Surgery with Turoctocog Alfa: Efficacy and Safety in Bleeding Prevention During Surgical Procedures - Results From the guardian™ Trials.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2228-2228
Author(s):  
Elena Santagostino ◽  
Steven R. Lentz ◽  
Mudi Misgav ◽  
Brigitte Brand ◽  
Pratima Chowdary ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Efficacy And Safety ◽  
Advisory Boards ◽  
Surgical Bleeding ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Hemostatic Efficacy ◽  
The Guardian ◽  
Extension Trial

Abstract Abstract 2228 Introduction: Novo Nordisk is developing turoctocog alfa, a human third generation recombinant FVIII for treatment of hemophilia A. During the pivotal trial in adult and adolescent previously treated patients with severe hemophilia A (guardian™1), subjects in need of surgery were able to participate in a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Pediatric (<12 years of age) previously treated patients in the guardian™3 trial were allowed to undergo minor surgery if needed during the trial. In addition, after completing these initial trials subjects were allowed to continue treatment with turoctocog alfa in the extension trial (guardian™2) which also includes a subtrial to document efficacy and safety of turoctocog alfa in prevention of surgical bleeding. Methods: We here describe surgeries performed within the guardian trials. For the ongoing guardian™2 extension trial, only cases included in the interim analysis (data cut-off 21NOV2011) are included. Results: In all, results from 10 major and 3 minor surgeries are included. Surgery indication was related to hemophilia joint disease in 8/13 cases. The hemostatic efficacy during and after surgery was rated on a 4-point scale (excellent, good, moderate and none) by the Investigator and/or Surgeon. Details and outcome of the individual surgeries performed are presented in Table 1. In addition, there were no safety concerns. Discussion: Prevention of surgical bleeding is an important aspect of hemophilia treatment. In the present 13 surgeries, including all surgeries performed with turoctocog alfa in the phase 3 guardian™ trials, hemostatic efficacy during and after was rated as either excellent or good in each case. The results support that turoctocog alfa has an excellent safety and efficacy profile for use in hemophilia A. Disclosures: Santagostino: Novo Nordisk and Pfizer: Research Funding; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau. Lentz:Novo Nordisk: Consultancy, Research Funding. Brand:Bayer: Travel support, Travel support Other; Novo Nordisk, Baxter, Pfizer: Advisory Boards, Advisory Boards Other; Novo Nordisk: Honoraria. Chowdary:Novo Nordisk: Consultancy. Savic:Novo Nordisk: Speakers Bureau. Lindblom:Novo Nordisk A/S: Employment.

scholarly journals Longitudinal Efficacy and Safety of N8-GP for Prophylaxis and Bleed Control in US Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3205-3205
Author(s):  
Allison P. Wheeler ◽  
Miguel A. Escobar ◽  
Susan Kearney ◽  
Janice M. Staber ◽  
Adam R. Wufsus ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Treatment Success ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
On Demand ◽  
Routine Prophylaxis ◽  
Previously Treated ◽  
Extension Trial

Abstract Introduction: N8-GP is an extended half-life recombinant factor VIII product indicated for use in patients with hemophilia A. The pathfinder trials evaluated routine prophylaxis and bleed control in previously treated patients aged ≥12 years (pathfinder2) and patients aged &lt;12 years (pathfinder5), including an extension trial (pathfinder8). The objective of the present analysis was to compare the efficacy and safety of N8-GP in US vs global (including US) patients. Methods: In the pathfinder2 trial, patients aged ≥12 years with severe hemophilia A were administered N8-GP 50 IU/kg every 4 days (Q4D) as routine prophylaxis or 20 to 70 IU/kg as on-demand treatment. Patients aged &lt;12 years received prophylaxis with N8-GP 60 IU/kg twice weekly in the pathfinder5 trial, and bleeding episodes were treated with 20 to 75 IU/kg. In the pathfinder8 extension trial, the investigator decided on which treatment arm the patient should be allocated based on previous treatment regimen and taking into account bleeding tendency. Results: See Table for efficacy in prophylaxis (median annualized bleeding rates [ABRs]) and bleed treatment (success rate). Median ABRs tended to decrease from 0.84 (global) and 0.86 (US) in pathfinder2 to 0.00 (global) and 0.00 (US) in pathfinder8 in patients aged ≥12 years on the prophylaxis regimen. In addition, in patients aged &lt;12 years, median ABRs decreased from 0.81 (global) and 0.76 (US) in pathfinder5 to 0.00 (global) and 0.49 (US) in pathfinder8. Treatment success rates for US patients were comparable to those for global patients across trials and 100% were rated "excellent" or "good" for patients aged &lt;12 years in pathfinder8. Overall, there were 59 treatment-related adverse events (AEs) in patients on the prophylactic regimen in pathfinder2, 13 of which occurred in US patients, and 11 treatment-related AEs in patients treated on-demand, 3 of which occurred in US patients. In pathfinder5, there were 16 treatment-related AEs, 7 of which occurred in US patients. In pathfinder8, there were 6 treatment-related AEs in patients aged ≥12 years, 3 of which were in US patients. In addition, there was 1 treatment-related AE in a non-US patient aged &lt;12 years. AEs included rash, redness, and injection site reactions. Across trials, 1 previously treated patient (an 18-year-old, from a US site) with an intron 22 inversion developed a low-titer inhibitor at 93 exposure days to N8-GP and was withdrawn when the titer progressed to &gt;5 Bethesda units. The patient returned to their previous FVIII product, and their inhibitor status was negative at follow-up. Conclusions: Efficacy of N8-GP was sustained during the main and extension pathfinder trials in both global and US patients. In addition, a favorable safety profile was maintained throughout the course of the program. Figure 1 Figure 1. Disclosures Wheeler: Novo Nordisk A/S: Consultancy; Bayer: Consultancy; BioMarin: Consultancy; HEMA Biologics: Consultancy; Spark: Consultancy; Takeda: Consultancy; UniQure: Consultancy. Kearney: Grifols: Research Funding; Daiichi Sankyo: Research Funding; CVS Pharmacy: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Wufsus: Novo Nordisk Inc: Current Employment. Ostrow: Novo Nordisk Inc: Current Employment. Lentz: Novo Nordisk Inc: Consultancy, Honoraria, Research Funding.

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 &gt;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 [&gt;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-&lt;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 &lt;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.

Immunogenicity of BAX 855 in Previously Treated Patients with Congenital Severe Hemophilia Α

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2594-2594
Author(s):  
Frank Michael Horling ◽  
Peter Allacher ◽  
Herwig Koppensteiner ◽  
Werner Engl ◽  
Fritz Scheiflinger ◽  
...  
Keyword(s):  
Adverse Events ◽  
Neutralizing Antibodies ◽  
Research Funding ◽  
Hemophilia A ◽  
De Novo ◽  
Coagulation Factor ◽  
Severe Hemophilia ◽  
Increased Risk ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Background and objectives BAX 855 (Antihemophilic Factor [Recombinant] pegylated, rurioctocog alfa pegol) is an extended half-life (EHL) recombinant human coagulation factor VIII (rFVIII) modified with polyethylene glycol (PEG) (Turecek et al., 2012). It was recently approved in the US and Japan for on-demand treatment of bleeding events and for prophylactic treatment for patients with congenital severe hemophilia A. The efficacy and safety of BAX 855 were extensively studied during clinical development of this compound (Konkle et al., 2015). The assessment of BAX855 immunogenicity was of particular interest because the development of neutralizing antibodies (FVIII inhibitors) is the most serious complication following replacement therapies with FVIII products. FVIII inhibitors develop in about 20-32% of previously untreated patients (Gouw SC et al., 2013) and with a rate of 1.55- 3.8 per 1000 patients per year in previously treated patients (Kempton CL, 2010) with severe hemophilia A. To fully understand the potential of BAX855 to induce antibody responses, both FVIII inhibitors and total FVIII-binding antibodies were assessed. Furthermore, potential antibody development against PEG-FVIII, PEG and CHO proteins was investigated. Methods The clinical protocols (ClinicalTrials.gov identifier: NCT02585960, NCT02210091, NCT01736475, NCT01913405, NCT01945593, NCT01599819, NCT02615691) and the methods used for antibody analytics (Whelan et al 2013; Lubich et al 2016) were previously described. ELISA technologies were used for the analysis of total binding antibodies, the Nijmegen modification of the Bethesda assay was used for the detection of FVIII inhibitors. Correlation analyses were done to assess any potential correlation between the development of antibodies and potential adverse events. Results None of the 243 subjects (6 PUPs and 237 PTPs) included in the analysis developed FVIII inhibitors (≥ 0.6 BU/mL) A total of 44 subjects tested positive for binding antibodies against FVIII, PEG-FVIII or PEG at single time points. 28 of these 44 subjects showed pre-existing antibodies against FVIII, PEG-FVIII, or PEG prior to first exposure to BAX 855, which disappeared during the study. 13 subjects who tested negative at screening developed transient antibodies against FVIII, PEG-FVIII, or PEG at one or two consecutive study visits after exposure to BAX 855. Antibodies were transient and not detectable at subsequent visits or at completion of the study. Five subjects showed positive results for binding antibodies at study completion or at the time of the data cutoff. No conclusion can be drawn whether these antibodies are of transient or persistent nature. There was no confirmed causal relationship between the appearance of binding antibodies against FVIII, PEG or PEG-FVIII and adverse events, nor was there an impact on hemostatic efficacy in any of the 44subjects. No subject had pre-existing antibodies or developed de novo antibodies to CHO proteins during the study at any time point. Conclusion Our data indicate that BAX855 did not show an increased risk for PTPs to develop FVIII inhibitors. We did not see any FVIII inhibitor development in PUPs, but the small number of overall exposures does not allow general conclusions for PUPs. Importantly, the data suggest that BAX855 did not induce immune responses associated with impaired treatment efficacy or with altered PK parameters. Disclosures Horling: Shire: Employment. Allacher:IMC Krems: Research Funding. Koppensteiner:Shire: Employment. Engl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership. Scheiflinger:Shire: Employment, Research Funding. Abbuehl:Baxalta (now part of Shire): Employment. Reipert:Shire: Employment.

scholarly journals 99.3% of Inhibitors in Severe Hemophilia a Develop before Exposure Day 75. Time to Change Definition of Previously Treated Patients; Data from 1038 Patients with Severe Hemophilia a of the Pednet Registry

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2472-2472
Author(s):  
Marijke Van den Berg ◽  
Kathelijn Fischer ◽  
Elena Santagostino ◽  
Herve Chambost ◽  
Karin Kurnik ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Definition Of

Abstract Introduction.In patients with hemophilia treated with factor VIII products, the development of inhibitory antibodies poses the largest safety risk. Especially during the first 50 exposure days (EDs), up to 37% of patients with severe hemophilia A have been reported to develop an inhibitor. To study neo-immunogenicity of products and new treatment strategies, patients have been distinguished into previously untreated (PUPs) and previously treated patients (PTPs); the latter defined as patients treated for more than 150 EDs. The number of 150 EDs was established in the eighties during a time when most patients received on-demand treatment and testing for inhibitors was not frequently performed. More recent studies on inhibitor incidence in PUPs with severe hemophilia A report that 50% of inhibitors develop within 14-15 EDs, however the cut-off number of EDs for a PUP to become a PTP is not well defined. The aim of this study was to define the number of EDs for PUPs to become PTPs based on long-term follow-up of patients with severe hemophilia A Methods.All patients with severe hemophilia A born after January 1, 2000, treated for at least 1 ED and followed prospectively until inhibitor development or the number of EDs at last follow-up, were included. The number of EDs at inhibitor development is the last exposure day before the first positive titer was reported. An inhibitor was defined as positive when at least two positive inhibitor titers were measured. Positivity was defined according to the cut-off level in each individual center's laboratory. Results.Of 1,038 PUPs with severe hemophilia A, 930 (89.6%) were followed until 75 EDs, 429 until 500 EDs and 212 until 1000 EDs. In total, 300 inhibitors developed, of which 298 (99.3%) within the first 75 EDs. Thereafter only two inhibitors developed, both low titer: after 249 and 264 EDs. Conclusion.Almost all inhibitors develop during the first 75 EDs. Patients with severe hemophilia A can be defined as PTP after 75 instead of 150 exposure days. A change of definition of PTP will increase the number of severe hemophilia A patients eligible for new therapies. Disclosures Santagostino: Bioverativ: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: 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; Roche: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees; Octapharma: Membership on an entity's Board of Directors or advisory committees. Male:SOBI: Speakers Bureau; Shire: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Speakers Bureau; Novo Nordisk: Speakers Bureau; Biotest: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Oldenburg:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: 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; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: 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; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: 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; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liesner:Baxalta: Consultancy, Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Sobi: Speakers Bureau; Bayer: Consultancy, Research Funding; Roche: Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau. Carcao:Shire: 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; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL-Behring: 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; Bioverativ/Sanofi: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:CSL Behring: Research Funding; Sobi: Research Funding; Bayer: Research Funding. Álvarez-Roman:Shire: Consultancy; NovoNordisk: Consultancy; SOBI: Consultancy. Koenigs:Gilead: Research Funding; CSL Behring: Consultancy, Research Funding; Pfizer: Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Intersero: Research Funding; Bioverativ: Consultancy; Roche/Chugai: Consultancy; EU (IMI, FP7): Research Funding; Sobi: Consultancy, Research Funding, Speakers Bureau; Shire: Consultancy, Research Funding; Novo Nordisk: Consultancy, Speakers Bureau; Biotest: Research Funding, Speakers Bureau; Jansen: Research Funding.

Efficacy and Safety of ReFacto AF for Surgical Hemostasis in Previously Treated Patients with Severe Hemophilia A.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3960-3960
Author(s):  
Jerzy Windyga ◽  
Luminita Rusen ◽  
Mona El-Hashimy ◽  
David A. Roth ◽  
Steven Arkin
Keyword(s):  
Blood Loss ◽  
Postoperative Period ◽  
Hemophilia A ◽  
Postoperative Blood Loss ◽  
Major Surgery ◽  
Efficacy And Safety ◽  
Epigastric Artery ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Total Knee

Abstract ReFacto AF (Albumin-Free Cell Culture Process) is a BDDrFVIII manufactured by a modified process designed to enhance viral safety relative to currently licensed ReFacto. Efficacy and safety of ReFacto AF for management of surgical hemostasis has been evaluated in an ongoing open label study of at least 25 efficacy evaluable previously treated patients, age ≥12 years, with severe hemophilia A [FVIII:C ≤ 2%] undergoing elective major surgery. ReFacto AF was to be administered for at least 6 postoperative days by bolus injection (BI) or by continuous infusion (CI) at the investigator’s discretion, and up to a maximum of 6 weeks following surgery. An interim analysis has been performed on the initial 22 patients. Fourteen (14) patients treated by BI received a total of 647 infusions (range 17 to 72 infusions per patient) for a cumulative total dose of 1,279,150 IU over 457 exposure days (ED), while 8 patients assigned to treatment by CI, including 1 patient who received only 1 dose for PK assessment, received a total dose of 348,618 IU over 140 total ED (range 1 to 64 ED per patient). Of the 21 patients who underwent major surgery, 18 were evaluable for efficacy and had the following procedures: 11 total knee replacements, 3 synovectomies, 1 left ulnar nerve transposition/release, 1 ventral hernia repair/scar revision, 1 knee arthroscopy, and 1 revision/debridement of the knee after total knee replacement. Investigator ratings of efficacy at the end of surgery and the initial postoperative period were all excellent or good [72% excellent (13/18) and 28% good (5/18) at the end of surgery; and 94% excellent (15/16) and 6% good (1/16) at the end of the initial postoperative period]. Blood loss was assessed for the intra- and post- operative periods. Sixteen (16) efficacy-evaluable patients had intraoperative blood loss; for all subjects, blood loss was rated normal. Ten (10) efficacy-evaluable patients had postoperative blood loss; in 9 cases the postoperative blood loss was rated normal, 1 case was rated abnormal due to hemorrhage following surgical trauma to the epigastric artery. Eleven (11) of 18 efficacy-evaluable patients were predicted to require transfusions during the intraoperative period; only 2 were transfused. No intraoperative transfusions were administered to the other 7 efficacy-evaluable patients. During the postoperative period 2 efficacy-evaluable patients received transfusions. One (1) of these had excessive hemorrhage following trauma to the epigastric artery during surgery, the other received 2 units of PRBCs in the postoperative period following normal blood loss. The most frequently reported treatment emergent adverse events (AEs) were fever, anemia and pain, not unexpected in the perioperative setting. Only one AE was related to ReFacto AF: a clinically silent low titer inhibitor was detected in one patient during a routine protocol-specified surveillance test before his surgery, after several injections of a plasma derived FVIII product that were preceded by only 1 dose of ReFacto AF. This patient had a left knee synovectomy, both of his hemostatic efficacy assessments were excellent, and he had less intraoperative blood loss than predicted. These interim data demonstrate that ReFacto AF is effective and safe when used for surgical prophylaxis in hemophilia A patients undergoing major surgery.

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

2019 ◽  
Vol 10 ◽  
pp. 204062071985847 ◽  
Author(s):  
Toshko Lissitchkov ◽  
Anna Klukowska ◽  
John Pasi ◽  
Craig M. Kessler ◽  
Robert Klamroth ◽  
...  
Keyword(s):  
Hemophilia A ◽  
High Titer ◽  
Clinical Trial Data ◽  
Severe Hemophilia ◽  
Efficacy And Safety ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Recombinant Fviii ◽  
Actual Incidence ◽  
Human Specific

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

scholarly journals Real-World Effectiveness and Safety of BAY 94-9027 (Damoctocog Alfa Pegol) in Previously Treated Patients with Hemophilia A (HEM-POWR): Online Patient Portal and LIFE-ACTIVE Sub-Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4943-4943
Author(s):  
Johannes Oldenburg ◽  
María Teresa Alvarez Román ◽  
Giancarlo Castaman ◽  
Maissaa Janbain ◽  
Tadashi Matsushita ◽  
...  
Keyword(s):  
Study Design ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Patient Portal ◽  
The Real ◽  
Patient Reported ◽  
Previously Treated Patients ◽  
Previously Treated

Background and Rationale: BAY 94-9027 (damoctocog alfa pegol) is a site-specifically PEGylated B-domain deleted recombinant factor VIII (FVIII) with an extended half-life, approved for prophylaxis or treatment of bleeds in previously treated patients (PTPs) aged ≥12 with hemophilia A. The efficacy and safety of BAY 94-9027 was demonstrated in two phase II/III clinical studies in PTPs with severe hemophilia A, however, real-world data are still being gathered. The aim of the HEM-POWR study is to assess the effectiveness and long-term safety of BAY 94-9027 in the real-world clinical setting. Patients will be introduced to an online patient portal that provides study information as well as access to eDiaries and electronic patient-reported outcomes (ePROs) to patients to facilitate retention over the duration of the study. Patients will also be given the opportunity to participate in LIFE-ACTIVE, a sub-study analyzing the relationship between the patients' regular daily activity and the efficacy parameters collected during HEM-POWR. Here we present the features of the patient portal and describe the LIFE-ACTIVE sub-study design. Study Design and Methods: HEM-POWR (NCT03932201) is a multinational, multicenter, non-interventional, open-label, prospective, phase IV, cohort study. It aims to enroll ≥200 PTPs with hemophilia A receiving BAY 94-9027 (on-demand, prophylaxis, or intermittent prophylaxis [as per local label]). Key exclusion criteria are presence or history of FVIII inhibitor (≥0.6 Bethesda units), diagnosis of any bleeding or coagulation disorder other than hemophilia A, or treatment with immune tolerance induction at enrollment. The primary objective of HEM-POWR is to assess the effectiveness of prophylaxis with BAY 94-9027 in the real-world setting through the collection of total bleeding events and analysis of annualized bleeding rate. Secondary objectives include long-term safety, joint health, location and number of target joints, hemostasis during surgery and PROs. Patient enrollment, adherence and retention can be difficult in observational hemophilia studies. The patient portal for this study aims to overcome these challenges by providing study- and product-related information. It also aims to lessen the burden for patients in the study by providing e-solutions to collect their study data, including the ability to complete the study diary, and PRO measures online. The portal also includes videos explaining the study and study procedures, and is country-customized with links to relevant websites. Patients participating in LIFE-ACTIVE will be asked to wear an ActiGraph CP Insight activity-tracking smart watch continually for four 30-day periods, at their initial visit and then at months 12, 24 and 36. Measurements recorded will include physical activity intensity and duration, general mobility, and sleep quality and duration. All data will be transferred to a secure, cloud-based system and patients will not be aware of the values measured by the device. Participating countries include, but may not be limited to Austria, Belgium/Luxemburg, Canada, Colombia, Finland, Germany, Greece, Italy, Japan, Netherlands, Portugal, Saudi Arabia, Denmark, Norway, Sweden, Slovenia, Spain, Switzerland, Taiwan, and USA. The study will run from 2019 until 2025, with an observation period of ≥60 months. Disclosures Oldenburg: Octapharma: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; Takeda (Shire): Consultancy, Research Funding, Speakers Bureau; Chugai: Consultancy, Speakers Bureau; Biotest: Consultancy, Research Funding, Speakers Bureau; Swedish Orphan Biovitrum: Consultancy, Speakers Bureau. Alvarez Román:CSL Behring: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Sobi: Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Speakers Bureau; Shire (Takeda): Research Funding, Speakers Bureau. Castaman:Shire: Speakers Bureau; Uniqure Kedrion: Speakers Bureau; Pfizer: Research Funding; CSL Behring: Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Novo Nordisk: Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Janbain:Shire (Vonvendi): Speakers Bureau; Genentech: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria; HTRS-MRA (Bioverativ Sanofi): Research Funding. Matsushita:uniQure: Consultancy, Honoraria; CSL: Consultancy, Honoraria; Bioverative: Research Funding; Pfizer: Consultancy, Honoraria; KM biologists: Consultancy, Honoraria, Research Funding; Novo Nordisk: Consultancy, Honoraria. Meijer:Sanquin: Research Funding; Pfizer, Sanquin, Uniqure: Research Funding; Uniqure, BMS, Aspen, Boehringer Ingelheim, Sanquin, Bayer: Consultancy, Honoraria; Bayer: Research Funding. Sanabria:Bayer: Employment. Reding:Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Genzyme: Consultancy, Honoraria, Speakers Bureau; Biomarin: Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau.

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