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 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 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.

scholarly journals Characteristics of Bleed-Free Patients on Every-5-Day Dosing in the Protect VIII (BAY 94-9027) Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2486-2486 ◽  
Author(s):  
Elena Santagostino ◽  
Bryce A. Kerlin ◽  
Claude Negrier ◽  
Liu Tian ◽  
Jonathan M. Ducore
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Main Study ◽  
Dose Frequency ◽  
Open Label ◽  
Advisory Committees ◽  
Post Hoc Analysis ◽  
Post Hoc

Abstract Background: BAY 94‐9027 is a B-domain-deleted recombinant factor VIII (FVIII) that is site-specifically PEGylated with a 60-kDa (2 x 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, in which patients could receive prophylaxis every 7 days (E7D), every 5 days (E5D), or twice-weekly (2×W). Patients in the E5D arm had a low median annualized bleeding rate (ABR) of 1.9. This post hoc analysis was conducted to identify clinical predictors for 'best responders' (patients with ABR = 0) during E5D prophylaxis with BAY 94-9027 in PROTECT VIII. 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. Prophylaxis patients received BAY 94-9027 25 IU/kg 2×W 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 E5D or 60 IU/kg 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 2×W. All patients randomized to the E5D arm (n = 43) remained on this dose-frequency throughout the main study. This post hoc analysis presents a description of baseline characteristics of best responders to E5D dosing, defined as patients with ABR = 0 during the main study period; the study was not powered to support a formal statistical comparison. Results: Of 43 patients randomized to E5D dosing, 24 (55.8%) had ABR ≥ 1 and 19 (44.2%) had ABR = 0, meeting the criterion for best responders. The median (95% CI) age was slightly higher for best responders, 38 years [30.0; 47.0] versus 31.5 [24.0; 41.0]), than patients with ABR ≥ 1. In the 12 months prior to the study, best responders had lower median (95% CI) bleeds (2.0 [0.0; 5.0] versus 10.0 [3.0; 21.0]) and joint bleeds (0.0 [0.0; 2.0] versus 8.0 [2.0; 12.0]) compared with patients with ABR ≥ 1. Most patients in both groups had previously received prophylaxis prior to study (84.2% and 70.8%, respectively). Fewer best responders had target joints (57.9%, versus 70.8% of patients with ABR ≥ 1); and those who did have target joints only 36.4% had ≥ 1 target joint, versus 47.1% of patients with ABR ≥ 1. Conclusions: Overall, the 43 patients receiving BAY 94-9027 E5D prophylaxis had a low median ABR of 1.9. The 19 of these patients who had an ABR of 0 (best responders) had numerically fewer bleeds in the 12 months prior to treatment initiation, particularly joint bleeds, and numerically fewer target joints, vs patients with ABR ≥ 1. Though requiring validation in a powered study, taken together, these results suggest the applicability of E5D BAY 94-9027 dosing across patient profiles, and that patients with a similar bleed and joint profile to those analyzed here may be able to achieve ABR of 0 with E5D BAY 94-9027. Disclosures Santagostino: Bayer, Shire, CSL Behring, Pfizer, Novo Nordisk, Grifols, Kedrion, Sobi, Bioverativ, Octapharma, Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Consultancy, 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; Roche: 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; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Tian:Bayer: Employment. Ducore:CSL Behring: Other: investigator; HemaBiologics: Consultancy, Other: investigator, travel support; OPKO: Other: investigator; Octapharma: Consultancy, Other: travel support, investigator , Research Funding; Bayer Healthcare: Consultancy, Other: travel support, investigator; Shire: Consultancy, Other: travel support, investigator; Pfizer: Other: investigator; Biomarin: Other: investigator; Spark Therapeutics: Consultancy, Other: investigator.

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 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 Impact of Systematic Pharmacokinetic (PK) Profiles in a Cohort of 29 Patients Treated with Conventional and Extended-Half Life (EHL) Products

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1123-1123
Author(s):  
Teresa Ceglie ◽  
Berardino Pollio ◽  
Irene Ricca ◽  
Maria Messina ◽  
Claudia Linari ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Factor Ix ◽  
Hemophilia B ◽  
Null Mutation ◽  
Severe Hemophilia ◽  
Factor Level ◽  
On Demand ◽  
Active Life ◽  
Genetic Assessment

Introduction. Prophylaxis with factor concentrates reduces bleeding events and improves quality of life for adults and children with severe hemophilia. However, the optimal dosing and infusion frequency is not yet established. Integration of PK data into decision making is gaining support, in particular at the transition between conventional and EHL products. Here we report about 29 PK data of patients affected by hemophilia treated at our centre since childhood. Improved quality of life was our first aim, supposed that decreasing frequency of infusions or increasing the target through factor level allows a more active life without increased risk of bleeding. Patients' characteristics and methods. 18 patients (62%) were ≤ 18 years of age at PK time. 16 were affected by severe hemophilia A, 5 by moderate hemophilia A, 6 by severe hemophilia B and 2 by moderate hemophilia B. At PK time, 28 patients were on prophylaxis and 1 was on demand with recombinant factor IX. Median age at onset of prophylaxis was 9 years (range 3 months-38 years). Genetic assessment was available in 24 patients. Of these, 37.5% and 62.5% were carriers of null and not null mutations respectively. 4 patients were undergone to PK with standard products (1 Octocog alfa, 1 Simoctocog alfa, 1 Octocog alfa-Kovaltry®, 1 Turoctocog alfa) in order to define timing and dosage of successive infusions, while 25 patients switched to EHL factors (15 Efmoroctocog alfa, 2 Ionoctocog alfa, 7 Albutrepenonacog alfa, 1 Eftrenonacog alfa). In 15 patients a population-based PK (popPK) according to WAPPS-Hemo program was also performed. The annualized bleeding rate (ABR) was counted from patient's home bleeding records for one year before PK until now. Results. According to PK data, 21 patients (75%) decreased infusion frequency (100% hemophilia B and 67% hemophilia A patients). The remaining 7 hemophilia A patients maintained the same timing in order to increase the through factor level. Notably, 1 hemophilia B patient switched from on demand treatment to prophylaxis with EHL product due to the more acceptable schedule. 66% of null mutation patients and 73% of not null mutation patients decreased timing. Of 28 patients available at follow-up, 32%, 50% and 18% decreased, increased and maintained the same annual average factor consumption/kg, respectively. All patients had a good adherence after switch. In particular, the on demand patient started a regular prophylaxis with optimal compliance. ABR displayed a reduction with a median of 0 (range 0-5) after PK analysis compared to 1 (range 0-12) before the switch. Full PK vs popPK data obtained using at least two individual PK sampling points were almost similar. Conclusions. Our results remark the necessity of PK study especially in children due to the inter-individual variability independent of genetic assessment. Regarding factor IX, PK allowed us to propose timing even longer than that recommended by prescribing indications resulting in a better personalized prophylaxis. Moreover, our study demonstrates that a full PK analysis is feasible also in children. However, given similar results, popPK could be more feasible in most patients. Regarding consumption, the reduction of only 32% of patients reflects our aim to maintain a high safety profile in an active pediatric population. Nevertheless, the mean annualized consumption was just 0.6-fold increased in the remaining patients. This approach led us to further reduce ABR and in some cases to obtain a persistent no-bleeding status even with a full active life. Disclosures No relevant conflicts of interest to declare.

Incidence and Outcome of Discontinuation of Prophylactic Treatment among Young Adults with Severe Hemophilia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3086-3086
Author(s):  
Karin van Dijk ◽  
Kathelijn Fischer ◽  
Johanna G. van der Bom ◽  
Elma Scheibel ◽  
Jørgen Ingerslev ◽  
...  
Keyword(s):  
Young Adults ◽  
Treatment Outcome ◽  
Chronic Disease ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Clinical Score ◽  
Annual Number ◽  
Severe Hemophilia ◽  
On Demand

Abstract Introduction Most of the current discussion about prophylaxis for severe hemophilia patients is on the dose and when to start. However, as hemophilia is a chronic disease, it is important to evaluate the duration of prophylaxis. The aim of this study was to study and compare adherence to prophylaxis and outcome of severe hemophilia patients. Methods All patients with severe hemophilia A and B (factor VIII/IX&lt;0.01 IU/ml), born between 1970 and 1980 and treated in Copenhagen, Århus (Denmark) or the Van Creveldkliniek, Utrecht (The Netherlands) were studied. Data on treatment were collected from the patients’ files from 1972 until 2003. In addition, a questionnaire on adherence to prophylaxis was used. For assessment of outcome the clinical score according to Gilbert and the radiological Pettersson score were used. Patients were categorized according to adherence to prophylactic treatment: patients who never discontinued prophylaxis (never), patients who temporarily discontinued prophylaxis (temporarily) and patients had switched to on demand regimen (permanently). Results 83 patients were studied. Median follow up was 19 years (range 6–29). Median age at start of prophylaxis was 5.9 years (interquartile range (IQR) 4.0–8.7). 34% of patients stopped taking prophylaxis temporarily and 35% stopped taking prophylaxis permanently at a median age of 21.5 years (IQR 18.4–24.4). Follow up since the last stop was 3.6 years (IQR 1.4–7.9), the annual number of joint bleeds on on demand treatment was 3.0 (IQR 1.4–8.7). The median clinical score was 3.0 points (IQR 1.0–6.0) in patients who never or temporarily stopped and 4.0 (IQR 0.0–6.3) in patients who permanently stopped taking prophylaxis. Pettersson scores were available for the Dutch patients and the median Pettersson score was 13 points (IQR 5–23) for patients who never or temporarily stopped and 13 (IQR 1–24) for patients who stopped permanently. The proportion of patients who discontinued prophylaxis and outcome parameters were similar for the Dutch and Danish patients. Conclusion Two thirds of young adults with severe hemophilia on prophylaxis discontinue prophylaxis at least once. One third permanently stop taking prophylaxis, while maintaining a low joint bleed frequency. Four years after switching to on demand treatment, outcome in these patients is similar to outcome in patients who continue taking prophylaxis.

Efficacy and Safety of Secondary Prophylactic Versus On-Demand Sucrose-Formulated Recombinant Factor VIII Treatment in Adults with Severe Hemophilia A: Results from a 13-Month Crossover Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 516-516 ◽  
Author(s):  
Peter Collins ◽  
Albert Faradji ◽  
Massimo Morfini ◽  
Monika Maas Enriquez ◽  
Eduard Gorina ◽  
...  
Keyword(s):  
Health Economics ◽  
Factor Viii ◽  
Crossover Study ◽  
Hemophilia A ◽  
Recombinant Factor Viii ◽  
Severe Hemophilia ◽  
Joint Function ◽  
On Demand ◽  
History Of ◽  
Male Patients

Abstract Many of the physical, psychosocial, and financial difficulties associated with severe hemophilia can be attributed to the effects of recurrent joint bleeds and chronic arthropathy. Regimens for clotting factor replacement treatment for hemophilia include prophylactic and on-demand therapy. A study in pediatric male patients with severe hemophilia A showed that prophylactic treatment with sucrose-formulated recombinant factor VIII (rFVIII-FS) resulted in prevention of joint damage and a decrease in the frequency of joint and other bleeds compared with on-demand therapy (Manco-Johnson MJ, et al. N Engl J Med.2007;357:535). A clinical trial was conducted in adult patients with severe hemophilia A and history of frequent bleeding to evaluate the effect of secondary rFVIII-FS prophylaxis on the number of joint bleeds after switching from on-demand rFVIII-FS therapy. Secondary study objectives were to compare these treatment strategies with regard to joint function, number of all bleeds, health-related quality of life, health economics, and safety. Male patients who were aged 30–45 years, had a negative inhibitor status, had a history of FVIII treatment (&gt;100 exposure days), and were using on-demand FVIII treatment before the study were eligible to participate in this prospective 13-month crossover study. During the first 6 months, all patients received on-demand rFVIII-FS treatment. Patients were then switched to prophylactic rFVIII-FS treatment (20–40 IU/kg 3 times per wk at a stable dose as determined by investigators based on the patient’s bleeding history) for the remaining 7 months, with the first month constituting a washout/stabilization run-in period. Patients were monitored throughout the 13 months for bleeds and health-economics parameters and were evaluated by the Gilbert score (joint function) and the Haemo-QoL questionnaire at baseline and at the end of the on-demand (at 6 mo) and prophylactic (at 13 mo) treatment periods. A total of 20 patients from 9 international sites participated in the study. Patients received a mean dose of 31 IU/kg/wk during the on-demand period, which increased to 86 IU/kg/wk during the prophylaxis period. Although 16/20 patients already had 1 to 4 target joints, mean (±SD) numbers of joint and total bleeds per patient significantly decreased during the prophylaxis period (1.5±2.1 and 1.9±3.3, respectively) compared with the on-demand period (18.5±11.6 and 23.7±13.3; P&lt;0.001 for both). Mean (±SD) total Gilbert scores indicated better joint function at the end of prophylaxis (19.8±11.7) vs on-demand (25.3±11.7; P&lt;0.001) treatment. During this short observation period, there was no statistically significant difference between treatments in the pharmacoeconomic variables assessed (days off work, general practitioner visits, and hospitalization days) or in the mean total Haemo-QoL score, although patients reported significantly fewer restrictions at work or school by the end of the prophylaxis period compared with the end of the on-demand period (P=0.016). There was a trend toward improved patient activity levels with prophylaxis. Similar numbers of patients reported adverse events (AEs) during on-demand (n=9, 45.0%) and prophylactic (n=10, 52.6%) treatment; AEs occurring in 2 patients (dysgeusia and headache) were considered treatment related. Serious AEs were reported by 1 patient during each treatment; neither serious AE was related to treatment. No de novo inhibitor development was observed during either treatment. In summary, prophylaxis with rFVIII-FS was well tolerated and reduced the frequency of joint and other bleeds compared with on-demand treatment in previously treated adults with severe hemophilia A and target joints.

Consumption Of FVIII Concentrate During On-Demand and Prophylactic Treatment With Human-cl rhFVIII In Prospective Clinical Studies In Adult Patients With Severe Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3595-3595 ◽  
Author(s):  
Andreas Tiede ◽  
Sigurd Knaub ◽  
Johannes Oldenburg ◽  
Johann Bichler
Keyword(s):  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Fold Increase ◽  
Human Cell Line ◽  
Adult Patients ◽  
Study Entry ◽  
Severe Hemophilia ◽  
Ample Evidence ◽  
Bleeding Rate ◽  
On Demand

Abstract Background There is ample evidence to support prophylactic treatment with factor VIII (FVIII) in children with severe hemophilia A (HA). Adults with severe HA are often treated on-demand and the potential benefit of regular prophylaxis is linked to a higher consumption of FVIII concentrates. During the clinical development of Human-cl rhFVIII, the first recombinant FVIII concentrate from a human cell line, its efficacy and safety was evaluated in previously treated adult patients (PTPs) during on-demand treatment only (GENA-01) and prophylaxis (GENA-08). Aims To compare post-hoc the annualized bleeding rate (ABR) and the consumption of FVIII concentrate in patients treated exclusively on-demand with those treated prophylactically. Methods Both prospective multi-centre studies were approved by the Ethics Committees of each participating institution and informed consent was obtained from the patient prior to any trial activity. In GENA-01, patients were to be treated on-demand for ≥6 months and ≥50 exposure days with protocol recommended doses ranging from 20 to 60 IU/kg, depending on the severity of the bleed. In GENA-08, patients were to be treated prophylactically with Human-cl rhFVIII every other day with 30-40 IU/kg for ≥6 months. Human-cl rhFVIII was also to be used in case of breakthrough bleeds. Results 22 PTPs with severe HA were enrolled in GENA-01, and 32 in GENA-08. The study populations were reasonably well comparable to each other (GENA-01 vs. GENA-08, mean±SD), regarding age (39.6±14.1 vs. 37.3±13.6 years), body mass index (23.9±4.8 vs. 25.8±4.9 kg/m2), hemophilia joint health score (38.4±30.3 vs. 34.6±32.2), race (>80% White in both studies) and historical bleeding sites. In GENA-08, the majority of patients (65.6%) had been treated prophylactically prior to study entry. Their historical mean±SD ABR was 6.6 ±11.3 (median: 2.0, range: 0-48.7) and their mean prophylactic dose/month was 293 IU/kg. The other 11 patients who had been treated on-demand had a mean±SD ABR of 47.4±34.6 (median: 36.5, range: 12.2-121.7). In GENA-01, all but 2 patients were treated on-demand prior to study entry. The historical mean±SD ABR of all GENA-01 patients was 49.5±35.9 (median: 44.6, range: 2.0-158.7). The ABR and FVIII consumption during the studies are shown in Table 1. Conclusion The data suggest that regular prophylactic treatment with Human-cl rhFVIII in adult PTPs with severe HA resulted in an approximately 25-fold reduction of bleeding rate, and a 3-fold increase of FVIII concentrate consumption. Disclosures: Tiede: Octapharma AG: Consultancy, Investigator Other. Knaub:Octapharma AG: Employment. Oldenburg:Octapharma AG: Consultancy, Investigator Other. Bichler:Octapharma AG: Employment.

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