scholarly journals Thrombin Generation and Bleeding Phenotype during Personalized Prophylaxis with Recombinant Human FVIII in Previously Treated Patients with Severe Hemophilia A

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1410-1410
Author(s):  
Yesim G. Dargaud ◽  
Robert Klamroth ◽  
Luminita Rusen ◽  
Jerzy Windyga ◽  
Johann Bichler ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Plasma Concentrations ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Spontaneous Bleeding ◽  
Advisory Boards ◽  
Bleeding Episodes ◽  
Equity Ownership

Abstract Background and objectives In apharmacokinetic (PK)-guided personalized prophylaxis study with human-cl rhFVIII(Nuwiq®), a factor VIII (FVIII) concentrate from a human cell line,58% of the previously treated adult patients (PTPs) with severe hemophilia A received 2 or fewer prophylactic infusions per weekwith a median dosing interval of3.5 days. Seventy-three percent (73%) of patients did not experience any bleeding and 83% had no spontaneous bleeding episodes during the 6-month personalized prophylaxis period. The objective of this analysis was to evaluate the relationship between endogenous thrombin generation (TG) as well as FVIII plasma concentrations with the bleeding phenotype. Study design and methods This prospective, open-label, multicenter study included 66 adult PTPs with severe hemophilia A. After the previously given FVIII concentrate was washed out, patients received human-cl rhFVIII(60 IU/kg) for PK evaluation. Individual PK data were analyzed to determine doses and injection intervals that would theoretically result in a trough FVIII plasma level of ≥1%. Individualized prophylaxis lasted 6 months. TG and FVIII:C plasma concentrations were measured before and during the PK assessment, and trough TG and FVIII:C levels were measured 2, 4 and 6 months after the start of personalized prophylaxis. For TG, blood was drawn in trisodium citrate tubes (0.106 M) containing 1.45 µM corn trypsin inhibitor, centrifuged twice to obtain platelet poor plasma, and stored frozen until central analysis. TG was initiated by adding tissue factor (1 pM), and endogenous thrombin potential (ETP) was measured using the calibrated, automated TG assay.FVIII:C was measured using one-stage (automated APTT, Trinity Biotech, Siemens BCX-XP) and chromogenic assays (Coatest SP FVIII Kit, Chromogenix, Siemes BCS-XP). Results Data on both baseline ETP and bleeding rate during PK-guided individualized prophylaxis were available for 32 patients. Twenty-one patients did not experience any bleeding episode, and 25 patients had no spontaneous bleeding episodes. The mean baseline ETP did not differ between patients with and without any bleeding (373 ± 334 vs 367 ± 168 nmol*min), but was considerably lower in patients who had spontaneous bleeding episodes compared with those without spontaneous bleeding episodes (164 ± 66 vs 426 ± 231 nmol*min). Data on trough ETPs and FVIII:C during personalized prophylaxis were available for 34 patients.Patients with low TG potential tended to experience more frequent spontaneous bleeding episodes during this phase of the protocol (Figure 1), while low FVIII:C levels seemed to be less related to spontaneous bleeding episodes. Conclusions Low TG capacity seems to be correlated with increased frequency of spontaneous bleeding episodes, irrespective of trough FVIII plasma levels. Further prospective studies should be carried out to evaluate the value of this global coagulation parameter in the personalization prophylactic treatment in patients with hemophilia A in comparison with trough FVIII coagulant activity. Figure 1 Figure 1. Disclosures Klamroth: Biogen Idec: Other: honoraria for advisory boards and speaker fees; Baxalta: Other: honoraria for advisory boards and speaker fees ; Bayer: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; SOBI: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; Octapharma: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees. Windyga:Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Alexion: Other: Speaker's honorarium; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Octapharma: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Baxalta, now part of Shire: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Patents & Royalties, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Bichler:Octapharma: Employment. Knaub:Octapharma: Employment. Negrier:NovoNordisk: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; LFB: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Travel support; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Pfizer: Research Funding; SOBI: Membership on an entity's Board of Directors or advisory committees; Baxter: Membership on an entity's Board of Directors or advisory committees.

Antithrombin Reduction Corrected Thrombin Generation in Samples from Hemophilia A and B Patients with Inhibitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 552-552 ◽  
Author(s):  
Gili Kenet ◽  
Tami Livnat ◽  
Emma Fosbury ◽  
Pratima Chowdary ◽  
Alfica Sehgal ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Equity Ownership

Abstract Background: Severe hemophilia A and B patients with inhibitors experience serious musculoskeletal hemorrhage as well as high risk of limb and life threatening bleeds. However, lack of effect of FVIII or FIX substitution therapy and short functional half-life of by-passing agents, leave these patients with very limited bleed preventive treatment options. ALN-AT3 (Alnylam Pharmaceuticals, Cambridge, MA, USA), a subcutaneously administered investigational RNAi therapeutic targeting reduction of antithrombin for potential treatment of hemophilia is currently in phase 1 clinical development in hemophilia A and B patients without inhibitors. Initial data from that ongoing study in 12 patients suggest an AT KD dependent correction of thrombin generation. This study aims to assess changes in peak thrombin generation in samples from patients with severe hemophilia A and B with inhibitors following in vitro reduction of antithrombin. Materials and methods: Citrated plasma samples were obtained from patients with severe hemophilia A and B with high responding inhibitors. Samples were spiked in vitro with isotype specific control IgG or a monoclonal antibody (Haemtech Inc, Essex Junction, VT, USA) targeting antithrombin knockdown of 50% and 90%. Dynamic formation of thrombin was measured by calibrated automated thrombin generation using 1pM tissue factor PPP reagent and 4μM phospholipid (Thrombinoscope, Maastricht, The Nederlands). The primary effect measure was peak thrombin (nM). Data were tested by a 1-way ANOVA and p<0.05 was considered statistically significant. Results: A total of 12 inhibitor hemophilia samples were investigated; 9 hemophilia A and 3 hemophilia B. All the control samples demonstrated a profound defect in thrombin generation with a median peak thrombin of 19.9 nM (range 6.7 - 42.4). Patients with severe hemophilia A and inhibitors had a median peak thrombin generation of 19.7 nM (range 6.7 - 42.4), whereas patients with severe hemophilia B and inhibitors had a median peak thrombin generation of 19.2nM (range 19.4 - 38.1). An AT reduction dependent improvement in peak thrombin generation was observed in all 12 tested plasma samples (Figure 1). In the first 12 subjects, peak thrombin generation was increased up to 363% from a mean of 22nM (control) to 39 nM (50% AT reduction) and 80nM (90% AT reduction) (p<0.05); levels comparable to thrombin generation observed in healthy male volunteers and in hemophilia patients treated with ALN-AT3. Conclusions: These in vitro data suggest that reduction of AT is a promising approach for restoring hemostatic balance and correcting thrombin generation in hemophilia patients with inhibitors. Furthermore, the present laboratory data compare well with clinical data generated with ALN-AT3 administered to patients with hemophilia A or B. Thus, both laboratory and emerging clinical data suggest that targeting antithrombin could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, infrequent dosing, and applicability to persons with hemophilia who have inhibitors, make ALN-AT3 a particularly encouraging investigational therapy. Figure 1. Figure 1. Disclosures Kenet: Bayer, Novo Nordisk: Other: Advisory Boards, Speakers Bureau; Opko Biologics: Consultancy, Other: Advisory Boards; BPL; Baxelta: Research Funding; Pfizer: Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Chowdary:Sobi: Membership on an entity's Board of Directors or advisory committees; CSL Behring: 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; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Sehgal:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Severe Bleeding Events in Hemophilia Α Patients Receiving Emicizumab Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1126-1126
Author(s):  
Karen L. Zimowski ◽  
Glaivy M. Batsuli ◽  
Paulette Bryant ◽  
Jenny McDaniel ◽  
Kelly Tickle ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Bleeding ◽  
Severe Hemophilia ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Acute Bleeding ◽  
Fviii Activity ◽  
Bleeding Episodes

Introduction : Emicizumab is a novel humanized bispecific antibody that mimics the function of activated coagulation factor VIII (fVIII). It has significantly changed the management of patients with hemophilia A and inhibitors by achieving baseline hemostatic control. Based on the HAVEN studies, emicizumab markedly reduces annualized bleeding rates and is FDA-approved for prophylaxis in hemophilia A patients of all ages, regardless of inhibitor status. In the HAVEN2 interim analysis, only 3/57 pediatric patients receiving emicizumab prophylaxis required treatment for an acute bleeding event after a 9-week median observation time. We report 3 patients with severe hemophilia A and a history of inhibitors receiving emicizumab prophylaxis with severe or refractory bleeding episodes to highlight the importance of vigilance and surveillance of children with severe hemophilia A on emicizumab. Methods: This retrospective analysis includes patients between 0-21 years of age with severe hemophilia A (fVIII activity < 1%) receiving emicizumab prophylaxis and admitted for the management of an acute bleeding episode following emicizumab's FDA approval in November 2017. Patients were followed at the Pediatric Hemophilia Treatment Center at the Hemophilia of Georgia Center for Bleeding & Clotting Disorders of Emory and the St. Jude Affiliate Clinic at Novant Health Hemby Children's Hospital. Data collected included demographics, past medical history including inhibitor status, bleeding history, and treatment modalities, and details regarding the presentation, management, and outcome of acute severe bleeding events. Due to the nature of the study, descriptive statistics were primarily used for data analysis. Results: Three patients with severe hemophilia A receiving emicizumab prophylaxis were admitted for the management of 4 severe bleeding episodes. All patients had a history of a fVIII inhibitor. Three of the 4 bleeding episodes were trauma-induced while 1 occurred spontaneously. For the traumatic episodes, all patients presented with worsening symptoms approximately 1 week following the inciting event. All patients had a normal aPTT at the time of presentation, ruling out a significant anti-drug antibody (emicizumab level not available). A patient with a low-titer inhibitor developed an epidural hematoma following a trampoline injury and was treated with continuous infusion of recombinant factor VIII (rfVIII), adjusting the rate to achieve chromogenic fVIII activity of 100% for 14 days. Following 14 days, he was started on rfVIII 50 IU/kg Q12 hours with a goal fVIII activity of 50%. His rfVIII dosing interval was gradually weaned to every other day while in inpatient rehabilitation. As outlined in Table 1, the remaining 3 bleeding events were initially managed with recombinant activated factor VII (rfVIIa) dosed at 80-90 mcg/kg/dose with escalating frequency for an average of 8 days. However, due to lack of improvement, treatment was changed to low-dose activated prothrombin complex concentrates (aPCC; 10-15 IU/kg/dose Q12-24 hours for an average of 7 days). In all 3 of these events, the hematomas improved after treatment with aPCC. No patient experienced thrombotic microangiopathy, thrombosis, or had evidence of DIC while receiving these treatment regimens. Discussion/Conclusion: Pharmacokinetic analysis of emicizumab suggests that following the standard 4-week loading phase, trough plasma emicizumab concentrations obtained prior to a 1.5 mg/kg once weekly maintenance dose correlates with at least 10-15 IU/dL equivalent fVIII activity. This degree of thrombin generation should be sufficient to prevent severe spontaneous bleeding episodes in most patients. However it does not preclude significant trauma-induced bleeding or spontaneous bleeding in inhibitor patients. Based on our cases, providers should maintain a high index of suspicion for acute bleeding in patients receiving emicizumab prophylaxis. Serious bleeding events, although rare, may have a more insidious onset in patients receiving emicizumab. Furthermore, despite the baseline hemostasis achieved with emicizumab, acute bleeding events may still require aggressive therapy. Our cases suggest that low-dose aPCC or continuous infusion fVIII may be feasible options for treating acute bleeding events in patients with hemophilia A and inhibitors receiving emicizumab prophylaxis. Disclosures Zimowski: Pfizer: Research Funding; National Hemophilia Foundation: Other: Medical Loan Reimbursement, Research Funding. Batsuli:Octapharma: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees. Bryant:Novo Nordisk: Other: PI on Novo Nordisk sponsored Studies. McDaniel:Genentech: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Research Funding. Meeks:Bayer: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees; HEMA Biologics: Membership on an entity's Board of Directors or advisory committees. Sidonio:Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees; Uniqure: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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

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

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

scholarly journals 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.

Dosing Long-Lasting Recombinant Factor VIII Fc Fusion Protein: Experience In The A-LONG Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3598-3598 ◽  
Author(s):  
Amy Shapiro ◽  
Margaret V. Ragni ◽  
Roshni Kulkarni ◽  
Sarah Kulke ◽  
James Potts ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Dose Interval ◽  
Severe Hemophilia ◽  
Prophylactic Regimen ◽  
Advisory Committees ◽  
Population Pk ◽  
Dosing Regimens ◽  
Equity Ownership

Abstract Introduction Prophylaxis with factor VIII (FVIII) in patients with severe hemophilia A requires frequent intravenous injections (3–4 per week), impacting compliance and outcomes. A long-lasting recombinant FVIII Fc fusion protein (rFVIIIFc) was developed to reduce the frequency of injections. The pharmacokinetics (PK), safety, and efficacy of rFVIIIFc were evaluated in the phase 3 A-LONG study and the primary results were reported recently (Mahlangu J, J Thromb Haemost 2013). To illustrate differences in dosing regimens and clinical outcomes with rFVIIIFc and currently available FVIII products, we compared the prestudy and on-study dose, dose interval, and bleeding rates for subjects in A-LONG who reported receiving a prophylactic regimen with any FVIII product prior to study entry. We also used population PK models to estimate trough FVIII levels on various dosing regimens of rFVIIIFc and rFVIII (Advate®). Methods Previously treated male patients who were ≥12 years old with severe hemophilia A were enrolled in A-LONG and assigned to 1 of 3 treatment arms: Arm 1, individualized prophylaxis with PK-driven dose and dose interval adjustments (25–65 IU/kg every 3–5 days); Arm 2, once weekly prophylaxis (65 IU/kg); and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. A 2-compartmental population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12-65 years old (16 from a phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment). A 2-compartment population PK model of Advate® was developed based on the single-dose PK profiles from 16 subjects in the phase 1/2a study and 30 subjects in the sequential PK subgroup in A-LONG. The population PK estimates for Advate® and rFVIIIFc from A-LONG were used for dosing simulations. We identified Arm 1 subjects who reported use of a prophylactic regimen at least 2 times a week with any FVIII product prior to study entry and compared their dosing regimens and bleeding rate in the 12 months prior to study with their rFVIIIFc dosing regimens and annualized bleed rate (ABR) on study. Only subjects on study for ≥ 6 months were included. The median ABR, dose, and dose interval during the last 3 months on study were analyzed. Results Of 165 total patients, 118 were in Arm 1, of whom 80 received a prophylactic regimen at least 2 times a week prestudy and were in the study for ≥ 6 months. Subjects were grouped by prestudy dosing interval. The table below provides prestudy and on study dose, dose interval, and bleeding rates for these groups. The majority of patients (65/80) reported a dosing interval of 3 times a week, with the most common dose of 25 IU/kg FVIII, and a median of 5.5 bleeding events 12 months prior to study entry. At the end of the study, these same patients were receiving ∼40 IU/kg rFVIIIFc twice a week (every 3.5 days) with a median ABR of 0. Population PK simulation indicated that 76.1% of patients treated with 40 IU/kg of rFVIIIFc twice a week would maintain FVIII levels above 1% at all times. In contrast, population PK simulation indicated that 42.3% of patients treated with 25 IU/kg of Advate® 3 times a week would maintain FVIII levels above 1% at all times. Overall, rFVIIIFc was well tolerated and no inhibitor development was detected during the A-LONG study. Conclusion The results from this descriptive analysis of dose, dose interval, and bleeding rates for subjects with severe hemophilia A who were on prophylaxis suggest that switching from current FVIII products to a rFVIIIFc regimen may allow for less frequent dosing to maintain FVIII activity >1%. Disclosures: Shapiro: Baxter: Consultancy, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Global steering committees, Global steering committees Other, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Inspiration: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; CSL Behring: Research Funding; Biogen Idec: Research Funding. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Smith Kline Glaxo: Consultancy, Research Funding; Tacere Benitec: Consultancy; Baxter: Research Funding; Bayer: Research Funding; CSL Behring: Research Funding; Merck: Research Funding; Novo Nordisk: Research Funding; Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Kulke:Biogen Idec: Employment. Potts:Biogen Idec: Employment. Neelakantan:Biogen Idec: Employment. Nestorov:Biogen Idec: Employment. Dumont:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Brennan:Biogen Idec: Employment; Biogen Idec: Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership.

Fitusiran, an Investigational RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia: Updated Results from a Phase 1 and Phase 1/2 Extension Study in Patients with Inhibitors

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1397-1397 ◽  
Author(s):  
K John Pasi ◽  
Pencho Georgiev ◽  
Tim Mant ◽  
Toshko Lissitchkov ◽  
Michael Desmond Creagh ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Phase 1 ◽  
Extension Study ◽  
Severe Hemophilia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background: Development of inhibitory antibodies, also known as "inhibitors," to replacement factor is considered the most serious unmet need in hemophilia and occurs in up to 30% of persons with severe hemophilia A, and 3-5% of persons with severe hemophilia B. Once inhibitors are present in high titer, treatment or prevention of bleeding can become more difficult due to the decreased responsiveness to factor concentrates, requiring bypassing agents (BPA) for bleed management. Current BPAs have a short half-life and are sub-optimally effective. Fitusiran is a subcutaneously (SC) administered investigational RNA interference (RNAi) therapeutic targeting the endogenous anticoagulant antithrombin (AT) as a means to improve thrombin generation and promote hemostasis in patients with hemophilia. Preliminary data from an ongoing Phase 1, multi-center, study showed that fitusiran was generally well tolerated in patients with hemophilia A or B with and without inhibitors and that administration of once-monthly SC doses of fitusiran led to dose-dependent AT lowering, thrombin generation increase, and decrease in bleeding frequency (Pasi KJ, et al. Haemophilia 2016, 22[Suppl 4]). Here we report the updated safety, pharmacodynamic (PD) effect, and clinical activity of fitusiran in patients with hemophilia with inhibitors as well as long term data from the Phase 1/2 extension study. Methods: We are conducting a multi-center Phase 1, four part (Part A: healthy volunteers; Parts B and C: patients with moderate to severe hemophilia A or B; Part D: patients with hemophilia A or B with inhibitors) study (NCT02035605) followed by a multi-center Phase 1/2 extension study (NCT02554773). Primary endpoints include safety and tolerability; secondary endpoints include AT activity, thrombin generation and exploratory evaluation of bleed pattern. In Part D, patients with inhibitors received once-monthly SC fixed doses of 50 or 80mg fitusiran. After receiving 3 monthly doses in the Phase 1 study, all patients were eligible to continue monthly dosing in the Phase 1/2 extension study. Utilization of BPA for breakthrough bleed management was permissible in these patients. Results: Part D of the Phase 1 study included 12 hemophilia A or B patients with inhibitors in 2 dosing cohorts (50mg SC, qM dosing cohort, n=6; 80mg SC, qM dosing cohort, n=6). Within the 50mg dosing cohort there were five patients with severe hemophilia A with inhibitors and one patient with severe hemophilia B with inhibitors; mean age: 33 ± 7 years; mean weight: 73 ± 17kg. Previously reported safety data from the 50mg dosing cohort demonstrated fitusiran was generally well tolerated in hemophilia A or B patients with inhibitors and that there were no serious adverse events related to study drug and no thromboembolic events. Monthly administration of fitusiran at the 50mg dose led to a mean maximal AT lowering of 81 ± 2% and mean maximal thrombin generation increase of 368 ± 113%. A preliminary, post-hoc analysis suggested a 49-100% reduction in bleeding frequency at the lower dose of 50mg during initial follow-up in the Phase 1 study. As of July 2016, the 80mg dose cohort has been fully enrolled and includes 6 patients with hemophilia A with inhibitors; mean age: 39 ± 15 years; mean weight: 75 ± 19kg, and 5 of the 6 patients in the initial 50mg cohort have transitioned to the Phase 1/2 extension study. Follow-up in the Phase 1, 80mg cohort and Phase 1/2 extension study is ongoing. Updated safety, tolerability and clinical activity from the Phase 1 and Phase 1/2 extension studies among all 12 patients with inhibitors will be presented. Conclusions: Emerging clinical data suggest that targeting AT is generally safe and could be a promising approach for promoting hemostasis in patients with hemophilia with inhibitors. Furthermore, the potential for low volume SC administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make fitusiran a potentially encouraging investigational therapy. Disclosures Pasi: Biogen: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Georgiev:Alnylam Pharmaceuticals: Consultancy. Chowdary:Bayer: Honoraria; Baxalta: 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; Sobi: Honoraria; Biogen: 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; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ragni:Novo Nordisk: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding; SPARK: Research Funding; Baxalta: Research Funding; CSL Behring: Research Funding; Shire: Consultancy; Vascular Medicine Institute: Research Funding; Tacere Benitec: Consultancy; OPKO: Research Funding. Soh:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Sorenson:Alnylam Pharmaceuticals: Employment, Equity Ownership.

The Bleeding Tendency In Relation To Predicted FVIII Activity Levels In Severe Hemophilia A Patients Treated With Recombinant Factor VIII Fc Fusion Protein

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3590-3590 ◽  
Author(s):  
John Pasi ◽  
James Potts ◽  
Shuanglian Li ◽  
Ping Wang ◽  
Sarah Kulke ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Negative Binomial ◽  
Hemophilia A ◽  
Bleeding Tendency ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Episodic Treatment ◽  
Fviii Activity ◽  
Bleeding Episodes

Abstract Introduction Prophylactic regimens with coagulation factor in patients with hemophilia A have been designed to maintain FVIII activity above 1 IU/dL, based on previous studies demonstrating that joints can be preserved and bleeding is minimized when circulating factor levels remain above this level (Nilsson IM, et al. J Intern Med 1992). Collins and colleagues confirmed this observation and demonstrated that increasing time spent under 1 IU/dL FVIII activity in patients on prophylaxis with recombinant FVIII (rFVIII) was associated with an increase in bleeding episodes and hemarthroses (Collins PW, et al. J Thromb Haemost 2009). The pharmacokinetics (PK), safety, and efficacy of rFVIII Fc fusion protein (rFVIIIFc) have been evaluated in the A-LONG study and recently reported (Mahlangu J, et al. J Thromb Haemost 2013). Briefly, previously treated male patients, ≥12 years old with severe hemophilia A, were enrolled in A-LONG and allocated to 1 of 3 treatment arms: Arm 1) individualized prophylaxis with dose and dosing interval adjustments (25–65 IU/kg every 3–5 days) based on PK and clinical indications, Arm 2, fixed dose (65 IU/kg) weekly prophylaxis, and Arm 3, episodic treatment (10–50 IU/kg) for bleeding episodes. The median annualized bleeding rates for individualized prophylaxis and weekly prophylaxis were 1.6 and 3.6, respectively, and 33.6 for episodic treatment. In this analysis, we evaluated the bleeding tendency in relation to predicted FVIII activity levels in 163 subjects in the A-LONG study. Methods A 2-compartment population PK model of rFVIIIFc was developed based on activity-time profiles in 180 severe hemophilia A subjects aged 12 – 65 years old (16 from a Phase 1/2a study and 164 from A-LONG collected over ≤ 52 weeks of treatment) (Neelakantan S, et al. J Thromb Haemost 2013). Individual post-hoc PK parameters were derived to construct continuous FVIII activity-time profiles for each dose administered over the course of the study for 163 subjects in A-LONG. The cumulative time under 1IU/dL FVIII levels for each individual on study was calculated and normalized to obtain annualized time under 1IU/dL. Negative binomial regression models were used to evaluate associations between the number of bleeding episodes (overall, spontaneous, traumatic, and joint) and annualized time (days) under 1IU/dL FVIII activity. Models were adjusted for age, body mass index, baseline HIV and HCV status, baseline von Willebrand factor, number of bleeding episodes in the 12 months prior to study entry, and each subject’s time on study. Results The predicted median annualized time under 1IU/dL FVIII activity for subjects on episodic treatment was 224.81 days, which was shortened to 51.55 days in subjects on a fixed prophylactic dose of 65 IU/kg of rFVIIIFc once weekly, and further reduced to 2.17 days in subjects on tailored prophylactic regimens (25 – 65 IU/kg, every 3 – 5 days). Multivariable negative binomial regression analysis showed that the number of overall bleeding episodes increased with increased time spent under 1IU/dL of FVIII activity level (p<0.001). A significant association was also observed for the time under 1IU/dL and the individual bleed types (spontaneous, traumatic, and joint) when analyzed separately. In addition, across all subtypes of bleeding, there was a significant decrease in the odds of being bleed-free for each one day increase in the time spent under 1IU/dL of FVIII activity. Conclusions In subjects treated with rFVIIIFc in the A-LONG study, there was a significant association between increased time spent under 1IU/dL of FVIII activity and increased bleeding tendency, as well as decreased odds of being bleed-free. The findings reinforce the importance of a therapeutic threshold of 1 IU/dL of FVIII activity as reported previously, and contribute to building a stronger foundation for designing effective rFVIIIFc prophylactic dosing regimens based on population PK simulations of FVIII activity. Disclosures: Pasi: Bayer: Membership on an entity’s Board of Directors or advisory committees; Bio Products Laboratory Ltd: Membership on an entity’s Board of Directors or advisory committees; OctaPharma : Membership on an entity’s Board of Directors or advisory committees, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding. Potts:Biogen Idec: Employment. Li:Biogen Idec: Employment. Wang:Biogen Idec: Employment. Kulke:Biogen Idec: Employment. Pierce:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment; Biogen Idec: 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.

Phase I, Randomized, Double-Blind, Placebo-Controlled, Single-Dose Escalation Study of the rFVIIa Variant (BAY 86–6150) In Hemophilia A or B with or without Inhibitors.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3679-3679 ◽  
Author(s):  
J.N. Mahlangu ◽  
M.J. Coetzee ◽  
M. Laffan ◽  
J. Windyga ◽  
T. T. Yee ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Hemophilia A ◽  
Employment Equity ◽  
Advisory Committees ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Bleeding Episodes ◽  
Equity Ownership

Abstract Abstract 3679 Bleeding episodes in hemophilia A or B patients with inhibitors to factors VIII or IX are commonly managed with bypassing agents such as recombinant factor VIIa (rFVIIa). However, currently available rFVIIa treatment is associated with variable response rates and a short elimination half-life, often necessitating the administration of multiple doses to control bleeding. BAY 86–6150, a human rFVIIa variant, was developed to provide a longer-acting and more potent activated factor VII in the management of bleeding episodes in patients with hemophilia who developed inhibitors. The safety, tolerability, pharmacodynamic/pharmacokinetic (PD/PK) profiles, and immunogenicity of BAY 86–6150 in nonbleeding patients with hemophilia was investigated in a phase I, randomized, double-blind, placebo-controlled, single-dose escalation study. The patient population comprised nonbleeding men aged 18–65 years with moderate or severe hemophilia A or B with or without inhibitors. 16 patients were randomized 3:1 to escalating doses of BAY 86–6150 at 6.5, 20, 50, or 90 μg/kg (n=3 each) or placebo (n=4). Patients were followed for 50 days postdose. The objective of the trial was to evaluate the safety and tolerability of BAY 86–6150, with adverse events (AEs) as the primary endpoint. Other endpoints included PK parameters, the effects of BAY 86–6150 on hemostasis markers and coagulation, and the immunogenicity of the compound. BAY 86–6150 was not associated with clinically significant AEs or dose-limiting toxicities and the PK parameters were linear over the dose range, with a half-life of 5–7 hours. Patients demonstrated consistent, dose-dependent thrombin generation ex-vivo in platelet-poor plasma (mean peak effect 26–237 nM thrombin from 6.5–90 μg/kg). Peak thrombin levels over time paralleled the presence of BAY 86–6150 by PK analysis, indicating that the drug in circulation retained activity. There were corresponding decreases in time and duration in the activated partial thromboplastin and prothrombin time testing. In contrast, there was no dose response seen in the thrombogenicity markers evaluated including antithrombin III, prothrombin fragment 1+2, TAT, and D-dimer. One patient demonstrated antibody activity to both BAY 86–6150 and to rVIIa as determined by ELISA testing at baseline. The level of inhibition and titer remained constant when evaluated in follow-up on day 29 and day 49. The data safety monitoring board recommended progression to the highest proposed dose (90 μg/kg). The phase II/III studies are designed to evaluate the clinical efficacy and safety as well as corresponding laboratory markers. Results of the present study suggest that the novel rFVIIa agent BAY 86–6150 is safe and has increased potency and a longer half-life compared with the currently available rFVIIa therapy. BAY 86–6150 may therefore have the potential to improve the treatment of bleeding episodes in hemophilic patients with inhibitors. Disclosures: Mahlangu: Bayer Helathcare: Consultancy, Honoraria, Speakers Bureau; NovoNordisk: Consultancy, Honoraria, Speakers Bureau; IAVI: Consultancy; Maxygen: Consultancy. Coetzee:Bayer Schering Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Laffan:Pfizer: 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, Research Funding; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees. Windyga:Bayer HealthCare Pharmaceuticals: Research Funding; Bayer, Baxter, Behring, NovoNordisk, Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Bayer HealthCare Pharmaceuticals: Research Funding. Schroeder:Bayer Schering Pharma AG: Employment, Equity Ownership. Haaning:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Siegel:Bayer HealthCare Pharmaceuticals: Employment, Equity Ownership. Lemm:Bayer Schering Pharma AG: Employment, Equity Ownership.

Phase II Trial of Rituximab in the Treatment of Inhibitors in Congenital Hemophilia A: Results of the RICH Study

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 27-27 ◽  
Author(s):  
Cindy A. Leissinger ◽  
Rebecca Kruse-Jarres ◽  
Suzanne Granger ◽  
Barbara A Konkle ◽  
Margaret V. Ragni ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Phase Ii ◽  
Null Hypothesis ◽  
Research Funding ◽  
Hemophilia A ◽  
High Titer ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Minor Response ◽  
Inhibitor Titer

Abstract Abstract 27 Antibodies (inhibitors) to exogenously administered factor VIII (FVIII) develop in as many as 30 – 40% of patients with severe hemophilia A. Patients with persistent inhibitors are at increased risk of serious, poorly controlled bleeding which results in significant morbidity and in some cases early death. Rituximab, a chimeric murine/human monoclonal antibody directed against CD20, suppresses circulating and tissue B cells and pre-B cells and has been used in the treatment of a variety of autoimmune and alloimmune disorders. The primary objective of this NHLBI Transfusion Medicine Hemostasis network-sponsored study was to evaluate the role of rituximab as an approach to inhibit the production of FVIII antibodies in patients with severe congenital hemophilia A and high titer inhibitors. Methods: This was a prospective, multi-institution, single-arm, open-label Phase II trial. Eligible subjects were males over 18 months of age with severe hemophilia A and a history of an inhibitor ≥5 Bethesda units (BU). Individuals who were HIV positive, undergoing immune tolerance, or receiving immune modulating therapies were excluded. Following a challenge dose of recombinant FVIII (rAHF-PFM) at 50 IU/kg, and evidence of an inhibitor titer ≥ 5 BU at 5 – 14 days after the challenge dose, subjects received rituximab 375 mg/m2 weekly for 4 weeks. Starting two weeks after the fourth rituximab treatment, inhibitor titers were drawn every 4 weeks. A major response was defined as a fall in the inhibitor titer to < 5 BU at any time up to and including week 22, with the titer remaining < 5 BU following re-challenge with FVIII. A minor response was defined as inhibitor falling to < 5 BU at any time up to and including week 22, with the anamnestic peak following re-challenge with FVIII between 5–10 BU and less than 50% of the original anamnestic peak. The null hypothesis was that no more than 5% of subjects treated with rituximab would be major responders. Results: A total of 23 subjects were enrolled; 21 received the initial FVIII challenge. Of these, 4 subjects did not meet the criteria to receive rituximab treatment, and 1 subject withdrew consent. A total of 16 subjects received at least one dose of rituximab and are included in this analysis. The median age was 14 y (range 4 – 38 y). Three subjects (18.8%) had a major response. If the null hypothesis were true, the probability of 3 or more major responses in 16 subjects would be 0.043, so the null hypothesis was rejected. One subject (6.2%) had a minor response to treatment. All 4 responders and 8 non-responders had a baseline inhibitor titer < 20 BU, resulting in a response rate of 33% in that group vs. 0% in the 4 subjects with a baseline inhibitor titer ≥ 20 BU. Discussion: Infusion of rituximab 375 mg/m2 once per week for four weeks was effective in reducing the anamnestic inhibitor response in 25% of severe hemophilia A subjects with inhibitors who were not receiving concurrent immune tolerance therapy. Those who responded tended to have lower baseline inhibitor levels compared to the group that did not meet the criteria for response. This Phase II study, designed as a proof of concept, demonstrated that rituximab may be useful in lowering inhibitor levels and anamnesis in some patients with inhibitors, but that the effect as a solo treatment strategy is modest, and possibly restricted to patients with inhibitor titers under 20 BU. Further studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies. Acknowledgments: The authors acknowledge the support of Genentech for the provision of rituximab and partial financial support for the study. The authors also acknowledge Baxter Healthcare Corporation for donating the recombinant FVIII used in the trial. Disclosures: Leissinger: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Rituximab, a drug approved for use in treating lymphoma, was studied for its efficacy in suppressing inhibitors against factor VIII in patients with hemophilia and high titer inhibitors. Kruse-Jarres:Baxter: Consultancy, Honoraria; Bayer:; Griforls: Consultancy, Honoraria; Inspiration: Consultancy, Honoraria; NovoNordisk: Consultancy, Honoraria. Konkle:Baxter Corporation: Consultancy, Research Funding; Bayer Corp: Consultancy; Inspiration Biopharmaceuticals: Research Funding; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees. Neufeld:Genentech: Research Funding; Baxter: Research Funding; Bayer: Research Funding. Bennett:Biogen IDEC: Honoraria. Valentino:Baxter Bioscience, Bayer Healthcare, GTC Biotherapeutics, NovoNordisk, Pfizer, CSL Behring, Inspiration Bioscience, and Biogen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document