A Cross-Sectional Study of the American Thrombosis and Hemostasis Network Dataset for Outcomes of Dental Extractions in People with Hemophilia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 346-346
Author(s):  
Heather Messenger ◽  
Chunla He ◽  
Michael Recht ◽  
Roshni Kulkarni
Keyword(s):  
Logistic Regression ◽  
Half Life ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Hemophilia A ◽  
Dental Extraction ◽  
Blood Disorders ◽  
On Demand ◽  
Bleeding Episodes ◽  
Women And Girls

Abstract BACKGROUND: Dental extraction (DE) is one of the most common procedures in people with hemophilia A or hemophilia B (PWH-A, PWH-B), yet little is known about impact of the type of hemophilia, hemostatic therapies, and bleeding outcomes. To date, there is no standard protocol for how to treat PWH undergoing DE. Similar overall bleeding rates occur with pre- and postoperative factor replacement (FRP) therapy and single dose preoperative FRP (11.9% and 11.4%, respectively) (DE. Bajkin et al. Haemophilia 2020). METHODS: We analyzed the American Thrombosis and Hemostasis Network dataset (ATHNdataset) to assess trends in prophylactic factor use and its impact on bleeding outcomes following dental extraction in PWH-A and PWH-B ≥2 years of age. A DE bleeding episode was defined as any oral or mouth bleeding occurring during or within one week following a DE procedure. Treated bleeds were defined as any oral or mouth bleeds treated with hemostatic medications during or within one week post-DE. Hospitalization and emergency department (ED) visit events were defined as any that occurred during or one day after a DE. Data on sociodemographic, clinical characteristics, and outcomes were collected prospectively between 2013 and 2019 at annual clinical visits to 134 ATHN-affiliated sites. Categorical variables were summarized using frequency and percentage. Logistic regression was used to evaluate associations between DE and sociodemographic and clinical variables. Simple logistic regression models were applied to identify factors potentially associated with dental bleeding episodes among PWH. RESULTS: Sociodemographic and clinical characteristics revealed that of the 19,048 PWH in the ATHNdataset, 1,157 subjects underwent 1,301 episodes of DE; a majority (74.9%) were diagnosed hemophilia A and 94.4% were male. The odds of a DE were approximately 148% higher among male PWH compared to female PWH (OR: 2.48; 95%CI: 1.93-3.20). PWH with severe disease were less likely to undertake DE than those with mild hemophilia (OR: 0.83; 95%CI: 0.72-0.95). Compared to PWH-B, PWH-A tended to have DEs at a younger age (<30 years). The chance of a DE did not differ by race, hemophilia type, and currently having or having a history of inhibitor. No significant associations were found between dental extraction, education or employment among PWH ages >18 years. Dental extraction clinical outcomes and related treatments indicated approximately 34% of PWH used prophylaxis versus on-demand therapy (18%) 292for dental/mouth bleeding. Approximately 5% of PWH who underwent DE reported oral/mouth bleeds within one week of the procedure. Of those bleeding episodes, 28.0% of hemophilia A patients and 12.5% of hemophilia B patients reported two or more oral/mouth bleeds during, and one-week post-DE. Rates of hospitalizations and ED visits were 7.4% and 1.3% respectively for PWH-A and 8.8% and 0.9% respectively for PWH-B. Among oral/mouth bleeds related to dental extraction, 34.0% and 50.0% patients with hemophilia A and B respectively received hemostatic therapies such as DDAVP, factor concentrates, or antifibrinolytics. Factors associated with DE bleeding were as follows: Dental extractions performed with prophylactic regimen were found to experience insignificantly fewer dental bleeding episodes (P>0.05). Similarly, no statistically significant difference in bleeding rate after DE was found in those using extended half-life factor (EHL) compared to standard half-life products (SHL). Prophylaxis was more prevalent among PWH-A compared to PWH-B (37.3% vs. 25.2% respectively). SHL products were more commonly used than EHL products for on-demand therapy (8.3% vs. 0.5% respectively) as well as prophylaxis (19.8% vs. 8.1%). PWH who have ever developed an inhibitor significantly increased the odds of dental bleeding (OR:2.09, 95%CI: 1.21-3.63). However, no significant relationship was found between inhibitor and DE bleedings among PWH who have been exposed to emicizumab (P=0.168). DISCUSSION: This is the largest study of DE outcomes in PWH. DE tends to be performed more in those with mild hemophilia and at an earlier age. The use of hemostatic therapies and factor prophylaxis is associated with insignificantly less bleeding. The ATHNdataset allowed studies of outcomes in a large cohort of PWH. This project was part of the ATHN CARE Award. Disclosures He: ATHN: Ended employment in the past 24 months. Recht: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment. Kulkarni: Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Genentech/Roche: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst Bioscience: Research Funding; Foundation for Women and Girls with Blood Disorders: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Improvement of Efficacy Outcomes in Patients Who Switched from Sucrose-Formulated rFVIII to BAY 81-8973 Prophylaxis in the LEOPOLD Clinical Trials

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-21
Author(s):  
Gili Kenet ◽  
Thomas Moulton ◽  
Erika Soltes Rak ◽  
Brian M. Wicklund ◽  
Sanjay P Ahuja
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Study Drug ◽  
Study Cohort ◽  
Efficacy And Safety ◽  
Old Patients ◽  
On Demand ◽  
Adults And Children ◽  
Previously Treated ◽  
Bleeding Episodes

Background BAY 81-8973 (Kovaltry®) is a full-length, unmodified, recombinant factor VIII (FVIII), indicated for on-demand treatment and control of bleeding episodes, perioperative management of bleeding and routine prophylaxis to reduce the frequency of bleeding episodes in adults and children with hemophilia A. It has the same amino acid sequence as sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). Pharmacokinetic comparisons confirmed BAY 81-8973 to have a longer half-life and lower clearance than FVIII-FS. The objective of this analysis was to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS prior to enrolling into the LEOPOLD clinical studies receiving BAY 81-8973. Methods LEOPOLD I (NCT01029340) Part B and LEOPOLD Kids (NCT01311648) were Phase 3, multinational, open-label studies that included male patients with severe hemophilia A receiving on-demand or prophylactic therapy, with ≥50 exposure days to any FVIII product and no history of FVIII inhibitors. Patients in LEOPOLD I were >12 years old and received 20-50 IU/kg BAY 81-8973 prophylaxis twice-weekly (2×W) or three times a week (3×W) for up to one year. Patients in LEOPOLD Kids were ≤12 years old and received 25-50 IU/kg BAY 81-8973 ≥2×W for six months. Dosing regimens for both studies were assigned by the investigator. In this analysis, efficacy and safety are assessed in the subset of patients in LEOPOLD I Part B and LEOPOLD Kids who were previously treated with FVIII-FS. Results In LEOPOLD I, 22 (35.5%) patients were previously treated with FVIII-FS with a median age of 27.0; in LEOPOLD Kids, 24 (47.1%) patients were previously treated with FVIII-FS with a median age of 5.0 (Table 1). In general, these switch cohorts had similar patient demographics to the whole study cohort (Table 1) and any differences did not affect the final analysis. Most patients did not change their dosing frequency when starting treatment with BAY 81-8973 but most increased their dose (FVIII-FS dose is 25 IU/kg 3×W [adults] or every other day [EOD; children]; BAY 81-8973 dose is 25-40 IU/kg 2×W or 3×W [>12 years] or 25-50 IU/kg 2×W, 3×W or EOD [≤12 years]). Switching from FVIII-FS to BAY 81-8973 resulted in lower median annualized bleeding rates (ABRs) in the LEOPOLD studies. In LEOPOLD I, median (Q1; Q3) total ABR decreased from 2.5 (0.0; 9.0) in the 12 months of FVIII-FS treatment prior to study entry, to 1.0 (0.0; 6.8) (Figure 1). In LEOPOLD Kids, median total ABR decreased from 3.0 (1.0; 12.0) to 2.0 (0.0; 6.0) for 0-<6 year old patients (n = 13) and from 4.0 (0.0; 10) to 0.0 (0.0; 2.1) for 6-12 year old patients (n = 11) after switching from FVIII-FS to BAY 81-8973 (Figure 1). Joint and spontaneous median ABRs were zero for <12 year old patients treated with BAY 81-8973. There were no study-drug-related adverse events (AEs) or serious AEs (SAEs) reported in patients switching from FVIII-FS to BAY 81-8973 in either LEOPOLD I Part B or LEOPOLD Kids (Table 2). One patient in the LEOPOLD Kids main study discontinued BAY 81-8973 due to a central venous catheter-related infection after six months of treatment, which was not considered study-drug-related. No FVIII inhibitors developed in any patients in either study. Conclusions Switching from FVIII-FS to BAY 81-8973 resulted in improved bleeding control in adults and children with hemophilia A and was well-tolerated. Disclosures Kenet: PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Wicklund:Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Shire (Takeda): Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria. Ahuja:Genentech: Consultancy, Honoraria; Sanofi Genzyme: Consultancy, Honoraria; XaTek, Inc.: Consultancy, Patents & Royalties, Research Funding.

scholarly journals Characteristics of Patients without Bleeding in a Pivotal Trial of Extended Half-Life, Pegylated, Full-length Recombinant Factor VIII (BAX 855) in the Treatment of Hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1105-1105
Author(s):  
Alice D. Ma ◽  
Robert Klamroth ◽  
Marilyn J. Manco-Johnson ◽  
Werner Engl ◽  
Jacqueline A Dyck-Jones ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Employment Equity ◽  
Advisory Committees ◽  
On Demand ◽  
Bleeding Episodes ◽  
Equity Ownership ◽  
The One

Abstract BAX 855 is a pegylated full-length recombinant factor VIII (PEG rFVIII) built on ADVATE (rFVIII) with an extended half-life and is in development for prophylaxis and treatment of bleeding in patients with hemophilia A. In the pivotal trial, previously treated patients (PTPs) received BAX 855 prophylaxis with a twice-weekly 45 IU/kg dosing regimen. Of 101 patients in the per protocol analysis set, 40 (39.6%) patients achieved zero bleeding during 6 months of prophylactic treatment with BAX 855, compared with the on-demand treatment arm in which every patient (n=17) experienced at least 1 bleeding episode. Pharmacokinetic parameters were assessed in a subset of patients with zero bleeding (n=9). Assessments were performed for rFVIII, for an initial infusion of BAX 855 and for a repeat infusion of BAX 855 after 6 months of treatment. Using the one-stage clotting assay, BAX 855 demonstrated an extended circulation time compared to rFVIII with a mean (standard deviation [SD]) half-life (T1/2) of 16.13 (3.827) hours vs 11.44 (2.250) hours (ratio BAX 855/rFVIII: 1.4). Over time, the 6 month assessment of BAX 855 T1/2 remained stable at 16.30 (3.137) hours (ratio repeat/initial BAX 855: 1.0), based on the one-stage clotting assay. Incremental recovery (IR) measurements were comparable with 2.41 (0.454) IU/dL for rFVIII and 2.62 (0.684) IU/dL for BAX 855. As expected, clearance (CL) was higher for rFVIII compared to BAX 855: 0.0380 (0.009) vs 0.0205 (0.007) dL/(kg*h). Historical annualized bleeding rates (ABRs) in the 40 patients without bleeding during prophylactic treatment were calculated based on the previous 3-6 months of each patient's diary or recall. Historical ABRs ranged from 0-80 with a median ABR of 7. However, patients may have either been receiving on demand or prophylactic FVIII treatment prior to entering the prophylactic arm of the trial, accounting for the range in ABRs. The median pre-trial ABR of patients in the on-demand arm, all of whom experienced bleeding, was much higher at 41.5 (range: 12.9-67.9). Of the 40 patients without bleeding who were in the prophylaxis arm of the trial, 31 received prophylaxis in their previous pre-trial regimen, while 9 had received on-demand treatment prior to enrolling in the trial. A target joint was defined as a single joint (ankles, knee, hip, or elbow) with ≥ 3 spontaneous bleeding episodes in any consecutive 6-month period. At screening, 30% of patients without bleeding on the study had 0 target joints, while 37.5% had 1-2 and 32.5% had ≥3 target joints. Of the patients who had >3 target joints at screening, there were 4 (10%) patients with 4 and 1 (2.5%) patient with 6 target joints at screening. In contrast, patients in the on-demand group (who had all been treated on-demand prior to the trial) had a higher incidence of target joints at screening: 11.8% of patients had 0 target joints, while 52.9% had 1-2 and 28.3% had ≥3 target joints. The presence or absence of preexisting arthropathy did not seem to influence the likelihood of having zero bleeding during the trial. In 65% of the patients without bleeding, arthropathy was present at screening. This is higher than was found in the patients treated on-demand (47.1%) who all experienced bleeding. A patient was considered to have arthropathy if it was indicated in the medical history or if the patient had joint surgery. Blood group types were collected on the patients without bleeding. The results showed: A-50%; B-12.5%; AB-7.5%; O-15%; unknown 15%. This is rather different than the blood types of the 17 on demand patients who all experienced joint bleeding: A-35.3%; B-5.9%; AB-17.6%; O-35.3%; unknown 5.9%. There were fewer blood group O patients among the patients without bleeding. While some of the characteristics of patients on prophylaxis without bleeding episodes were similar to those of patients treated on-demand who all experienced bleeding, patients without bleeding had fewer target joints at screening, lower median historical ABR, and lower incidence of blood type O. Disclosures Ma: Kedrion: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta: 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. Klamroth:Biogen and SOBI: Honoraria, Speakers Bureau; Bayer, Baxter, CSL Behring, Pfizer, Novo Nordisk, and Octapharma: Honoraria, Research Funding, Speakers Bureau. Manco-Johnson:Baxter/Baxalta, Bayer, CSL Behring, Biogen NovoNordisk: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding. Engl:Baxalta: Employment, Equity Ownership. Dyck-Jones:Baxalta: Employment. Abbuehl:Baxalta: Employment, Equity Ownership.

scholarly journals Improved Bleeding Outcomes in Patients Who Switched From Sucrose-Formulated rFVIII to BAY 94-9027 Prophylaxis in PROTECT VIII

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 6-7
Author(s):  
Mark Reding ◽  
Thomas Moulton ◽  
Erika Soltes Rak ◽  
Mindy L Simpson
Keyword(s):  
Single Dose ◽  
Adverse Events ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Main Study ◽  
On Demand ◽  
Study Enrollment ◽  
Previously Treated ◽  
To Receive

Background BAY 94-9027 (damoctocog alfa pegol; Jivi®) is a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated to extend its half-life compared with standard-half-life FVIII products, including sucrose formulated FVIII (FVIII-FS; Kogenate® FS/Helixate® FS). A previous pharmacokinetic study confirmed longer half-life and lower clearance with a single dose of BAY 94-9027 compared with a single dose of FVIII-FS. The phase 2/3 PROTECT VIII study (NCT01580293) demonstrated the efficacy, safety and utilization of BAY 94-9027 as prophylactic and on-demand therapy for adolescents and adults with severe hemophilia A, including during major and minor surgeries. This post hoc subgroup analysis of PROTECT VIII aimed to assess the efficacy and safety outcomes of patients with hemophilia A who were receiving FVIII-FS as FVIII replacement therapy prior to study enrollment. Methods In PROTECT VIII, 134 patients were treated with BAY 94-9027 for the main, 36-week study period. Patients with ≤1 breakthrough bleed during a 10-week run-in period treated with BAY 94-9027 25 IU/kg twice-weekly (2×W) prophylaxis were considered eligible for randomization and were thus randomized to receive BAY 94-9027 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the 26-week study period. Patients with >1 bleed, and thus ineligible for randomization (IFR), and those eligible for randomization but enrolled after randomized arms were full (EFR), were assigned to a 30-40 IU/kg 2×W regimen (Figure 1). In total, 114 patients received BAY 94-9027 prophylaxis and 20 patients were treated on-demand. Patients who completed the main study could enter into an optional extension, in which they could continue to receive BAY 94-9027 on any PROTECT VIII study regimen. This present analysis was designed to assess annualized bleeding rates (ABR), adverse events and FVIII utilization of a subset of PROTECT VIII patients who were previously treated with prophylaxis or on-demand FVIII-FS. Pre-study ABRs were based on patient recall of bleeding events during the 12 months prior to study entry. Results Of the 114 patients who received BAY 94-9027 prophylaxis in the PROTECT VIII main study period, 38 (33.3%) patients were previously treated with FVIII-FS (29 received prior prophylaxis, 9 received prior on-demand treatment) (Table 1). Of these, 8 (21%), 19 (50%) and 11 (29%) patients were treated with 2×W (n = 4 IFR; n = 4 EFR), E5D and E7D BAY 94-9027 regimens in PROTECT VIII, respectively. For patients treated with either prophylactic or on-demand FVIII-FS treatment in the 12-month pre-study period and who were eligible for randomization, median total and joint ABRs decreased during Weeks 10-36 with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens (Figure 2). In the 29 patients who switched from FVIII-FS prophylaxis regimens only prior to PROTECT VIII study entry, median (Q1; Q3) total ABRs also decreased from 7.0 (1.0; 14.0) pre-study to 0.0 (0.0; 2.1), 2.1 (0.0; 4.2), and 4.3 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens, respectively. Median joint ABRs also decreased in patients who were previously treated with prophylaxis regimens only with FVIII-FS, from 3.5 (0.0; 8.5) pre-study to 0.0 (0.0; 2.1), 1.1 (0.0; 4.0), and 2.2 (0.0; 5.7) with BAY 94-9027 2×W (EFR), E5D and E7D prophylaxis regimens during the main study period, respectively. The median dose of BAY 94-9027 administered per infusion in patients who switched from either on-demand or prophylaxis regimens of FVIII-FS was 38.7 IU/kg. One patient who switched from FVIII-FS discontinued BAY 94-9027 during PROTECT VIII due to an acute, resolved, hypersensitivity episode occurring after the start of the first infusion; no study-drug-related serious adverse events were reported. Overall, of patients who were treated with FVIII-FS in the 12 months prior to PROTECT VIII study enrollment, BAY 94-9027 was well-tolerated and the safety profile was similar to that of the overall prophylaxis patient population in PROTECT VIII (Table2). Conclusions Prophylaxis with BAY 94-9027 resulted in lower median total and joint ABRs compared with prior prophylaxis or on-demand treatment with FVIII-FS, resulting in improved efficacy with a similar safety profile. Disclosures Reding: Takeda: Consultancy, Honoraria, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; BioMarin: Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Moulton:Bayer: Current Employment. Soltes Rak:Bayer: Other: Employee of Belcan, contracted with Bayer. Simpson:HEMA Biologics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bioverativ/Sanofi: Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria.

Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation Study of the rFVIIa Variant (BAY 86–6150) In Hemophilia A or B with or without Inhibitors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3679-3679 ◽  
Author(s):  
J.N. Mahlangu ◽  
M.J. Coetzee ◽  
M. Laffan ◽  
J. Windyga ◽  
T. T. Yee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Employment Equity ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Bleeding Episodes ◽  
Equity Ownership

Abstract Abstract 3679 Bleeding episodes in hemophilia A or B patients with inhibitors to factors VIII or IX are commonly managed with bypassing agents such as recombinant factor VIIa (rFVIIa). However, currently available rFVIIa treatment is associated with variable response rates and a short elimination half-life, often necessitating the administration of multiple doses to control bleeding. BAY 86–6150, a human rFVIIa variant, was developed to provide a longer-acting and more potent activated factor VII in the management of bleeding episodes in patients with hemophilia who developed inhibitors. The safety, tolerability, pharmacodynamic/pharmacokinetic (PD/PK) profiles, and immunogenicity of BAY 86–6150 in nonbleeding patients with hemophilia was investigated in a phase I, randomized, double-blind, placebo-controlled, single-dose escalation study. The patient population comprised nonbleeding men aged 18–65 years with moderate or severe hemophilia A or B with or without inhibitors. 16 patients were randomized 3:1 to escalating doses of BAY 86–6150 at 6.5, 20, 50, or 90 μg/kg (n=3 each) or placebo (n=4). Patients were followed for 50 days postdose. The objective of the trial was to evaluate the safety and tolerability of BAY 86–6150, with adverse events (AEs) as the primary endpoint. Other endpoints included PK parameters, the effects of BAY 86–6150 on hemostasis markers and coagulation, and the immunogenicity of the compound. BAY 86–6150 was not associated with clinically significant AEs or dose-limiting toxicities and the PK parameters were linear over the dose range, with a half-life of 5–7 hours. Patients demonstrated consistent, dose-dependent thrombin generation ex-vivo in platelet-poor plasma (mean peak effect 26–237 nM thrombin from 6.5–90 μg/kg). Peak thrombin levels over time paralleled the presence of BAY 86–6150 by PK analysis, indicating that the drug in circulation retained activity. There were corresponding decreases in time and duration in the activated partial thromboplastin and prothrombin time testing. In contrast, there was no dose response seen in the thrombogenicity markers evaluated including antithrombin III, prothrombin fragment 1+2, TAT, and D-dimer. One patient demonstrated antibody activity to both BAY 86–6150 and to rVIIa as determined by ELISA testing at baseline. The level of inhibition and titer remained constant when evaluated in follow-up on day 29 and day 49. The data safety monitoring board recommended progression to the highest proposed dose (90 μg/kg). The phase II/III studies are designed to evaluate the clinical efficacy and safety as well as corresponding laboratory markers. Results of the present study suggest that the novel rFVIIa agent BAY 86–6150 is safe and has increased potency and a longer half-life compared with the currently available rFVIIa therapy. BAY 86–6150 may therefore have the potential to improve the treatment of bleeding episodes in hemophilic patients with inhibitors. Disclosures: Mahlangu: Bayer Helathcare: Consultancy, Honoraria, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Speakers Bureau; IAVI: Consultancy; Maxygen: Consultancy. Coetzee:Bayer Schering Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Laffan:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Windyga:Bayer HealthCare Pharmaceuticals: Research Funding; Bayer, Baxter, Behring, NovoNordisk, Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Bayer HealthCare Pharmaceuticals: Research Funding. Schroeder:Bayer Schering Pharma AG: Employment, Equity Ownership. Haaning:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Siegel:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Lemm:Bayer Schering Pharma AG: Employment, Equity Ownership.

Prophylactic Dosing of Anti-Inhibitor Coagulant Complex (FEIBA) Reduces Bleeding Frequency In Hemophilia A Patients with Inhibitors: Results of the Pro-FEIBA Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 720-720 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Eric Berntorp ◽  
Chiara Biasioli ◽  
Shannon Carpenter ◽  
Hyejin Jo ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Allergic Reaction ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Study Drug ◽  
Advisory Committees ◽  
Patient Age ◽  
On Demand ◽  
Bleeding Episodes

Abstract Abstract 720 Patients with congenital hemophilia and inhibitors are at increased risk for serious bleeding complications and progression to end-stage joint disease. Anecdotal reports and small case series suggest that regular doses of anti-inhibitor coagulant complex (AICC; FEIBA VH) may be effective in preventing bleeding episodes in patients with hemophilia A and inhibitors. The Pro-FEIBA study is the first prospective controlled clinical trial to study the efficacy of AICC in bleed prevention. Study Population and Design: The study was conducted in hemophilia A patients >2 years with a history of high-titer inhibitors who were using bypassing therapy for the treatment of bleeding episodes. Subjects on or planning immune tolerance therapy were excluded as were patients with thrombocytopenia or other bleeding disorders. This randomized, crossover study compared 6 months of AICC prophylactically dosed at 85 U/kg ± 15% on 3 nonconsecutive days per week (Prophy period) to 6 months of on-demand therapy (OD period) (target dose for the treatment of bleeds: 85 U/kg ± 15%). The 2 study periods were separated by a 3-month washout, during which time patients used on-demand therapy for bleeding. Patients were randomized to initially enter either the 6-month Prophy period or the 6-month OD period. Each patient then crossed-over to the alternate study period after a 3-month wash-out. Results: Thirty-four subjects were randomized; 26 subjects completed both study periods and were deemed evaluable per protocol (PP) for efficacy analysis of the primary outcome to compare bleeds in each 6-month treatment period. Eight subjects did not complete the study (1 patient in the Prophy treatment arm and 1 patient in the post-prophylaxis washout period died of complications associated with underlying illness and bleeding, 1 patient experienced an allergic reaction to study drug, 1 patient was lost to follow-up, and 4 patients withdrew from study). All randomized subjects were evaluated for safety. In the PP group, mean patient age was 26.9 years (median: 24.7; range: 2.8–67.9). In the total randomized group, mean patient age was 27.1 years (median: 28.7; range: 2.8–67.9). Of the 26 subjects who completed the study PP, 14 were randomized to enter the Prophy period first and then crossed-over to the OD period, while 12 subjects were initially randomized to enter the OD period and then crossed-over to the Prophy period. For the PP analysis, total bleeds and joint bleeds requiring treatment during the 2 study periods were compared (p-value is for the Wilcoxon signed-rank test of difference between OD and Prophy periods). In addition, bleeds for the 6-month period prior to enrollment were recorded retrospectively on study entry. Efficacy: Both total bleeds and joint bleeds were significantly reduced during the Prophy period as compared with the OD period (p < .0001) Table 1. There was no difference in bleed event rates based on randomization sequence (ie, no carry-over effect was detected when the Prophy period preceded the OD period). Safety: A total of 38 serious adverse events (SAEs) occurred, none of which was thrombotic in nature. One SAE was deemed by the study safety monitor to be related to the study drug (an allergic reaction). Otherwise, treatment was safe and well tolerated. Conclusion: These results in patients with hemophilia A and inhibitors show that AICC, dosed at 85 IU/kg +/&minus; 15% given on 3 non-consecutive days each week was associated with a 62% reduction in all bleeds and a 61% reduction in joint bleeds as compared with on-demand therapy. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: This is a report of a clinical trial using the Anti-Inhibitor Coagulant Complex, FEIBA, as prophylactic therapy to prevent bleeding in hemophilia patients with inhibitors. FEIBA is not currently licensed for use in prophylaxis in the US. Berntorp:Baxter: Consultancy, Honoraria, Research Funding. Negrier:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rocino:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Windyga:Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gringeri:Baxter: Consultancy, Honoraria, Research Funding; NovoNordisk: Honoraria.

scholarly journals Factor VIII Use in the Treatment of Breakthrough Bleeds in Hemophilia A Patients without Inhibitors on Emicizumab Prophylaxis: The Phase 3 HAVEN 3 Study Experience

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2395-2395
Author(s):  
Michael Callaghan ◽  
Benjamin Trzaskoma ◽  
Richard H. Ko ◽  
Lucy Lee ◽  
Anisha M. Patel ◽  
...  
Keyword(s):  
Factor Viii ◽  
Exposure Time ◽  
Cumulative Dose ◽  
Research Funding ◽  
Hemophilia A ◽  
Phase 3 ◽  
Breakthrough Bleeding ◽  
On Demand ◽  
Equity Ownership ◽  
The Individual

Introduction HAVEN 3 was a phase 3 study investigating the use of emicizumab as prophylaxis in adult and adolescent (≥12 years old) persons with hemophilia A (PwHA) without factor VIII (FVIII) inhibitors (NCT02847637; Mahlangu et al. 2018). HAVEN 3 demonstrated that emicizumab prophylaxis once weekly or every two weeks was safe and highly effective in bleed prevention. The primary analysis of HAVEN 3 included an intrapatient comparison of 48 participants who received FVIII prophylaxis in a non-interventional study (NIS) prior to enrollment in HAVEN 3. Compared with emicizumab prophylaxis during the HAVEN 3 study, emicizumab prophylaxis resulted in an annualized bleed rate that was 68% lower than the rate with previous FVIII prophylaxis (1.5 vs 4.8, p<0.001). No dosing guidance was provided regarding the use of on-demand FVIII in HAVEN 3, and investigators prescribed FVIII at their own discretion. In this subsequent analysis, we characterize the dose and frequency of replacement FVIII used for the treatment of breakthrough bleeding in these 48 participants. Methods The primary comparisons in our analyses are focused on on-demand FVIII use for breakthrough bleeding while participants were on FVIII prophylaxis during the NIS versus its use while on emicizumab prophylaxis during HAVEN 3. Any use of on demand FVIII other than to manage breakthrough bleeding (e.g. prior to activity) was not included in our analyses. Given that, collectively, the total exposure time to emicizumab during HAVEN 3 was more than twice the exposure time to FVIII prophylaxis during the NIS (75.8 vs 28.6 years respectively), any treatment comparisons are drawn on an annualized basis. Annualized on-demand FVIII use was calculated by dividing by the number of days in the efficacy period and multiplying the resulting daily consumption by 365.25 days. The number of infusions and cumulative doses of on-demand FVIII use are described at the participant level as well as at the individual bleed level and are presented descriptively for both the NIS and HAVEN 3 exposure periods. No formal statistical inferences (i.e. calculation of p-values) have been conducted. All analyses were based on an October 2018 data cutoff. Results A total of 48 participants who were treated with FVIII prophylaxis during the NIS were then treated with emicizumab prophylaxis during HAVEN 3 and thus make up the total cohort for our analyses. Annualized infusion rates of on-demand FVIII per participant and cumulative doses of on-demand FVIII (in international units [IU] per kilogram) per participant were higher during the FVIII prophylaxis period when compared with the emicizumab exposure period (mean 15.3 vs 7.2; median 3.6 vs 0.6 annual infusions per participant and mean 602.4 IU/kg vs 209.0 IU/kg; median 75.5 IU/kg vs 19.1 IU/kg, respectively). At the individual bleed level, FVIII infusions and total cumulative dose suggested that participants were administered a similar amount of medication to treat bleeds during both the NIS and HAVEN 3 study periods: median number of infusions per bleed were 1.0 (interquartile range [IQR]=1.0) versus 2.0 (IQR=3.0) and median cumulative doses were 43.5 (IQR=35.1) versus 50.0 (IQR=72.7) IU/kg, respectively (Table 1). Conclusions This analysis revealed a lower annualized infusion rate and a correspondingly lower annualized cumulative dose of FVIII for treatment of breakthrough bleeds during emicizumab prophylaxis compared with FVIII prophylaxis. At the individual bleed level, the amount of on-demand FVIII used per bleeding episode was comparable between NIS and HAVEN 3 exposure periods. Thus, based on this single analysis, it appears that patients received less on-demand FVIII during emicizumab prophylaxis compared with FVIII prophylaxis, as a result of overall reduction of bleed frequency, while the treatment of individual bleeds appeared similar regardless of the prophylaxis therapy administered. Disclosures Callaghan: Octapharma: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Global Blood Therapeutics: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Bayer: Consultancy, Speakers Bureau; Alnylum: Equity Ownership; Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Roche/Genentech: Speakers Bureau; Shire/Takeda: Speakers Bureau; Pfizer: Research Funding; Roche: Research Funding. Trzaskoma:Genentech: Employment, Equity Ownership. Ko:Genentech, Inc.: Employment. Lee:Genentech, Inc.: Employment. Patel:Genentech: Employment; Roche/Genentech: Equity Ownership. Tzeng:Genentech, Inc.: Employment. Shah:Genentech: Employment. Chang:Genentech, Inc.: Employment; Genentech/Roche: Equity Ownership. Niggli:F. Hoffmann-La Roche Ltd: Employment. Dhalluin:F. Hoffmann-La Roche Ltd: Employment. Mahlangu:Sanofi: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Biomarin: Research Funding; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; Unique: Research Funding.

scholarly journals Efficacy of rFVIIIFc for First-Time Immune Tolerance Induction (ITI) Therapy: Final Results from the Global, Prospective VerITI-8 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 2) ◽  
pp. LBA-5-LBA-5
Author(s):  
Lynn Malec ◽  
An Van Damme ◽  
Anthony Chan ◽  
Mariya Spasova ◽  
Nisha Jain ◽  
...  
Keyword(s):  
Half Life ◽  
Stock Options ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
High Dose ◽  
Severe Hemophilia ◽  
First Time ◽  
Inhibitor Titer ◽  
Privately Held

Abstract Introduction: Inhibitor development is a major complication of factor VIII (FVIII) replacement therapy, affecting approximately 30% of people with severe hemophilia A (Peyvandi et al Lancet 2016). Inhibitor eradication is the standard of care to restore responsiveness to FVIII; however, ITI regimens often require frequent high-dose factor injections over a long period (DiMichele et al Haemophilia 2007; Carcao et al Haemophilia 2021). Median (interquartile range [IQR]) time (months) to negative titer in the International ITI Study with high-dose FVIII was 4.6 (2.8-13.8) (n=31); negative titer to normal recovery was 6.9 (3.5-12.0) (n=23); and normal recovery to tolerance was 10.6 (6.3-20.5) (n=22) (Hay and DiMichele Blood 2012). Recombinant factor VIII Fc fusion protein (rFVIIIFc) is an extended half-life (EHL) FVIII that showed potential benefits for ITI in retrospective clinical data and case reports (Malec et al Haemophilia 2016; Groomes et al Pediatr Blood Cancer 2016; Carcao et al Haemophilia 2021). VerITI-8 (NCT03093480) is the first prospective study of rFVIIIFc in first-time ITI and follows on from the reITIrate (NCT03103542) study of rFVIIIFc for rescue ITI (Königs et al Res Pract Thromb Haemost, ISTH 2021). Aim: Describe outcomes in the verITI-8 study of first-time ITI with rFVIIIFc over 48 weeks in subjects with severe hemophilia A and high-titer inhibitors. Methods: VerITI-8 is a prospective, single-arm, open-label, multicenter study exploring efficacy of rFVIIIFc for first-time ITI in people with severe hemophilia A with high-titer inhibitors. Initial screening was followed by an ITI period in which all subjects received rFVIIIFc 200 IU/kg/day until tolerization or 48 weeks had elapsed (Figure). This was followed by tapered dose reduction to standard prophylaxis and follow-up. Key inclusion criteria included males with severe hemophilia A, high-titer inhibitors (historical peak ≥5 Bethesda units [BU]/mL), and prior treatment with any plasma-derived or recombinant standard half-life or EHL FVIII. Key exclusion criteria included coagulation disorder(s) other than hemophilia A and previous ITI. The primary endpoint was time to tolerization (successful ITI) with rFVIIIFc defined by inhibitor titer &lt;0.6 BU/mL, incremental recovery (IR) ≥66% of expected IR (IR ≥1.32 IU/dL per IU/kg) (both at 2 consecutive visits), and t ½ ≥7 hours (h) within 48 weeks. Secondary endpoints included number of subjects achieving ITI success, annualized bleed rates (ABR), and adverse events (AEs). Results: Sixteen subjects were enrolled and received ≥1 rFVIIIFc dose. Median (range) age at baseline was 2.1 (0.8-16.0) years, and historical peak inhibitor titer was 22.4 (6.2-256.0) BU/mL (Table). Twelve (75%), 11 (69%), and 10 (63%) subjects, respectively, achieved a negative inhibitor titer, an IR &gt;66%, and a t½ ≥7 h (ie, tolerance) within 48 weeks. Median (IQR) times in weeks to achieve these markers of success were 7.4 (2.2-17.8), 6.8 (5.4-22.4), and 11.7 (9.8-26.2) (ie, 2.7 [2.3-6.0] months to tolerance), respectively. One subject achieved partial success (negative inhibitor titer and IR ≥66%), and 5 subjects failed ITI, of which 2 had high inhibitors throughout, 2 experienced an increase in inhibitor levels, and 1 recorded a negative inhibitor titer at 282 days. Most bleeds occurred in the ITI period when median (IQR) ABRs (n=13) were 3.8 (0-10.1) overall, 0 (0-2.6) for spontaneous, 1 (0-4) for traumatic, and 0 (0-3.1) for joint. During tapering, median (IQR) ABRs (n=10) were overall, 0 (0-2.4); spontaneous, 0 (0-0); traumatic, 0 (0-1.3); and joint, 0 (0-0). All 16 subjects experienced ≥1 treatment-emergent AE (TEAE), the most frequent of which was pyrexia in 7 subjects (44%). One subject reported ≥1 related TEAE (injection site pain). Nine subjects (56%) experienced ≥1 treatment-emergent serious AE (TESAE). TESAEs occurring in ≥2 subjects included vascular device infection, contusion, and hemarthrosis. No treatment-related TESAEs, discontinuations due to AEs, or deaths were reported. Conclusions: rFVIIIFc is the first EHL FVIII with prospective data for first-time ITI in patients with severe hemophilia A with historical high-titer inhibitors. Evaluated within a 48-week timeframe, rFVIIIFc offered rapid time to tolerization (median 11.7 weeks; 2.7 months) with durable responses in almost two-thirds of subjects and was well tolerated. Optimizing ITI to eradicate inhibitors remains a priority. Figure 1 Figure 1. Disclosures Malec: CSL Behring: Consultancy; Genentech: Consultancy; HEMA Biologics: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy, Research Funding; Takeda: Consultancy; Bioverativ: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy; Bayer: Consultancy. Van Damme: Pfizer: Consultancy; Shire: Consultancy; Bayer: Consultancy. Chan: Bioverativ: Consultancy. Jain: Sanofi: Ended employment in the past 24 months; Takeda: Current Employment, Current holder of stock options in a privately-held company. Sensinger: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Dumont: Sanofi: Current Employment, Current holder of stock options in a privately-held company. Lethagen: Sobi: Current Employment, Current holder of stock options in a privately-held company. Carcao: Bayer, Bioverativ/Sanofi, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, and Shire/Takeda: Research Funding; Bayer, Bioverativ/Sanofi, CSL Behring, Grifols, LFB, Novo Nordisk, Pfizer, Roche, and Shire/Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Ablynx, Grifols, Kedrion, Novo Nordisk, Roche, Shire, and Sobi: Other: Personal Fees. OffLabel Disclosure: adheres to routine clinical practice

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, 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; Grifols: 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; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

Safety of Exposure to Recombinant Activated FVII (rFVIIa) Doses In Patients with Hemophilia and Inhibitors (CHwI) to Factors VIII or IX.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3675-3675 ◽  
Author(s):  
Amy D. Shapiro ◽  
Ellis J. Neufeld ◽  
David L. Cooper
Keyword(s):  
Clinical Trials ◽  
Single Dose ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Data Sources ◽  
On Demand ◽  
Frequency Of Use ◽  
The Us ◽  
Bleeding Episodes ◽  
Higher Doses

Abstract Abstract 3675 Background: The FDA-approved label for recombinant FVIIa (rFVIIa), for treatment of bleeding episodes and prevention of bleeding in surgical or invasive procedures in CHwI patients, recommends initial dosing with 90 mcg/kg as a bolus injection. Patients typically require 2–3 injections for bleed resolution. Based upon three clinical trials comparing a single dose of 270 mcg/kg to 3 doses of 90 mcg/kg, the single-dose 270 mcg/kg rFVIIa regimen was approved by the EMA in March 2007 for treatment of mild-to-moderate bleeds in hemophilic inhibitor patients. Published reports indicate that rFVIIa dosing utilized in clinical practice varies widely. Furthermore, the broad adoption of home treatment makes it difficult to estimate how frequently higher doses (doses > 90 mcg/kg) are used, particularly in the US, and whether or not higher doses pose safety concerns, namely development of thromboembolism. Objectives: To report the frequency of use of higher doses of rFVIIa for on-demand or prophylactic treatment in clinical trials and registries that included safety monitoring, particularly for occurrence of thromboembolic events (TEs). Methods: Data for on-demand treatment of bleeds with rFVIIa in patients with CHwI, were obtained from two published, prospective, randomized studies, one prospective, observational diary study in the US, and the ongoing US-based Hemophilia and Thrombosis Research Society (HTRS) registry database. Data on prophylactic use of rFVIIa in patients with CHwI were obtained from a published, prospective, randomized trial. Information on demographics, rFVIIa dosing, and frequency of TEs were collected and reported using descriptive statistics. Results: A total of 232 CHwI patients reported 20,496 rFVIIa doses administered either for on-demand treatment of 2,286 bleeding episodes or prophylactic treatment for 1,885 days. The majority (81%) of patients were diagnosed with hemophilia A and reported an inhibitor titer range of 0.5 – 20,000 BU, and 9% of patients were diagnosed with hemophilia B. Whites comprised 72% of patients for whom race information was available. Patient age ranged from < 1 year to 62 years, and adults (>18 years old) comprised 37% of the patients studied. All five data sources included use of rFVIIa doses > 90 mcg/kg, the dose recommended in the current US label. Doses of rFVIIa > 120 mcg/kg, > 160 mcg/kg and >240 mcg/kg comprised 40.2% (8,232 doses), 25.9% (5,316 doses) and 8.0% (1,644 doses), respectively, of the 20,496 doses administered to all patients, and comprised 30.8% (1,171 doses), 27.3% (1,037) and 12.1% (460), respectively, of the 3,800 doses administered specifically to adults (>18 years old). No TEs were reported across the five data sources irrespective of the dose administered. Conclusions: A comprehensive review of data of over 20,000 rFVIIa doses used for either prophylactic or on-demand treatment of bleeding episodes demonstrates the frequent use and safety of rFVIIa doses above the US FDA-approved dose. The absence of TEs in 8,232 higher doses (i.e. doses > 120 mcg/kg, including 460 doses > 240 mcg/kg in adults) suggests TEs are likely uncommon at doses up to 300 mcg/kg, and reaffirm the low TE incidence (0.2%) reported in CHwI trials at standard doses (≤ 90 mcg/kg). Substitution of fewer high doses in place of more frequent lower doses may provide improved compliance and avoid the need for short interval repetitive dosing. Evaluation of additional data sources such as the ongoing European ONE Registry, the recently completed PRO-PACT study (retrospective global chart review for assessment of prophylactic treatment), UKHCDO, and other global registries in countries where 270 mcg/kg dosing has been approved for clinical use, will enlarge the current data set and provide even better estimates of the frequency of use of higher doses of rFVIIa and occurrence of TEs across a larger, more global population. Disclosures: Shapiro: Novo Nordisk: Consultancy. Off Label Use: rFVIIa dosing for approved indications above the PI recommendations. Neufeld:Novo Nordisk: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Cooper:Novo Nordisk Inc.: Employment.

The Pharmacokinetics Of Turoctocog Alfa Are Consistent Over Different Concentrations and Production Lots

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4783-4783 ◽  
Author(s):  
Víctor Jiménez-Yuste ◽  
Sandra Lejniece ◽  
Robert Klamroth ◽  
Trine Saugstrup ◽  
Judi Moss
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Fixed Effects ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Pooled Data ◽  
One Stage ◽  
Chromogenic Assay ◽  
The One ◽  
Pharmacokinetic Difference

Introduction Turoctocog alfa is a B domain truncated human recombinant FVIII for treatment of patients with hemophilia A. The production yields a highly homogenous product with the same tyrosine sulphation as human FVIII. In order to confirm the consistency of turoctocog alfa pharmacokinetics (PK) over different production lots and vial strengths, a clinical trial was performed in 15 patients with severe hemophilia A. Aim To compare the PK of 3 lots of 2000 IU/vial and 1 lot of 3000 IU/vial of turoctocog alfa after i.v. administration of 50 IU/kg in patients with severe haemophilia A. Methods This was a multi-centre, open-label trial investigating the PK of 4 lots of turoctocog alfa (3 lots of 2000 IU/vial; Lots A, B and C, and 1 lot of 3000 IU/vial; Lot D) in patients with severe hemophilia A (FVIII<1%). The trial was performed as a two-period, incomplete block, cross-over trial, in which each patient was allocated at random to a predefined sequence of 2 different lots of turoctocog alfa. The FVIII activity was assessed using both the one-stage clot and chromogenic assays. Both the primary endpoint, normalized AUC (AUC*(planned dose/actual dose)), and the secondary PK endpoints were analyzed by ANCOVA on the log transformed values, with lot, visit and patient as fixed effects. Each of the three 2000 IU/vial lots was compared and tested against the 2 other 2000 IU/vial lots. If not significantly different on a 5% level, the 3 lots were pooled together and tested against the 3000 IU/vial lot. Results Fifteen patients with a mean age of 38.6 years (ranging from 21 to 60 years) were included from 3 hemophilia centres in 3 different countries. Three adverse events (AEs) were reported in the trial by 2 separate patients; all AEs were judged to be unlikely related to the trial product. There was no development of inhibitors. There was no pharmacokinetic difference observed between Lots A, B, C (2000 IU/vials) and there was no pharmacokinetic difference observed between the pooled data from lot A, B and C (2000 IU/vial) and lot D (3000 IU/vial) based on normalized AUC, half-life, incremental recovery and clearance. The estimated mean values (with 90% CI) for the PK parameters based on the chromogenic assay are presented in Table 1. The results were similar for the one-stage clot assay and the chromogenic assay. Conclusions No pharmacokinetic differences were observed between the three 2000 IU/vial lots (Lot A, Lot B and Lot C), nor were there pharmacokinetic differences between Lot D (3000 IU/vial) and pooled data from Lots A, B and C, based on normalized AUC, half-life, incremental recovery and clearance. There were no safety concerns and no inhibitor development in the trial. Disclosures: Jiménez-Yuste: Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Klamroth:Novo Nordisk, CSL Behring, Bayer, Baxter, Pfizer: Honoraria, Research Funding. Saugstrup:Novo Nordisk: Employment. Moss:Novo Nordisk: Employment.

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