Contributions
Abstract: S833
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:45 - 12:00
Location: Room A8
Background
LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with the T87Q point mutation which permits quantification of transgenic hemoglobin (Hb) in transduced cells. The safety and efficacy of LentiGlobin in patients with transfusion dependent β-thalassemia (TDT) was evaluated in the phase 1/2 Northstar (HGB-204; NCT01745120) study where 9/10 patients with non-β0/β0 genotypes were free from chronic packed red blood cell (pRBC) transfusions for a median of 29 months with a median Hb of 10.2 g/dL (Kwiatkowski, ASH 2017). To further improve clinical results, the LentiGlobin DP manufacturing process was modified to increase transduction rates.
Aims
To evaluate the efficacy and safety of LentiGlobin DP with these refinements in patients with TDT and non-β0/β0 genotypes in the ongoing phase 3 Northstar-2 study (HGB-207; NCT02906202).
Methods
Patients with TDT (≥100 mL/kg/yr of pRBCs or ≥8 pRBC transfusions/yr) underwent HSC mobilization with G-CSF and plerixafor. Collected HSCs were transduced with the BB305 LVV. Patients underwent myeloablative conditioning with pharmacokinetic-adjusted busulfan dosage, were infused with transduced cells, and were followed for engraftment, pRBC transfusion independence, VCN, HbAT87Q, adverse events (AEs), vector integration profile, and evidence of replication competent lentivirus (RCL). Summary statistics are presented as median (min – max).
Results
As of 13 October 2017, 7 patients with TDT and non-β0/β0 genotypes (age 20 [15 – 24] yrs) have been treated in Northstar-2 with a median follow-up of 3 (1 – 9) months. Data are reported for 6 treated patients with > 1 month follow-up. The time to neutrophil and platelet engraftment was 21.5 (17 – 26) and 44 (35 – 46) days, respectively. All patients successfully engrafted with no graft failure or death. AEs were consistent with myeloablative conditioning and no DP-related AEs were observed. Serious AEs after DP infusion included one AE each of transfusion reaction (grade 2) and hypotension (grade 3). No evidence of clonal dominance or RCL has been observed. As of 1 December 2017, 11 DP lots had been manufactured for 10 patients in Northstar-2 of which 9 could be assessed for % transduced CD34+ cells. In Northstar, 22 DP lots were manufactured for 18 patients. The refined manufacturing process used in Northstar-2 yielded higher DP VCNs (median 3.3 vs 0.7) and higher % transduced cells (median 82% vs 32%). In Northstar-2, peripheral blood VCN was 0.25 – 2.3 in 6 treated patients with 3 – 9 months of follow-up. The 3 patients with ≥ 6 months of follow-up have been transfusion-free for 7.5, 4.2, and 5.3 months with total Hb levels of 12.5, 8.4, and 11.5 g/dL at last visit. The first patient treated began phlebotomy 6 months post-infusion. By month 3, 5/6 patients had HbAT87Q levels of ≥ 6.5 g/dL, and total Hb of 10.4 – 12.5 g/dL with HbAT87Q contributing 58 – 91% of total Hb.
Conclusion
The refined manufacturing process for LentiGlobin in Northstar-2 has yielded higher DP VCNs and % transduced CD34+ cells. Early data suggest that these improved DP parameters translate into clinically significant levels of HbAT87Q that can result in near-normal or normal total Hb production allowing patients to be free of transfusions. The safety profile to date is similar to that observed in Northstar. Longer follow-up and results observed in additional patients in Northstar-2 will be presented.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Beta thalassemia, Gene therapy
Abstract: S833
Type: Oral Presentation
Presentation during EHA23: On Saturday, June 16, 2018 from 11:45 - 12:00
Location: Room A8
Background
LentiGlobin Drug Product (DP) contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with the T87Q point mutation which permits quantification of transgenic hemoglobin (Hb) in transduced cells. The safety and efficacy of LentiGlobin in patients with transfusion dependent β-thalassemia (TDT) was evaluated in the phase 1/2 Northstar (HGB-204; NCT01745120) study where 9/10 patients with non-β0/β0 genotypes were free from chronic packed red blood cell (pRBC) transfusions for a median of 29 months with a median Hb of 10.2 g/dL (Kwiatkowski, ASH 2017). To further improve clinical results, the LentiGlobin DP manufacturing process was modified to increase transduction rates.
Aims
To evaluate the efficacy and safety of LentiGlobin DP with these refinements in patients with TDT and non-β0/β0 genotypes in the ongoing phase 3 Northstar-2 study (HGB-207; NCT02906202).
Methods
Patients with TDT (≥100 mL/kg/yr of pRBCs or ≥8 pRBC transfusions/yr) underwent HSC mobilization with G-CSF and plerixafor. Collected HSCs were transduced with the BB305 LVV. Patients underwent myeloablative conditioning with pharmacokinetic-adjusted busulfan dosage, were infused with transduced cells, and were followed for engraftment, pRBC transfusion independence, VCN, HbAT87Q, adverse events (AEs), vector integration profile, and evidence of replication competent lentivirus (RCL). Summary statistics are presented as median (min – max).
Results
As of 13 October 2017, 7 patients with TDT and non-β0/β0 genotypes (age 20 [15 – 24] yrs) have been treated in Northstar-2 with a median follow-up of 3 (1 – 9) months. Data are reported for 6 treated patients with > 1 month follow-up. The time to neutrophil and platelet engraftment was 21.5 (17 – 26) and 44 (35 – 46) days, respectively. All patients successfully engrafted with no graft failure or death. AEs were consistent with myeloablative conditioning and no DP-related AEs were observed. Serious AEs after DP infusion included one AE each of transfusion reaction (grade 2) and hypotension (grade 3). No evidence of clonal dominance or RCL has been observed. As of 1 December 2017, 11 DP lots had been manufactured for 10 patients in Northstar-2 of which 9 could be assessed for % transduced CD34+ cells. In Northstar, 22 DP lots were manufactured for 18 patients. The refined manufacturing process used in Northstar-2 yielded higher DP VCNs (median 3.3 vs 0.7) and higher % transduced cells (median 82% vs 32%). In Northstar-2, peripheral blood VCN was 0.25 – 2.3 in 6 treated patients with 3 – 9 months of follow-up. The 3 patients with ≥ 6 months of follow-up have been transfusion-free for 7.5, 4.2, and 5.3 months with total Hb levels of 12.5, 8.4, and 11.5 g/dL at last visit. The first patient treated began phlebotomy 6 months post-infusion. By month 3, 5/6 patients had HbAT87Q levels of ≥ 6.5 g/dL, and total Hb of 10.4 – 12.5 g/dL with HbAT87Q contributing 58 – 91% of total Hb.
Conclusion
The refined manufacturing process for LentiGlobin in Northstar-2 has yielded higher DP VCNs and % transduced CD34+ cells. Early data suggest that these improved DP parameters translate into clinically significant levels of HbAT87Q that can result in near-normal or normal total Hb production allowing patients to be free of transfusions. The safety profile to date is similar to that observed in Northstar. Longer follow-up and results observed in additional patients in Northstar-2 will be presented.
Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical
Keyword(s): Autologous hematopoietic stem cell transplantation, Beta thalassemia, Gene therapy