Interim Results from a Dose Escalating Study of AMT-060 (AAV5-hFIX) Gene Transfer in Adult Patients with Severe Hemophilia B

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2314-2314 ◽  
Author(s):  
Frank W.G. Leebeek ◽  
Marco Tangelder ◽  
Karina Meijer ◽  
Giancarlo Castaman ◽  
Federica Cattaneo ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Low Dose ◽  
T Cell Response ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Dose Cohort ◽  
Advisory Boards

Abstract Introduction: The development of gene transfer for hemophilia is advancing rapidly and offers the potential to shift the disease severity from severe to mild with a single treatment. AMT-060 consists of an AAV5 vector with a gene cassette containing an LP1 liver specific promoter and codon-optimized wild type hFIX gene that has previously been shown to result in durable increases in FIX activity of at least 4 years1. This phase 1/2 study aims to investigate the safety and efficacy of AMT-060 in adult patients with severe hemophilia B. Methods: This is a multi-national, multi-center, open-label, dose-escalating study in patients with FIX activity ≤ 2% of normal, and a severe bleeding phenotype. To be eligible, patients had to require either prophylactic exogenous FIX, or on-demand exogenous FIX with more than 4 bleeds per year or suffer from hemophilic arthropathy. Ten patients were treated in two subsequent, escalating dose cohorts, with AMT-060 5x 1012 gc/kg (n=5) or 2x 1013 gc/kg (n=5). Patients received AMT-060 via a single intravenous infusion over 30 minutes. Efficacy assessments include endogenous FIX activity, measured at least 10 days after the most recent administration of exogenous FIX; reduction of exogenous FIX use; and annualized spontaneous bleeding rates. Safety assessments include treatment related adverse events and immunological assessments, including T-cell response to capsid antigens. Results : There were no screen failures for pre-existing antibodies against AAV5. The age of enrolled patients ranged from 33 to 72 years. At enrollment, nine patients were on FIX prophylaxis, and one patient in the high dose cohort used on-demand FIX therapy. At the time of submission, all ten patients have received AMT-060. The mean of all endogenous FIX activity values after cessation of prophylaxis in the low-dose cohort was 5.4% (95% CI 5.0-5.8%, range 3.1-6.7%; n=4), and stable during the 39 weeks of follow-up. Four out of five patients in the low-dose cohort were able to stop FIX prophylaxis. These patients demonstrated a mean reduction in annualized total FIX usage of 82% after treatment with AMT-060. For all five patients in the low-dose cohort, the mean annualized total FIX usage declined 75% after treatment with AMT-060. Following AMT-060 administration, one patient in the lower dose cohort had a mild, asymptomatic, elevation of ALT at week 10 that resolved with a seven weeks course of tapering prednisolone. No change in FIX activity, and no T-cell response or other possibly associated immunogenicity or inflammatory abnormalities were seen during the ALT elevation. Efficacy and safety results will be updated up to 52 weeks of follow up for the low-dose cohort. Initial efficacy and safety results from the higher-dose cohort up to 26 weeks of follow up will also be presented. Conclusions: Follow up of patients with severe hemophilia B who received either the low or higher dose of AMT-060 is ongoing. A single infusion of AMT-060 was generally well-tolerated. FIX activity increased to levels sufficient to provide endogenous prophylaxis in four of five patients in the low-dose cohort, relieving them from the need for exogenous FIX prophylaxis and resulting in marked decrease of FIX usage. 1Nathwani et al. NEJM 2014; 371:1994-2004 Disclosures Leebeek: UniQure: Consultancy; Netherlands Hemophilia Foundation: Research Funding; CSL Behring: Research Funding; Baxter: Research Funding. Tangelder:uniQure: Employment. Meijer:Baxter: Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Research Funding; Sanquin: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Bristol-Myers Squibb: Honoraria. Castaman:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Baxalta-Shire: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Cattaneo:Chiesi: Employment. Coppens:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; BMS/Pfizer: Consultancy, Honoraria, Research Funding; Sanquin: Consultancy, Honoraria, Research Funding. Klamroth:SOBI: Other: honoraria for advisory boards and speaker fees; uniqure: Other: honoraria for advisory boards and speaker fees; pfizer: Other: honoraria for advisory boards and speaker fees; NovoNordisk: Other: honoraria for advisory boards and speaker fees; Octapharma: 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; Biogen Idec: Other: honoraria for advisory boards and speaker fees; CSL Behring: Other: honoraria for advisory boards and speaker fees. Schutgens:CSL Behring: Research Funding; Sanquin: Research Funding. Hendriks:uniQure: Employment. Corzo:uniQure: Employment. Miesbach:Grifols: Honoraria; CSL Behring: Research Funding; Pfizer: Honoraria; uniQure: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals BIVV001: The First Investigational Factor VIII Therapy to Break Through the VWF Ceiling in Hemophilia A, with Potential for Extended Protection for One Week or Longer

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 636-636 ◽  
Author(s):  
Barbara A Konkle ◽  
Amy Shapiro ◽  
Doris Quon ◽  
Janice Staber ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Single Dose ◽  
Board Of Directors ◽  
Half Life ◽  
Research Funding ◽  
Low Dose ◽  
Hemophilia A ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Dose Cohort

Abstract Introduction: The standard of care for patients with severe hemophilia A is prophylactic factor VIII (FVIII) replacement. Conventional recombinant FVIII products are efficacious but require frequent administration because of their short half-life, which reflects the dependence of FVIII on von Willebrand factor (VWF). Recombinant FVIII Fc fusion protein (rFVIIIFc) provides an extended dosing interval, as well as joint protection and improved quality of life (Oldenburg et al, Haemophilia, 2018; Wang et al, Blood, 2016), with a well-characterized safety profile. While rFVIIIFc reduces the required administration frequency, longer prophylactic dosing intervals that also offer maximum overall protection are still an unmet need for patients with severe hemophilia A. Increasing the half-life of rFVIII is ultimately dependent upon decoupling FVIII and endogenous VWF. BIVV001 (rFVIII-VWF-XTEN) is a novel investigational rFVIII therapy with single-chain FVIII, the Fc domain of human immunoglobulin G1, 2 XTEN polypeptides, and the FVIII-binding D′D3 domain of VWF, designed to circulate in plasma independently of VWF, thereby breaking the VWF half-life ceiling. Here, we present the low-dose cohort results of EXTEN-A, a Phase 1/2a study assessing the safety and tolerability of a single dose of BIVV001, and the pharmacokinetic (PK) characteristics of a single dose of BIVV001 compared with rFVIII. Methods: EXTEN-A (NCT03205163) is an open-label, dose-escalation, multicenter study. Previously treated adult males with severe hemophilia A (<1 IU/dL [<1%] endogenous FVIII activity) with ≥150 exposure days to FVIII products were included. Patients were assigned to either the low-dose cohort (25 IU/kg of rFVIII and 25 IU/kg of BIVV001; n≥6) or the high-dose cohort (65 IU/kg of rFVIII and 65 IU/kg of BIVV001; n≥8). Escalation from the low-dose cohort, and enrolment of patients to the high-dose cohort was undertaken after assessment of available data from the low-dose cohort. After a screening and washout period of up to 28 days, patients received a single dose (25 or 65 IU/kg) of rFVIII. After a 3- to 4-day washout period, patients received a single dose of BIVV001 at the same dose level as rFVIII. Blood samples for PK analysis were collected for 3 days after dosing of rFVIII and up to 14 days after dosing of BIVV001. Inhibitor testing was performed 14 and 28 days following BIVV001 administration. Adverse events, clinical abnormalities in laboratory tests (including inhibitor development), and PK parameters were assessed. An interim analysis is planned, including the first 2 patients of the high-dose cohort. Results: Out of 7 patients enrolled in the low-dose cohort (25 IU/kg), 6 patients were dosed with BIVV001. Patients in this group were primarily white, with 1 patient of Asian descent, and 1 of Hispanic/Latino ethnicity. Patient ages ranged from 19 to 60 years. Low-dose BIVV001 was well tolerated and no inhibitors were detected through 28 days after BIVV001 dosing. Low-dose BIVV001 demonstrated an extended half-life of 37.6 hours, compared with a 12.1-hour half-life for rFVIII. Average FVIII activity post-infusion of BIVV001 was 12.2% at 5 days and 5.3% at 7 days. At least 8 patients will be enrolled in the high-dose cohort (65 IU/kg); preliminary data for the first 2 patients will be reported. Conclusions: BIVV001 was well tolerated in 6 patients with severe hemophilia A who were treated with a single low dose (25 IU/kg). No patient developed an inhibitor to FVIII. Low-dose cohort data demonstrated a breakthrough in the half-life of rFVIII therapy, with BIVV001 providing sustained FVIII levels that could potentially allow for more optimal, extended protection for patients. Disclosures Konkle: Genentech: Consultancy; Spark: Consultancy, Research Funding; Pfizer: Research Funding; Gilead: Consultancy; CSL Behring: Consultancy; Bioverativ: Research Funding; BioMarin: Consultancy; Sangamo: Research Funding; Shire: Research Funding. Shapiro:Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioMarin: Research Funding; Prometic Life Sciences: Consultancy, Research Funding; Bioverativ, a Sanofi Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sangamo Biosciences: Consultancy; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Other: International Network of Pediatric Hemophilia; OPKO: Research Funding; Octapharma: Research Funding; Kedrion Biopharma: Consultancy, Research Funding; Bio Products Laboratory: Consultancy; Daiichi Sankyo: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Research Funding. Quon:Bioverativ, a Sanofi Company: Speakers Bureau; Octapharma: Consultancy; Genetech: Consultancy, Speakers Bureau; Bayer: Consultancy; NovoNordisk: Consultancy, Speakers Bureau; Shire: Speakers Bureau. Staber:uniQure: Honoraria; NovoNordisk: Consultancy; Bayer: Honoraria. Suzuki:Chugai Pharmaceutical Co., Ltd: Research Funding, Speakers Bureau. Poloskey:Bioverativ: Employment. Rice:Bioverativ: Employment. Katragadda:Bioverativ: Employment. Rudin:Bioverativ: Employment, Equity Ownership. Fruebis:Bioverativ: Employment, Other: Clinical Development.

scholarly journals One Year Data from a Phase 2b Trial of AMT-061 (AAV5-Padua hFIX variant), an Enhanced Vector for Gene Transfer in Adults with Severe or Moderate-Severe Hemophilia B

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3348-3348
Author(s):  
Steven Pipe ◽  
Adam Giermasz ◽  
Giancarlo Castaman ◽  
Nigel S. Key ◽  
Susan U Lattimore ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Hemophilia B ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Human Factor Ix ◽  
Virus Serotype ◽  
Patient Reported

Background: Gene therapy for hemophilia offers the possibility of ameliorating the disease severity to a milder or functionally curative state through a single treatment. AMT-061 is an investigational gene therapy for hemophilia B comprising an adeno-associated virus serotype 5 (AAV5) vector containing a codon-optimized Padua variant human factor IX (FIX) gene with liver-specific promoter. Aims: Confirm that a single dose of AMT-061 will provide a minimum-therapeutic response of FIX activity 6-weeks post-dose in participants with severe or moderate-severe hemophilia B. Here, 1 year of follow-up will be presented for the first time. Methods: Phase 2b, open-label, multi-center trial (NCT03489291) in adult males with FIX ≤2% and without active hepatitis or uncontrolled HIV. Participants were not excluded based on neutralizing antibodies to AAV5. Participants received a single intravenous dose of AMT-061 (2x1013 gc/kg) and will be followed for 5-years. The primary endpoint was FIX activity at Week 6. Secondary endpoints include e-diary recordings of bleeds and FIX concentrate use, laboratory parameters, joint health, patient-reported outcomes, and adverse events (AEs). Results: All participants had FIX ≤1% (severe or moderately-severe FIX deficiency), required routine FIX prophylaxis, and had neutralizing activity to AAV5 at baseline. Following AMT-061 treatment, FIX activity increased rapidly (Figure) to a mean of 31% at Week 6. At Week 36, mean FIX activity increased further to 45% with FIX activity levels of 54%, 30% and 51% in participants 1-3 respectively. As of 36 weeks, there were no bleeds post-treatment and no requirement for FIX replacement aside from protocol-specified use for perioperative management in participant 3. There were no clinically significant elevations in liver enzymes and no participants required steroids related to the treatment. One participant experienced 2 mild AEs possibly related to treatment shortly after dosing (self-limiting headache and slightly elevated CRP). One patient had hip surgery due to worsening of pre-existing avascular necrosis deemed unrelated by investigator to AMT-061 and received FIX per protocol according to standard clinical practice. No participant developed inhibitors to FIX. Updated results to 52 weeks of follow-up will be presented. Conclusions: Sustained elevation of FIX activity into the mild-to-normative range were observed in all participants 36 weeks after treatment with AMT-061. AMT-061 was safe and well-tolerated with no requirement for immunosuppression. These data support the ongoing Phase 3 study. Figure Disclosures Pipe: Novo Nordisk: Consultancy; Apcintex: Consultancy; Roche/Genentech: Consultancy; BioMarin: Consultancy; Shire: Consultancy; Sanofi: Consultancy; uniQure: Consultancy; Pfizer: Consultancy; HEMA Biologics: Consultancy; Catalyst Bioscience: Consultancy; Freeline: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; Spark Therapeutics: Consultancy. Giermasz:Genentech/Roche: Consultancy, Other: Research, Speakers Bureau; Sangamo: Other: Research; BioMarin: Consultancy, Other: Research; uniQure: Consultancy, Other: Research; Bioverativ/Sanofi: Consultancy, Speakers Bureau. Castaman:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda (SHIRE): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Uniqure: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Werfen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Key:Uniqure BV: Research Funding. Leebeek:CSL Behring: Research Funding; Baxalta/Shire: Research Funding; uniQure BV: Consultancy, Research Funding. Miesbach:Bayer, Chugai, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire, UniQure: Speakers Bureau; Bayer, BioMarin, CSL Behring, Chugai, Freeline, Novo Nordisk, Octapharma, Pfizer, Roche, Takeda/Shire, UniQure: Consultancy; Bayer, Novo Nordisk, Octapharma, Pfizer, Takeda/Shire: Research Funding. Recht:Bioverativ, CSL Behring, Genentech, Kedrion, NovoNordisk, Pfizer, Shire, Uniqure: Consultancy; American Thorombosis & Hemostasis Network: Other: Immediate Past Chair; Bioverativ, Genentech, NovoNordisk Shire: Research Funding. Gomez:Alnylam: Consultancy; Novo Nordisk, Novartis, Pfizer, Sanofi, Takeda, UniQure: Research Funding. Long:Uniqure BV: Employment. Gut:Uniqure BV: Employment. von Drygalski:University of California San Diego: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; UniQure, Bayer, Bioverativ/Sanofi, Pfizer, Novo Nordisk, Biomarin, Shire, CSL Behring: Consultancy; Hematherix Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Founder.

Stable Factor IX Activity Following AAV-Mediated Gene Transfer in Patients with Severe Hemophilia B

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 752-752
Author(s):  
Andrew Davidoff ◽  
Edward GD Tuddenham ◽  
Savita Rangarajan ◽  
Cecilia Rosales ◽  
Jenny McIntosh ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Board Of Directors ◽  
Normal Values ◽  
Factor Ix ◽  
Hemophilia B ◽  
High Dose ◽  
Severe Hemophilia ◽  
Advisory Committees ◽  
Short Course

Abstract Abstract 752 Introduction: We are conducting a phase I/II clinical trial of factor IX gene transfer for severe hemophilia B. In the trial we are using a serotype-8 pseudotyped self-complementary adeno-associated virus (scAAV) vector expressing a codon-optimized coagulation factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco). We have previously reported the early safety and efficacy of our novel gene transfer approach in six patients with severe hemophilia B following a single peripheral vein infusion of one of three vector doses (low [2×1011 vector particles (vp)/kilogram weight (kg)], intermediate [6×1011 vp/kg], or high dose [2×1012 vp/kg]) (Nathwani et al, NEJM 365:2357–65, 2011). AAV-mediated expression of FIX at 1–6% of normal was established in all six participants with an initial follow-up of between 6–14 months following gene transfer. We now report longer follow-up of these participants, as well as data from two additional participants recently enrolled at the high dose level. Methods: We have now infused scAAV2/8-LP1-hFIXco in eight subjects with severe hemophilia B (FIX activity, <1% of normal values). Vector was administered without immunosuppressive therapy, and participants have now been followed for 3 months to 2½ years. FIX activity, serum transaminases, vector genomes in secretions/excretions, antibodies to FIX and AAV8, and AAV8 capsid-specific T-cells were monitored during the follow-up. Results: Each of the participants currently has AAV-mediated activity of FIX at 1 to 6% of normal levels. These levels have been stable in each during the follow-up period which is now greater than 1½ years for the first six participants. Five of the eight participants have discontinued FIX prophylaxis and remain free of spontaneous hemorrhage; in the other three, the interval between prophylactic injections has increased. None of the participants in the low or intermediate dose cohorts had evidence of transaminitis; each currently has FIX activity of 1–3% for over 1½ years. Of the four participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; two others had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these three participants received a short course of glucocorticoid therapy, which rapidly normalized their aminotransferase levels and maintained FIX levels in the range of 4 to 6% of normal values. The fourth participant has not had transaminitis three months after vector administration. Conclusions: This represents the first successful, long-term, gene therapy-mediated expression of a therapeutic protein from an AAV vector delivered to human liver. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. Larger numbers of patients followed for longer periods of time are necessary to fully define the benefits and risks and to optimize dosing. However, this gene therapy approach, even with its risk of mild, transient transaminitis, has the potential to convert the bleeding phenotype of patients with severe hemophilia B into a mild form of the disease or to reverse it entirely for a prolonged period of time following vector administration. (ClinicalTrials.gov number, NCT00979238). Disclosures: Chowdary: Novo Nordisk: Consultancy. High:Amsterdam Molecular Therapeutics: ; Baxter Healthcare: Consultancy; Biogen Idec: Consultancy; bluebird bio, Inc.: Membership on an entity's Board of Directors or advisory committees; Genzyme, Inc.: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: ; Sangamo Biosciences: ; Shire Pharmaceuticals: Consultancy.

scholarly journals Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 428-428
Author(s):  
Samuel John ◽  
Michael A. Pulsipher ◽  
Amy Moskop ◽  
Zhen-Huan Hu ◽  
Christine L. Phillips ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Ad Hoc ◽  
Age Groups ◽  
Advisory Committees ◽  
Advisory Boards

Abstract Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (&lt;18y and ≥18y) [Rives et al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age (&lt;18y and ≥18y). Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged &lt;18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest - including cytokine release syndrome (CRS) and neurotoxicity - were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged &lt;18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged &lt;18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the &lt;18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy. Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.

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

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

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

scholarly journals Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4457-4457 ◽  
Author(s):  
Franck Morschhauser ◽  
Ian Flinn ◽  
Ranjana H Advani ◽  
Catherine S. Diefenbach ◽  
Kathryn Kolibaba ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Clinical Activity ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Grade 5 ◽  
Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

Employing Factor IX Variants to Avoid Limitations Imposed by Immune Recognition of AAV Vector in Hemophilia B Gene Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3124-3124 ◽  
Author(s):  
Paul E. Monahan ◽  
Junjiang Sun ◽  
Tong Gui ◽  
David G Wichlan ◽  
Scott W McPhee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Specific Activity ◽  
Factor Ix ◽  
Hemophilia B ◽  
Ongoing Clinical Trial ◽  
Advisory Committees

Abstract Abstract 3124 Persistent factor IX expression and phenotypic improvement have been achieved in a human clinical trial for hemophilia B using liver-directed adeno-associated virus (AAV) gene therapy vectors. An ongoing clinical trial uses a vector incorporating self-complementing AAV (scAAV) genome form, factor IX codon optimization (FIXopt) and AAV serotype 8 capsid. As was seen in a previous single-strand AAV serotype 2 trial, dose escalation has been associated with apparent immune-mediated transient inflammation of vector-transduced liver, although in contrast to the previous trial persistent FIX expression has been maintained for the first time. Taken together, these important trials define a consistent threshold load of AAV capsid that has stimulated capsid-specific cytotoxic lymphocyte recognition and potential transaminitis. To advance the successes achieved in these trials while providing a clear margin of safety so that this immunogenic threshold need not be approached, we have pursued steps to limit further the AAV capsid load. Single amino acid substitutions at arginine 338 in the FIX catalytic domain generate FIX variants with increased specific activity. We separately substituted either R338A, R338Q, or R338L (FIX Padua) into a codon optimized human factor IX cDNA and evaluated F.IX expression in tissue culture following plasmid DNA transfection of HEK 293t cells. Each R338 substitution improved FIX specific activity, up to 10 times increased over wild type using the R338LFIXopt cDNA. We next generated scAAV8 vectors incorporating a liver-specific transthyretin (TTR) promoter to express optimized codon F.IX cDNA with or without the R338L substitution. FIX−/− mice receiving portal vein injection of 1 × 1010 vg/animal (4 ×1011 vg/kg) expressed 86.5% of normal FIX activity at 2 months post-transduction from the WTopt vector and 330% normal from the R338LFIXopt. Incorporation of R338Lopt variant resulted in at least 6 to 10 fold increase in FIX specific activity over a follow-up of > 40 weeks. At ten months following FIX gene delivery, mice underwent a tail transection bleeding challenge. FIX vector mice demonstrated therapeutic protection from this major bleeding challenge and furthermore all survived with no late rebleeding (a hallmark of hemophilic phenotype). Greater than 100% normal human FIX activity was maintained for >40 weeks following treatment with the R338LFIX vector (v. 26.3% at euthanasia in WTopt vector group). The prolonged follow-up permitted extended safety evaluation. Factor IX inhibitor antibodies were not detected in any mice throughout the follow-up; FIX-binding IgG1 and IgG2 were negative also. Thrombin/antithrombin III complexes (TAT) examined at 12 weeks and at >30 weeks of age in R338LFIXopt vector mice did not differ from levels in WTFIXopt vector-treated or age-matched C57Bl/6 hemostatically normal mice. Necropsy at 40–44 weeks after vector (1 year of age) showed only age-related changes with no microvascular or macrovascular thrombosis on H&E staining or specific immunostaining for fibrin/fibrinogen deposition; specific staining for fibrosis within myocardium or other sites was negative. We next synthesized a R338LFIXopt expression cassette containing the LP1 promoter/enhancer/intron sequence being used in the ongoing clinical trial and demonstrated equivalent FIX activity from either promoter construct. We then established that the R338LFIXopt vector gives a predictable dose-response across a range of doses as low as 1x 1010 vg/kg I.V. and as high as 4 × 1012 vg/kg I.V. Hemarthrosis is the most common bleeding complication in hemophilia and leads to chronic joint destruction. Bleeding was induced in the joint of FIX−/− mice that had been transduced 4 weeks earlier with the R338LFIX vector. Joints were collected at 2 weeks after induced bleed and the bleeding-induced joint damage was graded using an established histologic score. I.V. R338LFIXopt vector pretreatment resulted in protection against joint degeneration in a dose-dependent fashion in this most relevant clinical scenario. These preclinical studies demonstrate a safety :efficacy profile to advance hemophilia gene therapy using the scAAV8.R338LFIXopt vector. Disclosures: Monahan: Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Asklepios BioPharmaceutical: Patents & Royalties, Research Funding; CSL Behring: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaIN: Research Funding; Prolor-Biotech: Research Funding. McPhee:Asklepios Biopharmaceutical: Employment. Samulski:Asklepios Biopharmaceutical: Employment, Patents & Royalties.

Impact Of Baseline (BL) Mutations, Including Low-Level and Compound Mutations, On Ponatinib Response and End Of Treatment (EOT) Mutation Analysis In Patients (Pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 652-652 ◽  
Author(s):  
Michael W. Deininger ◽  
Neil P. Shah ◽  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Franck E. Nicolini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Single Mutation ◽  
Advisory Committees ◽  
Mutation Status ◽  
Low Level ◽  
Advisory Boards ◽  
Equity Ownership

Abstract Background In CML, the presence of BCR-ABL kinase domain (KD) mutations, including low-level mutations, can predict clinical responses to 2nd line BCR-ABL tyrosine kinase inhibitors (TKIs). In addition, sequential treatment with TKIs can lead to development of compound mutations (≥2 mutations in the same BCR-ABL allele) that can be highly TKI-resistant. Ponatinib is a potent BCR-ABL TKI that, preclinically, has demonstrated activity against all BCR-ABL mutations tested and suppresses the emergence of any single mutation at clinically achievable concentrations (40 nM with ≥30 mg/d). In vitro, higher ponatinib concentrations were required to suppress emergence of certain compound mutations on a background of T315I or E255V single mutations. We evaluated the impact of single, low-level, and compound mutations at BL on responses to ponatinib and EOT mutations in CP-CML pts in the phase 2 PACE trial. Methods Pts with CP-CML (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib and/or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR) by 12 mos. Median follow-up at analysis (1 Apr 2013) was 20 (0.1-28) mos, with a minimum follow-up of 18 mos for pts remaining on study. Next generation sequencing (NGS) and Sanger sequencing (SS) were done at a central laboratory. NGS was conducted on all BL samples (N=267) with the Ion Torrent PGM using chemistry that enabled read lengths up to 400 bp for detection of compound mutations; mutations observed at a frequency ≥1% are reported. SS was conducted on both BL and EOT samples. Results By NGS at BL, 267 mutations (amino acid substitutions in the ABL KD [M237-E507]) were detected among 163 (61%) pts; 106 (40%) mutations were low level mutations not detected by SS. 75 unique single mutations were observed: 27 were detected by SS and NGS, all 27 have been associated with resistance to TKIs other than ponatinib; 48 were low level mutations detected only by NGS, 5 have been associated with resistance to TKIs other than ponatinib. 12% of pts had only low level mutations. Overall, no mutations were detected in 39% of pts, 1 mutation in 37%, and ≥2 mutations in 24%. Compound mutations were detected in 65% of pts who had ≥2 mutations, representing 15% of pts overall (10% with 1, 5% with 2 to 4 compound mutations). 48 unique compound mutations were observed; T315I, F317L, and F359C/I/V were the most commonly observed mutations within compound mutations. Responses were seen in pts with each of the 20 unique single mutations present in >1 pt at BL by NGS, including Y253H, E255V/K, T315I, M351T, F359V. Responses were observed regardless of overall NGS BL mutation status (table). The high response rates and durability of response in pts with compound mutations suggest that, in general, the presence of compound mutations at BL did not adversely affect the activity of ponatinib. Of the 109 pts who discontinued, 84 had successful mutation assessments by SS at or near the EOT visit. 4 pts had mutations at EOT that were not detected by NGS at BL; all 4 involved compound mutations (T315I/F359V [100%/90%], T315I/M351T [100%/40%], Y253H/F359V [100%/100%; n=2]), with one or both of the involved mutations detected individually at BL or by history. Overall, 12 pts lost MCyR (none with T315I at BL); 6 of the 12 discontinued and had EOT mutations assessed, no changes from BL were observed. Conclusions Responses to ponatinib were observed regardless of BL mutation status. Interestingly, responses tended to be lower in pts without mutations, suggesting that BCR-ABL independent mechanisms may be involved. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. In general, ponatinib activity was not adversely affected by the presence of compound mutations at BL. Rarely, the development of compound mutations was observed at EOT in pts with one of the involved mutations at BL or by history. Early introduction of ponatinib may suppress the emergence of single BCR-ABL mutations, and, as a result, the development of compound mutations. NCT01207440 Disclosures: Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Hodgson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Goldman:ARIAD: Honoraria. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Soverini:Novartis, BMS, ARIAD: Consultancy. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Branford:Novartis, BMS, ARIAD: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 650-650 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Philipp D le Coutre ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Response Rates ◽  
Advisory Committees ◽  
Advisory Boards ◽  
Common Drug ◽  
Heavily Pretreated ◽  
History Of

Abstract Background Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL. Methods 449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study. Results Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%). Conclusions Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented. Disclosures: Cortes: Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:Ariad, Novartis, BMS: Consultancy; Ariad, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding.

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.

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