scholarly journals Longitudinal Assessment of Thrombin Generation in Patients with Hemophilia Receiving Fitusiran Prophylaxis: Phase II Study Results

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-37
Author(s):  
Claude Négrier ◽  
Margaret V. Ragni ◽  
John Pasi ◽  
Steven W. Pipe ◽  
Gili Kenet ◽  
...  
Keyword(s):  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Longitudinal Assessment ◽  
Open Label ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Scientific Advisory

Introduction: Thrombin plays a central role in hemostasis: in the initiation, amplification, and propagation phases of coagulation and in the formation of a stable fibrin clot. Normal hemostatic function requires a balance between procoagulant and anticoagulant proteins that regulate thrombin generation (Negrier et al. Blood Reviews. 2019). Co-inheritance of antithrombin deficiency in people with hemophilia is associated with a milder bleeding phenotype (Shetty et al. Br J Haematol. 2007; Bolliger et al. Thromb Haemost. 2010), supporting the hypothesis that a reduction in antithrombin levels will increase thrombin generation and thus normalize hemostasis in people with hemophilia. Fitusiran is a subcutaneously administered investigational RNA interference therapeutic targeting antithrombin for prophylactic treatment of patients with hemophilia A and B, with or without inhibitors. In a completed Phase I study, monthly subcutaneous administration of fitusiran was found to lower antithrombin levels, increase thrombin generation, and was generally well tolerated (Pasi et al. Blood. 2016; Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe the longitudinal assessment of thrombin generation with fitusiran in the Phase I/II open-label extension study (NCT02554773). Methods: The fitusiran Phase I dose-escalation study (NCT02035605) was followed by the Phase II open-label extension study (NCT02554773), which included male patients, >18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors, who were eligible to continue dosing with monthly subcutaneous fixed doses of fitusiran 50 mg or 80 mg. Thrombin generation was assessed monthly for the first 2 years and every 6 months thereafter using the calibrated automated thrombogram (CAT) assay. Results: Thirty-four patients aged 19-61 with hemophilia A (n=27; 13 with inhibitors and 14 without inhibitors) or hemophilia B (n=7; 2 with inhibitors and 5 without inhibitors) were treated for up to 4.7 years with a median exposure of approximately 2.6 years at the time of the data cut (March 10, 2020). Peak thrombin generation was assessed over the length of the study for each patient. Once-monthly subcutaneous dosing of 50 mg or 80 mg fitusiran prophylaxis over a period of 48 months resulted in sustained antithrombin lowering (a reduction of between 85% to 72% from baseline), which led to peak thrombin levels and an endogenous thrombin potential approaching the normal range seen in healthy volunteers (see figure). Additional subgroup analyses (hemophilia A and B, with or without inhibitor) will be conducted for presentation at the congress. Conclusions: Monthly fitusiran prophylaxis resulted in consistent peak thrombin generation levels in patients with hemophilia A and B, with or without inhibitors over an extended period of time. With the thrombin generation levels in people with hemophilia on fitusiran approaching that of normal healthy adults, this sustained lowering of thrombin has the potential to provide consistent bleed protection in patients over time. Disclosures Négrier: CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Ragni:Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Pasi:BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Roche: Honoraria, Other; Pfizer: Other; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia ; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; Sigilon: Research Funding; Tremeau: Research Funding; Sobi: Consultancy, Honoraria, Other. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Kenet:PI Healthcare, CSL Behring: Honoraria; Bayer, Pfizer, Takeda, BioMarin, Novo Nordisk: Speakers Bureau; Bayer, Pfizer, Roche, Alnylam (Sanofi), Shire: Research Funding; Bayer, Pfizer, BioMarin, Takeda, Roche, Novo Nordisk, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rangarajan:Sangamo: Research Funding; Takeda, Grifols, Roche, Reliance Life Sciences: Other: Conference support, Speakers Bureau. Kichou:Sanofi: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Long-Term Durability, Safety and Efficacy of Fitusiran Prophylaxis in People with Hemophilia a or B, with or without Inhibitors - Results from the Phase II Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Steven W. Pipe ◽  
John Pasi ◽  
Toshko Lissitchkov ◽  
Margaret V. Ragni ◽  
Claude Négrier ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Principal Investigator ◽  
Open Label ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Scientific Advisory ◽  
Open Label Extension

Introduction: Hemophilia is a bleeding disorder characterized by ineffective clot formation due to insufficient thrombin generation. The burden of disease for individuals with hemophilia is high, and less invasive treatment approaches are needed (Machin and Ragni. J Blood Med. 2018). Fitusiran is a once a month subcutaneously administered investigational RNA interference therapeutic targeting antithrombin as a means to improve thrombin generation and promote hemostasis in people with hemophilia A or B, with or without inhibitors. A completed Phase I study demonstrated that monthly subcutaneous administration of fitusiran was generally well tolerated and lowered antithrombin in a dose-dependent manner, resulting in increased thrombin generation and decreased bleeding frequency (Pasi et al. New Engl J Med. 2017). The aim of this abstract is to describe long-term durability, safety and efficacy of monthly fitusiran treatment for patients with hemophilia A or B, with or without inhibitors, in the Phase II open-label extension study. Methods: The fitusiran Phase I study (NCT02035605) followed by the Phase II open-label extension study (NCT02554773) included male patients, >18 years of age, with moderate or severe hemophilia A and B, with or without inhibitors. Patients received monthly fixed doses of fitusiran 50 mg or 80 mg subcutaneously. Exploratory post-hoc analysis of bleed events was used to calculate median annualized bleed rate in patients with hemophilia A and B, with or without inhibitors. Results: Thirty-four patients (hemophilia A, n=27 [13 with inhibitors and 14 without inhibitors]; hemophilia B, n=7 [2 with inhibitors and 5 without inhibitors) were enrolled in the Phase 2 open-label extension study, and were treated for up to 4.7 years with a median exposure of approximately 2.6 years (as of March 10, 2020). Once-monthly subcutaneous dosing of fitusiran prophylaxis lowered antithrombin (a reduction of between 85% to 72% from baseline) across patients over a sustained period of time. An exploratory analysis of bleeding events showed an overall median annualized bleed rate of 0.84 during the observation period (see figure). Breakthrough bleeds were managed successfully in accordance with the revised bleed management guidelines for reduced doses of bypassing agents and replacement factors. As of March 10, 2020, fitusiran was generally well tolerated and no anti-drug antibody formation was detected. Conclusions: Monthly fitusiran prophylaxis provided sustained antithrombin lowering in people with hemophilia A and B, with or without inhibitors, resulting in a low annualized bleeding rate over a median of 2.6 years in an open-label extension study. Disclosures Pipe: Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees; Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding. Pasi:Catalyst Biosciences: Consultancy, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Biotest: Consultancy, Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Alnylam (Sanofi): Other: Personal fees and nonfinancial support ; Octapharma: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia , Speakers Bureau; Pfizer: Other; Novo Nordisk: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia ; Roche: Honoraria, Other; Sobi: Consultancy, Honoraria, Other; Tremeau: Research Funding; Sigilon: Research Funding; ApcinteX: Consultancy, Other: Personal fees ; uniQure: Other: Grants and nonfinancial support , Research Funding; BioMarin: Consultancy, Honoraria, Other: Grants, personal fees, and nonfinancial support; honoraria as member of scientific advisory boards and symposia; Sanofi: Honoraria, Other: Personal fees and nonfinancial support; honoraria as member of scientific advisory boards and symposia, Research Funding; Takeda: Consultancy, Honoraria, Other: Personal fees; honoraria as member of scientific advisory boards and symposia . Lissitchkov:CSL Behring: Other: Principal investigator of clinical trials ; Bayer: Other: Principal investigator of clinical trials ; Novo Nordisk: Other: Principal investigator of clinical trials ; Octapharma: Other: Principal investigator of clinical trials ; Sanofi: Other: Principal investigator of clinical trials ; Roche: Membership on an entity's Board of Directors or advisory committees, Other: lecturer; Shire: Other: lecturer; Sobi: Membership on an entity's Board of Directors or advisory committees, Other: lecturer; Catalyst Biosciences: Other: Principal investigator of clinical trials . Ragni:Alnylam Pharmaceuticals Inc., Baxalta/Takeda, BioMarin, Bioverativ, and Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sangamo: Consultancy, Research Funding; Takeda: Research Funding; Bioverativ: Consultancy, Research Funding; Spark: Consultancy, Research Funding; BioMarin: Consultancy, Research Funding; Alnylam/Sanofi, ATHN, BioMarin, Bioverativ, Sangamo, Spark: Research Funding; Alnylam/Sanofi, BioMarin, Bioverativ, Spark: Consultancy; American Thrombosis Hemostasis Network: Other: Committee work; Baxalta/Takeda, CSL Behring, Genentech, a member of the Roche Group, OPKO Biologics, and Vascular Medicine Institute: Research Funding. Négrier:CSL, F. Hoffmann-La Roche Ltd, Sobi: Other: Travel support; CSL Behring, Octapharma, Shire/Takeda, Sobi: Research Funding; Bayer, Biomarin, CSL Behring, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, F. Hoffmann-La Roche Ltd, Sanofi, Shire/Takeda, Sobi, Spark: Consultancy. Yu:Sanofi: Other: was an employee and stockholder of Sanofi, at the time of study; Albireo Pharmaceuticals, Inc: Current Employment. Poloskey:Sanofi: Current Employment. Mei:Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson:Sanofi: Current Employment, Current equity holder in publicly-traded company.

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.

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.

A Subcutaneously Administered Investigational RNAi Therapeutic (ALN-AT3) Targeting Antithrombin for Treatment of Hemophilia: Interim Weekly and Monthly Dosing Results in Patients with Hemophilia A or B

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 551-551 ◽  
Author(s):  
K John Pasi ◽  
Pencho Georgiev ◽  
Tim Mant ◽  
Michael Desmond Creagh ◽  
Toshko Lissitchkov ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Advisory Board ◽  
Employment Equity ◽  
Advisory Committees ◽  
Educational Support ◽  
Monthly Dosing ◽  
Equity Ownership

Abstract Background: Hemophilia A and B are bleeding disorders characterized by a profound defect in thrombin generation (TG). Furthermore, in the presence of normal levels of endogenous anticoagulants a deficiency in factor VIII and IX results in major hemostatic imbalance and a bleeding phenotype. ALN-AT3 is a subcutaneously administered investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin (AT) that aims to restore the hemostatic balance by increasing TG. Methods: We are conducting a phase 1 multi-center study (NCT02035605) in healthy volunteers and patients with moderate to severe hemophilia A or B. Part A of this study has been completed and assessed a single ascending dose study in healthy volunteers. Parts B and C are multiple ascending dose studies in patients with hemophilia who are receiving weekly or monthly dosing, respectively. Primary endpoints are safety and tolerability. Secondary endpoints include PK, AT knockdown; change in thrombin generation and whole blood clot formation as measured by Calibrated Automated Thrombin generation and ROTEM thromboelastometry. Exploratory endpoints include evaluations of bleed pattern and control. Results: Part A enrolled 4 healthy volunteers, randomized (3:1) to 30 mcg/kg ALN-AT3 or placebo; no serious adverse events (SAE) or injection site reactions were observed. A total of 12 patients with severe hemophilia (10 hemohilia A; 2 hemophilia B) were enrolled in Part B and received 3 weekly subcutaneous doses of ALN-AT3 at 15 (n=3), 45 (n=6), and 75 (n=3) mcg/kg. Similar to part A, weekly administration of ALT-AT3 was generally safe and well tolerated in patients with hemophilia; no SAEs, discontinuations, clinical thromboembolic events or clinically significant D-dimer increases were reported. In the 75 mcg/kg dosing cohort, the mean maximum AT knockdown was 59% (p<0.05, relative to baseline), with nadir levels achieved between days 28 and 42. Maximum plasma AT knockdown of 86% was achieved, resulting in thrombin generation increases that correlated with AT knockdown and a bleed-free period of 114 days in the patient achieving the highest level of AT knockdown. The association between AT KD and TG was assessed in a post hoc exploratory analysis in which AT KD was categorized into tertiles. Part C aims to enroll several cohorts (n=3 per cohort) and will assess a monthly dosing schedule (x3 doses) of ALN-AT3. Patients in cohort 1 and 2 were dosed at 225 and 450 mcg/kg, respectively. Up to 4 additional cohorts may be enrolled within Part C. Updated safety, PK, AT knockdown, TG results as well as bleed patterns from Parts B and C will be presented. Conclusions: Emerging clinical data suggest that targeting AT could be a promising approach for restoring hemostatic balance in hemophilia. The potential for low volume subcutaneous administration, monthly dosing, and applicability to patients with hemophilia A and B with and without inhibitors make ALN-AT3 a potentially encouraging investigational therapy. Disclosures Pasi: Octapharma: Research Funding; Biogen, Octapharma, Genzyme, and Pfizer: Consultancy, Honoraria. Off Label Use: ALN-AT3 is an investigational RNAi therapeutic targeting the endogenous anticoagulant antithrombin.. Mant:Quintiles: Employment, Equity Ownership. Creagh:Bayer Healthcare UK: Honoraria. Austin:SOBI: Other: member of advisory board and received educational support; Pfizer: Other: member of advisory board and received educational support; Novo Nordisk: Other: member of advisory board and received educational support; CSL Behring: Other: member of advisory board and received educational support; Bio Products Laboratory: Other: member of advisory board and received educational support; Bayer: Other: member of advisory board and received educational support; Baxter: Other: member of advisory board and received educational support. Brand:Alnylam: Honoraria. Chowdary:Bayer: Consultancy; Biogen Idec: Consultancy; Baxter: Consultancy; CSL Behring: Consultancy, Research Funding; Novo Nordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; SOBI: Consultancy. Ragni:Tacere Benitec: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Bristol Myers Squibb: Research Funding; Biogen: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dimension: Research Funding; Bayer: Research Funding; SPARK: Research Funding; Genentech Roche: Research Funding; Pfizer: Research Funding; Vascular Medicine Institute: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; CSL Behring: Research Funding. Chen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Akinc:Alnylam Pharmaceuticals: Employment, Equity Ownership. Sorensen:Alnylam Pharmaceuticals: Employment, Equity Ownership. Rangarajan:Octapharma: Other: Investigator.

scholarly journals Emicizumab Subcutaneous Dosing Every 4 Weeks for the Management of Hemophilia A: Preliminary Data from the Pharmacokinetic Run-in Cohort of a Multicenter, Open-Label, Phase 3 Study (HAVEN 4)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 86-86
Author(s):  
Victor Jimenez-Yuste ◽  
Midori Shima ◽  
Katsuyuki Fukutake ◽  
Michaela Lehle ◽  
Sammy Chebon ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Preliminary Data ◽  
Research Funding ◽  
Hemophilia A ◽  
Prediction Interval ◽  
Open Label ◽  
Phase 3 ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Expansion Cohort

Abstract Introduction Emicizumab is a novel, subcutaneously (SC) administered, recombinant, humanized, bispecific monoclonal antibody that is under investigation for the prevention of bleeds in persons with hemophilia A (PwHA). Emicizumab restores the function of activated coagulation FVIII, which is deficient in PwHA, by bridging activated FIX and FX to enable effective hemostasis. Due to its mechanism of action, emicizumab is not expected to induce or be affected by anti-FVIII antibodies (inhibitors) and is thus being assessed in PwHA both with and without inhibitors. Once-weekly emicizumab prophylaxis was shown to substantially reduce bleed rates by 87% in PwHA with inhibitors compared with no prophylaxis in the Phase 3 HAVEN 1 study (Oldenburg et al. NEJM 2017; July 10: epub). An interim analysis of the HAVEN 2 study showed that once-weekly emicizumab also prevented or reduced bleeds in pediatric PwHA with inhibitors (&lt;12 years of age) (Young et al. RPTH 2017;1 (S2): Abstract OC 24.1). The ongoing HAVEN 3 study (NCT02847637) will assess emicizumab prophylaxis in PwHA without inhibitors. The ongoing multicenter, open-label, Phase 3 HAVEN 4 study (NCT03020160) is assessing emicizumab administered every 4 weeks (Q4W) to PwHA with and without inhibitors; the study consists of a pharmacokinetic (PK) run-in phase followed by an expansion phase. The objective of the PK run-in phase of HAVEN 4 reported here was to investigate the PK and preliminary efficacy and safety outcomes of an emicizumab dose that was previously not assessed in a phase 1 study. Methods Eligible patients in the HAVEN 4 study were aged ≥12 years with congenital hemophilia A with or without inhibitors. In the PK run-in phase, patients must have been receiving episodic (on-demand) treatment with FVIII replacement therapy or bypassing agents with documentation of treatment for ≥24 weeks prior to study entry; the on-study regimen is 6 mg/kg Q4W. The regimen being investigated in the subsequent expansion cohort includes a loading dose of 3 mg/kg SC QW for 4 weeks followed by emicizumab 6 mg/kg Q4W for ≥24 weeks. Results At the data cutoff of April 10, 2017, 7 patients with severe hemophilia A had enrolled into the PK run-in cohort - 4 patients without inhibitors and 3 patients with inhibitors, of which 6 patients were aged ≥18 years of age and followed for a minimum of 6 weeks. Individual observed PK profiles were within the 95% prediction interval computed from a population PK model based on clinical data from a 1.5 mg/kg QW regimen (Figure). Emicizumab PK parameters derived after single SC administration of 6 mg/kg emicizumab (Table) were consistent with values observed in previous studies with emicizumab (Uchida et al. Blood 2016; 127 (13):1633-1641). During the observation period (median, 8 weeks), 14 adverse events (AEs) were reported in 5 patients at the time of data cut-off, including 1 Grade 3 serious AE (worsening of hypertension); no AEs were considered related to study drug. No anti-drug antibodies were detected. Also, 6 of 7 patients had no bleeds while receiving Q4W emicizumab; 1 patient experienced 3 spontaneous nose bleeds on Study Days 12, 14 and 21, which did not require treatment. Conclusions Preliminary data from the HAVEN 4 study showed that Q4W dosing of emicizumab at 6 mg/kg exhibited a PK behavior that was consistent with prior predictions, leading to an expected steady-state concentration average similar to the clinically confirmed dosing regimen (i.e., 1.5 mg/kg/QW). The safety and efficacy results from this PK run-in cohort enabled the opening of the HAVEN 4 expansion cohort, and provided promising support for a Q4W emicizumab prophylaxis regimen for the management of hemophilia A. The HAVEN 4 study is fully enrolled (N=48, including the PK run-in cohort patients). Disclosures Jimenez-Yuste: Roche: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding. Shima: Pfizer: Honoraria, Research Funding; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Honoraria, Research Funding; Biogen: Consultancy, Honoraria; Kaketsuken: Honoraria; Novo: Honoraria, Research Funding; Bayer: Honoraria, Research Funding. Fukutake: EPS: Research Funding; Cimic: Research Funding; Sekisui Medical: Consultancy, Honoraria, Speakers Bureau; Roche Diagnostics: Honoraria, Speakers Bureau; Bioverative: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbott: Honoraria, Speakers Bureau; Kaketsuken: Honoraria; Japan Blood Products Organization: Honoraria, Research Funding; Pharmaceutical Co., Ltd: Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LSI Medience: Consultancy; SRL Inc: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Siemens: Speakers Bureau; CSL Behring: Consultancy, Honoraria, Research Funding; Chuugai: Consultancy, Honoraria, Speakers Bureau; Octapharma AG: Honoraria; Torii Pharmaceutical Co., Ltd: Speakers Bureau. Lehle: F. Hoffmann La Roche: Employment. Chebon: F. Hoffmann-La Roche Ltd: Employment. Retout: F. Hoffmann La Roche: Employment. Portron: F. Hoffmann La Roche: Employment. Levy: Genentech, Inc.: Employment.

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.

scholarly journals A Multi-Center, Open Label, Phase I/II Study to Assess the Safety and Efficacy of Tenalisib Given in Combination with Romidepsin in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-10
Author(s):  
Swami P. Iyer ◽  
Auris Huen ◽  
Bradley Haverkos ◽  
Weiyun Z. Ai ◽  
Craig Okada ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Family Member ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Optimal Dose ◽  
Open Label ◽  
Advisory Committees ◽  
Expansion Cohort

Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A&gt;.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

scholarly journals The Role of Antithrombin Lowering in Patients with Hemophilia: Hemostatic Control Pre- and Post-Fitusiran Dosing Interruption

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2477-2477 ◽  
Author(s):  
Margaret V. Ragni ◽  
Pencho Georgiev ◽  
Michael Desmond Creagh ◽  
Toshko Jelev Lissitchkov ◽  
Steve K. Austin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Thrombin Generation ◽  
Time Course ◽  
Hemophilia A ◽  
Hemophilia B ◽  
Phase 2 ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Clinical Hold

Abstract Introduction Hemophilia A and hemophilia B are rare bleeding disorders characterized by insufficient thrombin generation due to deficiencies in factors VIII or IX, respectively. Standard treatment for hemophilia is currently based on replacement of the deficient factor with factor concentrate. This, unfortunately, subjects the patient to the risk of developing neutralizing antibodies, or inhibitors, against replacement factor VIII or IX. Individuals with inhibitors become refractory to standard replacement therapy, a serious complication for as many as one-third of patients with severe hemophilia A and a lower proportion of patients with hemophilia B. Fitusiran is a once-monthly subcutaneously administered investigational RNA interference therapeutic that targets antithrombin (AT) to improve thrombin generation (TG) and promote hemostasis in patients with hemophilia A or hemophilia B with or without inhibitors. In September 2017, fitusiran dosing in the Phase 2 open-label extension (OLE) study was temporarily suspended to investigate a case of fatal cerebral venous sinus thrombosis. Following this investigation, fitusiran dosing resumed in December 2017 with protocol amendments for bleed management dosing and safety monitoring. During the temporary dosing suspension, AT levels, TG, bleeding events, and frequency of factor replacement and bypassing agents were assessed. Methods Before the dosing suspension, 33 patients (hemophilia A=27, hemophilia B=6) were enrolled, of whom 28 patients continued treatment over 20 months in the Phase 2 OLE study, with a median of 11 months on study. As of June 2018, data collected monthly during the clinical hold included AT levels, TG, and description and management of treated bleeding events before and during the clinical hold, which were used to estimate annualized bleeding rates (ABRs) and bleeding rates per month. Results AT activity in patients previously receiving fitusiran demonstrated a progressive increase during the interruption of fitusiran dosing. Median %AT increased to >60% after a 5-month period compared with the last data point before dosing interruption. These data confirm our previous findings that discontinuation of fitusiran results in gradual recovery of AT activity over time. Subjects also demonstrated a concomitant steady decrease in TG during the interruption of fitusiran dosing, which occurred over a similar time course to that of AT recovery. Consistent with both the increase in AT activity and decrease in TG, preliminary analysis shows the median overall ABR increased from 1.43 events/year before the dosing interruption to 6.07 events/year during the dosing interruption. Conclusions During a period of fitusiran dosing suspension, recovery of AT activity was accompanied by a decrease in TG and an increase in bleeding events. These observations provide support for the therapeutic hypothesis that AT activity lowering by fitusiran leads to an increase in TG and improved hemostasis. Phase 3 studies of fitusiran are ongoing. Disclosures Ragni: Bioverativ: Consultancy, Research Funding; MOGAM: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Research Funding; SPARK: Consultancy, Research Funding; Shire: Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Sangamo: Research Funding; Biomarin: Membership on an entity's Board of Directors or advisory committees, Research Funding. Georgiev:Alnylam: Consultancy. Lissitchkov:Novo Nordisk: Other: Investigator fees as a participant of the clinical trial. Austin:Pfizer: Research Funding. Chowdary: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; Freeline: Consultancy; Bayer: Honoraria; Baxalta (Shire): 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; Swedish Orphan Biovitrum AB (Sobi): Honoraria; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Foster:Sanofi Genzyme: Employment. Yu:Sanofi Genzyme: Employment. Benson:Sanofi Genzyme: Employment. Madigan:Alnylam Pharmaceuticals Inc: Employment. Nguyen:Alnylam Pharmaceuticals Inc: Employment. Ali:Sanofi Genzyme: Employment. Kadam:Sanofi Genzyme: Employment. Jain:Sanofi Genzyme: Employment. Pasi:Octapharma: Honoraria; Catalyst Bio: Honoraria; Bayer: Speakers Bureau; Shire: Speakers Bureau; NovoNordisk: Speakers Bureau; Sobi: Honoraria; Apcintex: Honoraria; Biomarin: Honoraria, Research Funding; Pfizer: Speakers Bureau; Alnylam: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding.

scholarly journals The Relationship of Joint Range of Motion to Factor Activity in Patients with Hemophilia A and B without Prophylaxis: A Longitudinal Assessment of the CDC-UDC Hemophilia Dataset

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 756-756
Author(s):  
Michael Wang ◽  
Michael Recht ◽  
Neeraj Iyer ◽  
David L Cooper ◽  
John Michael Soucie
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia A ◽  
Severe Disease ◽  
Longitudinal Assessment ◽  
Advisory Committees ◽  
Joint Range Of Motion ◽  
Joint Range ◽  
The Relationship ◽  
Over Time

Abstract Background: Recurrent joint bleeding in severe congenital hemophilia results in arthropathy and functional impairment. Clinical and epidemiologic evidence suggest that patients with moderate and mild hemophilia also experience joint bleeding, particularly with factor activity (FA) levels below 15-20%. While arthropathy and joint interventions have been reported in mild-moderate hemophilia, the longitudinal assessment of arthropathy development and relationship to FA has not been reported. Methods: During the Centers for Disease Control and Prevention (CDC) Universal Data Collection (UDC) surveillance initiative (1998-2011), joint range of motion (ROM) measurements were taken on each of 10 joints (shoulders, elbows, hips, knees and ankles) by trained care providers using standardized methods at each comprehensive visit. Data were extracted from male patients with hemophilia (PWH) age ≥2 years with baseline FA levels ≤ 40%, excluding those who had been prescribed prophylaxis or had evidence of an inhibitor at any time. ROM measures from all 10 joints combined for each subject and data collected similarly on a population without bleeding or joint disorders (Soucie JM, Haemophilia 2012) age 12-20 males) were used to calculate a proportion of normal ROM (PN-ROM) measure for each study subject and each normal male using the 12-20 year old normals as the reference. Because very young subjects have greater ROM than 12 - 20 year olds, the PN-ROM value for these subjects could exceed 100%. Least square means of the PN-ROM values for subjects in categories of these characteristics were compared using general linear regression. Data collected from 2 to 14 UDC visits for each subject were analyzed using mixed model repeated measures linear regression to evaluate the effects of patient characteristics on the rate of ROM loss over time. Results: There were 6,703 (4,807 hemophilia A) eligible PWH with 30,102 UDC visits (mean 4.5 per patient). Of these, 26% had severe and 31% moderate hemophilia, 52% were youth or teens, 10% were either black or Hispanic, and 45% were overweight or obese. PN-ROM declined with age (106% for youngest to 85% for oldest subjects), and was associated with hemophilia severity, race/ethnicity, obesity, and viral illnesses. The relationship between PN-ROM and the combination of age and baseline FA level (Table) showed values for most PWH were within 10 percent of similarly aged normals. Only PWH ≥30 years old with FA ≤2% and those ≥50 years old with FA ≤5% had mean PN-ROM values &gt;10% less than controls; those ≥40 years old with FA &lt;1% had PN-ROM values &gt;20% less than controls. The figures demonstrate that the loss in PN-ROM is linear with the steepest decline among subjects with severe disease, and the overall magnitude of the decline appears to be greater for subjects with hemophilia A than B. In the multivariate analysis subjects with &lt;1% FA had a 0.428 percent greater decrease in PN-ROM each year relative to those with 16% - 40% FA and this excess decrease was highly statistically significant (p &lt; 0.001). A similar significant effect was seen among subjects with either 1% - 5% or 6% - 9% FA, however, the magnitude of the decrease in the PN-ROM (0.126 for both) was about one-fourth that seen among those with severe hemophilia. FA levels from 10% to 15% did not significantly influence the rate of PN-ROM change over time relative to those with FA &gt;15%. Those with hemophilia B lost PN-ROM at a 0.05 percent slower rate than those with hemophilia A (p &lt; 0.001). Conclusion: The effect of FA level on ROM loss is far greater than that of any of the other characteristics, but only for patients with FA levels less than 10%. This emphasizes the need to maintain a high index of suspicion in individuals with moderate and low-mild hemophilia and of older age. The effect of hemophilia type (A vs B) on rate of ROM loss is about one-tenth that of having severe disease, and may be one reason for the difficulty in proving that hemophilia B has a less severe phenotype. Figure Figure. Disclosures Wang: Acerta Pharma: Consultancy, Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Dava Oncology: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; June Therapeutics: Research Funding; Kite Pharma: Research Funding; Onyx: Research Funding; Pharmacyclics: Research Funding; Proteolix: Honoraria, Research Funding. Recht: Biogen: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding. Iyer: Novo Nordisk Inc.: Employment. Cooper: Novo Nordisk Inc.: Employment.

Recombinant Porcine Factor VIII Corrects Thrombin Generation and Improves Clot Structure In Vitro in Plasma Containing Anti-Factor VIII Inhibitory Antibodies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Claude Negrier ◽  
Shannon L. Meeks ◽  
Johannes Oldenburg ◽  
Uri Martinowitz ◽  
Jean-Claude Bordet ◽  
...  
Keyword(s):  
Factor Viii ◽  
Board Of Directors ◽  
Inhibitory Activity ◽  
Research Funding ◽  
Thrombin Generation ◽  
Hemophilia A ◽  
Cross Reactivity ◽  
Advisory Committees ◽  
Clot Structure

Abstract Abstract 2282 Introduction: Treatment of bleeding episodes in patients with hemophilia A who have developed inhibitory antibodies can be challenging. Using human factor VIII (FVIII) and, historically, porcine FVIII in patients with a low inhibitor titer are therapeutic options, and provide ease of monitoring. A B-domain deleted recombinant porcine FVIII (rpFVIII; OBI-1), which may possess low cross-reactivity to anti-human FVIII antibodies, is being investigated for the treatment of bleeding episodes in individuals with congenital hemophilia A and inhibitors, and in those with acquired hemophilia. The in vitro capacity of this molecule to correct hemostasis has been further characterized. Methods: This is an international, multicenter in vitro study. Individuals with hemophilia A and inhibitor antibodies were recruited during routine out-patient visits between January 2011 and March 2011. Written and signed informed consent was obtained prior to venepuncture. Blood was obtained from volunteers with congenital hemophilia A and inhibitors attending routine visits at participating hemophilia treatment centers. A single blood sample was obtained from consenting individuals under protocols approved by Institutional Review Boards/Ethical Committees. In vitro spiking experiments with OBI-1 were conducted using FVIII-deficient plasma with and without anti-FVIII inhibitory activity. Three control inhibitor plasmas were provided, composed of FVIII deficient plasma to which the anti-C1 monoclonal antibody (MAb) to human FVIII (Sanquin, Amsterdam, the Netherlands) was added at two concentrations to reach anti-human FVIII inhibitory activity of 4.9 Bethesda Units (BU)/mL and 32.8 BU/mL with anti-porcine anti-FVIII inhibitory activity of 2.7 BU/mL and 19.1 BU/mL, respectively; and FVIII deficient plasma to which “polyclonal” mixture of the anti-C1 MAb, along with an anti-A2 and 2 anti-C2 MAbs was added. Plasma from eight patients with hemophilia A and inhibitors was tested. Hemostatic correction by OBI-1 was assessed by thrombin generation measurement (Calibrated Analytical Thrombography assay, Synapse BV, Maastricht, The Netherlands) and clot structure using electron microscopy. Epitope mapping of the inhibitor patient plasma was undertaken at a central laboratory (Atlanta, Georgia, USA) using an Enzyme-Linked Immunosorbent Assay (ELISA) with human/porcine FVIII hybrids as the antigen. Results: The results showed a dose-dependent and anti-porcine titer dependent correction of thrombin generation parameters (peak and ETP) with OBI-1 at concentrations equivalent to 100 IU/dL, 200 IU/dL, and 400 IU/dL, which paralleled a correction of the clot structure (number and diameter of fibrin fibres). These results were only dependent on the anti-porcine titer. In samples with high titers of anti-porcine inhibitor (>10 BU), little or no restoration of the diminished thrombin generation was observed when various OBI-1 concentrations were added to the plasma. In the plasmas with high anti-human titers (≥10 BU/mL) the dominant epitope was C2 in 3 plasmas, A2 in 1 plasma, and indeterminate in 3 plasmas. The plasmas with no restoration of the thrombin generation with even the highest dose of OBI-1 all had antibody detected to more than one domain of FVIII or were not able to be mapped due to high porcine cross-reactivity. Conclusion: In vitro data obtained with spiking experiments using OBI-1 indicate that it has the potential to correct surrogate markers of hemostasis depending on the anti-porcine FVIII titer which may translate into in vivo effectiveness. Further investigation into the epitope specificity of responsive and non-responsive inhibitor plasmas correlation with effectiveness is warranted. Disclosures: Negrier: Inspiration Biopharmaceuticals: Honoraria, Research Funding. Meeks:Inspiration Biopharmaceuticals: Research Funding. Oldenburg:SOBI: Membership on an entity's Board of Directors or advisory committees; Catalyst: Membership on an entity's Board of Directors or advisory committees; Inspiration: Consultancy, Honoraria, Research Funding; LFB: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria, Research Funding; CSL Behring: Consultancy, 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, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen Idec: Honoraria; Octapharma: Consultancy, Honoraria, Research Funding. Bordet:Inspiration Biopharmaceuticals: Research Funding. Poetzsch:Inspiration Biopharmaceuticals: Research Funding. Al Dieri:Synapse BV: Employment. Dargaud:Inspiration Biopharmaceuticals: Research Funding. Hemker:Synapse BV: Employment. Eckmann:Sanquin Diagnostic Services: Employment. Gomperts:Inspiration Biopharmaceuticals: Employment. Lee:Inspiration Biopharmaceuticals: Employment.

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