scholarly journals Resolution of Sickle Cell Disease Manifestations in Patients Treated with Lentiglobin Gene Therapy: Updated Results from the Phase 1/2 Hgb-206 Group C Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 990-990 ◽  
Author(s):  
Julie Kanter ◽  
John F. Tisdale ◽  
Markus Y. Mapara ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Research Funding ◽  
Phase 1 ◽  
Globin Gene ◽  
Post Treatment ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership

Background β-globin gene transfer into hematopoietic stem cells (HSCs) could reduce or eliminate sickle cell disease (SCD)-related manifestations. LentiGlobin for SCD gene therapy contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV), encoding a human β-globin gene with the anti-sickling T87Q mutation (βA-T87Q). The safety and efficacy of LentiGlobin for SCD is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554). The initial 7 patients (Group A) were treated with LentiGlobin made from bone marrow harvested HSCs. The protocol was modified to improve HbAT87Q production by including pre-harvest red blood cell (RBC) transfusions, increasing the total busulfan exposure, and using a refined LentiGlobin manufacturing process (Group B, n=2). An additional modification was made for Group C patients where HSC collection by plerixafor mobilization followed by apheresis was instituted. Data from these Group C patients are discussed here. Results from patients in Groups A and B are reported separately. Methods Patients (≥ 18 years) with severe SCD (including those with recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were screened for eligibility. Patients received 240 µg/kg of plerixafor 4-6 hours prior to HSC collection via apheresis. CD34+ cells were transduced with BB305 LVV. Patients underwent myeloablative busulfan conditioning and subsequent LentiGlobin drug product (DP) infusion. Patients were monitored for adverse events (AEs), engraftment, vector copy number (VCN), total hemoglobin (Hb) and HbAT87Q expression, hemolysis markers, and SCD clinical manifestations. Data are presented as median (min-max). Results: As of 7 March 2019, 19 Group C patients, aged 26 (18-36) years, had initiated mobilization/apheresis and 13 patients were treated with LentiGlobin for SCD gene therapy. Median DP VCN, % transduced cells, and CD34+ cell dose in the 13 treated patients were: 3.8 (2.8-5.6) copies/diploid genome (c/dg), 80 (71-88) %, and 4.5 (3.0-8.0) x 106 CD34+ cells/kg, respectively. The median follow-up was 9.0 (1.0-15.2) months. Twelve patients achieved neutrophil and platelet engraftments at a median of 19 (15-24) days and 28 (19-136) days, respectively. As of the data cut-off, engraftment was not yet evaluable in 1 patient at 1-month post-infusion. All patients stopped red blood cell (RBC) transfusions within about 3 months post-LentiGlobin gene therapy. Median total hemoglobin (Hb) and Hb fractions in patients at various time points are shown in Figure 1. Median HbS levels were at or below 50% in all patients with at least 6 months follow-up. The median total Hb at last visit in 8 patients with at least 6 months of follow-up, was 11.5 (10.2-15.0) g/dL, with a corresponding HbAT87Q median contribution of 5.3 (4.5-8.8) g/dL and a median HbS 5.7 (4.8-8.0) g/dL. Of these 8 patients, 6 had a history of VOCs or ACS. The median annualized VOC+ACS rate in these patients was 5.3 (3-14) pre-treatment and decreased to 0 (0-2) post-treatment. One Grade 2 VOC was observed 3.5 months post-treatment. No ACS or serious VOCs were observed in Group C patients' post- treatment. Lactate dehydrogenase, reticulocyte count, and total bilirubin at last visit post-LentiGlobin infusion were 225.0 (130.0-337.0) U/L, 150.0 (42.1-283.0) 109/L, 22.2 (3.42-39.3) µmol/L, respectively, trending towards normalization. The most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7) post-DP infusion. Serious AEs were reported in 6 patients post-LentiGlobin treatment, most common being nausea and vomiting. To date, there have been no DP-related AEs or graft failure, vector-mediated replication competent lentivirus detected, or clonal dominance reported. Longer follow-up and additional patient data will be presented. Summary The safety profile of LentiGlobin gene therapy for SCD remains consistent with single-agent busulfan conditioning and underlying disease. Patients in HGB-206 Group C experienced high-level, sustained expression of gene-therapy derived hemoglobin, with median HbS levels reduced to ~50% and median total Hb levels of 11.5 g/dL at 6 months. The cessation of clinical complications (no ACS or serious VOCs) and decreased hemolysis suggest a strong therapeutic effect after LentiGlobin gene therapy in patients with SCD. Disclosures Kanter: Peerview: Honoraria; NHLBI: Membership on an entity's Board of Directors or advisory committees; Rockpointe: Honoraria; SCDAA: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Imara: Consultancy; Jeffries: Consultancy; Modus: Consultancy; Guidepoint Global: Consultancy; GLG: Consultancy; Cowen: Consultancy; bluebird bio, Inc: Consultancy; Medscape: Honoraria; Sangamo: Consultancy. Kwiatkowski:Terumo: Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc.: Employment, Equity Ownership. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding. Walters:AllCells, Inc: Consultancy; TruCode: Consultancy; Editas Medicine: Consultancy.

scholarly journals Interim Results from a Phase 1/2 Clinical Study of Lentiglobin Gene Therapy for Severe Sickle Cell Disease

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1176-1176 ◽  
Author(s):  
Julie Kanter ◽  
Mark C. Walters ◽  
Matthew M. Hsieh ◽  
Lakshmanan Krishnamurti ◽  
Janet Kwiatkowski ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Globin Gene ◽  
Advisory Committees ◽  
Cell Dose ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms and long-term complications of severe sickle cell disease (SCD). LentiGlobin Drug Product (DP) is a gene therapy product containing autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed in fetal hemoglobin (γ-globin). In two ongoing studies, subjects with transfusion-dependent β-thalassemia (Studies HGB-204 and HGB-205) or SCD (Study HGB-205) receiving LentiGlobin DP have demonstrated sustained expression of 3-9 g/dL therapeutic hemoglobin (HbAT87Q) and have shown marked improvements in clinical symptoms 1 year post-treatment. Study HGB-206 is a multi-center, Phase 1/2 safety and efficacy study of LentiGlobin DP in adults with severe SCD. We previously (ASH 2015) presented results from 2 subjects, who had 3 and 6 months of follow-up after LentiGlobin treatment. We now present data from 7 treated subjects, 4 of whom have ≥6 months of follow-up data. Subjects (≥18 years of age) with severe SCD (history of recurrent vaso-occlusive crisis [VOC], acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were screened for eligibility. Following bone marrow harvest (BMH), CD34+ cells were transduced with the BB305 vector. Subjects underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. Safety assessments include adverse events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL). After infusion, subjects are monitored for hematologic engraftment, vector copy number (VCN), HbAT87Q expression, and other laboratory and clinical parameters. As of July 2016, 7 subjects with severe SCD (median age: 26 years, range 18-42 years) have received LentiGlobin DP in this study. All subjects successfully underwent BMH, with a median of 2 harvests required (range 1-4). Fifteen Grade 3 AEs in 5 subjects were attributed to BMH: pain (n=10), anemia (n=3) and VOC (n=2); all resolved with standard measures. Table 1 summarizes cell harvest, DP characteristics, and lab results. The median LentiGlobin DP cell dose was 2.1x10e6 CD34+ cells/kg (range 1.6-5.1) and DP VCN was 0.6 (0.3-1.3) copies/diploid genome. Median post-infusion follow-up as of July 2016 is 7.1 months (3.7-12.7 months). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 22 days (17-29 days). The toxicity profile observed from start of conditioning to latest follow-up was consistent with myeloablative conditioning with single-agent busulfan. To date, there have been no DP-related ≥Grade 3 AEs or serious AEs, and no evidence of clonal dominance or RCL. The BB305 vector remains detectable at low levels in the peripheral blood of all subjects infused, with median VCN 0.08 (0.05-0.13, n=7) at last measurement. All subjects express HbAT87Q, with a median of 0.4g/dL (0.1-1.0 g/dL, n=7) at 3 months; most subjects demonstrated modest increases over time, and the 2 subjects with the longest follow-up expressed 0.31 and 1.2 g/dL HbAT87Q at 9 months. All 4 subjects with ≥6 months of follow-up experienced multiple VOCs in the 2 years prior to study entry (2-27.5 VOCs annually). Since LentiGlobin DP infusion, 3 of these 4 subjects have had fewer VOCs, although this trend may be confounded by the short follow-up, the effects of transplant conditioning, and/or post-transplant RBC transfusions. The decrease in VCN between DP and peripheral cells contrasts with previous reports of successful LentiGlobin gene therapy in ongoing studies HGB-204 and HGB-205. The relatively low in vivo VCN in this study appears to result in the lower HbAT87Q expression seen to date. We are exploring multiple hypotheses as to the etiology of the VCN drop between DP and peripheral blood, including the adverse impact of sickle marrow pathology on HSCs, the adequacy of myeloablation, and the magnitude of the transduced cell dose. We will provide an update on study data and ongoing efforts to increase in vivo VCN in patients with SCD, such as increasing the transduced cell dose through alternate HSC procurement methods or enhancing the DP VCN through manufacturing improvements. Disclosures Kanter: Novartis: Consultancy. Walters:Bayer HealthCare: Honoraria; AllCells, Inc./LeukoLab: Other: Medical Director ; ViaCord Processing Laboratory: Other: Medical Director ; Leerink Partners, LLC: Consultancy; Kiadis Pharma: Honoraria; bluebirdBio, Inc: Honoraria. Kwiatkowski:Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shire Pharmaceuticals: Consultancy; Sideris Pharmaceuticals: Consultancy; Apopharma: Research Funding; Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Kuypers:Children's Hospital Oakland Research Institute: Employment; bluebird bio: Consultancy. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Research Funding; Baxalta (now part of Shire): Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mast: Research Funding; Eli Lily: Research Funding.

scholarly journals Current Results of Lentiglobin Gene Therapy in Patients with Severe Sickle Cell Disease Treated Under a Refined Protocol in the Phase 1 Hgb-206 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1026-1026 ◽  
Author(s):  
John F. Tisdale ◽  
Julie Kanter ◽  
Markus Y. Mapara ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
Grade 3

Abstract Background β-globin gene transfer has the potential for substantial clinical benefit in patients with sickle cell disease (SCD). LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin gene therapy is being evaluated in the ongoing Phase 1 HGB-206 study (NCT02140554). Results in the initial 7 patients treated with LentiGlobin DP from steady state bone marrow harvested (BMH) HSCs using original DP manufacturing process (Group A) demonstrated stable HbAT87Q production in all patients, but at levels below the anticipated target. The protocol was thus amended to include pre-harvest RBC transfusions, optimize myeloablation by targeting higher busulfan levels, and use a refined DP manufacturing process (Group B); additionally, HSC collection by plerixafor mobilization/apheresis was instituted (Group C). Data from patients in Group C, treated under the modified protocol with DPs manufactured from plerixafor-mobilized HSCs using the refined process, are reported here. Results in patients in Groups A and B are reported separately. Methods Patients with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Patients in Group C received ≥2 months of transfusions to reach Hb of 10 - 12 g/dL and <30% HbS before HSC collection. Patients received 240 μg/kg of plerixafor 4 - 6 hours before HSCs were collected by apheresis and CD34+ cells were transduced with the BB305 LVV at a central facility. Following myeloablative conditioning with busulfan, the DP was infused, and patients were monitored for adverse events (AEs), engraftment, peripheral blood (PB) vector copy number (VCN), HbAT87Q expression, and HbS levels. Summary statistics are presented as median (min - max). Results As of 15 May 2018, 11 Group C patients (age 25 [18 - 35] years) had undergone mobilization/apheresis, 9 patients had DP manufactured (median 1 cycle of mobilization [1 - 3]) and 6 patients had been treated. Cell dose, DP VCN and % transduced cells in the 6 treated patients were: 7.1 (3 - 8) x 106 CD34+ cells/kg, 4.0 (2.8 - 5.6) copies/diploid genome (c/dg) and 81 (78 - 88) % transduced cells. The median follow-up was 3.0 (1.2 - 6.0) months. Patients achieved neutrophil engraftment at a median of 19 (18 - 20) days. Platelet engraftment was achieved at a median of 28 (12 - 64) days in 4 patients; platelet engraftment was pending in 2 patients. Two of 11 patients experienced 4 grade ≥3 AEs associated with plerixafor mobilization/HSC collection: 1 had vaso-occlusive pain and hypomagnesaemia, and the other had vaso-occlusive pain and non-cardiac chest pain. The toxicity profile from DP infusion to last follow-up in the 6 treated patients was consistent with myeloablative conditioning. Febrile neutropenia (n=5) and stomatitis (n=4) were the most common non-hematologic grade ≥3 AEs. Serious AEs were reported in 3 patients post-DP infusion: splenic hematoma, non-cardiac chest pain and mucosal inflammation. To date, there have been no DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. In the 6 treated patients, PB VCN at last visit ranged from 1.4 - 2.9 c/dg. In the 3 patients with 3 months follow-up, total Hb levels were 11.7 g/dL, 9.8 g/dL and 9.2 g/dL, and HbAT87Q levels were 4.7 g/dL, 3.2 g/dL and 3.5 g/dL. One additional patient with 6 months follow-up was off transfusions and had total Hb of 14.2 g/dL, of which 62% (8.8 g/dL) was vector-derived HbAT87Q and 36% (5.1 g/dL) was HbS. All 4 patients had HbAT87Q (median 39%) levels higher than or equal to HbS (median 31%) at the 3-month visit. Summary HGB-206 protocol changes and refined DP manufacturing have improved the LentiGlobin DP characteristics resulting in significantly improved outcomes. In addition, the HbAT87Q expression is comparable to, or exceeds, HbS levels as early as 3 months post DP infusion. These data support the feasibility of plerixafor-mediated CD34+ cell collection in patients with severe SCD and the efficacy of gene therapy. The safety profile of LentiGlobin gene therapy remains consistent with single-agent busulfan conditioning. Additional data and longer follow-up will determine the clinical effect of increased HbAT87Q/HbS ratios. Disclosures Kanter: Global Blood Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Sancilio: Research Funding; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees. Mapara:Incyte: Consultancy. Kwiatkowski:Novartis: Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding. Schmidt:GeneWerk GmbH: Employment; German Cancer Research Center: Employment; bluebird bio: Consultancy. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Celgene: Research Funding; Baxalta/Shire: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Research Funding; Biomarin: Research Funding; La Jolla Pharmaceutical: Research Funding. Walters:Sangamo Therapeutics: Consultancy; bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director.

Update from the Hgb-205 Phase 1/2 Clinical Study of Lentiglobin Gene Therapy: Sustained Clinical Benefit in Severe Hemoglobinopathies

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2311-2311 ◽  
Author(s):  
Jean-Antoine Ribeil ◽  
Salima Hacein-Bey-Abina ◽  
Emmanuel Payen ◽  
Michaela Semeraro ◽  
Magrin Elisa ◽  
...  
Keyword(s):  
Research Funding ◽  
Lentiviral Vector ◽  
Phase 1 ◽  
Globin Gene ◽  
Advisory Committees ◽  
Study Visit ◽  
Transfusion Requirements ◽  
Cd34 Cells ◽  
Equity Ownership

Abstract Introduction: β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms of severe sickle cell disease (SCD) and reduce or eliminate transfusion requirements in transfusion-dependent β-thalassemia (TDT). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector, which encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed with γ-globin. We previously reported proof of concept for LentiGlobin DP treatment in severe SCD and early data from 4 treated patients with TDT. We now report 18 months of follow-up for the patient with SCD and between 9 and 30 months of follow-up for the 4 patients with TDT. Patients (5-35 years of age) with severe SCD (e.g. ≥2 acute chest syndrome episodes or ≥2 vaso-occlusive crises [VOC] in preceding year/in year prior to regular transfusions) or TDT (≥100mL/kg of packed red blood cells [RBCs] per year) were enrolled. Following mobilization and apheresis (for TDT) or bone marrow harvest (for SCD), autologous CD34+ cells were transduced with the BB305 lentiviral vector. Patients underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. After infusion, patients were monitored for hematologic engraftment, vector copy number (VCN), and HbAT87Q expression. Disease-specific assessments included transfusion requirements for TDT, or VOCs and hospitalizations for SCD. Safety assessments included adverse events (AEs) and integration site analysis. Results: As of July 2016, 1 patient with severe SCD (male; 13 years old) and 4 patients with TDT (2 male, 2 female; 16-19 years old) have received LentiGlobin DP in Study HGB-205. The median LentiGlobin DP cell dose was 8.9 (range 5.6-13.6) x 106 CD34+ cells/kg with a DP VCN of 1.2 (range: 0.8-2.0) vector copies/diploid genome. Median post-infusion follow-up as of July 6, 2016 is 20.8 months (range 9.5-31.3). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 17 days (range 14-38 days). VCN in peripheral blood has remained generally consistent from Month 3 in all patients with a range of 0.2 to 3.4 at last measurement. The toxicity profile observed from start of conditioning to latest follow-up remains consistent with myeloablative conditioning with single-agent busulfan, with no DP-related ≥Grade 3 AEs or serious AEs and no evidence of clonal dominance reported to date. Three patients with TDT have β0/βE genotypes and 1 is homozygous for the severe β+ mutation IVS1 nt 110 G>A. The 2 patients who have completed the 2-year primary follow-up period (both β0/βE) have not required RBC transfusions for 31 and 28 months, with total Hb of 10.9 and 13.5 g/dL, and HbAT87Q expression of 7.7 and 10.1 g/dL, respectively, at most recent study visit. Iron chelation has been discontinued and phlebotomy initiated for 1 of the patients. The remaining patient with β0/βE genotype has 9 months of follow-up and has not required transfusions since 4 days post-LentiGlobin DP infusion, achieving a total Hb of 11.3 g/dL at last study visit. The patient with the severe IVS1 genotype has 12 months of follow-up and has been free of transfusions for 9 months, with a total Hb of 8.3 g/dL at last study visit. The patient with severe SCD, who prior to study enrollment received regular RBC transfusions, has experienced no clinical symptoms or complications of SCD in the 18 months since treatment, despite discontinuing transfusions 3 months after LentiGlobin DP infusion. Total Hb in this patient was 12.5 g/dL, with 6.6 g/dL HbAT87Q (53%) and 5.7 g/dL HbS (45%) at last study visit. Compared with values at screening, unconjugated bilirubin had dropped 78% (50 to 11 μmol/L), lactate dehydrogenase had dropped 54% (626 to 287 U/L), and reticulocyte count had dropped 45% (238x109/L to 132x109/L) by Month 18. Conclusions: Data from this ongoing Phase 1/2 clinical study suggest that treatment with LentiGlobin DP can result in sustained production of therapeutic HbAT87Q, which ameliorates the clinical and biochemical effects of severe SCD and TDT, with an acceptable safety profile. Gene therapy presents a potentially promising therapy for patients with severe hemoglobinopathies. Further follow-up and additional data from patients are needed to confirm the encouraging results seen to date in this study. Disclosures Ribeil: Bluebirdbio: Consultancy; Addmedica: Research Funding. Payen:bluebird bio: Patents & Royalties. Hermine:Alexion: Research Funding; Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Asmal:bluebird bio: Employment, Equity Ownership. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. De Montalembert:Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Leboulch:bluebird bio, Inc: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Lentiglobin Gene Therapy for Patients with Transfusion-Dependent β-Thalassemia (TDT): Results from the Phase 3 Northstar-2 and Northstar-3 Studies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1025-1025 ◽  
Author(s):  
Franco Locatelli ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
John Porter ◽  
Martin G. Sauer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Peripheral Blood ◽  
Research Funding ◽  
Additional Data ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
La Jolla

Abstract Background Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease caused by impaired β-globin production, leading to severe anemia, lifelong transfusion dependence with iron overload and serious comorbidities. Gene therapy (GT) offers a potentially transformative option for these patients. LentiGlobin GT contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. The safety and efficacy of LentiGlobin in patients with TDT was assessed in the phase 1/2 Northstar study in which 8/10 patients with non-β0/β0 genotypes and 3/8 patients with a β0/β0 genotype stopped transfusions. A refined manufacturing process to improve drug product (DP) characteristics is being evaluated in the studies presented here. Methods Northstar-2 (HGB-207; NCT02906202) and Northstar-3 (HGB-212; NCT03207009) are ongoing, international, single-arm, phase 3 studies in patients with TDT (≥ 100 mL/kg/yr of red blood cells [RBCs] or ≥ 8 RBC transfusions/yr) and non-β0/β0 genotypes or a β0/β0 genotype, respectively. HSCs were collected by apheresis after G-CSF and plerixafor mobilization. CD34+ HSCs were transduced with the BB305 LVV using a refined manufacturing process. Patients received single-agent, myeloablative busulfan conditioning and transduced cells were infused. The primary endpoint in Northstar-2 is the proportion of patients achieving transfusion independence (TI, weighted average hemoglobin [Hb] ≥ 9g/dL without RBC transfusions for ≥ 12 months continuously) and in Northstar-3 is the proportion of patients achieving transfusion reduction (≥ 60% reduction in transfused RBC volume post-DP infusion compared to pre-DP infusion). Patients were evaluated for engraftment, DP and peripheral blood vector copy number (VCN), GT-derived Hb (HbAT87Q), adverse events (AEs), vector integration, and evidence of replication competent lentivirus (RCL). Patients are followed for 2 years and offered participation in a long-term follow-up study. Results Eleven patients (median age 20 [min - max: 12 - 24] years) with TDT and non-β0/β0 genotypes (5 β+/β0, 4 βE/β0, 2 β+/β+) have been treated in Northstar-2 as of May 15, 2018 with a median follow-up of 8.5 (min - max: 0.3 - 16.2) months. DPs had a median cell dose of 7.4 x 106 (min - max: 5.0 - 19.4 x 106) CD34+ cells/kg, median VCN of 3.4 (min - max: 2.4 - 5.6) copies/diploid genome (c/dg) and a median of 82% (min - max: 53 - 90%) CD34+ cells were transduced. Median time to neutrophil and platelet engraftment was 21.5 (min - max: 16 - 28) and 44.5 (min - max: 34 - 84) days, respectively, in 10 patients; 1 patient was not yet evaluable. Serious AEs after DP infusion included 2 events of grade 4 liver veno-occlusive disease treated with defibrotide and 1 event each of hypotension, hypoxia, sepsis, and transfusion reaction, all resolved. Only 1 AE (grade 1 abdominal pain) was related to LentiGlobin. There were no deaths or graft failure and no evidence of vector-mediated RCL or clonal dominance. Of 8 patients with ≥ 6 months follow-up, 7 have stopped RBC transfusions. At last study visit, peripheral blood VCN was 1.1 - 5.0 c/dg and total Hb was 11.1 - 13.3 g/dL of which 7.6 - 10.2 g/dL (68 - 92%) was contributed by HbAT87Q. Median Hb at month 6 was 11.9 (min - max: 11.2 - 13.3) g/dL. The first treated patient achieved TI. The additional patient with ≥ 6 months follow-up had no transfusions for 11 months, however had a peripheral blood VCN of 0.2 c/dg and resumed transfusions due to symptomatic anemia. Bone marrow assessment of dyserythropoesis and data with longer follow-up will be presented. Two patients, 26- and 7- years old, have been treated in Northstar-3. Both had 2 DP lots manufactured with DP VCNs of 2.9/3.3 and 3.4/3.9 c/dg and 82%/85% and 78%/78% CD34+ cells were transduced, respectively. Both successfully engrafted. Additional data for these patients will be presented. Summary Seven of 8 patients with TDT and non-β0/β0 genotypes produced sufficient HbAT87Q to stop chronic transfusions following LentiGlobin GT in Northstar-2. The safety profile appears consistent with busulfan myeloablative conditioning with no grade ≥ 3 DP-related AEs. Initial results show DP characteristics in Northstar-3 are consistent with those in Northstar-2. Additional data from Northstar-3 will determine the impact of HbAT87Q production on transfusion reduction in patients without endogenous β-globin production. Disclosures Locatelli: bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walters:AllCells Inc.: Other: Medical Director; ViaCord Processing Lab: Other: Medical Director; bluebird bio: Research Funding; Sangamo Therapeutics: Consultancy. Kwiatkowski:Terumo: Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; bluebird bio: Consultancy, Honoraria, Research Funding. Porter:Agios: Honoraria; Cerus: Honoraria; Novartis: Consultancy. Thuret:Addmedica: Research Funding; bluebird bio: Research Funding; Novartis: Research Funding. Kulozik:bluebird bio: Consultancy, Honoraria. Lal:Terumo Corporation: Research Funding; Celgene Corporation: Research Funding; Insight Magnetics: Research Funding; Bluebird Bio: Research Funding; La Jolla Pharmaceutical Company: Consultancy, Research Funding; Novartis: Research Funding. Thrasher:Orchard Therapeutics: Consultancy, Equity Ownership; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Elliot:bluebird bio: Employment, Equity Ownership. Tao:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Thompson:Amgen: Research Funding; Baxalta/Shire: Research Funding; La Jolla Pharmaceutical: Research Funding; Novartis: Research Funding; bluebird bio: Consultancy, Research Funding; Celgene: Research Funding; Biomarin: Research Funding.

scholarly journals Outcomes for Initial Patient Cohorts with up to 33 Months of Follow-up in the Hgb-206 Phase 1 Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1080-1080 ◽  
Author(s):  
Julie Kanter ◽  
John F. Tisdale ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
Markus Y. Mapara ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Total Bilirubin ◽  
Employment Equity ◽  
Advisory Committees ◽  
Group A ◽  
Equity Ownership ◽  
Group B

Abstract Background Sickle cell disease (SCD) is a progressively debilitating genetic disease causing significant morbidity and early mortality for which a universal curative therapy is lacking. Expression of an anti-sickling β-globin via gene transfer into hematopoietic stem cells (HSCs) may reduce or eliminate SCD symptoms. LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling substitution (T87Q). The safety and efficacy of LentiGlobin in adults with severe SCD is being evaluated in the ongoing multi-center Phase 1 study HGB-206 (NCT02140554). The first 7 patients (Group A) received DP from bone marrow harvested (BMH) HSCs and demonstrated stable but sub-optimal gene therapy-derived hemoglobin (HbAT87Q). The protocol was amended to include pre-harvest transfusions, increased target busulfan levels and a refined DP manufacturing process (Group B). The study is now enrolling patients in Group C, treated under modified protocol and including DP manufactured from plerixafor-mobilized HSCs. Data from patients in fully enrolled Groups A and B are shown here. Methods Patients ≥18 years old with severe SCD, as previously described, were enrolled. CD34+ cells from BMH were transduced with the BB305 LVV to produce LentiGlobin DP. Following myeloablative busulfan conditioning, patients were infused with DP. Group A patients received DP from the original manufacturing process. One Group B patient (1313) received DPs from a combination of original and refined manufacturing processes, while the other (1312) was entirely from the refined process. Adverse events (AEs), engraftment, vector copy number (VCN) in peripheral blood (PB), Hb fractions, and hemolysis markers were monitored. Results Nine patients (7 Group A, 2 Group B) with severe SCD (median age 26 [min - max: 18 - 42] years) were treated with LentiGlobin gene therapy. DP characteristics are shown in Table 1 and were improved in Group B patients, with higher VCNs, cell doses and % transduced cells compared to Group A. As of May 15, 2018, all Group A patients had completed ≥2 years follow-up and enrolled in a long-term follow-up study. Median follow-up was 24.2 (min - max: 22.8 - 32.9) months in Group A; 14.3 and 8.5 months for Group B patients 1313 and 1312. All patients engrafted. The toxicity profile was consistent with myeloablative conditioning. Serious AEs were reported in 8 patients; vaso-occlusive pain (n=5) was most common. No grade ≥3 DP-related AEs and importantly, no evidence of graft failure, veno-occlusive liver disease, replication competent lentivirus or clonal dominance were observed. All patients demonstrate stable PB VCN and HbAT87Q levels over prolonged follow-up. In Group A, PB VCN and HbAT87Q levels were modest, with a median of 0.1 c/dg and 0.8 g/dL at last visit, respectively (Table 1). Unsupported total Hb in 6/7 patients (1 patient is on transfusions) ranged from 7.1 - 11.4 g/dL. Total bilirubin and lactate dehydrogenase (LDH) at last visit vs. baseline decreased by a median of 46% (n=7) and 24% (n=6), respectively, while reticulocyte count increased by a median of 8% (n=7). With modest HbAT87Q production the annualized vaso-occlusive events (VOEs) rate decreased 17 - 100% compared to the 2-years pre-DP infusion (n=6; Figure 1). PB VCN and HbAT87Q in Group B patients were improved (Table 1). Total Hb at last visit was 11.0 g/dL in patient 1313 (29% HbAT87Q). In patient 1312, who received DP entirely from refined manufacturing, total Hb was 12.8 g/dL, with HbAT87Q contributing 56%. Total bilirubin and LDH normalized in both Group B patients, reticulocyte count decreased in patient 1312 (Table 1). Changes in VOE rates will be presented. Summary In the initial HGB-206 cohorts (Groups A and B), the safety profile of LentiGlobin gene therapy observed to date, is consistent with myeloablative busulfan conditioning. While HbAT87Q levels in Group A are sub-optimal, they are stable through ≥2 years of follow-up and most patients show a decrease in VOEs, suggesting that even modest HbAT87Q production may improve the clinical status of patients with SCD. Patients in Group B had improved DP characteristics, increased PB VCN and HbAT87Q levels with normalization of Hb in 1 patient and normalization of LDH and total bilirubin in both. Improvements in DP manufacturing correlate with increased levels of therapeutic HbAT87Q and could lead to significant clinical benefit. Disclosures Kanter: NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sancilio: Research Funding; Pfizer: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kwiatkowski:bluebird bio: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Apopharma: Research Funding; Terumo: Research Funding; Novartis: Research Funding. Mapara:Incyte: Consultancy. Schmidt:German Cancer Research Center: Employment; bluebird bio: Consultancy; GeneWerk GmbH: Employment. Miller:bluebird bio: Employment, Equity Ownership. Pierciey:bluebird bio: Employment, Equity Ownership. Shi:bluebird bio: Employment, Equity Ownership. Ribeil:bluebird bio: Employment, Equity Ownership. Walters:bluebird bio: Research Funding; ViaCord Processing Lab: Other: Medical Director; AllCells Inc.: Other: Medical Director; Sangamo Therapeutics: Consultancy. Thompson:La Jolla Pharmaceutical: Research Funding; Biomarin: Research Funding; Novartis: Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; Amgen: Research Funding; Baxalta/Shire: Research Funding.

scholarly journals Exploring the Drivers of Potential Clinical Benefit in Initial Patients Treated in the Hgb-206 Study of Lentiglobin for Sickle Cell Disease (SCD) Gene Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2061-2061 ◽  
Author(s):  
Mark C. Walters ◽  
John F. Tisdale ◽  
Janet L. Kwiatkowski ◽  
Lakshmanan Krishnamurti ◽  
Markus Y. Mapara ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Benefit ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Group A ◽  
Equity Ownership ◽  
Grade 3 ◽  
Group B

Background LentiGlobin for SCD gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling substitution (T87Q). Its safety and efficacy are being studied in the ongoing multi-center Phase 1/2 HGB-206 trial (NCT02140554). Initial patients received LentiGlobin drug product (DP) using bone marrow-harvested (BMH) CD34+ HSCs transduced with the BB305 LVV under original manufacturing. All patients had successful engraftment but levels of gene therapy-derived hemoglobin (HbAT87Q) were lower than expected. Despite this, hemolysis markers and the annualized rate of vaso-occlusive crisis (VOCs) plus acute chest syndrome (ACS) were reduced post-infusion. Here, we provide an update on these patients and explore factors that may contribute to the clinical benefit. Data on patients treated more recently are presented separately. Methods Adults with SCD-related complications (previously described) were enrolled in HGB-206. All patients received myeloablative busulfan conditioning before DP infusion. The initial group (Group A; N=7) was treated with DP from BMH HSCs using the original LentiGlobin manufacturing process. The protocol was amended, and 2 patients were subsequently treated in Group B with DP from BMH HSCs. Patient 1 had DP made with original and refined manufacturing processes and patient 2 had DP made only with the refined process. Patients were followed for 2 years in HGB-206 and offered participation in the LTF-303 study for long-term follow-up. Adverse events (AEs), Hb fractions, and additional laboratory and clinical parameters were monitored. Results As of 7 March 2019, the median follow-up post-DP infusion was 35.8 (min-max: 29.8-44.5) months in Group A; it was 17.2 and 20.2 months for Group B patients 1 and 2. There was full hematological recovery with no graft failure. The safety profile of LentiGlobin post-DP infusion was consistent with myeloablative busulfan conditioning and underlying SCD. No cases of Grade ≥ 3 DP-related AEs, veno-occlusive liver disease, vector-mediated replication competent lentivirus or clonal dominance were observed. Three years after LentiGlobin gene therapy, one Group A patient developed myelodysplastic syndrome, reported as unlikely related to LentiGlobin. The patient subsequently received an HLA-haploidentical donor transplant. The annualized rate of VOCs plus ACS from LentiGlobin infusion to last follow-up was reduced by a median of 89 (min-max 10-100) % compared to that in the 2-year interval before enrollment in the 8 patients who had a history of VOC and/or ACS. One Group A patient who had a stroke pre-DP infusion has not had any red blood cell (RBC) transfusions through ~3 years post-DP infusion and no stroke recurrence. Median HbAT87Q levels were 1.0 (min-max 0.7-2.8) g/dL for Group A and 3.4 g/dL for Group B patient 1 at last visit and were stable for up to 3.5 years follow-up (Figure 1A). In several patients, HbF levels increased post-LentiGlobin treatment, peaking at ~2-6 months, and remaining higher at last visit compared to 1-month post-DP infusion. At last visit, the median HbF level was 0.6 (min-max 0.1-1.8) g/dL for all Group A and 0.8 g/dL for Group B patient 1 (Figures 1B and 2). In these patients, the median fraction of anti-sickling Hb (HbAT87Q + HbF + HbA2) was 22.9 (min-max 14.2-29.8) % and 39.4%, respectively. Patient 2 in Group B, who had DP made entirely using refined manufacturing process, had no HbF but produced high levels of HbAT87Q (7.5 g/dL) that contributed to 53.7% of total Hb. Summary In the HGB-206 Group A patients, the modest expression of gene therapy-derived HbAT87Q is accompanied by an induction of HbF. Elevated HbF levels have been shown to be associated with reduced severity of SCD. The resulting 14-30% of anti-sickling Hb observed in Group A patients, while not likely to be curative, showed clinical benefit as suggested by a reduction in the annualized rate of VOC plus ACS. Further, Group A and B patients have maintained HbAT87Q production, demonstrating the durability of gene therapy-derived β-globin gene expression. There have been no Grade ≥ 3 DP-related AEs in LentiGlobin-treated patients with up to 3.5 years of follow-up. Longer follow-up will help determine whether the initial induction of HbF, as is common after myeloablation, will be sustained and continue to contribute to therapeutic anti-sickling Hb levels. Disclosures Walters: Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy. Kwiatkowski:Apopharma: Research Funding; Imara: Consultancy; Celgene: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Terumo: Research Funding; Novartis: Research Funding. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Miller:bluebird bio, Inc.: Employment, Equity Ownership. Pierciey:bluebird bio, Inc.: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Kanter:Rockpointe: Honoraria; GLG: Consultancy; Guidepoint Global: Consultancy; Novartis: Consultancy, Honoraria; Imara: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Medscape: Honoraria; Peerview: Honoraria; bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; Jeffries: Consultancy; Cowen: Consultancy. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding.

Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Update from the Northstar Hgb-204 Phase 1/2 Clinical Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1175-1175 ◽  
Author(s):  
Alexis A. Thompson ◽  
Janet Kwiatkowski ◽  
John Rasko ◽  
Suradej Hongeng ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Lentiviral Vector ◽  
Phase 1 ◽  
Advisory Committees ◽  
Transfusion Requirements ◽  
Post Infusion ◽  
Equity Ownership

Abstract BACKGROUND Allogeneic hematopoietic stem cell (HSC) transplant is potentially curative for patients with β-thalassemia major or, as more broadly defined, transfusion dependent β-thalassemia (TDT). However, HSC transplant is generally restricted to younger patients with matched sibling donors. Gene therapy could provide a transformative treatment for a broader population of patients with TDT, including those who are older or lack an appropriate donor. HGB-204 is an international, multi-center Phase 1/2 clinical study investigating the safety and efficacy of LentiGlobin Drug Product (DP), a gene therapy product containing autologous HSCs transduced ex vivowith the BB305 lentiviral vector, in patients with TDT. We previously reported initial data in 13 treated patients with 0 to 19 months follow-up. Study enrollment is complete, and all 18 patients have undergone DP infusion. Here, we report new results on the study's full cohort of 18 patients, 14 of whom have ≥ 6 months of follow-up, including 1 who has completed the primary 24-month analysis period. METHODS Patients (12 to 35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. HSC mobilization was accomplished with granulocyte colony stimulating factor (G-CSF) and plerixafor, and HSCs were harvested by apheresis. In a centralized manufacturing facility, CD34+-selected stem cells were transduced with the BB305 lentiviral vector, which encodes the human β-globin gene engineered to contain a single point mutation (AT87Q) and is regulated by the β-globin locus control region. Patients underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells (LentiGlobin DP). Patients were monitored for hematologic engraftment, vector copy number (VCN), hemoglobin AT87Q (HbAT87Q) expression, and transfusion requirements. Safety assessments including adverse clinical events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL) were evaluated post-infusion. RESULTS Eighteen patients with TDT (β0/β0 [n=8], β0/βE [n=6], β0/β+ [n=1], β0/βx [n=1] and β+/β+ [n=2] genotypes) have received LentiGlobin DP. The median age of the 13 female and 5 male patients treated was 20 years (range: 12-35 years). The median DP VCN was 0.7 (range: 0.3-1.5 copies/diploid genome) and the median cell dose was 8.1 x 106 CD34+ cells/kg (range: 5.2-18.1 x 106 cells/kg). Patients engrafted with a median time of 18.5 days (range: 14-30 days) to neutrophil recovery. The toxicity profile observed was typical of myeloablative conditioning with single agent busulfan. There have been no ≥ Grade 3 DP-related AEs and no evidence of clonal dominance or RCL during a median follow-up of 14.4 months post-infusion (range: 3.7-27.0 months; cut-off date: 27 June 2016). To date, patients with at least 6 months of follow-up achieved a median HbAT87Q level of 4.7 g/dL at 6 months (range: 1.8-8.9 g/dL; n=14), with a median VCN in peripheral blood of 0.4 (range: 0.2−1.0; n=13). Of these, all patients with non-β0/β0 genotypes and ≥12 months of follow-up (n=5) have remained free of transfusions (median 19.4 months without transfusion; range: 15.3 to 24.0 months) with a median total Hb of 11.6g/dL (range: 9.0-11.9 g/dL) at the most recent follow-up visit. While patients with β0/β0genotypes and ≥12 months of follow-up (n=5) have continued to require transfusions, annual median transfusion volumes have decreased 60% (from median 171.9 ml/kg/year at baseline [range: 168.1-223.2ml/kg/year] to 67.8 ml/kg/year post-treatment [range: 14.8-123.7 ml/kg/year]). CONCLUSIONS In the largest TDT gene therapy trial to date, all patients have demonstrated therapeutic Hb expression without ≥ Grade 3 DP-related AEs. The levels of HbAT87Q in patients with at least 6 months of follow-up have exceeded the study primary endpoint (≥ 2g/dL) in 13/14 (93%) patients and are sustained in the 10 patients with ≥12 months of follow up. Compared to their baseline, all patients with β0/β0 genotypes have considerably reduced transfusion requirements. Notably, following a single infusion of LentiGlobin DP, patients with genotypes other than β0/β0 have discontinued transfusions and remain free of transfusions to date. These early results support the continued development of LentiGlobin DP as a treatment for TDT. Disclosures Thompson: Amgen: Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Mast: Research Funding; ApoPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eli Lily: Research Funding; Baxalta (now part of Shire): Research Funding. Kwiatkowski:Luitpold Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Apopharma: Research Funding; Ionis pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sideris Pharmaceuticals: Consultancy; Shire Pharmaceuticals: Consultancy. Rasko:GSK: Honoraria; IMAGO BioSciences: Consultancy, Equity Ownership; Genea: Consultancy, Equity Ownership; Rarecyte: Consultancy, Equity Ownership; Australian government and philanthropic foundations: Research Funding; Cure The Future Foundation: Other: Voluntary non-executive Board Member; Royal College of Pathologists of Australasia Foundation: Other: Voluntary non-executive Board Member; Office of the Gene Technology Regulator (OGTR) Australian Government: Membership on an entity's Board of Directors or advisory committees. Schiller:Incyte Corporation: Research Funding. Ho:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. von Kalle:bluebird bio: Consultancy; GeneWerk: Equity Ownership. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Petrusich:bluebird bio: Employment, Equity Ownership. Asmal:bluebird bio: Employment, Equity Ownership. Walters:Kiadis Pharma: Honoraria; Bayer HealthCare: Honoraria; Leerink Partners, LLC: Consultancy; ViaCord Processing Laboratory: Other: Medical Director ; AllCells, Inc./LeukoLab: Other: Medical Director ; bluebirdBio, Inc: Honoraria.

scholarly journals Flipping the Switch: Initial Results of Genetic Targeting of the Fetal to Adult Globin Switch in Sickle Cell Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1023-1023 ◽  
Author(s):  
Erica B. Esrick ◽  
Christian Brendel ◽  
John P Manis ◽  
Myriam A Armant ◽  
Helene Negre ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Lentiviral Vector ◽  
Employment Equity ◽  
Advisory Committees ◽  
Cd34 Cells ◽  
Equity Ownership ◽  
Initial Results

Abstract Autologous gene therapy (GT) for beta-hemoglobinopathies has demonstrated encouraging early safety and efficacy using addition of a sickling-resistant globin gene to stem cells. Another therapeutic strategy for sickle cell disease (SCD) is erythroid-specific inactivation of BCL11A, which is a validated repressor of gamma globin expression (Sankaran et al. Science 2011). This approach has the distinct advantage of simultaneously inducing fetal hemoglobin (HbF) while coordinately decreasing sickle hemoglobin (HbS). Since hemoglobin (Hb) polymerization in sickle red cells is highly dependent on the intracellular concentration of HbS and is strongly inhibited by HbF, effective BCL11A repression should prevent the sickling phenotype within red cells. We have shown that erythroid-specific expression of microRNA-adapted shRNAs (shRNAmiR) targeting BCL11A effectively induces HbF in human erythroid cells derived from transduced HSCs, largely attenuating the hematologic effects of SCD in a murine model while avoiding negative effects in HSCs and B lymphocytes (Brendel et al. JCI 2016). Here we report the initial results of a pilot clinical study utilizing a shRNAmiR lentiviral vector (LVV) targeting BCL11A for autologous GT in SCD patients. Transduction of hematopoietic cells with GMP lentiviral vector (BCH_BB-LCRshRNA(miR)) expressing the shRNAmiR for BCL11A in an erythroid-specific fashion showed no toxicity in engraftment and genotoxicity assays, efficient transduction rates of 80-95% of CD34+-derived erythroid colony forming cells from healthy donors and SCD patients, and >95% of transduced erythroid colonies demonstrating HbF levels of 50-95% of total Hb. Transduction at clinical scale with plerixafor mobilized CD34+ cells from three SCD donors yielded vector copies of 3.7 - 5.2/cell. Patients with severe SCD were screened for eligibility according to an IND enabled, IRB-approved investigator-initiated protocol. The first cohort included patients ≥ 18 years old. After at least 3 months of protocol-required transfusions, autologous CD34+ cells were collected by plerixafor mobilization and apheresis, and then transduced under GMP conditions with the BCH_BB-LCRshRNA(miR) vector. As of July 28, 2018, 3 patients representing the adult cohort had undergone a total of 3 (n=2) or 4 (n=1) days of mobilization. Mean single-day apheresis yields were 3.2 (range 1.5 - 6.8) x 106 CD34+ cells/kg. No Grade 3 or 4 AEs were attributed to mobilization and collection, although one subject developed an incidentally-discovered line-associated atrial clot and pulmonary embolism. Transduced cell products for these 3 patients have cell doses of 3.3 - 6.7 x 106 CD34+ cells/kg, VCN of 3.3 - 5.1 copies per cell and >95% vector-positive CD34+-derived colonies. One subject (BCL002), who had been regularly transfused for 17 years, has undergone infusion of gene-modified cells after myeloablative busulfan conditioning and achieved neutrophil engraftment after 22 days. Post-infusion follow-up is 78 days. At the time of the last analysis 76 days after GT and 64 days after last RBC transfusion (Table 1) subject BCL002 had a sustained Hb of >10 g/dL and, compared to pre-GT, there was a notable absence of irreversibly sickled cells on peripheral smear and a persistently low absolute reticulocyte count consistent with markedly reduced hemolysis. Hb electrophoresis showed 23.3% HbF, 51.8% HbS and 22.3% HbA (from residual transfused cells) with a HbF/(HbF+HbS) ratio of 29.7%. At day 76, the number of F cells had risen to 59.7% with 12pg HbF/F cell. In flow-sorted immature erythroid cells γ-globin mRNA was >80% of total β-like globins in the graft-derived population and BCL11A protein was reduced by ~90%. Adverse events observed from the start of conditioning until latest follow-up were consistent with myeloablative conditioning, and there have been no product-related adverse events and no SCD-related complications. These early results show: (1) feasibility of enrollment, cell procurement, and GMP manufacturing of gene modified CD34+ cells in 3 adult SCD patients; (2) the first proof of principle demonstrating shRNAmiR-based gene knockdown in humans, and (3) successful rapid induction of HbF in the first patient infused, with marked attenuation of hemolysis in the early phase of autologous reconstitution. Based on the trajectory of increasing HbF/(HbF+HbS), near full suppression of the SCD phenotype is expected. Disclosures Esrick: Bluebird Bio: Honoraria. Negre:bluebird bio: Other: Spouse employed by bluebird Bio. Dansereau:Bluebird Bio: Consultancy. Braunewell:Bluebird Bio: Employment, Equity Ownership. Christiansen:Bluebird Bio: Employment, Equity Ownership, Other: Salary. Nikiforow:Kite Pharma: Consultancy. Achebe:Luitpold Pharmaceutical: Consultancy; AMAG Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; Syros pharmaceuticals: Consultancy. Negre:Bluebird Bio: Employment, Equity Ownership, Other: Salary. Heeney:Sancilio Pharmaceuticals: Consultancy, Research Funding; Ironwood: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Vertex/Crisper: Other: Data Monitoring Committee; Pfizer: Research Funding; Astra Zeneca: Consultancy, Research Funding. Williams:Bluebird Bio: Research Funding.

scholarly journals Results from the Completed Hgb-205 Trial of Lentiglobin for β-Thalassemia and Lentiglobin for Sickle Cell Disease Gene Therapy

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3358-3358 ◽  
Author(s):  
Elisa Magrin ◽  
Michaela Semeraro ◽  
Alessandra Magnani ◽  
Hervé Puy ◽  
Annarita Miccio ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Weighted Average ◽  
Employment Equity ◽  
Advisory Committees ◽  
Long Term Follow Up ◽  
Equity Ownership

Background LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding human β-globin with a T87Q substitution. This substitution confers anti-sickling properties to the gene therapy-derived hemoglobin (HbAT87Q) and allows for its quantification in transduced HSCs. The proof of concept for LentiGlobin gene therapy in patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) was established in the recently completed HGB-205 study (NCT02151526). Herein, we provide the safety and efficacy outcomes and long-term follow-up data for all 7 treated patients, 4 with TDT and 3 with SCD. Methods Patients 5−35 years old with TDT (≥ 100 mL/kg of packed red blood cells [pRBCs]/year) or severe SCD (e.g., ≥ 2 acute chest syndromes [ACS] or ≥ 2 vaso-occlusive crises in the preceding year or the year before regular transfusions) were enrolled. CD34+ HSCs were obtained by mobilization and apheresis in patients with TDT or by bone marrow harvest in patients with SCD. Following collection, cells were transduced with the BB305 LVV. Patients underwent busulfan myeloablative conditioning and were infused with transduced cells. Patients were monitored for engraftment, adverse events (AEs), HbAT87Q levels, and other hematologic and clinical parameters. After 2 years in HGB-205, patients transitioned into the long-term follow-up study, LTF-303 (NCT02633943). Summary statistics are shown as median (min-max). Results As of June 2019, patients with TDT (n=4) and SCD (n=3) had a median follow-up of 49.6 (40.5-60.6) and 28.5 (25.5-52.5) months, respectively. Table 1 shows patient and drug product characteristics and several key efficacy outcomes. All patients achieved HSC engraftment. LentiGlobin safety profile was consistent with busulfan myeloablative conditioning and, in case of SCD, with the underlying disease state. The most common non-hematologic Grade ≥ 3 AEs post-LentiGlobin gene therapy (≥ 2 patients) for patients with TDT were stomatitis (n=4) and increased aspartate aminotransferase (n=2), and for patients with SCD were ACS (n=2) and vaso-occlusive pain (n=2). In all 4 patients with TDT, total Hb and HbAT87Q levels remained generally stable up to 5 years post-LentiGlobin infusion. Three of 4 patients achieved transfusion independence (TI; defined as weighted average Hb ≥ 9g/dL without pRBC transfusions for ≥ 12 months), for an ongoing duration of 56.3 (38.2-57.6) months. Weighted average total Hb during TI was 11.4 (10.5-13.0) g/dL. One patient has been off transfusions for 37.5 months and had total Hb of 7.7 g/dL, which was below the ≥ 9 g/dL requirement to meet the protocol definition of TI. At last visit, HbAT87Q levels in these 4 patients ranged from 6.2-11.2 g/dL, which contributed 73.8-86.8% of the total Hb. The first patient treated with LentiGlobin for SCD experienced one vaso-occlusive pain episode, which developed at 30 months after LentiGlobin gene therapy following a case of acute gastroenteritis with fever and dehydration. The second SCD patient had 2 serious AEs (SAEs) of ACS approximately 6 and 8 months after LentiGlobin gene therapy. The patient resumed chronic pRBC transfusions and hydroxyurea treatment and subsequently experienced 2 SAEs of vaso-occlusive pain; no additional SAEs of vaso-occlusive pain or ACS were reported during the last 16 months of follow-up after LentiGlobin infusion. The third SCD patient had no episodes of vaso-occlusive pain or ACS during 25.5 months of follow-up post-LentiGlobin gene therapy as of the data cut-off. Two patients with SCD who have been off chronic pRBC transfusions, showed improvement in hemolysis markers post-LentiGlobin treatment and stabilization of HbAT87Q expression at approximately 6 months post-LentiGlobin infusion. Total Hb levels for patients with SCD at last visit were 13.0 g/dL (patient 1), 9.4 g/dL (patient 2), and 9.8 g/dL (patient 3), with corresponding HbAT87Q contributions of 47.9%, 7.9%, and 25.8%, respectively. Summary With up to 5 years of follow-up, treatment with LentiGlobin gene therapy was well tolerated and resulted in improvement in hematologic parameters and disease-related symptoms. Further results from the completed study will be presented. Disclosures Hermine: Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding. Brousse:bluebird bio, Inc: Consultancy; AddMedica: Consultancy. El Nemer:Hemanext: Other: Other. Bartolucci:Novartis: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees. Asmal:bluebird bio, Inc: Employment, Equity Ownership. Whitney:bluebird bio, Inc: Employment, Equity Ownership. Gayron:bluebird bio, Inc: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Cavazzana:SmartImmune: Other: Founder.

scholarly journals Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3063-3063 ◽  
Author(s):  
Michael J. Mauro ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Neil P. Shah ◽  
Dale L. Bixby ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Phase 1 ◽  
Chronic Phase ◽  
Molecular Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Phase 1 Trial ◽  
Equity Ownership

Abstract Background: Ponatinib, an oral tyrosine kinase inhibitor with potent activity against native and mutant BCR-ABL1, is approved for patients with refractory chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated, or for patients with the T315I mutation. The efficacy and safety of ponatinib in patients with resistant/refractory hematologic malignancies were evaluated in a phase 1 trial (NCT00660920). Here, we report 4-year follow-up data from chronic-phase (CP)-CML patients; final data (approximately 5-year follow-up) will be presented. Methods: In this open-label, dose-escalation, phase 1 trial, 81 patients with resistant/refractory hematologic malignancies (CP-CML, 43 patients; accelerated-phase CML, 9 patients; blast-phase CML, 8 patients; Ph+ ALL, 5 patients) were enrolled. Patients were treated with ponatinib at a starting dose of 2 mg/d - 60 mg/d; intra-patient dose escalation was permitted. In Oct 2013, dose reduction instructions were provided in response to an observed accumulation of arterial occlusive events (AOEs) with longer follow-up across the ponatinib clinical program. For data presented herein, the data cutoff date is 2 Feb 2015, with median follow-up of 53.1 months (range, 1.7 - 69.9 months) for CP-CML patients. Results: Among CP-CML patients, at baseline, median age was 55 years and median time since diagnosis was 6.6 years; BCR-ABL1 kinase domain mutations were reported in 63% of patients, with T315I confirmed at a central laboratory in 28% of patients. Patients were heavily pretreated, with 37% having received 2 prior TKIs and 60% having received ≥3 prior TKIs. Of 43 CP-CML patients, 22 (51%) remained on ponatinib treatment at data cutoff. Adverse events (AEs; 26%) and disease progression (9%) were the most common reasons for discontinuation of treatment. Cumulative response rates were: major cytogenetic response (MCyR), 72%; complete cytogenetic response (CCyR), 65%; major molecular response (MMR; assessed at a central laboratory), 56%; molecular response 4 (MR4), 42%; MR4.5, 28%. Responses were durable (Table), with median durations of response not reached for MCyR, CCyR, and MMR. Among patients who received ponatinib at starting doses of ≤30 mg/d (n = 15), MCyR was achieved by 67%, CCyR by 53%, and MMR by 47%; ponatinib dose was ≤30 mg/d in all but one of these patients at the time of response. Of 19 patients who were ongoing and in MCyR as of Oct 2013, 13 had their dose reduced; all 13 dose-reduced patients maintained MCyR at data cutoff. Of the 22 ongoing patients at the time of the present analysis, 18 (82%) had CCyR and 17 (77%) had MMR or better (MMR, 6 patients; MR4, 1 patient; MR4.5, 9 patients; MR5, 1 patient) as their response at the data cutoff; 14/22 (64%) ongoing patients were receiving 15 mg/d as their current dose as of the data cutoff. Rash (65%), fatigue (63%), abdominal pain (58%), headache (58%) and arthralgia (53%) were the most common treatment-emergent AEs. The incidence of AOEs (any/serious) was 40%/30% (by subcategory: cardiovascular, 30%/21%; cerebrovascular, 9%/7%; peripheral vascular, 14%/9%). Conclusions: With median follow-up of over 4 years in this phase 1 study, ponatinib continues to provide clinical benefit to heavily pre-treated CP-CML patients, approximately half of whom continue to receive ponatinib, with a majority in deep response that has been long-lasting; final study data will be presented. The most common treatment-emergent AEs were consistent with the AE profile across the clinical program. Potential for long-term benefit, demonstrated herein, versus risk should be considered when using ponatinib in this patient population. Study sponsor: ARIAD Pharmaceuticals, Inc. Disclosures Mauro: BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Shah:ARIAD: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Research Funding; Plexxikon: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment, Equity Ownership. Santillana:ARIAD: Employment, Equity Ownership. Heinrich:Novartis: Consultancy, Patents & Royalties, Research Funding; Pfizer: Consultancy; Bayer: Research Funding; BMS: Research Funding; Blueprint Medicines: Consultancy; MolecularMD: Consultancy, Equity Ownership; ARIAD: Consultancy, Research Funding; Onyx: Consultancy. Druker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; CTI BioPharma Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Talpaz:Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

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