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 <1%). Patients were previously untreated, or had <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 Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3185-3185
Author(s):  
Robert F. Sidonio ◽  
Alexis A. Thompson ◽  
Flora Peyvandi ◽  
Canan Albayrak ◽  
Seoh Leng Yeoh ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Tolerance Induction ◽  
High Dose ◽  
Severe Hemophilia ◽  
Publicly Traded ◽  
Open Label ◽  
Fviii Inhibitor ◽  
Recombinant Fviii

Abstract Background The development of inhibitors to exogenous factor VIII (FVIII) is a serious treatment complication in patients with hemophilia A. Immune tolerance induction (ITI) is the only proven method for the eradication of FVIII inhibitors. This prospective, multicenter, open-label, phase 3 study (NCT02615691) is being conducted to determine the safety, immunogenicity, and efficacy of the extended half-life (EHL) recombinant FVIII rurioctocog alfa pegol (Adynovate ®; Baxalta US Inc., a Takeda company, Lexington, MA, USA) in previously untreated patients (PUPs) with severe hemophilia A. The data presented here aims to evaluate the efficacy and safety of ITI therapy with rurioctocog alfa pegol in patients who developed FVIII inhibitors. Methods Eligible patients were ˂6 years of age with severe hemophilia A (FVIII <1%) and <3 exposure days (ED) 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 inhibitors prior to screening (≥0.6 Bethesda units [BU]) were excluded from the study. 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). Patients who developed a high-titer FVIII inhibitor (>5.0 BU) or low-titer FVIII inhibitor (≥0.6 BU to ≤ 5.0 BU) plus poorly controlled bleeding despite increased FVIII doses and/or bypassing agents, were eligible for ITI therapy. Dosing for ITI therapy ranged between 50 IU/kg 3 × weekly (low dose) and 100-200 IU/kg daily (high dose) at investigator discretion. This protocol-specified interim analysis was conducted after 50 patients had completed ≥50 EDs without developing confirmed inhibitors to rurioctocog alfa pegol or had developed a confirmed FVIII inhibitor at any time. The data cut-off was 30 August 2019. The primary endpoint of this study was the success rate of ITI with rurioctocog alfa pegol. Success was defined as an inhibitor titer persistently <0.6 BU, FVIII incremental recovery (IR) ≥66% of baseline following 84- to 96-hour wash-out, and FVIII half-life ≥6 hours (dependent on protocol version). Secondary endpoints included the rates of partial success and failure of ITI, and annualized bleeding rate (ABR) during ITI. The number and percentage of patients reporting adverse events (AEs) and serious AEs (SAEs) were recorded for patients treated with ITI. 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 did not meet the eligibility criteria (screen failures) and 4 discontinued prior to treatment. 10 patients developed an inhibitor to rurioctocog alfa pegol (high titer: n=5; low titer: n=5), of these, 6 patients were enrolled to receive ITI and only 5 of these (83.3%) actually received ≥1 dose of rurioctocog alfa pegol for the treatment of FVIII inhibitors (low dose: n=3; high dose: n=2). Of these 5 patients, 1 completed high-dose ITI therapy and this was successful (based on negative inhibitor titer and IR ≥66% of baseline). The remaining 4 patients were continuing in the study at the time of the data cut-off. Of the 5 patients who received ≥1 dose of ITI, 4 (80.0%) had a total of 17 AEs, 3 (60.0%) experienced 8 SAEs, and 1 experienced a treatment-related SAE of FVIII inhibition. It is important to note that the onset date of FVIII inhibitor development in this patient occurred prior to initiation of ITI. One patient experienced 2 catheter-related AEs, both of which resolved, and no patients experienced thrombotic AEs, study procedure-related AEs, or AEs leading to discontinuation of treatment. 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 that rurioctocog alfa pegol has a safety profile consistent with previous studies. In addition, these interim data suggest that using a high-dose regimen for ITI therapy is potentially efficacious in PUPs who have developed FVIII inhibitors, although only 1 patient had completed ITI at the time of this interim analysis. Disclosures Sidonio: Pfizer: Consultancy; Octapharma: Consultancy, Research Funding; Catalyst: Consultancy; Novo Nordisk: Consultancy; Bayer: Consultancy; Guardian Therapeutics: Consultancy; Genentech: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Biomarin: Consultancy. Thompson: Global Blood Therapeutics: Current equity holder in publicly-traded company; CRISPR Therapeutics: Research Funding; Vertex: Research Funding; Editas: Research Funding; Graphite Bio: Research Funding; Novartis: Research Funding; Agios: Consultancy; Beam: Consultancy; Celgene/BMS: Consultancy, Research Funding; Biomarin: Research Funding; Baxalta: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Peyvandi: Bioverativ: Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Spark: Honoraria; Takeda: Honoraria; Roche: Honoraria; Grifols: Honoraria. Yeoh: Grifols: Honoraria; Roche: Honoraria; Pfizer: Honoraria; Takeda: Honoraria. Lam: Takeda: Consultancy, Honoraria; Roche: Honoraria; Bayer: Honoraria; Pfizer: Consultancy, Honoraria. Maggiore: IQVIA: Current Employment. Engl: Takeda: Current equity holder in publicly-traded company; Baxalta Innovations GmbH, a Takeda company: Current Employment. Allen: Takeda: Current equity holder in publicly-traded company; Takeda Development Center Americas, Inc.: Current Employment. Tangada: Takeda Development Center Americas, Inc: Current Employment; Takeda: Current equity holder in publicly-traded company.

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.

Inhibitor Development in Previously Untreated Patients with Severe Hemophilia a Treated with Nuwiq®, a New Generation Recombinant FVIII of Human Origin

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 327-327 ◽  
Author(s):  
Raina Liesner ◽  
Marina Abashidze ◽  
Olga Aleinikova ◽  
Carmen Altisent ◽  
Mark J. Belletrutti ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Recombinant Fviii ◽  
New Generation

Abstract Background Studies have shown that the incidence of inhibitor development varies between FVIII concentrates, with some suggesting that recombinant FVIII (rFVIII) concentrates produced in hamster cell lines pose a greater risk of inhibitor development than plasma-derived (pd) von Willebrand factor (VWF)-containing FVIII (pdFVIII/VWF) products. In the SIPPET study, the cumulative incidence of high-titer inhibitorswith hamster-cell derived rFVIII products was 28.4% vs 18.6% for pdFVIII/VWF (Peyvandi F et al. N Engl J Med 2016; 374:2054-2064). These studies did not include new generation rFVIII products produced in human cell lines. Nuwiq® (Human-cl rFVIII) is the first and only new-generation rFVIII produced in human cells without chemical modification or protein fusion. The pharmacokinetics, efficacy and safety of Nuwiq® have been examined in previously treated patients (PTPs) with severe hemophilia A, and no inhibitors have been reported in 201 PTPs. The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe hemophilia A is currently being assessed in the ongoing NuProtect study. Methods The NuProtect study was initiated in 2013 and is being conducted in 17 countries and 38 centers worldwide. One hundred evaluable (110 enrolled) male PUPs of all ages and ethnicities are being studied for 100 exposure days (EDs) or a maximum study participation of 5 years. The patients were to have received no treatment with FVIII concentrates or other blood products containing FVIII prior to study entry. The primary objective of the NuProtect study is to assess the immunogenicity of Nuwiq® by determining inhibitor activity (≥0.6 BU) using the Nijmegen modified Bethesda assay in a central laboratory. Intensive screening for inhibitors is scheduled every 3-4 EDs until 20 EDs, then every 10-12 EDs until 100 EDs, and every 3 months until study completion. Secondary endpoints include assessment of hemostatic efficacy in prophylaxis, in the treatment of bleeds and in surgical prophylaxis, as well as safety and tolerability. All patients undergo F8 gene mutation analysis. Results Data from 85 treated PUPs have been included in the first pre-planned interim analysis (May 2016) of which 66 PUPs had ≥20 EDs (by which time the majority of inhibitors are likely to have arisen). The median age at first treatment was 13 months (range: 3-135). Of the 59 patients with available F8 gene mutation analysis, 1 (1.7%) had no identifiable mutation, 44 (74.6%) had mutations conferring a high risk of inhibitor development and 47 (81.0%) had null mutations. Data analysis in May 2016 showed that only 8 of the 66 PUPs treated with Nuwiq® for ≥20 EDs had developed a high-titer inhibitor after a median of 11.5 EDs (range 6-24). Five of the 66 PUPs developed a low-titer inhibitor, 4 (80%) of which were transient. Only 2 patients developed an inhibitor (1 high-titer) after 20 EDs. The cumulative incidence of high-titer inhibitors in PUPs treated with Nuwiq® is 12.8% (95% CI: 4.49-21.15) (Figure 1). The cumulative incidence of low-titer inhibitors was 8.4% (95% CI: 1.28-15.59) and of all inhibitors was 20.8% (95% CI: 10.68-30.95). No patient developed an inhibitor after 25 EDs. The incidence has remained consistent since the start of the study in 2013. Twelve of 13 patients who developed inhibitors had the causative F8 gene mutation detected, all of which were null, and all but one were high-risk. Conclusions PUPs treated with Nuwiq® for ≥20 EDs had 12.8% cumulative incidence of high-titer inhibitorsat the time of interim analysis (8 of 66 PUPs) despite the fact that 81% of patients had gene mutations known to be associated with increased inhibitor risk (e.g. null mutations). These interim data support the low rate of inhibitor development in PUPs treated with Nuwiq® - a human-cell derived (not chemically modified or protein fused) recombinant FVIII. Final data from the NuProtect study are expected in 2018 and will provide further insights into the development of inhibitors in PUPs with severe hemophilia A. Figure 1. Cumulative incidence of inhibitor development Figure 1. Cumulative incidence of inhibitor development Disclosures Liesner: CSL Behring: Consultancy, Honoraria, Research Funding; Biogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Altisent:Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Grifols: Consultancy; Pfizer: Consultancy, Research Funding; CSL Behring: Consultancy, Research Funding; Octapharma: Consultancy. Belletrutti:Shire Pharmaceuticals (formerly Baxalta): Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; NovoNordisk: Other: Travel support. Borel-Derlon:LFB: Other: Reference expert and national coordinator for VWD; Shire - Baxalta: Research Funding; Octapharma: Research Funding; NovoNordisk: Other: Expert for scientific committee. Ducore:CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Sigaud:Shire - Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Risk Differential in Inhibitor Development in the First Days of Treatment By Product Class: A Sippet Analysis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 330-330
Author(s):  
Flora Peyvandi ◽  
Antonino Cannavò ◽  
Isabella Garagiola ◽  
Roberta Palla ◽  
Frits Rosendaal ◽  
...  
Keyword(s):  
Research Funding ◽  
Hemophilia A ◽  
Cox Regression ◽  
High Titer ◽  
Hazard Ratio ◽  
Time Interval ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Fviii Inhibitor ◽  
Over Time

Abstract BACKGROUND: Administration of factor VIII (FVIII) concentrates to patients with severe hemophilia A has nearly normalized their life expectancy; however, a substantial number of previously untreated patients (PUPs) develop neutralizing alloantibodies (inhibitors) against FVIII that complicate the benefits of treatment and make the management of these patients difficult and costly. Recently a randomized clinical trial (SIPPET) showed that the risk of inhibitor development is nearly doubled in previously untreated and minimally treated patients with severe hemophilia A treated with recombinant products (rFVIII) compared with plasma-derived (pdFVIII) products containing von Willebrand factor (VWF). AIM: The aim of this post-hoc analysis of the SIPPET study was to assess the early risk of inhibitor development every 5 exposure days (EDs) and to see whether or not there was a difference between the two arms of plasma-derived FVIII and recombinant FVIII products over the course of time of FVIII exposure. METHODS: 251 children were enrolled in the SIPPET study and randomized to receive a single pd or rFVIII (4 different brands of each). The outcomes were any FVIII inhibitor levels ≥ 0.4 Bethesda Units (BU) and high-titer inhibitors (peak levels > 5 BU). Patients were tested for inhibitors before entry and at regular intervals during 50 EDs, 3 years or the development of an inhibitor. Patients who had not reached 50 EDs by the time of study termination were censored. To study the risk over time, survival analysis by Kaplan-Meier and Cox regression were repeated for every 5 EDs to assess the association of source of FVIII with inhibitor development over time. RESULTS: 76 out of 251 patients developed an inhibitor and of those 50 were high-titer; all occurred before 40 EDs. Over the complete observation period, users of rFVIII products had a 87% higher rate of inhibitor development than users of pdFVIII (hazard ratio (HR) 1.87; 95% confidence interval (CI95) 1.17-2.96). The hazard ratio was particularly high during the first 5 EDs, both for all (HR 3.14, CI95% 1.01-9.74) and high-titer inhibitor development (HR 4.19, CI95% 1.18-14.8). After the first 5 EDs, the difference between two arms was less pronounced and quickly dropped to the overall difference of 1.87. Table 1 shows the cumulative incidence per time interval for each of the product classes. CONCLUSION : The risk of inhibitor development during replacement therapy occurs more early (0-5 EDs) in patients treated with rFVIII than in those treated with pdFVIII, and remains high until 15 EDs. For pdFVIII, the highest risk came later (6-10 EDs) and this peak lasted shorter. The results of this analysis shows the relevance of the early exposure days for inhibitor development. Table 1. Table 1. Disclosures Peyvandi: Alexion: Other: research funding paid to Luigi Villa Foundation, Research Funding; Novo Nordisk: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Bayer: Speakers Bureau; Kedrion Biopharma: Consultancy, Other: research funding paid to Luigi Villa Foundation, Research Funding; LFB: Consultancy; CSL Behring: Speakers Bureau; Biotest: Other: research funding paid to Luigi Villa Foundation, Research Funding, Speakers Bureau; Octapharma: Consultancy; Ablynx: Membership on an entity's Board of Directors or advisory committees, Other: research funding paid to Luigi Villa Foundation, Research Funding; SOBI: Speakers Bureau; Grifols: Speakers Bureau. Palla:Pfizer: Other: travel support . Mannucci:Bayer: Speakers Bureau; Grifols: Speakers Bureau; Kedrion: Speakers Bureau; NovoNordisk: Speakers Bureau.

scholarly journals Efficacy and Safety Results from a Phase 3b, Open-Label, Multicenter, Continuation Study of Rurioctocog Alfa Pegol for Prophylaxis in Previously Treated Patients with Severe Hemophilia A

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2483-2483 ◽  
Author(s):  
Eric S. Mullins ◽  
Barbara A Konkle ◽  
Catherine E. McGuinn ◽  
Werner Engl ◽  
Srilatha D. Tangada
Keyword(s):  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Open Label ◽  
Advisory Committees ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Equity Ownership ◽  
Recombinant Fviii

Abstract Background: Patients with severe hemophilia A experience substantial morbidity and mortality due to frequent spontaneous and traumatic bleeding episodes, especially in joints. Prophylaxis with standard half-life factor VIII (FVIII) is the standard of care to prevent bleeds. Extended half-life products benefit patients by reducing the number of infusions without impacting the treatment efficacy. Methods: This phase 3b, prospective, open-label, multicenter, continuation study (NCT# 01945593) investigated the safety and efficacy of a PEGylated recombinant FVIII with an extended half-life, rurioctocog alfa pegol (SHP660, BAX 855, ADYNOVATE®, Shire, Lexington, MA, USA), for prophylaxis and treatment of bleeding in patients with severe hemophilia A (FVIII <1%). Eligible children and adults were ≤75 years of age and had either completed a previous rurioctocog alfa pegol study (NCT# 01599819, 01736475, 02210091, 02615691, 01913405, or 02585960) and were willing to immediately transition to the continuation study, or were naïve to rurioctocog alfa pegol but had received treatment with plasma-derived or recombinant FVIII for ≥150 (in patients ≥6 years of age) or ≥50 (in patients <6 years of age) exposure days. Patients received prophylactic rurioctocog alfa pegol at least twice weekly, either at a fixed dose (FD; 45 ± 5 IU/kg in patients ≥12 years of age; 50 ± 10 IU/kg in those <12 years of age; dose adjustment ≤80 ± 5 IU/kg allowed) or with pharmacokinetically (PK)-tailored dosing (≤80 ± 5 IU/kg) to maintain FVIII trough levels ≥3%. The co-primary endpoints assessed were the incidence of FVIII inhibitory antibody development (as measured by ≥0.6 BU in the Nijmegen modification of the Bethesda assay) and the spontaneous annualized bleed rate (ABR). Secondary endpoints included overall hemostatic efficacy ratings and occurrence of adverse events (AEs). Results: The study began in October 2013 and completed in March 2018. Overall, 216 patients receiving prophylaxis were eligible and included in the safety/full analysis dataset (≥1 dose received). Of these, 215 were male, the mean (SD) age at enrollment was 22.8 (15.7) years, the mean (SD) number of documented previous rurioctocog alfa pegol exposure days was 57.0 (39.6), the total ABR over 3-6 months prior to enrollment in the continuation study (including patients naïve to rurioctocog alfa pegol or receiving on-demand or prophylactic treatment with rurioctocog alfa pegol) was mean (SD) 4.7 (12.6), median (range) 0.0 (0-69). Most patients (206; 95.4%) had participated in a previous rurioctocog alfa pegol study. Overall, 215 patients received ≥1 dose in the FD regimen and 25 received ≥1 dose in the PK regimen. These patients received a mean (SD) of 1.72 (0.29) and 2.11 (0.61) prophylactic infusions per week, respectively, with a mean (SD) dose per infusion of 51.15 (8.11) IU/kg and 52.14 (17.03) IU/kg, respectively. None of the patients developed a confirmed FVIII inhibitor in this study and only 1 treatment-related allergic or hypersensitivity reaction (a nonserious mild AE) was reported. Nonserious AEs assessed by the investigators to be related to treatment occurred in 11/216 (5.1%) patients. Serious AEs (SAEs) occurred in 33 (15.3%) patients; there were no SAEs assessed by the investigators to be related to treatment. Descriptive statistics on spontaneous, joint, and total ABR by prophylactic regimen are shown in the Table. The overall total ABR in all patients was mean (SD) 2.5 (3.1), median (range) 1.6 (0.0-19.5). Overall hemostatic efficacy was rated as good or excellent in 88.5% of all bleeds and 89.4% of all bleeds were treated with 1 or 2 infusions. Conclusions: These results show that in previously treated patients with severe hemophilia A, rurioctocog alfa pegol prophylaxis in FD- and PK-tailored regimens was well tolerated and effective. None of the patients developed FVIII inhibitory antibodies, and a decrease in mean total ABR was reported in these patients compared with baseline. Disclosures Mullins: Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konkle:Genentech: Consultancy; CSL Behring: Consultancy; Gilead: Consultancy; Pfizer: Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy; Bioverativ: Research Funding; Shire: Research Funding; Sangamo: Research Funding. McGuinn:CSL Behring: Consultancy; BioMarin: Consultancy; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spark: Consultancy, Research Funding; Genentech: Consultancy; Shire: Research Funding; Pfizer: Research Funding. Engl:Shire: Employment, Equity Ownership. Tangada:Shire: Employment, Equity Ownership.

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.

A Case-Control Study of Candidate Immunoregulatory Genes Reveals Haplotypes That Influence Inhibitor Risk in Severe Hemophilia A.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 218-218
Author(s):  
Jay N. Lozier ◽  
Idan Menashe ◽  
James J. Goedert ◽  
Philip S. Rosenberg
Keyword(s):  
Case Control Study ◽  
Hemophilia A ◽  
Family Studies ◽  
Case Control ◽  
Marginal Effect ◽  
Severe Hemophilia ◽  
Inhibitor Development ◽  
Fviii Inhibitor ◽  
Fv Leiden ◽  
Control Study

Abstract Abstract 218 Introduction: Inhibitor antibodies to FVIII develop in ∼20% of patients with severe hemophilia A, and are the most important adverse events associated with FVIII replacement therapy. Mutations in the FVIII gene are the major determinant of inhibitor risk, but variations in immune response genes, such as IL10 or TNFα, (Astermark, et al, 2006a, 2006b) may also confer risk of inhibitor development and variations in the CTLA4 gene may protect against inhibitors (Astermark et al, 2006c). Specific Objective: Using a case-control study design we sought to confirm and extend previous observations of inhibitor risk modifying genes seen in family studies. Candidate genes were selected based on previous clinical or animal studies and included cytokines involved in the TH1/TH2 immune responses, and genes thought to decrease demand for FVIII therapy (e.g., FV Leiden and prothrombin 20210 polymorphisms). Materials and Methods: We used the CEU population data in the HapMap database to select haplotype tagging SNPs in IL1α/β, IL2, IL4, IL6, IL10, IL12A/B, IL13, IL17A, IL22, TNFα, CTLA4, interferon-γ, TGFβ, zinc α-2 glycoprotein I, IL1RN, and the FVIII gene, as well as the FV Leiden and prothrombin 20210 gene polymorphisms. A total of 366 tagging SNPs were selected with a goal of covering the entire coding and regulatory regions of the genes (spanning from 20kb 5' to 10kb 3' of the gene's coding sequence), resulting in 100% coverage of potential haplotypes (r2 = 1.0). DNA was purified from 915 Caucasian, severe hemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls) who participated in the Multicenter Hemophilia Cohort Studies I & II. Subjects were classified as having an inhibitor to FVIII on the basis of at least one inhibitor titer ≥1.0 Bethesda unit. SNP genotypes were determined by Sequenom MALDI-TOF spectroscopy. Haplotype frequencies were estimated using expectation maximization (EM) algorithm, and generalized linear models (GLM) were used to assess the marginal effect of SNPs and haplotypes on FVIII inhibitor development risk after adjusting for HIV infection and HCV persistence (prevalence in controls, 46% and 77%, respectively). Results: Of the 366 SNPs, 298 (81%) had unambiguous genotypes in >80% of the subjects and consequently qualified to the association analyses. Significant associations were seen between loci in the IL10, IL12A, IL1, IL2, TNFα, & IL17A genes and inhibitor development. Particularly, individuals carrying an 8 SNP haplotype located ∼10 kb 5' to the IL10 initiation start site were at higher risk to develop inhibitors than individuals with the most common haplotype (OR:1.54, 95% CI:1.15–2.06, p-value = 0.004). This haplotype covers a region that includes the IL10G microsatellite previously studied by Astermark et al (2006a), as well as the nearby IL10R microsatellite. Interestingly, the effect of this haplotype on FVIII inhibitor development was larger among HIV+ subjects in our study (OR: 1.81, 95% CI: 1.18–2.77 vs. OR: 1.28, 95% CI: 0.85–1.93 for HIV+ and HIV- subjects, respectively). A similar phenomenon was seen with haplotypes in the IL12A and IL2 genes. Additional haplotypes in genes for IL1α, IL1β, TNFα, and IL17A significantly increased or decreased risk for inhibitor development. No association was seen between FVIII haplotypes and inhibitors in this group of Caucasian subjects with hemophilia A, in contrast to the findings in African-Americans by Viel et al (2009). Also, no significant effect on inhibitor risk was seen for the factor V Leiden or prothrombin 20210 polymorphisms. Conclusions and Future Directions: Our large case-control study confirms the findings in family studies that IL10 and TNFα genotypes confer risk for inhibitor development in Caucasians with severe hemophilia A, which differed by HIV status and were of lower magnitude than seen previously in family studies. We identified four other genes in which certain haplotypes alter inhibitor risk. More work is needed to identify inhibitor associations in non-Caucasian populations and to corroborate and more specifically define our novel associations in Caucasians. Moreover, whole genome association and other studies should be considered to identify additional modifier genes and potential targets for intervention to prevent inhibitors. Disclosures: No relevant conflicts of interest to declare.

The EPIC Study: A Clinical Trial To Assess Whether Early Low Dose Prophylaxis In The Absence Of Immunological Danger Signals Reduces Inhibitor Incidence In Previously Untreated Patients (PUPs) With Hemophilia A

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 576-576 ◽  
Author(s):  
Guenter Auerswald ◽  
Karin Kurnik ◽  
Jan Blatny ◽  
Armin J Reininger
Keyword(s):  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
Venous Access ◽  
Patient Specific ◽  
Missense Mutations ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Inhibitor Development ◽  
Danger Signals

Abstract Background Inhibitor development is a complex, multifactorial immune response involving both patient-specific and treatment-related factors. Of the known risk factors, intensive treatment at an early age has been shown to be significant, and clinical observations have suggested that early prophylaxis (i.e. first exposure to FVIII in the absence of a bleed in the first year of age) may protect patients from inhibitor development by inducing FVIII tolerance. Aim This study aimed to assess prospectively if a once-weekly, low-dose prophylactic regimen started before 1 year of age and before the onset of a severe bleeding phenotype (i.e. joint bleed), together with the minimization of immunological danger signals, could reduce the incidence of inhibitor formation in PUPs with severe and moderately severe hemophilia A to 15% or less. Methods The EPIC study was a Phase 3b, prospective, single arm, historically-controlled, international multicenter study to assess the incidence rate of inhibitor formation in PUPs with severe and moderately severe hemophilia A during the first 50 exposure days (EDs) of treatment with ADVATE starting with a once-weekly, low-dose (ADVATE 25 IU/kg once weekly), prophylactic regimen. If clinically indicated, it was permissible to increase the frequency of dosing to 2 or 3 times per week. In addition, infusions during the first 20 EDs had to be given 3 to 4 days before or after any vaccinations, which had to be given subcutaneously, not intramuscularly; infusions had to be avoided if the subject had high fever (above 38°C [100°F]). Main enrolment criteria were: severe and moderately severe hemophilia A (FVIII ≤2%), age <1 year, ≤3 EDs to any FVIII-containing product used for treatment of minor bleeds or for precautionary infusions following injury, adequate venous access (without need for central venous access device), no life-threatening conditions (intracranial hemorrhage, severe trauma) or requirement for surgery at the time of enrollment, no evidence of inhibitor ≥0.6 BU in Nijmegen-modified Bethesda assay at study start, no hemostatic defect other than hemophilia A, no clinically significant chronic disease other than hemophilia A,. Information about type of FVIII gene defect was obtained in 17 subjects. FVIII inhibitor tests were performed at screening, at study infusion #3, 6, 10, 15, 20, 30, 40, and 50, and at any other time point if an inhibitor was suspected. Positive inhibitor testing had to be confirmed by 2 positive inhibitor tests on samples drawn at least 1 week apart. Results A total of 22 subjects were enrolled in the study. Of 20 subjects who met all entry criteria, 19 received treatment; of these, all had severe hemophilia A (FVIII<1%). At study entry 11 of these 19 patients were never exposed to FVIII before (PUPs), while the remaining 8 patients had been treated with FVIII concentrates before. FVIII gene mutation analysis revealed intron 22 inversions in 8 out of 17 subjects, hemizygous missense mutations resulting in a stop-codon in 2 subjects, frame-shift mutations in 2 subjects, and hemizygous missense mutations in 5 subjects. A total of 8 subjects developed a confirmed inhibitor: 2 of these 8 subjects had only borderline positivity at inhibitor testing (never above 0.6 BU) with absence of any anti-FVIII antibodies (IgG, IgA, IgM and IgG subclasses) as tested by ELISA. Thus incidence of inhibitors >0.6 BU in PUPs were 27%. A total of 67 major protocol deviations (PD) were reported in 15 patients: 44 PDs of these were reported in 10 subjects and were related to the treatment regimen and therefore have contrasted with the protocol intention, which was to minimize immunological danger signals and low dose prophylactic regimen. As a result of the observed inhibitor incidence the study was terminated based on futility analysis, i.e. the probability to achieve the primary end-point of inhibitor rate reduction to ≤15%. Details on inhibitor patients will be presented. Discussion The EPIC study showed no safety issue as confirmed by the Data Safety Monitoring Board. To align treatment decisions in the presence of danger signals (which are not completely avoidable in children around 1 year of age) with a demanding study protocol was found to be challenging. Thus the hypothesis that an early low dose prophylaxis in the absence of immunological danger signals might reduce inhibitor incidence in PUPs with hemophilia A could neither be verified nor disproved within this study. Disclosures: Auerswald: Novo Nordisk: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kurnik:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Biotest: Consultancy, Research Funding; CSL-Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Blatny:Baxter: speaker fee Other. Reininger:Baxter Innovations GmbH: Employment.

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.

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