Recombinant Factor IX in Surgical Management of Hemostasis in Hemophilia B Patients: A Prospective Clinical Trial

Abstract Management of hemostasis with factor IX replacement during surgical procedures on patients with hemophilia B is vital to patient safety. A recombinant factor IX (rFIX, nonacog gamma, RIXUBIS, BAX 326) presents a treatment alternative for hemophilia B; nonacog gamma is manufactured with no materials of human or animal origin, and includes as two-step virus inactivation (solvent/detergent treatment and nanofiltration). This multi-national clinical trial was conducted to investigate the efficacy and safety of nonacog gamma for perioperative use in previously-treated patients with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B. Interim results of 14 (11 major) surgeries showed that nonacog gamma is safe and effective in maintaining hemostasis in the surgical setting;1 the results of all 38 surgeries are presented here. Previously-treated hemophilia B immunocompetent patients aged 12 to 65 years with no evidence of a history of FIX inhibitors were eligible for participation if they were either: 1) participating in another trial with nonacog gamma and required an emergency or elective major or minor surgical, dental, or other invasive procedure; or 2) if not participating in any other nonacog gamma clinical study, they required elective major surgery and had been treated previously with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 exposure days. Pre-operative FIX levels were targeted at 80%-100% of normal for major, and 30%-60% of normal for minor surgeries, through an individualized nonacog gamma dosing approach. Hemostatic efficacy was evaluated intra- and post-operatively by determination of actual versus predicted blood loss and a semi-quantitative 4-point hemostatic efficacy rating scale (excellent, good, fair, none); safety was assessed in terms of the occurrence of adverse events. Thirty patients participated in this study, 10 of whom underwent multiple surgeries and were re-enrolled for each surgery. Of a total of 38 surgeries performed, 21 were major (14 orthopedic) and 17 were minor. Hemostatic efficacy for 37/38 surgeries (including 20/21 major surgeries) had a rating of 'excellent' and one was 'good' (a knee joint replacement). At drain removal (n=14), the ratings for all major surgeries were either 'excellent' (10/14) or 'good' (4/14). On postoperative day 3, 6 of 7 major surgeries where no drain was employed had a rating of 'excellent', and one had a rating of 'good'. At discharge from hospital, 12/21 were 'excellent', 7/21 were 'good' and 2 were 'fair' (both had ratings of 'excellent' intraoperatively and at drain removal). For 16/21 major surgeries, the actual blood loss was below (n=8) or equal to (n=8) the average predicted blood loss and the mean post-operative blood loss was 552.4 mL (range: 11-1100 mL) in subjects who had a drain placed. For 12/17 minor surgeries, actual intraoperative blood loss was below the average predicted blood loss, for 4/17 minor surgeries, the actual intraoperative blood loss matched the average predicted blood loss, and for 1 minor surgery (intra-articular infiltration) actual blood loss was between the average predicted and maximum predicted blood loss. Nonacog gamma was safe and well tolerated. One possibly related AE (hemorrhagic anemia) was reported. This event was resolved at the completion of the study. No thrombogenic events or severe allergic reactions, nor induction of inhibitory antibodies to FIX or total binding antibodies to FIX were observed. Conclusion: Nonacog gamma provides a safe and effective treatment alternative for perioperative management of hemostasis in hemophilia B patients in a variety of surgical settings. References 1 Windyga J, Lissitchkov T, Stasyshyn O, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8. Disclosures Windyga: CSL Behring: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: 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; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: 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; Octapharma: 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. Mamonov:Baxalta (Now part of Shire): Research Funding. Chapman:Baxalta (Now part of Shire): Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Abbuehl:Shire, formerly Baxalta and Baxter: Employment, Equity Ownership.

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Pharmacokinetic Profile of Nonacog Gamma (recombinant factor IX) in Previously-Treated Patients with Severe or Moderately Severe Hemophilia B

Blood ◽

10.1182/blood.v128.22.4978.4978 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4978-4978

Author(s):

Jerzy Windyga ◽

Toshko Jelev Lissitchkov ◽

Miranda Chapman ◽

Srilatha D. Tangada ◽

Nirjhar Chatterjee

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Pivotal Trial ◽

Advisory Committees ◽

Recombinant Factor Ix ◽

Previously Treated Patients ◽

Previously Treated ◽

Equity Ownership

Abstract Pharmacokinetic (PK) parameters are important surrogate indicators for hemostatic efficacy replacement therapy in the treatment of haemophilia patients. Nonacog gamma (Rixubis) is a recombinant factor IX (rFIX) concentrate that is manufactured using two viral inactivation steps (solvent/detergent treatment and nanofiltration) and without any materials of animal origin. Clinical trials of nonacog gamma included a comprehensive evaluation of PK in hemophilia B patients across multiple age groups and a direct comparison to determine equivalence with another licensed, commercially-available factor IX product. The objective of this evaluation was to assess the factor IX activity across clinical development with nonacog gamma. PK parameters for nonacog gamma were evaluated in a non-bleeding state in previously-treated patients with severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B in three prospective clinical trials (a pivotal trial in adults,1 a pediatric trial in children aged 2 to 12 years,2 and a third trial in patients undergoing surgical procedures3). Factor IX activity was determined using a one-stage clotting assay. In the pivotal trial, PK equivalence with a comparator recombinant factor IX product (nonacog alfa) was determined by the ratio of AUC0-72 h (area under the plasma concentration versus time curve from 0 to 72 hours post-infusion), per dose with a type I error of 5% for the two-sided 90% confidence interval (equivalence margin: 80% to 125%). Windyga et al. (2014) established bioequivalence of nonacog gamma with a comparator recombinant factor IX in the pivotal trial (N=27), as the 90% CI for the ratio of the AUC0-72 h per dose ranged from 103% to 109%.1 A plot of mean factor IX activity levels versus time after start of infusion on a linear scale and log scale (figure 1a and 1b) depicts the equivalence throughout the 72-hour follow-up period. A similar pattern can be observed in the linear and log regression for mean factor IX activity in pediatric patients (N=23). These results are further supported by consistent PK parameters determined prior to surgical intervention in the surgery trial (N=12).3 Two important PK parameters determined in each study were as follows: mean [STD] T ½ 26.70h (9.55), incremental recovery (IR) 0.87 (0.22) for nonacog gamma and 27.87h (9.22), IR 0.76 (0.20) for the comparator rFIX in the pivotal trial, 25.31h (3.130), IR 0.67 (0.16) in the pediatric trial, and 23.60h (3.60), IR 1.06 (0.35) in the surgery trial. Conclusion Factor IX activity of nonacog gamma throughout its clinical development support previous finding of its equivalence with another licensed recombinant factor IX concentrate in patients with severe to moderately severe hemophilia B. References 1. Windyga J, Lissitchkov T, Stasyshyn O, et al. Pharmacokinetics, efficacy and safety of BAX326, a novel recombinant factor IX: a prospective, controlled, multicentre phase I/III study in previously treated patients with severe (FIX level <1%) or moderately severe (FIX level ≤2%) haemophilia B. Haemophilia. 2014 Jan;20(1):15-24. 2. Urasinski T, Stasyshyn O, Andreeva T, et al. Recombinant factor IX (BAX326) in previously treated paediatric patients with haemophilia B: a prospective clinical trial. Haemophilia. 2015 Mar;21(2):196-203. 3. Windyga J, Lissitchkov T, Stasyshyn O, et al. Efficacy and safety of a recombinant factor IX (Bax326) in previously treated patients with severe or moderately severe haemophilia B undergoing surgical or other invasive procedures: a prospective, open-label, uncontrolled, multicentre, phase III study. Haemophilia. 2014 Sep;20(5):651-8. Disclosures Windyga: 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; Nordisk: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Sanofi: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau; Biogen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, 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; Octapharma: 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; Aspen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Chapman:Baxalta (Now part of Shire): Employment, Equity Ownership. Tangada:Baxalta US Inc., now part of Shire: Employment, Equity Ownership. Chatterjee:Baxalta (Now part of Shire): Employment, Equity Ownership.

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Pharmacokinetics Of Recombinant Factor IX Fc Fusion Protein (rFIXFc) In Pediatric Subjects With Hemophilia B: An Interim Analysis Of The Kids B-LONG Study

Blood ◽

10.1182/blood.v122.21.3599.3599 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3599-3599

Author(s):

Kathelijn Fischer ◽

Roshni Kulkarni ◽

Myles Bradbury ◽

Margaret V. Ragni ◽

Savita Rangarajan ◽

...

Keyword(s):

Board Of Directors ◽

Half Life ◽

Interim Analysis ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Employment Equity ◽

Advisory Committees ◽

Age Cohorts ◽

Equity Ownership

Abstract Introduction Prophylaxis with factor IX (FIX) is the optimal treatment for patients with hemophilia B; however, due to the short half-life of currently available FIX products, frequent injections may be required to prevent bleeding episodes. To prolong half-life and reduce injection frequency, a long-acting recombinant FIX Fc fusion protein (rFIXFc) consisting of one rFIX molecule covalently linked to the Fc domain of immunoglobulin G1 (IgG1) was developed. In a phase 3 study in adults and adolescents, rFIXFc had a 2.43-fold increase in half-life and 50% reduction in clearance (CL) compared with FIX (BeneFIX®) (J Thromb Haemost. 2013;11[2]:241). The Kids B-LONG study (NCT01440946) was designed to evaluate the pharmacokinetics (PK), safety, and efficacy of rFIXFc prophylaxis in previously treated pediatric subjects with hemophilia B. The objective of this planned interim analysis was to determine the PK parameters of rFIXFc in subjects enrolled in Kids B-LONG and compare these parameters to their pre-study FIX PK parameters. Methods This multicenter, open-label, phase 3 study is currently enrolling previously treated subjects aged<12 years with severe hemophilia B (≤2 IU/dL endogenous FIX), at least 50 exposure days (EDs) to FIX products, and no inhibitors to FIX. Subjects are stratified into two age cohorts (<6 and 6 to<12 years of age). A weekly prophylactic regimen of 50-60 IU/kg of rFIXFc is administered to all subjects, with subsequent dose and interval adjustments based upon PK data and bleeding frequency. Subjects will continue treatment until they achieve 50 EDs. The primary endpoint is the incidence of inhibitor formation. A sequential PK analysis is performed to compare the PK parameters of rFIXFc with that of pre-study FIX products. PK sampling of pre-study FIX occurs at baseline prior to first dose of FIX (50 IU/kg) and at 5 additional time points through 48 hours. PK sampling of rFIXFc occurs prior to first dose of 50 IU/kg rFIXFc and at 7 additional time points through 168 hours following the first dose; a washout period of 96 hours is required before the first dose of both pre-study FIX and rFIXFc. Plasma FIX activity is measured using the one-stage clotting assay calibrated against a commercially available FIX plasma standard and the FIX activity-over-time profiles are analyzed by non-compartmental analysis (NCA) using the PK data analysis software Phoenix™ WinNonlin 6.2.1.51. A data cut-off date of 23 April 2013 was used to report PK data in this interim analysis. Results At the time of this interim analysis, 24 subjects were enrolled and had received at least one dose of pre-study FIX and/or rFIXFc. Of 18 subjects with evaluable PK profiles, 15 had complete PK profiles for both pre-study FIX (BeneFIX®, Haemosolvex®, or Alphanine®) and rFIXFc. A comparison of PK parameters for rFIXFc versus FIX for both age cohorts is presented in Table 1. rFIXFc had a more than 3-fold prolongation in half-life and a more than 60% reduction in CL compared to the FIX products. Conclusion In comparison to currently available FIX products, rFIXFc had a prolonged half-life and reduced CL in pediatric subjects, which was similar to previous observations in adults and adolescents. The final analysis of the Kids B-LONG study will provide further PK information and evaluate the safety and efficacy of rFIXFc in children. Disclosures: Fischer: Biogen Idec, Baxter, Novo Nordisk, Bayer: Membership on an entity’s Board of Directors or advisory committees; Baxter, Bayer, Novo Nordisk, Pfizer: Research Funding. Kulkarni:Biogen Idec, Novo Nordisk, Baxter : Membership on an entity’s Board of Directors or advisory committees. Ragni:Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb, Smith Kline Glaxo, Tacere Benitec: Consultancy; Baxter, Bayer, Biogen Idec, Bristol Myers Squibb, CSL Behring, Merck, Novo Nordisk, Pfizer, Smith Kline Glaxo: Research Funding. Rangarajan:Baxter, Pfizer: Research Funding; Biogen Idec : Membership on an entity’s Board of Directors or advisory committees. Dong:Biogen Idec: Employment, Equity Ownership. Li:Biogen Idec: Employment, Equity Ownership. Jiang:Biogen Idec: Employment, Equity Ownership. Nugent:Biogen Idec: Employment, Equity Ownership. Pierce:Biogen Idec: Employment, Equity Ownership. Allen:Biogen Idec: Employment, Equity Ownership.

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Spk-9001: Adeno-Associated Virus Mediated Gene Transfer for Hemophilia B Achieves Sustained Mean Factor IX Activity Levels of >30% without Immunosuppression

Blood ◽

10.1182/blood.v128.22.3.3 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3-3 ◽

Cited By ~ 13

Author(s):

Lindsey A. George ◽

Spencer K. Sullivan ◽

Adam Giermasz ◽

Jonathan M. Ducore ◽

Jerome M. Teitel ◽

...

Keyword(s):

Immune Response ◽

Gene Transfer ◽

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: Earlier data demonstrated long-term expression of factor IX (mean FIX:C ~5.1%) following AAV8-mediated gene transfer at 2 x1012 vg/kg in hemophilia B (Nathwani et al., 2014). While the clinical improvement imparted by stable FIX levels is clear, these levels of expression fall short of trough values obtained by long-acting FIX prophylaxis (Santagostino et al. 2016), and of natural history data suggesting that levels of ~12% are required to eliminate spontaneous hemarthroses (den Uijl et al. 2011). Achieving higher levels of FIX:C with dose escalation has not been possible without eliciting a dose-dependent, capsid-specific immune response that may prevent sustained expression and efficacy (Mingozzi et al. 2007, Monahan et al. 2015). We sought to develop a highly efficient vector capsid and expression cassette that could be administered at low doses to achieve hemostatic FIX expression without need for immunosuppression. Methods: The investigational product, SPK-9001, utilizes a bioengineered AAV capsid (Spark100) with liver specific tropism. The prevalence of neutralizing antibodies (NAb) to Spark100 among sampled hemophilia B sera was 40% (Anguela et al. 2015). The expression cassette is a codon-optimized, single-stranded transgene encoding FIX Padua, a naturally occurring variant with a single amino acid substitution (R338L) that confers ~8-fold greater specific activity compared to wild-type FIX (Simioni et al. 2009). Data on bleeding and factor infusions in the year prior to enrollment were retrospectively compiled. Laboratory values, bleeding frequency, FIX consumption, changes in activity and quality-of-life via Haem-A-QoL were prospectively evaluated after vector infusion. Results: We enrolled 9 subjects, of whom 2 failed screening for liver fibrosis and 7 were infused with SPK-9001 at a dose of 5 x1011 vg/kg. Infused subjects were adult males ages 18-52 years with baseline FIX:C </=2% and Spark100 NAb titer of <1:1 or 1:1. Table 1 outlines infused subject data with a follow up interval of >2-34 weeks after vector infusion. Figure 1 outlines subject vector-derived FIX:C for the first 12 weeks. There have been no vector or procedure related adverse events. Steady-state FIX expression is reached by 12 weeks after vector infusion, resulting in a mean FIX:C of 32.3% ±6.5%. To date, no subjects required immunosuppression or demonstrated evidence of a cytotoxic immune response (characterized by loss of FIX activity, elevation of transaminase values >/=1.5-times the upper limit of normal, and positive IFN-gammaELISPOT response to capsid peptides). No subjects developed a FIX inhibitor or demonstrated ELISPOT reactivity to the FIX (R338L) gene product. Subject 3 infused with FIX concentrate for a suspected ankle bleed 2 days after vector infusion. Beyond this, no subjects required factor or experienced any bleeding events. The 4 subjects previously maintained on prophylaxis safely stopped without break-through bleeding. As of today (cumulative 724 days post vector infusion), total factor consumption was reduced by 543,589 IU, tantamount to a cumulative savings of $1,182,298 USD.Six of 7 subjects report increased physical activity and improved quality of life. Conclusion: As of 8/4/2016, we report the highest and most consistent levels of sustained vector-derived FIX:C following FIX gene transfer. Levels of FIX:C achieved by SPK-9001 permitted termination of prophylaxis, prevention of bleeding, and nearly complete cessation of factor use. Despite the heterogeneity in subjects with respect to presence and extent of hemophilic arthropathy, age, and co-morbidities, consistency of transgene expression and clinical outcomes have been observed in all participants studied to date. A vector dose of 5x1011 vg/kg is the lowest dose currently reported in hemophilia gene transfer trials; the absence of any observed CD8+ T cell immune response supports the hypothesis that lowering the dose can reduce or eliminate the risk of a capsid-specific immune response and maximize efficacy. In summary, preliminary data suggest SPK-9001 safely and consistently produces sustained elevation in FIX:C levels sufficient to prevent spontaneous hemarthroses without the need for factor consumption or immunosuppression. Disclosures Ducore: Octapharama: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; 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 (Shire): Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Cuker:Biogen-Idec: Consultancy, Research Funding; T2 Biosystems: Research Funding; Genzyme: Consultancy; Stago: Consultancy; Amgen: Consultancy. McGuinn:Spark: Research Funding; Biogen: Research Funding; Novo Nordisk: Research Funding; Baxalta: Research Funding. Luk:Spark Therapeutics, Inc.: Employment. Wright:Spark Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties: SPK-9001. Chen:Spark Therapeutics, Inc.: Employment. Hui:Spark Therapeutics, Inc.: Employment. Wachtel:Spark Therapeutics, Inc.: Employment. Urich:Spark Therapeutics, Inc.: Employment. Takefman:Spark Therapeutics, Inc.: Employment. Couto:Spark Therapeutics, Inc.: Employment. Carr:Pfizer, Inc.: Research Funding. Anguela:Spark Therapeutics, Inc.: Employment, Patents & Royalties: SPK-9001. High:Spark Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties: SPK-9001.

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Spontaneous Bleeding and Poor Bleeding Response with Extended Half-Life Factor IX Products: A Survey of Select US and Canadian Hemophilia Treatment Centers

Blood ◽

10.1182/blood-2019-126196 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2407-2407 ◽

Cited By ~ 2

Author(s):

Lynn M Malec ◽

Stacy E. Croteau ◽

Michael Callaghan ◽

Davide Matino ◽

Kenneth Dale Friedman ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Bleeding Events ◽

Advisory Committees ◽

Spontaneous Bleeding ◽

Recombinant Factor Ix ◽

Traumatic Bleeding ◽

Hemophilia Treatment Centers

Background: Factor IX (FIX) has distinct pharmacokinetic properties compared to factor VIII including significant distribution to the extravascular space. Extravascular distribution and binding to type IV collagen is important in hemostasis but not readily measureable in clinical practice for patients with hemophilia B receiving factor products. We previously reported data regarding use of EHL-FIX products in a cohort of patients who demonstrated issues with spontaneous bleeding and poorly controlled bleeding events; we now report data from an expanded cohort including performance of all EHL-FIX products available in US and Canada. Aims: To characterize the use and performance of EHL-FIX in clinical practice at six hemophilia treatment centers (HTCs). Methods: An electronic survey regarding center specific use of EHL-FIX amongst patients with severe hemophilia B (HB) was sent in summer 2019, including 4 previously surveyed centers and 2 additional centers. Providers were asked if patients utilizing EHL-FIX for prophylaxis had experienced 1) spontaneous/minimally traumatic bleeding events at factor levels >10% or 2) poorly controlled bleeding events requiring more frequent/higher doses of EHL-FIX than anticipated in addition to patterns of EHL-FIX product switching. Results: Surveyed HTCs cared for 90 patients with HB including 67 (74%) who utilized EHL-FIX, including 26 (39%) recombinant factor IX (FIX) albumin fusion protein (rFIX-FP), 37 (55%) recombinant factor IX Fc fusion protein (rFIXFc), and 4 (6%) received glycopegylated recombinant FIX (rFIX-GP). All patients had severe hemophilia B with the exception of one smaller center also contributing data regarding moderate HB patients on prophylaxis. All centers reported having patients with unexpected spontaneous/minimally traumatic bleeding and poorly controlled bleeding which did not seem to be dependent on age (median age 14.5 years, range 1.4-44). This occurred in 18 patients on prophylaxis, including 16 of 26 (62%) patients using rFIX-FP, and 2 of 4 (50%) of patients using rFIX-GP. Conclusions: Although plasma FIX activity levels have driven prophylaxis and bleed management decisions, clinical experience suggests novel properties of EHL-FIX may impact hemostasis. Although achieving seemingly adequate FIX plasma troughs (>10%), limited clinical experience suggests patients with SHB may have a differential response to EHL-FIX, noted in our cohort with FIX-FP and rFIX-GP. Successful bleed prevention or control in SHB may be predicted by the distribution of FIX in circulation and extravascular space, and the presence of FIX in tissues at time of injury. These data demonstrate the importance of real-world monitoring of efficacy of new FIX products and suggest the need for more robust mechanisms to understand the hemostatic performance of products. Disclosures Malec: Bayer: Honoraria; Spark: Honoraria; CSL: Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Honoraria. Croteau:Novo Nordisk: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Octapharma: Honoraria; Octapharma: Honoraria; Genentech: Consultancy, Honoraria; Pfizer: Research Funding; Spark Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Research Funding; Spark Therapeutics: Research Funding; Pfizer: Research Funding; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Shire: Consultancy, Honoraria. Callaghan:Biomarin, Bioverativ, Grifols, Kedrion, Pfizer, Roche/Genentech, Shire, and Spark Therapeutics: Consultancy; Alnylum: Equity Ownership; Bayer: Consultancy, Speakers Bureau; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Global Blood Therapeutics: Consultancy; Novonordisk: Consultancy, Speakers Bureau; Octapharma: Consultancy; Pfizer: Research Funding; Roche: Research Funding; Shire/Takeda: Speakers Bureau; Roche/Genentech: Speakers Bureau. Matino:Bayer: Honoraria, Research Funding; Sobi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Bioviiix: Honoraria; Sanofi: Honoraria. Friedman:CSL: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Instrumentation Laboratory: Consultancy; Siemens: Consultancy. Sidonio:Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; 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; Biomarin: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding.

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Long Term Safety and Efficacy of Recombinant Factor IX Fc Fusion Protein (rFIXFc) Prophylaxis in Children with Hemophilia B: Interim Results of the B-Yond Extension Study

Blood ◽

10.1182/blood.v128.22.4976.4976 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4976-4976 ◽

Cited By ~ 1

Author(s):

Jonathan M. Ducore ◽

Kathelijn Fischer ◽

Roshni Kulkarni ◽

Beatrice Nolan ◽

Carolyn M. Bennett ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Factor Ix ◽

Hemophilia B ◽

Advisory Committees ◽

Safety And Efficacy ◽

Treatment Groups ◽

Recombinant Factor Ix ◽

Bleeding Episodes

Abstract Introduction: The phase 3 Kids B-LONG study (NCT01440946) demonstrated the safety, efficacy, and pharmacokinetics of prophylactic recombinant factor IX Fc fusion protein (rFIXFc) for the prevention and treatment of bleeding episodes in children with severe hemophilia B. The ongoing rFIXFc extension study B-YOND (NCT01425723) is evaluating long-term safety and efficacy of rFIXFc in children and adults with hemophilia B. The safety and efficacy data for pediatric subjects from the second B-YOND interim data cut (11 Sep 2015) are reported here. Methods: The Kids B-LONG study enrolled males aged <12 years with severe hemophilia B (≤2 IU/dL endogenous factor IX [FIX] activity) who had ≥50 exposure days (EDs) of a prior FIX product. Subjects completing Kids B-LONG (median time on study: 49.4 wk) could enroll in 1 of 3 prophylactic treatment groups in B-YOND: weekly prophylaxis (WP; 20-100 IU/kg every 7 d), individualized prophylaxis (IP; 100 IU/kg every 8-16 d), or modified prophylaxis (MP, to optimize prophylaxis with IP or WP). Subjects could change treatment groups at any point in B-YOND. The primary endpoint was development of inhibitors (neutralizing antibody value ≥0.6 BU/mL as measured by the Nijmegen-modified Bethesda assay). Secondary outcomes included annualized bleeding rate (ABR) and rFIXFc exposure days (EDs). Additional outcomes included adverse events (AEs) and evaluation of treatment of bleeding episodes. This analysis reports data for pediatric B-YOND subjects (includes subjects who were <12 y at enrollment into Kids B-LONG) treated with ≥1 dose of rFIXFc. Results: At the time of the second B-YOND interim data cut, 27 subjects had completed Kids B-LONG and enrolled in B-YOND (<6 y cohort, n=13; 6 to <12 y cohort, n=14). Ten subjects had completed (ie, ended participation in the study without premature discontinuation), 16 subjects were ongoing in B-YOND, and 1 subject withdrew due to subject request. From the start of Kids B-LONG to the second B-YOND interim data cut, subjects had a median (range) 2.3 y (0.9-3.0 y) of treatment with rFIXFc, and a median (range) 127.0 (50.0-183.0) cumulative rFIXFc EDs.No inhibitors were observed. AEs were generally typical of the pediatric hemophilia B study population. There were no reports of serious allergic reactions or anaphylaxis associated with rFIXFc, and no vascular thrombotic events; no subjects had AEs related to the study drug. Median (interquartile range [IQR]) overall, spontaneous, and traumatic ABRs were low in both age groups for subjects in the IP and WP treatment groups (Figure; 1 subject in each age cohort was in the MP group [data not shown]). Median (IQR) joint ABRs were 0.0 (0.0-2.2) for subjects < 6 years in the WP treatment group and 0.9 (0.0-2.7) and 1.1 (0.0-2.4) for subjects 6 to <12 years in WP and IP treatment groups, respectively. Regardless of age or treatment group, the majority of bleeding episodes were controlled with 1-2 intravenous injections (<6 y, 97.3%; 6 to <12 y, 97.2%). At the end of Kids B-LONG, 26/27 subjects were dosing once weekly and 1/27 subject was dosing every 5 days. Compared with these dosing intervals, 14.8% of subjects lengthened, 77.8% of subjects did not change, and 7.4% of subjects decreased their prophylactic dosing interval during B-YOND. The median (IQR) dosing interval during B-YOND for pediatric subjects in the IP treatment groups was 10.0 [10.0, 10.7] days. Compared with the end of B-LONG, the median (IQR) total weekly prophylactic dose of rFIXFc was similar at the second B-YOND interim data cut (60.0 [50.0-60.0] vs 60.0 [57.0-70.0]). Conclusion: These data confirm the long-term safety of rFIXFc with maintenance of low ABRs and extended-interval prophylaxis in children with hemophilia B. 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 Ducore: Octapharama: Membership on an entity's Board of Directors or advisory committees; Baxalta (Shire): Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Fischer:Baxter: Consultancy, Research Funding, Speakers Bureau; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Speakers Bureau; Biogen: Consultancy; Biotest: Consultancy, Speakers Bureau; Baxalta/Baxter: Consultancy, Research Funding, Speakers Bureau; Wyeth: Research Funding; Pfizer: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy. Kulkarni: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; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: 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; Baxter: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nolan:Sobi: Research Funding; Biogen: Research Funding. Perry:Biogen: Consultancy, Honoraria; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yuan:Biogen: Employment, Equity Ownership. Ramirez-Santiago:Biogen: Employment, Equity Ownership. Ferrante:Sobi: Employment. Lethagen:Sobi: Employment.

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Perioperative Management of Hemostasis with Recombinant FIX Fc Fusion Protein in Subjects Undergoing Surgery in the B-YOND Study

Blood ◽

10.1182/blood.v126.23.1083.1083 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1083-1083

Author(s):

Margareth Castro Ozelo ◽

Johnny Mahlangu ◽

Godfrey Chan ◽

Margareta Holmstrom ◽

Nicolas Novitzky ◽

...

Keyword(s):

Blood Loss ◽

Board Of Directors ◽

Research Funding ◽

Perioperative Management ◽

Major Surgery ◽

Employment Equity ◽

Advisory Committees ◽

Pediatric Subject ◽

Rehabilitation Period ◽

Equity Ownership

Abstract Background: The phase 3 B-LONG (adults/adolescents ≥12 years of age) and Kids B-LONG (children <12 years of age) studies demonstrated the safety and efficacy of recombinant FIX Fc fusion protein (rFIXFc) for the control and prevention of bleeding episodes in subjects with severe hemophilia B (FIX levels ≤2 IU/dL). Eligible subjects from either study could continue rFIXFc treatment in the ongoing extension study, B-YOND, during which surgical procedures were allowed. Aims: To describe rFIXFc efficacy and safety in B-YOND subjects undergoing surgery. Methods: B-YOND subjects who underwent surgery received an investigator-determined rFIXFc regimen. Major surgery endpoints included rFIXFc dosing, investigator/surgeon assessment of hemostatic response (4-point scale: excellent, good, fair, poor/none), blood loss, number of transfusions, and safety. For minor surgeries, hemostatic response and dosing are summarized. Surgeries performed up to cutoff for the interim analysis (17 October 2014) were included. For safety analyses, the surgery subgroup included subjects who underwent major surgery during B-YOND and those who underwent major surgery in the parent study but had their surgical/rehabilitation period during B-YOND. Results: Fifteen major surgeries were performed in 8 subjects (7 adults/adolescents and 1 child <12 years of age), most commonly orthopedic procedures (9/15 surgeries). In adults/adolescents undergoing major surgery, the median total rFIXFc dose on the day of surgery was 135.92 IU/kg (range, 60.6-317.9 IU/kg); 12 of these 14 surgeries required a single rFIXFc infusion to maintain hemostasis during surgery. The number of adults and adolescents undergoing major surgery who required an infusion decreased from Day 0 to Day 14. A single rFIXFc infusion of 99.43 IU/kg was required on the day of surgery for the single major surgery in a pediatric subject (tonsillectomy). Of 15 major surgeries, 14 surgeries were assessed for hemostatic response to rFIXFc and all were rated as excellent (n = 13, including the single pediatric surgery) or good (n = 1). Among 12 major surgeries with estimates, blood loss ranged from 0-1,000 mL intraoperatively and 0-1,000 mL postoperatively (for the single pediatric subject, blood loss was 50 mL intraoperatively and 0 mL postoperatively). One additional subject had an estimated intraoperative blood loss of 5,000 mL during liver transplantation and was the only subject who required transfusion (6 units of packed cells, 4 units of platelet concentrate, and 4 units of fresh frozen plasma intraoperatively), consistent with previously reported blood loss for this procedure in the general population (Yuasa et al. Transfusion 2005;45:879). Hemostatic response for this surgery was rated as excellent. No subject reported a bleeding episode during the postoperative/rehabilitation period. Among 12 subjects in the surgery subgroup (8 with major surgery during B-YOND; 4 with major surgery in B-LONG and a surgical/rehabilitation period during B-YOND), 3 subjects (25%) reported ≥1 adverse event (AE) during the perioperative management period. One subject who underwent major surgery experienced 2 serious AEs (anal sphincter atony and epididymitis; considered unrelated to treatment) during the perioperative management period. All AEs were assessed by the investigator as unrelated to treatment and resolved. Of 25 minor surgeries performed in 17 adults/adolescents (none in children), approximately half were dental procedures (12/25 surgeries). No rFIXFc was administered on the day of surgery for 2 minor surgeries. For the other 23 surgeries, the median number of rFIXFc infusions was 1.0 (range, 1-3) and the median total dose of rFIXFc was 79.84 IU/kg (range, 38.5-200.0). Hemostatic response was assessed in 10 of 25 minor surgeries; all were rated as excellent (n = 9) or good (n = 1). Summary/Conclusion: Hemostasis with rFIXFc during surgery was rated favorably by investigators/surgeons, with comparable blood loss to what would be expected for subjects without hemophilia. Taken together with results from the B-LONG and Kids B-LONG studies, these data indicate that rFIXFc is well-tolerated and efficacious for the management of perioperative hemostasis in individuals with severe hemophilia B. Disclosures Ozelo: Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding. Mahlangu:Bayer, CSL, Novo Nordisk, and Biogen: Research Funding, Speakers Bureau; Biotest: Speakers Bureau; Roche: Research Funding; Amgen: Speakers Bureau. Perry:Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biogen: Consultancy, Honoraria. Yuan:Biogen: Employment, Equity Ownership. Cristiano:Biogen: Employment, Equity Ownership. Mei:Biogen: Employment, Equity Ownership.

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Maintenance of Health-Related Quality of Life in the Phase 4 BYOND Study of Bosutinib for Pretreated Chronic Phase Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2019-124344 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4157-4157

Author(s):

Tim H Brümmendorf ◽

Carlo Gambacorti-Passerini ◽

Camille Abboud ◽

Justin M. Watts ◽

Gianantonio Rosti ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Chronic Phase ◽

Well Being ◽

Employment Equity ◽

Advisory Committees ◽

Starting Dose ◽

Previously Treated ◽

Equity Ownership

Background: Bosutinib is approved at a starting dose of 500 mg once daily (QD) in patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to prior treatment and at a starting dose of 400 mg QD in newly diagnosed patients with chronic phase (CP) CML. Approval of bosutinib after prior therapy was based on a phase 1/2 study in patients previously treated with imatinib ± dasatinib and/or nilotinib. After long-term follow-up (≥4 years), durable responses and maintenance of health-related quality of life (HRQoL) were seen in patients after prior imatinib (CP CML second-line [CP2L] cohort [n=284]) or prior imatinib + dasatinib and/or nilotinib (CP CML third/fourth-line [CP3L/CP4L] cohort [n=115/4]). As a post-authorization commitment to the European Medicines Agency, the BYOND study is providing additional safety and efficacy data for bosutinib in patients with CML after failure of prior tyrosine kinase inhibitor (TKI) treatment. Cumulative confirmed major cytogenetic response rate by 1 year (primary endpoint; not powered) in evaluable patients with CP CML was 75.8% after 1 or 2 prior TKIs (n=99) and 62.2% after 3 prior TKIs (n=45). Cumulative complete cytogenetic response rate anytime on treatment was 86.0%, 83.9%, and 73.3% in the CP2L, CP3L, and CP4L cohorts, respectively. Patients had high rates of molecular responses across all lines of treatment. Evaluation of HRQoL through patient-reported outcome (PRO) measures is an exploratory objective of BYOND. Methods: BYOND (NCT02228382) is an ongoing, phase 4, single-arm, open-label study of bosutinib at a starting dose of 500 mg QD in patients with CML and resistance/intolerance to prior treatment. At baseline and during treatment, patients were asked to complete the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu v4) instrument, a 44-item, valid assessment of HRQoL in patients with leukemia. Each item was scored on a scale from 0 to 4, with higher scores indicating better HRQoL. Changes in HRQoL that are clinically meaningful to a patient have been defined as the minimal important difference (MID) for most FACT-Leu domains. We report PRO results at Month 12 of bosutinib treatment in the CP CML cohorts; for comparison, we present PRO data at Month 12 from the CP CML cohorts of the phase 1/2 study of bosutinib in previously treated patients. Results: At baseline, most FACT-Leu scores were similar (<5% difference) in the CP2L and CP3L cohorts of the BYOND study (Table); social and functional well-being scores were lower and the emotional well-being score was higher in the CP2L cohort. Baseline FACT-Leu scores were lower in the CP4L cohort, with >5% differences seen for physical and emotional well-being compared with the CP2L cohort, and for physical, social, and functional well-being, FACT-General (FACT-G) total, FACT-Leu total, and trial outcome index (TOI) FACT-Leu compared with the CP3L cohort. At Month 12, no mean change in a FACT-Leu domain score met the MID (Figure), indicating preservation of baseline HRQoL across all cohorts. Mean changes in FACT-Leu scores from baseline to Month 12 were similar in the CP2L cohorts of the BYOND study and the phase 1/2 study. HRQoL trends were also generally similar in the CP3L cohort of BYOND and the CP3L/4L cohort of the phase 1/2 study, in which 97% of patients received third-line bosutinib. Conclusions: HRQoL was maintained from baseline in patients with CP CML following 12 months of bosutinib treatment in the BYOND study. HRQoL changes at Month 12 were comparable to those observed in previously treated patients in the initial phase 1/2 study of bosutinib, wherein long-term efficacy and HRQoL stability were subsequently reported. In addition, FACT-G scores in the BYOND study were consistent with those previously reported for general populations as well as patients with various cancers. Maintenance of HRQoL is important for patients with CP CML who potentially will receive lifelong TKI treatment, and the PRO results from BYOND suggest bosutinib is a well-tolerated treatment option, thus providing further support for its use in patients with CP CML resistant/intolerant to prior TKIs. Relationships between molecular response and HRQoL in the BYOND study are being explored. Disclosures Brümmendorf: University Hospital of the RWTH Aachen: Employment; Merck: Consultancy; Ariad: Consultancy; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Abboud:Jazz Pharma: Speakers Bureau; Novartis: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017), Research Funding; Agios: Other: Member on an entity's Board of Directors or advisory committees (Ended 12/30/2017); Tetraphase Pharmaceuticals: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; NKarta: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Watts:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Russell-Smith:Pfizer: Employment, Equity Ownership. Viqueira:Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Giles:Actuate Therapeutics Inc: Employment; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Novartis: Consultancy. Hochhaus:MSD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding.

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Efficacy and Safety of Ponatinib According to Prior Approved Tyrosine Kinase Inhibitor (TKI) Therapy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CP-CML): Results From the PACE Trial

Blood ◽

10.1182/blood.v120.21.3749.3749 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3749-3749

Author(s):

Dong-Wook Kim ◽

Jorge E. Cortes ◽

Javier Pinilla-Ibarz ◽

Philipp le Coutre ◽

Ronald Paquette ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Efficacy And Safety ◽

Employment Equity ◽

Advisory Committees ◽

Kaplan Meier ◽

Previously Treated ◽

Equity Ownership

Abstract Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.

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An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS

Blood ◽

10.1182/blood-2019-131930 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3926-3926

Author(s):

Tapan M. Kadia ◽

Gautam M. Borthakur ◽

Elias Jabbour ◽

Marina Y Konopleva ◽

Farhad Ravandi ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Nucleoside Analogues ◽

Dna Breaks ◽

Employment Equity ◽

Advisory Committees ◽

Previously Treated ◽

Equity Ownership ◽

Refractory Aml

Acute myeloid leukemia (AML) is characterized by clonal proliferation of neoplastic myeloid precursor cells resulting in impaired hematopoiesis. Despite initial responses to intensive induction therapy, relapses are frequent and most patients die in less than 5 years (National Cancer Institute 2015). Nucleoside analogues represent an important category of anti-leukemic cytotoxic drugs. Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML. Sapacitabine is a novel, orally bioavailable nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading eventually to production of double-strand DNA breaks and/or G2 cell cycle arrest. In phase 1 and 2 clinical trials, sapacitabine has induced complete remission (CR), CR with incomplete platelet count recovery (CRp), partial remission (PR), and major hematological improvement (HI) in patients with AML and MDS. A subset of these responding patients were previously treated with other nucleoside analogues, suggesting that the anti-leukemic activity of sapacitabine is not limited by resistance to other nucleoside analogues (Kantarjian H et al, JCO, 2010, ASH, 2013). Two clinical studies have demonstrated the synergistic activity of venetoclax in combination with hypomethylating agents or low-dose ara-C in newly diagnosed AML, leading to its recent approval by the FDA for the front-line treatment of this disease. The synergy between venetoclax and cytotoxic therapy in AML models is mediated by combined targeting of the anti-apoptotic BCL2 and MCL1 mechanisms (Teh T-C et al, Leukemia, 2018). Cytotoxic drugs induce apoptosis through genotoxic damage, TP53 activation and increased expression of pro-apoptotic NOXA and PUMA (Villunger A et al, Science, 2003) - features that have also been demonstrated for sapacitabine (Green S et al. Br J Cancer 2010). Although most cytotoxic agents do not directly affect MCL1 levels, increased levels of the pro-apoptotic NOXA and PUMA proteins can inactivate MCL1 to synergize with venetoclax to induce apoptosis. The combination of CNDAC (2'-C-cyano-2'-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411. A synergistic increase in apoptosis induction was observed when CNDAC and ABT737 were combined (Frame S. et al, 14th EHA, 2009, Abs 0761). The above findings support the conduct of a clinical study (NCT01211457) evaluating a combination of sapacitabine with venetoclax in patients with relapsed/refractory AML and MDS. This is an entirely oral treatment regimen. The primary objective is to evaluate the safety and efficacy of two dosing schedules of sapacitabine given concomitantly with venetoclax: twice daily for 5 consecutive days or twice daily for 3 consecutive days per week for 2 weeks. One treatment cycle is 4 weeks. Dose will be escalated in increments of 50 mg twice daily. RP2D is the highest dose level at which ≤2 of 6 patients experience a dose-limiting toxicity during the first 2 treatment cycles. Eligible patients are ≥18 years with previously treated AML or MDS and ≥10% blasts in bone marrow or peripheral blood; adequate bone marrow, renal and liver functions are required. Treatment will continue until progression of disease, unacceptable toxicity or changes in patient condition that renders patients ineligible for further treatment. Laboratory tests and bone marrow aspirate/biopsy will be performed to assess responses according to standard criteria. Disclosures Kadia: Bioline RX: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Jazz: 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; BMS: Research Funding. Borthakur:Agensys: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Merck: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; Oncoceutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Arvinas: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Konopleva:Kisoji: Consultancy, Honoraria; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding. Ravandi:Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:celgene: Consultancy, Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Zheleva:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Blake:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties. Chiao:Cyclacel Ltd: Employment, Equity Ownership, Patents & Royalties.

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Efficacy of Pomalidomide, Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Post-Lenalidomide: Results from a Systematic Literature Review and Indirect Treatment Comparison

Blood ◽

10.1182/blood-2019-123639 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2201-2201

Author(s):

Katja C. Weisel ◽

Sujith Dhanasiri ◽

Aline Gauthier ◽

Amie Padhiar ◽

Eva Casal ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Treatment Comparison ◽

Significant Difference ◽

Previously Treated ◽

Indirect Treatment ◽

Equity Ownership

Background: The current standard of care in MM, lenalidomide (LEN), is frequently used as part of first-line (1L) treatment (tx) or as maintenance tx following autologous stem cell transplantation; therefore, there is a growing need for appropriate tx options in patients (pts) with relapsed/refractory MM (RRMM) previously treated with LEN. OPTIMISMM is the first and only phase 3 trial in early RRMM (median 1-2 prior lines) to specify prior LEN tx as an inclusion criterion. The trial showed a significant improvement in progression-free survival (PFS) with pomalidomide + bortezomib (BORT) + dexamethasone (DEX) (PVd) vs BORT + DEX (Vd) (median PFS 11.2 months (mo) [95% confidence interval (CI): 9.66-13.73] vs 7.1 mo [5.88-8.48]; hazard ratio [HR] = 0.61, 95% CI: 0.49-0.77; P < 0.0001). How the PVd results from the OPTIMISMM trial compare with results achieved with other tx options for LEN-exposed pts with RRMM has not been established. Aim: This analysis aimed to put the phase 3 OPTIMISMM (PVd) trial results into perspective by comparing with results achieved for other tx options post LEN. Methods: A systematic literature review (SLR) was conducted in May 2018 and updated in Dec 2018, in line with National Institute for Health and Care Excellence (NICE) and Cochrane guidelines, to identify randomized controlled trial (RCT) data on efficacy outcomes in LEN-exposed pts with early RRMM. Electronic database searches were performed in Embase®, MEDLINE, and the Cochrane Library, and study eligibility criteria were defined using the PICOS framework. Searches were restricted to Jan 2004 onward. Descriptive statistics were used to assess between-trial heterogeneity in study design, baseline demographics, and clinical characteristics. Where the evidence network and heterogeneity assessment suggested an indirect treatment comparison (ITC) was feasible, the analysis was conducted in the Bayesian framework, according to the NICE Decision Support Unit guidelines. Results: ENDEAVOR and CASTOR were the only relevant trials that reported PFS in pts with RRMM previously treated with LEN. Comparator txs included carfilzomib + DEX (Kd) (ENDEAVOR) and daratumumab + BORT + DEX (DVd) (CASTOR). OPTIMISMM was designed to prospectively evaluate pts who had prior LEN, whereas ENDEAVOR and CASTOR reported only pt subgroups with prior LEN; all studies reported the number of pts who were refractory to LEN, with values varying from 18% (DVd) in CASTOR to 71% (PVd) in OPTIMISMM (Table). Differences in prognostic baseline characteristics were noted between the overall study populations in OPTIMISMM and ENDEAVOR; as the corresponding data were not available for CASTOR, a full assessment of heterogeneity was not possible. Although Vd initially seemed to link the network of evidence, the comparator arm of the CASTOR trial had a fixed 8-cycle Vd tx duration, whereas pts randomized to the comparator arm in OPTIMISMM and ENDEAVOR received Vd continuously until disease progression. As the Vd arms could not be considered comparable, DVd was excluded from the ITC. Based on data from ENDEAVOR and OPTIMISMM, PVd could only be compared with Kd and Vd. Based on the ITC, Vd was associated with a statistically significant shorter PFS vs PVd (HR PVd vs Vd = 0.62, 95% credible interval [Crl]: 0.50-0.76) in the prior-LEN RRMM population. No statistically significant difference was observed in PFS for Kd vs PVd (HR PVd vs Kd = 0.90, 95% Crl: 0.62-1.28). It is important to note that pt characteristics vary between these trials, particularly regarding prior LEN. Discussion: Due to increasing use of LEN in the 1L setting and as maintenance tx, a growing population of pts with early RRMM are treated with LEN. This SLR found that OPTIMISMM is the only study to date to prospectively investigate the efficacy of regimens in this population. Only 2 other RCTs were identified that reported data for pts with prior LEN, and in both cases, these were subgroups of the overall trial population, thus limiting the robustness of the comparator data. HRs for PFS from the ITC aligned with those from OPTIMISMM, confirming the superiority of PVd over Vd. The ITC between PVd and Kd found no statistically significant difference between these regimens. Comparison with DVd was not possible given the differences in design between CASTOR and OPTIMISMM. Further studies in pts previously treated with LEN are warranted, given the impact of prior tx on outcomes for pts with early RRMM. Disclosures Weisel: Janssen: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Juno: Consultancy. Dhanasiri:Celgene Corporation: Employment, Equity Ownership. Gauthier:Amaris Consulting: Employment, Equity Ownership; Celgene Corporation: Consultancy. Padhiar:Amaris Consulting: Employment. Casal:Celgene Corporation: Employment. Richardson:Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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