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

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

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

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

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

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

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

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

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

scholarly journals Long-Term Safety and Efficacy of rFVIIIFc in Adults and Adolescents with Severe Hemophilia A: A Longitudinal Analysis of A-LONG and ASPIRE

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1087-1087 ◽  
Author(s):  
K John Pasi ◽  
David J Perry ◽  
Johnny Mahlangu ◽  
Barbara A Konkle ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Treatment Groups ◽  
Equity Ownership

Abstract Background: Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care for patients with hemophilia A; however, prophylactic treatment with conventional FVIII products usually requires frequent intravenous infusions (3-4 times/week). Recombinant FVIII Fc fusion protein (rFVIIIFc), which is produced in a human cell line, binds the neonatal Fc receptor and utilizes the natural IgG recycling pathway to prolong the half-life of FVIII. The safety, efficacy and prolonged half-life of rFVIIIFc in adults and adolescents with severe hemophilia A were demonstrated in the phase 3 A-LONG study (NCT01027377, completed) and ASPIRE extension study (NCT01454739, ongoing). Here, we report cumulative long-term data on the safety and efficacy of rFVIIIFc in participants in these studies. Methods: This longitudinal analysis includes cumulative data from A-LONG and ASPIRE (as of the interim data cut, 6 January 2014) for subjects treated with ≥1 dose of rFVIIIFc (n=164). A-LONG evaluated 2 prophylaxis regimens-individualized (IP): 25 IU/kg on day 1 and 50 IU/kg on day 4 to start, then 25-65 IU/kg every 3-5 days, to target a 1-3 IU/dL FVIII trough level, and weekly (WP): 65 IU/kg dosed once weekly-as well as episodic (on-demand) treatment. Subjects completing A-LONG and meeting enrollment criteria for ASPIRE could participate in the IP, WP, or episodic treatment groups, or, if optimal dosing could not be achieved with IP or WP, in an additional modified prophylaxis (MP) treatment group. Subjects could change treatment groups at any point during ASPIRE. For efficacy analyses, data were summarized according to the treatment group in which each subject participated, for the time period they were in that treatment group; thus, subjects may be included in the analysis of more than one treatment group. Outcomes evaluated included: incidence of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay at a central laboratory, confirmed upon retesting within 2 to 4 weeks), adverse events (AEs), annualized bleeding rate (ABR), treatment of acute bleeds, and prophylactic dose and dosing interval. Results: Of the 164 subjects dosed with rFVIIIFc during A-LONG, 153 completed the study and 150 enrolled in ASPIRE. At the time of the interim data cut, 140 subjects were ongoing in ASPIRE. Cumulatively, subjects had a median (IQR) of 25.5 (24.6, 26.7) months of rFVIIIFc treatment, and a median (IQR) of 183.0 (120.5, 232.5) rFVIIIFc exposure days (EDs). No inhibitors were reported. The estimated inhibitor incidence rate (95% CI) was 0.0% (0.0, 2.2) overall (N=164), and 0.0% (0.0, 2.7) in subjects with ≥100 rFVIIIFc EDs (n=136). The type and incidence of AEs observed were consistent with those expected for the general hemophilia population. 84.8% of subjects reported ≥1 AE on study, with the majority assessed by the investigator as mild and unrelated to rFVIIIFc treatment. 17.7% of subjects experienced at least 1 SAE; none were assessed by the investigator as related to rFVIIIFc. There were no reports of anaphylaxis or serious hypersensitivity events, and no serious vascular thrombotic events. Median ABRs for subjects on IP and WP (MP was not an option during A-LONG) were generally lower with rFVIIIFc treatment compared with prestudy FVIII (Figure). In the IP treatment group, the year 1 and year 2 median spontaneous ABRs were 0.0. Overall, 89.1% of bleeding episodes were controlled with 1 infusion; 97.3% with 1 or 2 infusions. Among subjects treated with FVIII prophylaxis prior to entering A-LONG (n=79), 86% were dosed at least 3 times/week. With rFVIIIFc, 96% of these subjects extended their dosing interval compared with their prestudy product, while the median (IQR) total weekly prophylactic dose was comparable (prestudy FVIII: 78.0 [60.0, 102.0] IU/kg; on-study rFVIIIFc: 75.0 [70.0, 113.2] IU/kg). Conclusions: Longitudinal data from patients with severe hemophilia A treated with rFVIIIFc in A-LONG and ASPIRE demonstrate long-term safety, with no inhibitors observed in any subjects, and efficacy in the prevention and treatment of bleeding. Low median ABRs were maintained with extended prophylactic dosing intervals, without an increase in median prophylactic factor consumption. Figure 1. Figure 1. Disclosures Pasi: Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria; Octapharma: Research Funding. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Mahlangu:Roche: Research Funding; Biotest: Speakers Bureau; Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Amgen: Speakers Bureau. Konkle:Baxalta: Consultancy, Research Funding; Biogen: Consultancy, Research Funding; CSL Behring: Consultancy, Other: IDMC chair; Pfizer: Other: IDMC member; Octapharma: Research Funding; Novo Nordisk: Consultancy. Rangarajan:Grifols, Pfizer, and Baxter: Research Funding; Grifols: Honoraria; Sobi: Membership on an entity's Board of Directors or advisory committees; LFB: Other: Conference support. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Cristiano:Biogen: Employment, Equity Ownership. Dong:Biogen: Employment, Equity Ownership. Tsao:Biogen: Employment, Equity Ownership. Pierce:Biogen: Equity Ownership, Other: Former employee. Allen:Biogen: Employment, Equity Ownership.

Long-Term Efficacy of rFVIIIFc Prophylaxis in Pediatric, Adolescent, and Adult Subjects with Target Joints and Severe Hemophilia A

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3520-3520
Author(s):  
Bryce A. Kerlin ◽  
Roshni Kulkarni ◽  
Beatrice Nolan ◽  
Michael Wang ◽  
K John Pasi ◽  
...  
Keyword(s):  
Treatment Group ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Phase 3 ◽  
Advisory Committees ◽  
Episodic Treatment ◽  
Bleeding Episodes

Abstract Background: The phase 3 A-LONG and Kids A-LONG studies demonstrated the safety and efficacy of recombinant FVIII Fc fusion protein (rFVIIIFc) for control and prevention of bleeding episodes in subjects with severe hemophilia A. The ongoing rFVIIIFc extension study, ASPIRE (Clinicaltrials.gov #NCT01454739), evaluates long-term safety and efficacy of rFVIIIFc in adults/adolescents and children who completed A-LONG and Kids A-LONG, respectively. Aims: To evaluate the long-term efficacy of rFVIIIFc in subjects with target joints at entry into the parent studies (A-LONG, Kids A-LONG). Methods: A-LONG and Kids A-LONG were Phase 3, open-label, multicenter studies in males aged ≥12 years (A-LONG) or <12 years (Kids A-LONG) with severe hemophilia A (<1 IU/dL endogenous FVIII activity) and prior FVIII treatment. Subjects in A-LONG were enrolled into 1 of 3 arms: Arm 1, individualized prophylaxis (IP); Arm 2, weekly prophylaxis (WP); or Arm 3, episodic treatment. All Kids A-LONG subjects received rFVIIIFc prophylaxis. Upon completing A-LONG or Kids A-LONG, eligible subjects could enroll in ASPIRE. There are 4 treatment groups in ASPIRE: IP; WP; modified prophylaxis (MP; for subjects in whom optimal dosing could not be achieved with individualized or weekly prophylaxis); or episodic treatment. Subjects can change treatment groups upon entry or at any point during ASPIRE. Subjects aged ≥12 years can participate in any treatment group; subjects aged <12 years can participate in the individualized and modified prophylaxis groups only. Self-reported prestudy 12-month bleeding history and on-study annualized bleeding rate (ABR), including overall ABR and ABR in target joints present at baseline were evaluated. The current analysis evaluated subjects with ≥1 target joint (major joint with ≥3 bleeding episodes in a 6-month period) at entry into the parent study with available prestudy and on-study data. Outcomes were analyzed over the cumulative duration of the parent study through the ASPIRE interim datacut (January 6, 2014). Subjects were evaluated in each treatment group they participated in, for the duration they were in that treatment group (because of the ability to switch groups, subjects may be included in >1 group). Results: The analyzed population included 111 adult/adolescent and 13 pediatric subjects with target joints at entry into A-LONG and Kids A-LONG, respectively. Median (range) cumulative duration of treatment with rFVIIIFc on A-LONG/ASPIRE was 110 (24-162), 79 (2-110), 80 (45-86), and 33 (16-116) weeks for the IP (n = 82), WP (n = 26), MP (n = 12), and episodic treatment (n = 18) groups, respectively; for Kids A-LONG/ASPIRE, median (range) duration was 51 (22-58) and 16 weeks for the IP (n = 13) and MP (n = 1) prophylaxis groups, respectively. Among 111 A-LONG subjects, there were 287 target joints at baseline (located in the elbow [n = 100; 34.8%], ankle [n = 92; 32.1%], knee [n = 63; 22.0%], shoulder [n = 17; 5.9%], wrist [n = 9; 3.1%], and hip [n = 6; 2.1%]). Among 13 Kids A-LONG subjects, there were 15 target joints at baseline (located in the ankle [n = 10; 66.7%], elbow [n = 4; 26.7%], and knee [n = 1; 6.7%]). In subjects with target joints at baseline, median on-study overall ABRs with rFVIIIFc prophylaxis for adults/adolescents (Fig. 1A) and children (Fig. 1B) tended to be lower than prestudy bleeding rates. On-study, both provoked and spontaneous target joint median ABRs were low. A total of 47.6%, 42.3%, and 41.7% of subjects in the IP, WP, and WP groups, respectively, had no target joint bleeding episodes during A-LONG/ASPIRE; for Kids A-LONG subjects, 53.8% of subjects in the IP group had no target joint bleeding episodes on-study. Median average total weekly rFVIIIFc prophylactic doses and median dosing intervals during A-LONG/ASPIRE and Kids A-LONG/ASPIRE for subjects with target joints at baseline were similar to those for the overall study populations. Summary/Conclusion: For subjects with target joints at baseline, efficacy data from the phase 3 and extension trials suggest that long-term use of extended half-life rFVIIIFc prophylaxis is effective for prevention of target joint bleeding. Disclosures Kerlin: Bayer Healthcare US and Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding. Kulkarni:Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; BPL: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding, Speakers Bureau. Nolan:Biogen and Sobi: Research Funding. Wang:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Pasi:Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Liesner:Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Biogen, Novo Nordisk, Baxter, and Pfizer: Other: Sponsorship to meeting. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Tsao:Biogen: Employment, Equity Ownership. Allen:Biogen: Employment, Equity Ownership.

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.

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

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

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

Animal Testing of Retroviral-Mediated Gene Therapy for Factor VIII Deficiency

1999 ◽  
Vol 82 (08) ◽  
pp. 555-561 ◽  
Author(s):  
Douglas Jolly ◽  
Judith Greengard
Keyword(s):  
Gene Therapy ◽  
Factor Viii ◽  
Hemophilia A ◽  
Joint Damage ◽  
Coagulation Factor ◽  
The United States ◽  
Severe Hemophilia ◽  
Factor Viii Gene ◽  
Bleeding Episodes

IntroductionHemophilia A results from the plasma deficiency of factor VIII, a gene carried on the X chromosome. Bleeding results from a lack of coagulation factor VIII, a large and complex protein that circulates in complex with its carrier, von Willebrand factor (vWF).1 Severe hemophilia A (<1% of normal circulating levels) is associated with a high degree of mortality, due to spontaneous and trauma-induced, life-threatening and crippling bleeding episodes.2 Current treatment in the United States consists of infusion of plasma-derived or recombinant factor VIII in response to bleeding episodes.3 Such treatment fails to prevent cumulative joint damage, a major cause of hemophilia-associated morbidity.4 Availability of prophylactic treatment, which would reduce the number and severity of bleeding episodes and, consequently, would limit such joint damage, is limited by cost and the problems associated with repeated venous access. Other problems are associated with frequent replacement treatment, including the dangers of transmission of blood-borne infections derived from plasma used as a source of factor VIII or tissue culture or formulation components. These dangers are reduced, but not eliminated, by current manufacturing techniques. Furthermore, approximately 1 in 5 patients with severe hemophilia treated with recombinant or plasma-derived factor VIII develop inhibitory humoral immune responses. In some cases, new inhibitors have developed, apparently in response to unnatural modifications introduced during manufacture or purification.5 Gene therapy could circumvent most of these difficulties. In theory, a single injection of a vector encoding the factor VIII gene could provide constant plasma levels of factor in the long term. However, long-term expression after gene transfer of a systemically expressed protein in higher mammals has seldom been described. In some cases, a vector that appeared promising in a rodent model has not worked well in larger animals, for example, due to a massive immune response not seen in the rodent.6 An excellent review of early efforts at factor VIII gene therapy appeared in an earlier volume of this series.7 A summary of results from various in vivo experiments is shown in Table 1. This chapter will focus on results pertaining to studies using vectors based on murine retroviruses, including our own work.

Human-Cl Rhfviii Effectively and Safely Prevents Bleeding Episodes in Previously Treated Adult Patients with Severe Haemophilia A

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1132-1132
Author(s):  
Sigurd Knaub ◽  
Toshko Lissitchkov ◽  
Kingsley Hampton ◽  
Mario Von Depka ◽  
Savita Rangarajan ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Research Funding ◽  
Prophylactic Treatment ◽  
Hemophilia A ◽  
Haemophilia A ◽  
Severe Haemophilia ◽  
Open Label ◽  
Bleeding Rate ◽  
Previously Treated

Abstract Abstract 1132 The main purpose of this prospective, multi-center, open-label phase 3 study was to assess the efficacy of prophylactic treatment with Human-cl rhFVIII, the first human cell-line derived recombinant FVIII, in previously treated patients (PTPs) with severe haemophilia A. Patients were to receive 30–40 international units (IU) FVIII of Human-cl rhFVIII per kg every other day for 6 months. Efficacy of preventing and treating bleeds were judged using objective criteria taking the monthly bleeding rate and the number of infusions needed to manage a break-through bleed into account. In-vivo recovery (IVR) was determined at the beginning of the study and after 3 and 6 months. FVIII:C was measured by validated chromogenic (CHR) and one-stage (OS) assays in a central laboratory, which also assigned drug potencies. Inhibitor activity was determined using the Nijmegen modification of the Bethesda assay before the first administration and at defined intervals thereafter. Thirty-two patients between 18 and 75 years of age were enrolled from 11 centres in Europe and treated prophylactically for 6.0±0.9 months (mean ± SD) with a mean prophylactic dose of 32.8 IU/kg. Sixteen patients never bled, 11 patients bled once and 5 more than once. The mean total and spontaneous monthly bleeding rate was 0.188±0.307 and 0.095±0.211, respectively. Efficacy of the prophylactic treatment was “excellent” in all patients for spontaneous BEs and “excellent” or “good” in all patients but one for all types of bleeds. All treatments of bleeds were rated as “excellent” (71.4%) or “good” (28.6%). The IVR at baseline was 2.6±0.5 % per IU/kg for the CHR and 2.2±0.5 % per IU/kg for the OS assay and remained stable during the study. A total of 2921 infusions were given in the study. Human-cl rhFVIII was well tolerated and no patient experienced a related serious adverse event. No FVIII inhibitors were detected. Conclusion: The data indicate that Human-cl rh FVIII is safe and efficacious in preventing and treating bleeds in PTPs with severe haemophlia A. Disclosures: Knaub: Octapharma AG: Employment. Lissitchkov:Octapharma AG: PI Other. Tuddenham:College London: Consultancy, Employment, Gene therapy for hemophilia A, Gene therapy for hemophilia A Patents & Royalties, Research Funding. Collins:Octapharma AG: Consultancy. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Bichler:Octapharma AG: Employment.

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

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

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

Sign in / Sign up

Export Citation Format

Share Document