Bluebird Bio's: Lentiglobulin Infusion Showed Durable Expression of Modified Form Functional Beta-Globin in Sickle Cell Disease


- LentiGlobin gene therapy for sickle cell disease (bb1111) is an investigational treatment SCD being developed by BlueBird Bio. 
- Designed to add functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) 
- Ongoing Phase 3 clinical study to evaluate the efficacy and safety of the gene therapy candidate
- Results from phase 2 study showed durable expression of function copy of β-globin gene (βA-T87Q-globin gene) up to 30 months after infusion
- Prevented vasculo-occlusive pain crisis in all subjects treated with Lentiglobin.

LentiGlobin for SCD was designed to add functional copies of a modified form of the β-globin gene (βA-T87Q-globin gene) into a patient’s own hematopoietic (blood) stem cells (HSCs). Once patients have the βA-T87Q-globin gene, their red blood cells can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, with the goal of reducing sickled red blood cells, hemolysis, and other complications.

Treatment Platform
Subjects will receive treatment with a single dose of Drug Product manufactured with autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis, transduced with BB305 lentiviral vector (LVV) encoding the human beta-A-T87Q globin gene.
Plerixafor mobilization and apheresis will also be used for the collection of rescue cells.

Regulatory Status
The U.S. Food and Drug Administration granted orphan drug designation, fast track designation, regenerative medicine advanced therapy (RMAT) designation and rare pediatric disease designation for LentiGlobin for SCD.
LentiGlobin for SCD received orphan medicinal product designation from the European Commission for the treatment of SCD, and Priority Medicines (PRIME) eligibility by the European Medicines Agency (EMA) in September 2020

Clinical Development Program
bluebird bio’s clinical development program for LentiGlobin for SCD includes the completed Phase 1/2 HGB-205 study, the ongoing Phase 1/2 HGB-206 study, and the ongoing Phase 3 HGB-210 study.

BB305 Lentiviral Vector in Sickle Cell Disease (Phase 3 Study)
This is a non-randomized, open-label, multi-site, single-dose, Phase 3 study in approximately 35 adults and pediatric subjects ≥2 and ≤50 years of age with sickle cell disease (SCD). The study will evaluate hematopoietic stem cell (HSC) transplantation (HSCT) with LentiGlobin BB305 Drug Product for SCD.

Primary Outcome Measures
  • Proportion of subjects meeting Globin Response criteria [ Time Frame: 1-24 months post-transplant ]
  • Subjects must meet the below criteria for a continuous period of at least 6 months after drug product infusion in order to be considered having achieved Globin response:
  • Weighted average HbAT87Q percentage of total Hb* ≥30% AND
  • Weighted average total Hb* increase of ≥3 g/dL compared to baseline total Hb* OR weighted average total Hb* ≥10 g/dL
  • total Hb is the non-transfused total Hb; it is HbS + HbF + HbA2 + HbAT87Q

GB-206 (Phase 1/2 open-label study)
GB-206 is an ongoing, Phase 1/2 open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for sickle cell disease (SCD) that includes three treatment cohorts: Groups A (n=7), B (n=2) and C (n=32).
 A refined manufacturing process designed to increase vector copy number (VCN) and further protocol refinements made to improve engraftment potential of gene-modified stem cells were used for Group C. Group C patients also received LentiGlobin for SCD made from HSCs collected from peripheral blood after mobilization with plerixafor, rather than via bone marrow harvest, which was used in Groups A and B of HGB-206.

Results from Phase 2 Study
In patients with six or more months of follow-up whose hemoglobin fractions were available (n=22), median levels of gene therapy-derived anti-sickling hemoglobin, HbAT87Q, were maintained with HbAT87Q contributing at least 40% of total hemoglobin at Month 6. At last visit reported, total hemoglobin ranged from 9.6 – 15.1 g/dL and HbAT87Q levels ranged from 2.7 – 8.9 g/dL. At Month 6, the production of HbAT87Q was associated with a reduction in the proportion of HbS in total hemoglobin; median HbS was 50% and remained less than 60% at all follow-up time points. All patients in Group C were able to stop regular blood transfusions by three months post-treatment and remain off transfusions as of the data cut-off.

Nineteen patients treated in Group C had a history of severe VOEs, defined as at least four severe VOEs in the 24 months prior to informed consent (annualized rate of severe VOE min-max: 2.0 – 10.5 events) and at least six months follow-up after treatment with LentiGlobin for SCD. There have been no reports of severe VOEs in these Group C patients following treatment with LentiGlobin for SCD. In addition, all 19 patients had a complete resolution of VOEs after Month 6.