ASH: Gene therapy reduces transfusion needs in beta-thalassemia major

ORLANDO – Lentiviral gene therapy with LentiGlobin BB305 boosts beta-globin production in patients with beta-thalassemia, but frees only some from lifelong dependence on blood transfusions, updated results of the Northstar study show.

Five patients with non-Beta-0/Beta-0 genotypes were able to stop transfusions shortly after their infusion, and remain transfusion independent for up to 16.4 months.

In four patients with the more severe form of beta-thalassemia, the Beta-0/Beta-0 genotype, red blood cell transfusion volume was reduced by 33% to 100%, with one patient stopping transfusions entirely, Dr. Mark C. Walters of the University of California-San Francisco Benioff Children’s Hospital in Oakland reported at the annual meeting of the American Society of Hematology.

Preliminary findings reported over the last two years have raised hopes that the experimental lentiviral-based therapy could be a functional cure for beta-thalassemia major and severe sickle cell disease.

Patients with beta-thalassemia major, also called Cooley’s anemia, rely on frequent blood transfusions to correct the anemia, with less than a quarter undergoing curative treatment with an allogeneic hematopoietic transplant.

In the ongoing Northstar study, 13 patients with transfusion-dependent beta-thalassemia major have been infused as of Oct. 28, 2015 with autologous CD34-positive cells transduced ex-vivo with LentiGlobin BB305 (Bluebird bio, Cambridge, Mass.), a self-inactivating, second-generation lentiviral vector containing a functioning, engineered beta-globin gene (A-T87Q). Their median age was 21 years and 11 were women.Vector-derived hemoglobin A^T87Q was detectable at 6 months in 8 of 9 evaluable patients with at least six months follow-up and in 100% at 9 months, Dr. Walters reported. The median HbA^T87Q level was 4.9 g/dL at 6 months, 6.5 g/dL at 9 months, and 4.2 g/dL at 12 months.

The difference in transfusion independence between genotypes is explained by endogenous non-HbAT87Q production, he said during a press briefing. While lentiglobin production was the same in patients with Beta-0/Beta-0 and non-Beta-0/Beta-0 genotypes, the Beta-0/Beta-0 patients made much smaller amounts of native hemoglobin.

Three serious post-infusion events occurred: grade 2 thrombosis, grade 3 skin infection and grade 3 veno-occlusive liver disease.

Importantly, there was no evidence of clonal dominance or replication competent lentivirus with up to 19 months follow-up.

“This is a significant advancement in the treatment of thalassemia for several reasons,” Dr. Walters told reporters. “First, compared to a bone marrow transplant, which is the only curative therapy that’s been approved, this appears to be a safer treatment in that none of these patients had a life-threatening complication. Second, because the treatment uses a thalassemia patient’s own stem cells, this bypasses the need to find a healthy bone marrow donor and thus should be more broadly available to patients affected by this disease.”

Dr. George Daley of Harvard Medical School in Boston and moderator of the press briefing, agreed that the results are an welcome advancement after decades of disappointments in the field of gene therapy including the development of insertional mutigenesis.

In addition to the Northstar study (Ab. 201), results will be presented at the meeting from a second study examining LentiGlobin BB305 gene therapy for severe sickle cell disease and beta-thalassemia major (Ab. 202) and from the recently expanded phase I HGB-206 study in severe sickle cell disease (Ab. 3233).

Sickle cell disease represents a much larger potential market for LentiGlobin BB305, with an estimated 90,000 to 100,000 Americans affected compared with about 15,000 patients in America and Europe living with beta-thalassemia major.

[email protected]

ORLANDO – Lentiviral gene therapy with LentiGlobin BB305 boosts beta-globin production in patients with beta-thalassemia, but frees only some from lifelong dependence on blood transfusions, updated results of the Northstar study show.

Five patients with non-Beta-0/Beta-0 genotypes were able to stop transfusions shortly after their infusion, and remain transfusion independent for up to 16.4 months.

In four patients with the more severe form of beta-thalassemia, the Beta-0/Beta-0 genotype, red blood cell transfusion volume was reduced by 33% to 100%, with one patient stopping transfusions entirely, Dr. Mark C. Walters of the University of California-San Francisco Benioff Children’s Hospital in Oakland reported at the annual meeting of the American Society of Hematology.

Preliminary findings reported over the last two years have raised hopes that the experimental lentiviral-based therapy could be a functional cure for beta-thalassemia major and severe sickle cell disease.

Patients with beta-thalassemia major, also called Cooley’s anemia, rely on frequent blood transfusions to correct the anemia, with less than a quarter undergoing curative treatment with an allogeneic hematopoietic transplant.

In the ongoing Northstar study, 13 patients with transfusion-dependent beta-thalassemia major have been infused as of Oct. 28, 2015 with autologous CD34-positive cells transduced ex-vivo with LentiGlobin BB305 (Bluebird bio, Cambridge, Mass.), a self-inactivating, second-generation lentiviral vector containing a functioning, engineered beta-globin gene (A-T87Q). Their median age was 21 years and 11 were women.Vector-derived hemoglobin A^T87Q was detectable at 6 months in 8 of 9 evaluable patients with at least six months follow-up and in 100% at 9 months, Dr. Walters reported. The median HbA^T87Q level was 4.9 g/dL at 6 months, 6.5 g/dL at 9 months, and 4.2 g/dL at 12 months.

The difference in transfusion independence between genotypes is explained by endogenous non-HbAT87Q production, he said during a press briefing. While lentiglobin production was the same in patients with Beta-0/Beta-0 and non-Beta-0/Beta-0 genotypes, the Beta-0/Beta-0 patients made much smaller amounts of native hemoglobin.

Three serious post-infusion events occurred: grade 2 thrombosis, grade 3 skin infection and grade 3 veno-occlusive liver disease.

Importantly, there was no evidence of clonal dominance or replication competent lentivirus with up to 19 months follow-up.

“This is a significant advancement in the treatment of thalassemia for several reasons,” Dr. Walters told reporters. “First, compared to a bone marrow transplant, which is the only curative therapy that’s been approved, this appears to be a safer treatment in that none of these patients had a life-threatening complication. Second, because the treatment uses a thalassemia patient’s own stem cells, this bypasses the need to find a healthy bone marrow donor and thus should be more broadly available to patients affected by this disease.”

Dr. George Daley of Harvard Medical School in Boston and moderator of the press briefing, agreed that the results are an welcome advancement after decades of disappointments in the field of gene therapy including the development of insertional mutigenesis.

In addition to the Northstar study (Ab. 201), results will be presented at the meeting from a second study examining LentiGlobin BB305 gene therapy for severe sickle cell disease and beta-thalassemia major (Ab. 202) and from the recently expanded phase I HGB-206 study in severe sickle cell disease (Ab. 3233).

Sickle cell disease represents a much larger potential market for LentiGlobin BB305, with an estimated 90,000 to 100,000 Americans affected compared with about 15,000 patients in America and Europe living with beta-thalassemia major.

[email protected]

ORLANDO – Lentiviral gene therapy with LentiGlobin BB305 boosts beta-globin production in patients with beta-thalassemia, but frees only some from lifelong dependence on blood transfusions, updated results of the Northstar study show.

Five patients with non-Beta-0/Beta-0 genotypes were able to stop transfusions shortly after their infusion, and remain transfusion independent for up to 16.4 months.

In four patients with the more severe form of beta-thalassemia, the Beta-0/Beta-0 genotype, red blood cell transfusion volume was reduced by 33% to 100%, with one patient stopping transfusions entirely, Dr. Mark C. Walters of the University of California-San Francisco Benioff Children’s Hospital in Oakland reported at the annual meeting of the American Society of Hematology.

Preliminary findings reported over the last two years have raised hopes that the experimental lentiviral-based therapy could be a functional cure for beta-thalassemia major and severe sickle cell disease.

Patients with beta-thalassemia major, also called Cooley’s anemia, rely on frequent blood transfusions to correct the anemia, with less than a quarter undergoing curative treatment with an allogeneic hematopoietic transplant.

In the ongoing Northstar study, 13 patients with transfusion-dependent beta-thalassemia major have been infused as of Oct. 28, 2015 with autologous CD34-positive cells transduced ex-vivo with LentiGlobin BB305 (Bluebird bio, Cambridge, Mass.), a self-inactivating, second-generation lentiviral vector containing a functioning, engineered beta-globin gene (A-T87Q). Their median age was 21 years and 11 were women.Vector-derived hemoglobin A^T87Q was detectable at 6 months in 8 of 9 evaluable patients with at least six months follow-up and in 100% at 9 months, Dr. Walters reported. The median HbA^T87Q level was 4.9 g/dL at 6 months, 6.5 g/dL at 9 months, and 4.2 g/dL at 12 months.

The difference in transfusion independence between genotypes is explained by endogenous non-HbAT87Q production, he said during a press briefing. While lentiglobin production was the same in patients with Beta-0/Beta-0 and non-Beta-0/Beta-0 genotypes, the Beta-0/Beta-0 patients made much smaller amounts of native hemoglobin.

Three serious post-infusion events occurred: grade 2 thrombosis, grade 3 skin infection and grade 3 veno-occlusive liver disease.

Importantly, there was no evidence of clonal dominance or replication competent lentivirus with up to 19 months follow-up.

“This is a significant advancement in the treatment of thalassemia for several reasons,” Dr. Walters told reporters. “First, compared to a bone marrow transplant, which is the only curative therapy that’s been approved, this appears to be a safer treatment in that none of these patients had a life-threatening complication. Second, because the treatment uses a thalassemia patient’s own stem cells, this bypasses the need to find a healthy bone marrow donor and thus should be more broadly available to patients affected by this disease.”

Dr. George Daley of Harvard Medical School in Boston and moderator of the press briefing, agreed that the results are an welcome advancement after decades of disappointments in the field of gene therapy including the development of insertional mutigenesis.

In addition to the Northstar study (Ab. 201), results will be presented at the meeting from a second study examining LentiGlobin BB305 gene therapy for severe sickle cell disease and beta-thalassemia major (Ab. 202) and from the recently expanded phase I HGB-206 study in severe sickle cell disease (Ab. 3233).

Sickle cell disease represents a much larger potential market for LentiGlobin BB305, with an estimated 90,000 to 100,000 Americans affected compared with about 15,000 patients in America and Europe living with beta-thalassemia major.

[email protected]