scholarly journals Safety and Efficacy of Turoctocog Alfa in Prevention and on-Demand Treatment of Bleeding Episodes in Patients with Hemophilia A

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3790-3790
Author(s):  
Dragana Janic ◽  
Irina Matytsina ◽  
Mudi Misgav ◽  
Johannes Oldenburg ◽  
Margareth C Ozelo ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Open Label ◽  
Main Trial ◽  
Safety And Efficacy ◽  
Safety Concerns ◽  
On Demand ◽  
Prevention And Treatment

Abstract Background Turoctocog alfa is a B-domain truncated recombinant factor VIII (rFVIII) product for the prevention and treatment of bleeds in patients with hemophilia A. The ongoing guardian™2 trial using turoctocog alfa consists of a main trial with planned visits, a surgery subtrial for patients who need to undergo surgery during the main trial, and an on-demand subtrial based on a regulatory requirement to collect data for at least 10 patients treated on-demand for 6 months. The guardian™2 trial is an open-label, prospective, international extension to pivotal trials in adults and adolescents (aged 12-65 years; guardian™1) and children (aged <12 years; guardian™3). Patients who completed the pharmacokinetic trials (NN7008-3600, NN7008-3893, or NN7008-4015), and new patients involved in the on-demand subtrial, also participated in guardian™2. We report an analysis of new long-term safety and efficacy data from the main guardian™2 trial and on-demand subtrial of turoctocog alfa. Methods Male patients with severe hemophilia A (FVIII ≤1%) without inhibitors (<0.6 Bethesda units [BU]) were enrolled from 19 countries. Turoctocog alfa was used prophylactically (20-50 IU/kg every second day or 20-60 IU/kg three times weekly) and on-demand (20-200 IU/kg/day) to treat bleeds. The primary safety endpoint was inhibitor development (≥0.6 BU/mL). All adverse events were reported. The main efficacy endpoints included hemostatic success when treating bleeds (excluding patients with missing evaluations), number of turoctocog alfa infusions required to stop bleeds, annualized bleeding rate (ABR), and consumption of turoctocog alfa. Safety and efficacy were assessed at the interim cut-off date, March 25, 2015. Results Prophylaxis and on-demand treatment were received by 199 and 19 patients, respectively (equivalent to 589 and 12.5 years of exposure to turoctocog alfa, respectively). Turoctocog alfa was used to treat 1508 bleeds in 162 patients receiving prophylaxis, and for 320 bleeds in 19 patients receiving on-demand treatment. No FVIII inhibitors, hypersensitivity, allergic reactions, or other safety concerns were reported in the main trial or on-demand subtrial for any patients. Treatment of bleeds was successful ('excellent' or 'good' response) in 90% of patients receiving prophylaxis and in 97% of those treated on-demand; the overall proportion of bleeds stopped with 1-2 injections was 90.7%, and 95.7% taking up to three injections. The median ABR (bleeds/patient/year) was 1.48 (mean Poisson estimated ABR: 2.56) for patients treated prophylactically, and 30.3 (mean Poisson estimated ABR: 25.56) for patients treated on-demand. Mean turoctocog alfa consumption (IU/kg/year/patient) was 5335 for patients on prophylaxis and 1707 for patients treated on-demand. Mean prophylactic dose was 32 IU/kg. Mean dose for treatment of bleed from start to stop was 61 IU/kg for patients on prophylaxis and 44 IU/kg for patients treated on-demand. Conclusion The latest data from the ongoing guardian™2 trial demonstrate the long-term safety and efficacy of turoctocog alfa for the prevention and treatment of bleeds in patients with severe hemophilia A. No FVIII inhibitors or other safety concerns have been reported. Compared with on-demand treatment, prophylaxis resulted in ~3-fold higher consumption of turoctocog alfa, and a 90% reduction in bleed rates. Disclosures Janic: Pfizer: Other: Paid Instructor, Research Funding; Bayer: Other: Paid Instructor, Research Funding; Baxter: Other: Paid Instructor, Research Funding; Novo Nordisk: Other: Paid Instructor, Research Funding; Octopharma: Research Funding. Matytsina:Novo Nordisk: Employment. Misgav:Novo Nordisk: Speakers Bureau. Ozelo:Bayer: Research Funding; Baxter: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Research Funding; Biogen: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau. Recht:Kedrion: Consultancy; Biogen Idec: Research Funding; Novo Nordisk: Consultancy, Research Funding; Baxalta: Research Funding. Korsholm:Novo Nordisk: Employment, Equity Ownership. Savic:Novo Nordisk: Other: Investigator. Santagostino:Novo Nordisk: Consultancy; Pfizer: Consultancy; Grifols: Consultancy; Sobi: Consultancy; Baxalta: Consultancy; Roche: Consultancy; CSL Behring: Consultancy; Kedrion: Consultancy; Octapharma: Consultancy; Biogen Idec: Consultancy; Bayer: Consultancy.

scholarly journals Decrease in Overall and Joint Bleeding Rates with Extended-Interval Dosing: > 4 Years of Bay 94-9027 Prophylaxis in the Protect VIII Extension

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1206-1206 ◽  
Author(s):  
Mark T. Reding ◽  
Shadan Lalezari ◽  
Ingrid Pabinger ◽  
Monica Maas Enriquez ◽  
Jonathan M. Ducore
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Extension Study ◽  
Study Patient ◽  
Severe Hemophilia ◽  
Main Study ◽  
Dose Frequency ◽  
Open Label ◽  
On Demand ◽  
Intent To Treat

Abstract Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of bleeds and joint bleeds with BAY 94-9027 prophylaxis during the PROTECT VIII trial and its extension of more than 4 years. Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 previous exposure days (ED). Prophylaxis patients received 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous joint or muscle bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on any regimen used in the main study. Prophylaxis patients who switched regimen after 7 days of the extension were analyzed together in a variable frequency group. Overall and joint annualized bleeding rates (ABRs) were calculated based on documentation in electronic patient diaries. Here, we present data for patients receiving prophylaxis. Results: The intent-to-treat population in the PROTECT VIII extension study included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 patients previously included in the main study (13 did not continue into the extension). At data cut-off (31 January 2018), patients had spent a median time of 3.9 years in the study since enrolment. Patients in the prophylaxis arms had spent a median (range) of 1163 (449; 1579) days in the extension study (approx. 3.2 years), with a median of 211 (96; 318) ED. Most (71) patients had completed 3 years of treatment, 53 had completed 4 years and 33 had completed 5 years of treatment with BAY 94-9027. During the extension, most patients in the 2×W, E5D, or E7D groups did not change regimen (96%, 78% and 65%, respectively). Eleven patients (E5D, 7; E7D, 4) switched to 2×W treatment. Median ABR was 1.6 in prophylaxis patients in the extension, while median joint ABR was 0.9. These values were lower than ABRs during the 6-month main study, of 2.1 and 1.9 for ABR and joint ABR, respectively. In the extension, ABR remained low across all prophylaxis regimens (Table). These values were lower than ABRs for the corresponding treatment groups in the main study (Table). Joint ABR also remained low across extension study patient groups receiving different BAY 94-9027 prophylaxis regimens, and again this was lower than joint ABR in the main study for each group (Table). Conclusions: In the PROTECT VIII extension study, the majority (79/107, 74%) of prophylaxis patients remained on the same dose-frequency of BAY 94-9027during total time in the extension study. Median ABR and joint ABR were lower over the 3-5 years of extension study than in the main study for prophylaxis patients; this was true for the combined prophylaxis cohort and for the 2×W, E5D and E7D BAY 94-9027 prophylaxis groups. Bleed rates were lowest for patients who stayed in the E7D group. Taken together, these results demonstrate that the 2×W, E5D and E7D dose-frequency options for BAY 94-9027 prophylaxis allow patients a decreasingly low rate of bleeds and joint bleeds once treated with a suitable individual regimen. Disclosures Reding: Genentech: Other: Advisory Board. Pabinger:Bayer, Baxalta/Shire, Novo, Pfizer, Biotest, CSL Behring: Honoraria; CSL Behring and Novo.: Research Funding. Maas Enriquez:Bayer: Employment. Ducore:HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; CSL Behring: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator; Shire: Consultancy, Other: travel support, investigator; Bayer Healthcare: Consultancy, Other: travel support, investigator.

scholarly journals Interim Analysis of the Extension Study with rVIII-SingleChain in Previously Untreated Patients (PUPs) with Severe Hemophilia A (CSL627-3001)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 162-162
Author(s):  
Elena Santagostino ◽  
Kathelijn Fischer ◽  
Christoph Koenigs ◽  
Claudia Djambas Khayat ◽  
Samantha Lucas ◽  
...  
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Safety And Efficacy ◽  
Inhibitor Development ◽  
On Demand ◽  
Peak Titer

Background: rVIII-SingleChain is a novel B-domain truncated recombinant Factor VIII comprised of covalently bonded FVIII heavy and light chains designed to have a high binding affinity to von Willebrand factor. Aims: This multicenter, open-label, phase III extension study investigates the safety and efficacy of rVIII-SingleChain for prophylaxis and on-demand treatment of bleeding episodes in 50 previously untreated patients (PUPs) for at least 50 Exposure Days (EDs). An ITI substudy was implemented to allow the use of rVIII-SingleChain to attempt inhibitor eradication for PUPs who develop an inhibitor to FVIII. Method: PUPs with severe hemophilia A (no prior exposure to any FVIII product, and endogenous Factor VIII &lt;1%) were assigned by the investigator to a prophylaxis or on-demand treatment regimen. Inhibitors were assessed monthly. Patients diagnosed with an inhibitor to FVIII (two consecutive central laboratory [CL] results of ≥0.6 BU/mL) could be enrolled into the ITI substudy or remain in the main study. The ITI substudy regimens are: 50 IU/kg 3x/week (low), 100 IU/kg daily (medium), or 200 IU/kg daily (high). Inhibitor eradication was defined as two consecutive CL results of &lt;0.6 BU/mL. One subject was withdrawn per protocol due to high titer inhibitor diagnosis prior to ITI substudy implementation. Results: As of March 28, 2019, 23 PUPs were treated with rVIII-SingleChain. Median age: 1 y (range 0-5). Mean (SD) time on study: 21.6 (12.6) months. Race distribution; Asian 2, Black 7, White 14. There have been 147 bleeding events treated with rVIII-SingleChain rated for hemostatic efficacy by the investigator. While patients were inhibitor negative, the overall treatment success (rating of excellent/good) was 93%, and the annualized spontaneous bleeding rate (AsBR) was 0.58. The adverse event profile was as expected, as the most frequently occurring adverse events were upper respiratory tract infections and inhibitors. Twelve subjects (52%) [95% CI 31%, 73%] were diagnosed with an inhibitor to FVIII; 6 (26%) high titer (peak titer ≥5 BU/mL), and 6 (26%) low titer (peak titer &lt;5 BU/mL). Seven of 11 inhibitor negative subjects achieved &gt;50 EDs, 1 achieved 47 EDs, and 3 achieved &lt;20 EDs. The median ED for inhibitor development (initial result) was 10, range 4-23. All PUPs enrolled had ≥1 risk factor for inhibitor development (Table 1) including genetic mutation, age of first exposure, initial treatment reason and assigned regimen, as well as bleeding events and infections; inhibitor positive and negative subjects were comparable. Of the 12 inhibitor positive subjects, 11 continued treatment with rVIII-SingleChain, 7 were treated with approximately 50 IU/kg 3x/week (low dose ITI), 3 with an increased prophylaxis regimen, 1 with no change in regimen, and 0 with high or medium dose ITI regimen (Table 2). Eight of 11 (73%) inhibitor positive subjects (2 high titer, 6 low titer) achieved eradication; 5 low titer subjects were eradicated within 6 months. The clinically relevant inhibitor subjects (2 high titer, and 1 persistent low titer) achieved eradication in a median of 15.7 months, 2 using low dose ITI, and 1 using increased prophylaxis. Eradicated patients were negative for a median of 13.6 months, and no inhibitor relapse was observed. Three remaining inhibitor positive patients are early in their rVIII-SingleChain inhibitor treatment (2.1, 3.5, and 5.4 months). Detailed analysis of the antibody signature was performed, and revealed epitope isotypes and subclass distribution comparable to other FVIII molecules. Conclusion: Overall, rVIII-SingleChain demonstrates a positive benefit:risk profile for safety and efficacy in PUPs. The crude high titer inhibitor rate is 26% which is consistent with other rFVIII products, whereas the crude low titer inhibitor rate is currently 26% which is on the higher end in comparison to other rFVIII products. Immunological analyses suggest a low affinity antibody population in subjects with low titer inhibitors. The majority of subjects (73%) who continued treatment with rVIII-SingleChain achieved eradication on a low dose ITI or prophylaxis regimen of approximately 50 IU/kg 3x/week or less. Additional time on study for the currently enrolled subjects is required to determine the final inhibitor and eradication rates in PUPs treated with rVIII-SingleChain. Disclosures Santagostino: Pfizer: Consultancy, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Shire / Takeda: Consultancy, Speakers Bureau. Koenigs:Roche: Consultancy; CSL Behring: Research Funding, Speakers Bureau; Bayer Vital GmbH: Research Funding, Speakers Bureau; Biotest AG: Research Funding, Speakers Bureau; Intersero: Research Funding; Grifols: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau. Djambas Khayat:Novo Nordisk: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Lucas:CSL Behring: Employment. Salazar:CSL Behring: Employment. Brainsky:CSL Behring: Employment. Chung:CSL Behring: Employment. Goldstein:CSL Behring: Employment. Mahlangu:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Spark: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomarin: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Unique: Research Funding; Catalyst Biosciences: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Research Funding, Speakers Bureau; Baxalta: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals ASPIRE Final Results Confirm Established Safety and Sustained Efficacy for Up to 4 Years of Treatment With rFVIIIFc in Previously Treated Subjects With Severe Hemophilia A

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1192-1192 ◽  
Author(s):  
Beatrice Nolan ◽  
Johnny Mahlangu ◽  
Guy Young ◽  
Barbara A Konkle ◽  
K. John Pasi ◽  
...  
Keyword(s):  
Treatment Group ◽  
Safety Profile ◽  
Treatment Duration ◽  
Research Funding ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Severe Hemophilia ◽  
Open Label ◽  
Previously Treated

Abstract Introduction: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care in hemophilia A, given its natural mechanism of action, strict homeostatic regulation, and consistent safety profile. Recombinant FVIII Fc fusion protein (rFVIIIFc) is an extended half-life therapy that demonstrated safety and efficacy in previously treated pediatric, adolescent, and adult subjects with severe hemophilia A in the Phase 3 A-LONG and Kids A-LONG trials (NCT01181128 and NCT01458106, respectively) (Young et al, J Thromb Haemostas, 2015; Mahlangu et al, Blood, 2014). Herein, the final results are reported from ASPIRE (NCT01454739), the long-term extension trial of those 2 studies. Methods: This was an open-label, multicenter, long-term trial of previously treated subjects of all ages with severe hemophilia A. Subjects received 1 of the 4 following regimens: individualized prophylaxis (IP; rFVIIIFc 25‒60 IU/kg every 3-5 days, or twice weekly), weekly prophylaxis (WP; rFVIIIFc 65 IU/kg every 7 days), modified prophylaxis (MP; personalized dosing), or episodic treatment (ET; on-demand dosing based on bleeding episodes). Subjects <12 years of age were eligible for only IP or MP. Investigators could switch a subject's treatment group at any time; therefore, each subject may appear in >1 treatment group. The primary endpoint was development of inhibitors. Secondary endpoints included annualized bleeding rates (ABRs), joint ABRs, spontaneous joint ABRs, exposure days (ED), and factor consumption. Descriptive statistics were used for analysis. Analyses were performed separately based on parent study. Results: A total of 211 subjects (150 were from A-LONG and 61 were from Kids A-LONG) enrolled in ASPIRE, and 186 subjects (132 from A-LONG and 54 from Kids A-LONG) completed the study. Subjects from Kids A-LONG had a median (range) age of 6.0 (2-12) years. Of the subjects from the A-LONG study enrolled to ASPIRE, the median (range) age was 31.0 (13-66) years. Most subjects received IP regardless of parent study (Kids A-LONG: IP [n=59], MP [n=3]; A-LONG: IP [n=110], WP [n=27], MP [n=21], ET [n=13]). No inhibitors were observed throughout the study, and the overall safety profile of rFVIIIFc was consistent with the parent studies and prior interim analyses. ABRs remained low throughout the entirety of ASPIRE in subjects prescribed IP (Table 1). For subjects from the Kids A-LONG study, the median (range) number of ED during ASPIRE was 332.0 (18.0-467.0) days. Total median (range) treatment duration was 166.6 (14.4-203.0) weeks. The median (range) number of ED for A-LONG subjects was 267.5 (8.0-660.0) days. Total median treatment duration was 201.4 (5.1-274.6) weeks. Overall, the median (range) duration of treatment with rFVIIIFc was 4.1 (0.4, 5.9) years. From the end of the parent study to the end of ASPIRE, the rFVIIIFc dosing interval increased for 6.6% and 21.1% of subjects from Kids A-LONG and A-LONG, respectively (Table 2). There was no change in median weekly factor consumption from the end of either parent study to the end of ASPIRE. For subjects from Kids A-LONG, the median (IQR) was 0.0 (0.0‒3.2), while the median (IQR) for those from A-LONG was 0.0 (0.0‒0.0). Conclusions: Throughout up to 4 years of treatment with rFVIIIFc in the ASPIRE extension study, no inhibitors were reported, and low ABRs and extended dosing intervals were sustained. These data are consistent with the well-characterized safety profile and durable efficacy of rFVIIIFc prophylaxis in previously treated subjects of all ages with hemophilia A. Disclosures Nolan: Bayer: Research Funding; CSL Behring: Research Funding; Sobi: Research Funding. Mahlangu:Sanofi: Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Alnylam: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding; Biogen: Research Funding, Speakers Bureau; Chugai: Consultancy; Catalyst Biosciences: Consultancy, Research Funding; Amgen: Consultancy; Biomarin: Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; LFB: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Sobi: Research Funding, Speakers Bureau; Spark: Consultancy, Research Funding. Young:Bayer: Consultancy; Bioverativ: Consultancy, Honoraria; Kedrion: Consultancy; Novo Nordisk: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Konkle:Sangamo: Research Funding; Gilead: Consultancy; Spark: Consultancy, Research Funding; BioMarin: Consultancy; CSL Behring: Consultancy; Genentech: Consultancy; Bioverativ: Research Funding; Pfizer: Research Funding; Shire: Research Funding. Pasi:Shire: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bayer: Speakers Bureau; Octapharma: Honoraria; Pfizer: Speakers Bureau; Biomarin: Honoraria, Research Funding; Sobi: Honoraria; Bioverativ: Honoraria, Research Funding; NovoNordisk: Speakers Bureau; Catalyst Bio: Honoraria; Apcintex: Honoraria. Oldenburg:Novo Nordisk: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Grifols: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Swedish Orphan Biovitrum: Honoraria, Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Anti-FIXa/X bispecific antibodies , Research Funding, Speakers Bureau. Tripkovic:Sobi: Employment. Rudin:Bioverativ: Employment, Equity Ownership.

scholarly journals Immunogenicity, Efficacy and Safety of Rurioctocog Alfa Pegol in Previously Untreated Patients with Severe Hemophilia a: Interim Results from an Open-Label Multicenter Clinical Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3184-3184
Author(s):  
Robert F. Sidonio ◽  
Christine Knoll ◽  
Flora Peyvandi ◽  
Oleksandra Stasyshyn ◽  
Ali Bulent Antmen ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Open Label ◽  
Inhibitor Development ◽  
On Demand ◽  
Fviii Inhibitor ◽  
Hemostatic Efficacy ◽  
Recombinant Fviii

Abstract Background Management of severe hemophilia A includes on-demand treatment or prophylaxis with replacement factor VIII (FVIII) concentrate. FVIII inhibitors can develop following exposure to exogenous FVIII in approximately 30% of previously untreated patients (PUPs), typically in the first 50 exposure days (EDs), with serious complications. This is the first study evaluating the safety, immunogenicity, and hemostatic efficacy of rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA), an extended half-life (EHL) recombinant FVIII, in PUPs with severe hemophilia A. Methods This prospective, open-label, multi-center, phase 3 study (NCT02615691) was conducted in patients ˂6 years of age with severe hemophilia A (FVIII &lt;1%). Patients were previously untreated, or had &lt;3 EDs to rurioctocog alfa pegol, octocog alfa, or plasma transfusion at any time prior to screening. Patients with detectable FVIII inhibitory antibodies at screening or a history of FVIII inhibitory antibodies prior to screening (≥0.6 Bethesda units) were not eligible. Patients received intravenous rurioctocog alfa pegol as prophylaxis (25-50 IU/kg, up to 80 IU/kg ≥1 × weekly) and/or on-demand therapy (10-50 IU/kg, up to 80 IU/kg depending on bleed severity). Prophylaxis was started before 3 years of age or after a maximum of 2 joint bleeds, whichever occurred first. The primary endpoint was the incidence of FVIII inhibitor development. Secondary endpoints included safety and efficacy (annualized bleeding rate [ABR] and hemostatic efficacy). This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing an inhibitor to FVIII or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. Demographic and baseline characteristics were summarized using continuous and categorical data. The incidence of FVIII inhibitor development was calculated using the Clopper Pearson exact 95% CI computed for the proportion of patients who developed FVIII inhibitors during the study. ABR was analyzed by point and interval estimates derived from a negative binomial model with treatment regimen as a covariate. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) was recorded for all patients receiving rurioctocog alfa pegol. Informed consent and ethics approval were obtained. Results As of the data cut-off, 59 (73.8%) of 80 enrolled patients had received ≥1 dose of rurioctocog alfa pegol; 18 patients (screen failures) did not meet the eligibility criteria and 4 discontinued prior to treatment. 54 patients received prophylaxis and 35 received on-demand treatment at any time during the study period. The mean (SD) patient age at baseline was 11.8 (8.2) months. The number of patients with 0 EDs prior to screening was 36 (61.0%), with 9 (15.3%) patients having 1 ED and 14 (23.7%) having 2 EDs. Overall, 32 patients had a family history of hemophilia A. A large deletion, intron 1 or intron 22 inversion, or substitution nonsense hemophilia gene mutation was present in 29 (49.2%) patients and 21 (35.6%) had either a small deletion, small duplication, or substitution missense gene mutation. Of the 52 patients who qualified for this interim analysis, 10 developed an inhibitory antibody to rurioctocog alfa pegol during the study; the incidence of inhibitor development was 0.192 (95% CI, 0.096-0.325) (10/52). Rurioctocog alfa pegol exposure data and ABRs for patients receiving prophylaxis or on-demand treatment are presented in Table 1. At bleed resolution, hemostatic efficacy was rated by patients as "excellent" for 88/269 bleeds (32.7%) and "good" for 73/269 bleeds (27.1%). Overall, 52 (88.1%) patients receiving rurioctocog alfa pegol experienced a total of 283 AEs, and 13 patients experienced 14 rurioctocog alfa pegol-related AEs (including 10 SAEs). SAEs occurred in 24 patients, 10 of whom experienced 10 treatment-related SAEs of FVIII inhibitor development. Discussion This is the first prospective study of the EHL recombinant FVIII rurioctocog alfa pegol for the treatment of PUPs with severe hemophilia A. These preliminary results demonstrate a relatively low inhibitor rate compared with other EHL recombinant FVIII products and a safety and efficacy profile consistent with that previously observed for rurioctocog alfa pegol in the treatment of bleeding episodes in patients with hemophilia A. Figure 1 Figure 1. Disclosures Sidonio: Guardian Therapeutics: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; Octapharma: Consultancy, Research Funding; Novo Nordisk: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst: Consultancy. Peyvandi: Takeda: Honoraria; Spark: Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Bioverativ: Honoraria; Grifols: Honoraria. Stasyshyn: Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Research Funding; Shire: Consultancy; Grifols: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Antmen: Takeda: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Novo Nordisk: Consultancy. Yeoh: Takeda: Honoraria; Pfizer: Honoraria; Roche: Honoraria; Grifols: Honoraria. Maggiore: IQVIA: Current Employment. Engl: Baxalta Innovations GmbH, a Takeda company: Current Employment; Takeda: Current equity holder in publicly-traded company. Allen: Takeda Development Center Americas, Inc.: Current Employment; Takeda: Current equity holder in publicly-traded company. Tangada: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc: Current Employment.

scholarly journals Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in Previously Treated Children with Severe Hemophilia a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1414-1414
Author(s):  
Guy Young ◽  
Raina Liesner ◽  
K John Pasi ◽  
Beatrice Nolan ◽  
Stefan Lethagen ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Safety And Efficacy ◽  
Dosing Interval ◽  
Treatment Groups ◽  
Previously Treated ◽  
Equity Ownership

Abstract Background: Factor VIII (FVIII) prophylaxis is the standard of care for patients with hemophilia A; however, conventional FVIII products usually require frequent intravenous infusions (3-4 times/week). The safety, efficacy, and prolonged half-life of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated children with severe hemophilia A were demonstrated in the phase 3 Kids A-LONG study (NCT01458106, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in children <12 years of age in these studies as of the second interim data cut (8 Dec 2014). Methods: Subjects who completed Kids A-LONG and met the enrollment criteria for ASPIRE could participate in the individualized prophylaxis (IP; 25-80 IU/kg every 2-5 days, or 20-65 IU/kg on Day 1 and 40-65 IU/kg on Day 4 if twice weekly), or the modified prophylaxis (MP; for subjects in whom optimal dosing could not be achieved with IP) treatment groups. Subjects could switch treatment groups in ASPIRE once 12 years of age. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2 to 4 weeks apart and performed at the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and changes to prophylactic consumption and dosing interval. Outcomes were analyzed over the cumulative duration of Kids A-LONG through the second ASPIRE interim data cut (8 Dec 2014). Results: 61/67 subjects who completed Kids A-LONG enrolled in ASPIRE (<6 y, n = 30; 6 to <12 y, n = 31). As of the second interim data cut, 47 subjects were ongoing in ASPIRE; no subjects changed treatment groups during ASPIRE. Median (IQR) cumulative rFVIIIFc exposure days (EDs) for all subjects who received ≥1 intravenous injection (N = 69) were 190.0 (153.0-208.0) days; the median (interquartile range [IQR]) duration of rFVIIIFc treatment was 1.7 (1.5-2.0) years. No inhibitors were reported. The estimated inhibitor incidence rate (95% confidence interval) was 0.0% (0.0, 5.2) overall and 0.0% (0.0, 6.1) in subjects with ≥100 rFVIIIFc EDs (n = 59). The type and incidence of AEs observed were consistent with those expected for a pediatric hemophilia population. 95.7% of subjects reported ≥1 AE on-study; 36/448 were serious and 2/448 were assessed as related to rFVIIIFc treatment by Investigators. 30.4% of subjects experienced ≥1 serious AE; none were assessed by Investigators as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP (n = 57) were generally lower with rFVIIIFc compared with prestudy FVIII (Figure).In the IP group, the ASPIRE Year 1 and Year 2 median (IQR) spontaneous ABRs were 1.0 (0.0-1.0) and 0.0 (0.0-2.3), respectively, for the <6 y cohort (n = 27), and 0.0 (0.0-1.0) and 0.0 (0.0-0.0), respectively for the 6 to <12 y cohort (n = 30).Overall, 79.8% and 95.8% of bleeding episodes were controlled with 1 or ≤2 intravenous injections, respectively. Among subjects treated with FVIII prophylaxis pre-Kids A-LONG who remained on a prophylaxis regimen (n = 54), the median (IQR) dosing interval was lengthened (prestudy FVIII: 2.3 [2.0, 2.3] days; on-study rFVIIIFc: 3.5 [3.5, 3.5] days) and the median (IQR) total weekly prophylactic consumption was similar (prestudy FVIII: 100.0 [78.0, 120.0] IU/kg; on-study rFVIIIFc: 95.0 [75.0, 113.0] IU/kg). Conclusions: Longitudinal data from previously treated children with severe hemophilia A treated with rFVIIIFc in Kids A-LONG/ASPIRE confirm long-term safety, with no inhibitors observed in any subjects, and maintained efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without increased factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Young: Biogen: Consultancy, Speakers Bureau; Kedrion: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Baxter: Consultancy. Liesner:Pfizer: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Pasi:Biogen: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding. Lethagen:Sobi: Employment. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Mahlangu:Bayer: Research Funding, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding; Amgen: Speakers Bureau; Biotest: Speakers Bureau; Baxalta: Consultancy.

Longitudinal Analysis of Long-Term Safety and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIFc) in Adults/Adolescents with Severe Hemophilia a

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1413-1413
Author(s):  
Barbara Konkle ◽  
K John Pasi ◽  
David J Perry ◽  
Johnny Mahlangu ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Dosing Intervals

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylaxis with conventional FVIII products usually requires frequent intravenous injections (3-4 times/week). The safety, efficacy, and prolonged half-life of rFVIIIFc in previously treated adults and adolescents (≥12 y) with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01181128, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in study participants as of the second interim data cut (8 Dec 2014). Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the second interim data cut 8 Dec 2014) for subjects treated with ≥1 dose of rFVIIIFc. A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on Day 1 and 50 IU/kg on Day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment (ET). Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or ET groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) group. Subjects could change treatment groups at any point during ASPIRE. Efficacy analyses were performed using data summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL identified and confirmed on 2 separate samples drawn approximately 2-4 weeks apart and performed by the central laboratory as measured by the Nijmegen-modified Bethesda assay), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic consumption and dosing interval compared to pre-A-LONG (prestudy). Results: Of 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE; at the time of this second interim data cut, 97 subjects were ongoing in ASPIRE, 40 subjects had completed the study, and 13 subjects withdrew. Cumulatively, subjects had 38,662 rFVIIIFc exposure days (EDs), inclusive of surgery. As of this second interim data cut (8 Dec 2014), no inhibitors were observed; the type and incidence of adverse events (AEs) observed were typical of previous hemophilia A populations studied. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were lower with rFVIIIFc compared with prestudy FVIII for subjects on prestudy prophylaxis or ET (Figure). In the IP group, the median (interquartile range [IQR]) spontaneous ABRs in Years 1, 2, and 3 on-study were 0.0 (0.0, 2.0), 0.0 (0.0, 1.0), and 0.0 (0.0, 1.0), respectively. In the WP treatment group, the median (IQR) spontaneous ABRs in Years 1, 2, and 3 on-study were 1.0 (0.5, 3.0), 0.5 (0.0, 2.1), and 0.0 (0.0, 1.0), respectively. Overall, 88.5% and 97.0% of bleeding episodes were controlled with 1 or ≤2 intervenous injections, respectively. Among subjects treated with FVIII prophylaxis prestudy (n = 79), 86% were dosed at least 3 times/week prestudy. Compared with prestudy dosing intervals, dosing intervals with rFVIIIFc were extended in 96.2% of subjects, were shortened in 2.5% of subjects, and were unchanged in 1.3% of subjects. The median (IQR) total weekly prophylactic consumption was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.8] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE confirm long-term safety, with no inhibitors observed in any subject. Low median ABRs were maintained, and rFVIIIFc demonstrated efficacy in the prevention and treatment of bleeding episodes. Prophylactic dosing intervals were extended, without an increase in median prophylactic factor consumption. This research was funded by Biogen and Sobi. Biogen and Sobi reviewed and provided feedback on the abstract. The authors had full editorial control of the abstract and provided their final approval of all content. Disclosures Pasi: Biogen: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Bayer: Research Funding, Speakers Bureau; CSL: Consultancy, Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Roche: Consultancy, Research Funding; Baxalta: Consultancy. Rangarajan:Baxter: Research Funding; Baxalta, now part of Shire: Other: Investigator Clinical Studies, Research Funding; Biogen: Consultancy; Biotest: Research Funding; Grifols: Consultancy, Research Funding; Pfizer: Research Funding; Novo Nordisk: Research Funding. Brown:Baxter: Consultancy; Biogen: Consultancy; Novo Nordisk: Consultancy. Hanabusa:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees; KaketsuKen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pabinger:Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Winding:Sobi: Employment. Glazebrook:Biogen: Employment, Equity Ownership. Lethagen:Sobi: Employment. Jackson:Biogen: Consultancy, Research Funding; Pfizer: Research Funding; Bayer: Research Funding; Baxalta/Shire: Research Funding; Novo Nordisk: Research Funding; Baxter: Consultancy, Research Funding.

scholarly journals Pegylated, full-length, recombinant factor VIII for prophylactic and on-demand treatment of severe hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (9) ◽  
pp. 1078-1085 ◽  
Author(s):  
Barbara A. Konkle ◽  
Oleksandra Stasyshyn ◽  
Pratima Chowdary ◽  
David H. Bevan ◽  
Tim Mant ◽  
...  
Keyword(s):  
Adverse Events ◽  
Half Life ◽  
Hemophilia A ◽  
Full Length ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Key Points ◽  
Prevention And Treatment ◽  
Inhibitory Antibodies

Key Points BAX 855, a pegylated full-length rFVIII with extended half-life, was highly effective in the prevention and treatment of bleeding events. No subjects receiving BAX 855 developed FVIII inhibitory antibodies nor experienced unexpected adverse events.

scholarly journals Real World Use of Extended Half-Life Products and the Impact on Bleeding Events and Joint Health in the United States

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1195-1195 ◽  
Author(s):  
Lynn M. Malec ◽  
Char M Witmer ◽  
Julie Jaffray ◽  
Peter A. Kouides ◽  
Kristina M. Haley ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
Advisory Board ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
On Demand ◽  
Joint Health

Abstract Background : The hemophilia treatment landscape has evolved substantially in the last several years with the approval of extended half-life (EHL) products which reduce the burden of prophylaxis. Data reported from the American Thrombosis and Hemostasis Network (ATHN) as of June 2017 indicate that 21% of patients with moderate or severe hemophilia A, and 42% of patients with moderate or severe hemophilia B, receive prophylaxis utilizing an EHL. As new treatments become available and are adopted into practice, it is important to recognize the need for evaluation of efficacy, safety, and economic impact of their use outside of the clinical trial setting. We aimed to characterize the real world impact of EHL products by collecting detailed information on bleeding rates, joint health and quality of life amongst patients cared for at ATHN-affiliated Hemophilia Treatment Centers. We hypothesized that use of EHL products were utilized in at least 30% of patients and would lead to decreased ABRs and improved joint health. To date 67 of a planned 135 subjects have been enrolled, constituting this interim analysis. Methods:Subjects were recruited from seven U.S. Hemophilia Treatment Centers. Subjects with severe hemophilia A or B ≤ 30 years of age on prophylaxis or demand therapy were eligible for enrollment. Subjects excluded from study were those with a recent joint bleed (within the last 2 weeks) or those unwilling to complete all elements of the study. Data were collected during a one-time encounter concurrent with an appointment for clinical evaluation, including demographic information, treatment regimen, product type, frequency, location and severity of all bleeds, Hemophilia Joint Health Scores (HJHS), and Quality of life (QoL). Bleeding rates in subjects receiving prophylaxis were compared with those receiving on demand therapy by type treatment, EHL vs standard half-life (SHL), and by hemophilia type. Severity of bleeding events (mild, moderate, or severe) and HJHS were compared by prophylaxis groups. Results: A total of 67 patients were enrolled and eligible for analysis. This included 58 subjects with severe hemophilia A, and 9 subjects with severe hemophilia B. The mean age of the cohort was 15 years (median 12 years, IQR 8 - 21 years). For these patients whose race information was known, 89.1% were Caucasian, 3.3% African-American, 3.3% Asian, and 4.7% were of mixed or 'other' race. Eleven out of 61 (18.0%) subjects with known ethnicity were Hispanic. Among 59 patients whose treatment type were available, the majority were on prophylaxis (n=53; 89.8%) as compared to on demand therapy (n=6; 10.2%). The average annualized bleeding rate (ABR) was 2.8 amongst all individuals. As expected, the ABR was substantially lower in those receiving prophylaxis (ABR=1.0) as compared to on demand therapy (ABR=18.6) (p<0.001). Additionally, HJHS in those receiving prophylaxis was lower (mean HJHS= 3.9), meaning less evidence of joint damage, than in those receiving demand therapy (mean HJHS= 8.8) (p=0.162). For patients with severe hemophilia A, the ABR was lower in those individuals receiving EHL (ABR= 0.5) versus SHL (ABR= 1.5), although this did not reach statistical significance (p=0.136). All subjects with severe hemophilia B enrolled to date receive EHL products (n=9) therefore no comparison of ABR could be made between EHL and SHL products; the ABR in this group was 0.9. In patients with severe hemophilia A, there was a higher HJHS for those receiving EHL (mean HJHS= 7.0) versus those receiving SHL (mean HJHS = 2.1) (p=0.053). For patients with severe hemophilia B, all of whom received EHL, the mean HJHS was lower than in the hemophilia A cohort (mean HJHS=1.2). Conclusions: We report real-world bleeding events and joint health in patients with severe hemophilia A and B utilizing EHL and SHL products across a wide U.S. geographic distribution. As anticipated, there is substantial bleed reduction with prophylaxis versus on demand therapy. In our severe hemophilia A cohort, the ABR for patients receiving EHL products was similar to ABRs reported in clinical trials, suggesting clinical trial data may be reflective of real world use. Patients with severe hemophilia A receiving EHL for prophylaxis had a lower ABR than those receiving SHL, although the early impact is not reflected in the HJHS score. Longer follow-up will be necessary to determine the impact of EHL on HJHS. Disclosures Malec: Bioverativ: Research Funding; Bayer: Consultancy; Bioverativ: Consultancy; Shire: Consultancy. Jaffray:Octapharma: Consultancy; Bayer: Consultancy; CSL Behring: Consultancy, Research Funding. Kouides:UniQure: Other: DSMB; Octapharma: Research Funding. Sidonio:Octapharma: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board; Kedrion: Research Funding; Biomarin: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board. Abshire:CSL: Consultancy; Shire: Consultancy; Novo Nordisk: Other: DSMB. White:Asklepios: Other: Scientific Advisory Board; Novo Nordisk: Consultancy; Shire: Other: Physician Leadership Group; Bayer: Other: GRAC; Bioverativ: Other: DSMB; Biomarin: Other: DSMB; Invitrox: Other: Scientific Advisory Board; Pfizer: Equity Ownership. Ragni:CSL Behring: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Bioverativ: Consultancy, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Extended Interval Prophylaxis with Bay 94-9027 for > 4 Years Leads to Median Spontaneous Annualized Bleeding Rates < 1 in the Protect VIII Extension

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1189-1189
Author(s):  
Mindy Simpson ◽  
Sanjay Ahuja ◽  
Despina Tseneklidou-Stoeter ◽  
Shadan Lalezari
Keyword(s):  
Hemophilia A ◽  
Extension Study ◽  
Variable Frequency ◽  
Severe Hemophilia ◽  
Main Study ◽  
Open Label ◽  
Treatment Groups ◽  
On Demand ◽  
Intent To Treat ◽  
Extension Period

Abstract Introduction: BAY 94-9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 × 30-kDa) polyethylene glycol (PEG) to extend its half-life. The efficacy and safety of BAY 94-9027 as prophylactic and on-demand therapy for patients with severe hemophilia A were demonstrated in the phase II/III PROTECT VIII trial. This analysis provides an updated assessment of the frequency of spontaneous bleeds with BAY 94-9027 prophylaxis during the PROTECT FVIII trial and its extension of more than 4 years. Methods: PROTECT VIII was a partially randomized, open-label trial of 134 males aged 12-65 years with severe hemophilia A (FVIII < 1%) and ≥ 150 FVIII exposure days (ED). Prophylaxis patients received BAY 94-9027 25 IU/kg twice weekly for a 10-week run-in period. Patients with ≤ 1 spontaneous or joint bleed during this period were randomized to 45-60 IU/kg every 5 days (E5D) or 60 IU/kg every 7 days (E7D) for the main 26-week study period; patients enrolling after the randomization arms were full, or with ≥ 2 bleeds in the run-in period, received 30-40 IU/kg twice weekly (2×W). Following completion of the main PROTECT VIII trial, patients could enter an extension, continuing BAY 94-9027 prophylaxis on either their regimen or switch regimens at the beginning or at any time during the extension. Prophylaxis patients who switched regimen at any time later than 7 days after the beginning of the extension period, were analyzed together in a variable frequency group. Annualized bleeding rates (ABRs) of spontaneous and trauma bleeds were calculated. Results: The intent-to-treat population in the PROTECT VIII study extension included 121 subjects (prophylaxis, n = 107; on demand, n = 14) of the 134 previously treated with BAY 94-9027 in the main study. At data cut-off (31 January 2018), patients in the prophylaxis arms had spent a median (range) of 3.9 (0.8; 5.4) years on-study (main and extension studies combined; a median of 3.2 years were in the extension), with 223 (23; 563) ED. Median dose of BAY 94-9027 prophylaxis during the extension study was 47.8 IU/kg/infusion, with total FVIII consumption of 3488 IU/kg/year. The overall adherence was 100%. At data cut-off or last visit, 34, 45 and 28 patients were in the 2xW, E5D and E7D treatment arms, respectively. During the extension period, median spontaneous ABR (Q1; Q3) was 0.7 (0.0; 2.9) in patients receiving BAY 94-9027 prophylaxis; 2×W (n = 23, 0.8 [0.0; 3.1]), E5D (n = 33, 0.7 [0.0; 2.9]), E7D (n = 23, 0.2 [0.0; 0.8]), or at a variable frequency (n = 28, 1.8 [0.7; 4.3]). This was consistent with median spontaneous ABRs (Q1; Q3) in the main study of 0.0 (0.0; 4.0), 0.0 (0.0; 4.0) and 1.9 (0.0; 6.3) for patients receiving BAY 94-9027 infusions 2×W (n = 24), E5D (n = 43), or E7D (n = 43), respectively; and with spontaneous ABRs for the last 12 months of the extension study of 1.5 (0.0; 2.0), 1.0 (0.0; 3.0) and 0.0 (0.0; 0.0) for these treatment groups (1.0 [1.0; 2.12] in the variable group). Rates of trauma bleeding were consistent across the study periods, with a median ABR of 0.0 in each prophylaxis group in the main study (0.0 [0.0; 2.0] for all prophylaxis patients), 0.3 (0.0; 1.3) for all prophylaxis patients in the extension and 0.0 (0.0; 1.0) for all prophylaxis patients in the last 12 months of the extension. Conclusions: Most patients were treated every 5 or 7 days with BAY 94-9027. Median spontaneous ABR remained < 1 with prophylaxis for > 4 years in all treatment groups (2×W, E5D and E7D). Disclosures Ahuja: Bayer: Honoraria; Bioverativ: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Tseneklidou-Stoeter:Bayer: Employment.

scholarly journals The results of the use of Octofactor in patients with moderate and severe hemophilia A (data from a prospective, multicenter, open-label, observational study)

2019 ◽  
Vol 6 (2) ◽  
pp. 30-47
Author(s):  
N. I. Zozulya ◽  
O. I. Yastrubinetskaya ◽  
S. S. Belyaeva ◽  
V. M. Potapkova ◽  
I. L. Davydkin ◽  
...  
Keyword(s):  
Single Dose ◽  
Medical Practice ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Clotting Factor ◽  
Severe Hemophilia ◽  
Efficacy And Safety ◽  
Open Label ◽  
Spontaneous Bleeding ◽  
On Demand

Relevance. In accordance with the guidelines on the clinical investigation of clotting factor VIII products of the European Medicines Agency and guidelines on pharmacovigilance of the Eurasian Economic Union, after registration of a new drug, it is recommended to study its efficacy and safety on a large population of patients in a standard medical practice to clarify and identify new data.Materials and methods. In a prospective, multicenter, open-label, uncontrolled observational study, the efficacy and safety of the domestic recombinant B-domain deleted blood clotting factor FVIII (FVIII) (moroctocog alfa, Octofactor®, JSC “GENERIUM”) in patients with moderate and severe hemophilia A in the context of standard medical practice (study protocol number CI-51/15). Patients received the drug in terms of standard medical practice for the purpose of prophylactic treatment or on demand treatment. For prophylactic treatment Octofactor was administered to patients according to the instructions for medical use in a single dose of 20–40 IU/kg every 2–3 days. In the case of bleeding a single dose of Octofactor was calculated taking into account the severity and localization of bleeding in accordance with the instructions for medical use. The results of the treatment were analyzed for a period of 52 ± 2 weeks. The main parameter for evaluating the efficacy was the frequency of spontaneous bleeding that occurred within 48–72 hours after the administration of the Octofactor. Additional parameters for evaluating the efficacy included: the severity of spontaneous bleeding arising during the prophylactic treatment; the number of injections and the total dose of the Octofactor to stop 1 episode of bleeding; the amount of Octofactor used during the entire observation period (52 ± 2 weeks) and for 1 month both for prophylaxis and for stopping the bleeding that occurred; an indicator of the efficacy of therapy on the scale for determining the response to treatment of acute hemarthrosis (World Federation of Hemophilia, WFH).Results.According to the results of the screening survey 237 male patients aged from 19 to 78 years old (mean age 35.2 ± 11.1 years) with moderate and severe hemophilia A (FAS-population) were included in the study. The efficacy of therapy was evaluated in 202 patients who underwent all the planned procedures during the observation period (PP-population). 193 (95.5 %) patients received prophylactic treatment, 9 (4.5 %) patients received on-demand treatment. Evaluation of the efficacy of treatment was carried out on the basis of basic and additional parameters. The main parameter for evaluating the efficacy – the frequency of spontaneous bleeding that occurred within 48–72 hours after the administration of the Octofactor – was 52 ± 2 weeks within 1.4 ± 2.9 cases. At the same time, the proportion of spontaneous bleeding that occurred within 48–72 hours after administration of the Octofactor preparation was 45.2 % of the total number of spontaneous bleeding and 15.6 % of the total number of all bleeding in patients who received prophylactic treatment. Among 608 spontaneous bleeding that occurred in patients receiving prophylactic treatment, 287 (47.2 %) of the bleeding were mild, 289 (47.5 %) were moderate and 32 (5.3 %) were heavy. Of the 275 spontaneous bleeding that occurred within 48–72 hours after administration of the study drug for prophylactic purposes, 117 (42.5 %) episodes were mild, 146 (53.1 %) were moderate, and 12 (4.4 %) were severe. With prophylactic administration the average single dose of the Octofactor was 2036.3 ± 884.7 IU, or 27.3 ± 11.2 IU/kg, in the treatment of bleeding occured during prophylactic treatment – 2227.7 ± 1087 IU, in the treatment of bleeding in patients receiving the drug only on demand – 2280.7 ± 1037.2 IU. The average monthly intake of the drug by one patient in prophylactic treatment was 19.75 ± 9.75 thousand IU, while the average monthly consumption of the drug for preventing bleeding from one patient was 17.16 ± 9.13 thousand IU for stopping bleeding against the background prevention – 3.87 ± 3.97 thousand IU. One patient who received on-demand treatment had an average monthly average of 13.47 ± 13.46 thousand IU of the Octofactor preparation. For stopping 1 bleeding, on average, 1.7 ± 1.7 injections of the Octofactor preparation were required, in the prophylactic treatment group – 1.8 ± 1.8, and in the on-demand treatment group – 1.5 ± 1.1. In the overwhelming majority of cases, patients of both groups showed excellent and good response to all treatment of acute hemarthrosis on the scale of the WFH on all visits, the reaction was moderate in a few episodes, and only in 1 case of acute hemarthrosis there was no response to the drug administration. The safety of therapy was evaluated in 228 patients who received at least 1 Octofactor administration during the study (mITT-population). There were 66 adverse events in 40 patients, 10 of them were associated with the use of the drug, the most significant of which were the formation of inhibiting antibodies to FVIII in low titer (1.5 U) in 1 patient and the development of allergic reactions in 2 patients.Conclusions.Under the conditions of standard medical practice the efficacy and safety of Octofactor was confirmed for both prophylactic treatment and on-demand bleeding treatment in adult patients with severe and moderate hemophilia A.

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