Bluebird Reports New and Updated Data on Sickle Cell Gene Therapy Program at ASH

Bluebird Bio reported new and updated phase 1/2 data of its experimental gene therapy HGB-206 (formerly LentiGlobin for SCD, bb1111) gene therapy for sickle cell disease following enhancements to the manufacturing protocols and treatment process.

The company said in addition to continued complete resolution of severe vaso-occlusive events (VOEs), patients in its pivotal Group C achieved near normal levels of key hemolysis markers and experienced sustained improvements in patient-reported quality of life following treatment.

Investigators presented data in two oral sessions at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition at the Georgia World Congress Center in Atlanta. Select data from the Group C cohort of the HGB-206 study were simultaneously published in The New England Journal of Medicine.

“Data presented at ASH and published today in The New England Journal of Medicine affirm that this lentiviral gene transfer for sickle cell disease has the potential to improve the day-to-day reality of people living with sickle cell disease by eliminating the disruptive, painful crises that can occur multiple times per month,” said John Tisdale, chief of the Cellular and Molecular Therapeutics Branch of NHLBI. “Sickle cell is a complex and often misunderstood disease that is associated with more symptoms and long-term effects than pain alone. It is encouraging to see that the treatment fundamentally impacted the pathophysiology of patients’ disease through the sustained production of vector-derived anti-sickling hemoglobin to substantially reduce sickling and hemolysis.”

Clinical studies evaluating lovo-cel in sickle cell disease represent the largest sickle cell disease gene therapy data set to date. As of February 17, 2021, 49 patients have been treated with lovo-cel with up to six years of patient follow-up (median: 24 months) across the HGB-205, HGB-206, and HGB-210 clinical studies, representing more than 109 total patient-years of data. The phase 1/2 HGB-206 trial includes Groups A, B, and C, reflecting progressive adaptations to the treatment and manufacturing processes.

Sickle cell disease is a serious, progressive and debilitating genetic disease caused by a single mutation in the β-globin gene that leads to the production of abnormal sickle hemoglobin (HbS). HbS causes red blood cells (RBCs) to become sickled and fragile, resulting in chronic hemolytic anemia, vasculopathy, and unpredictable, painful VOEs requiring frequent hospitalization. In the U.S., the median age of death for someone with sickle cell disease is 43-46 years. Additionally, one in four people living with sickle cell disease experience a stroke by age 45.

In the HGB-206 study, VOEs are defined as episodes of acute pain with no medically determined cause other than a vaso-occlusion, lasting more than two hours and severe enough to require care at a medical facility. This includes acute episodes of pain, acute chest syndrome, acute hepatic sequestration and acute splenic sequestration. A severe VOE requires a 24-hour hospital stay or emergency room visit or at least two visits to a hospital or emergency room over a 72-hour period, with both visits requiring intravenous treatment.

Lovo-cel adds 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 RBCs can produce anti-sickling hemoglobin (HbAT87Q) that decreases the proportion of HbS, thereby reducing sickled RBCs, hemolysis, and other complications.

“The remarkable depth and breadth of data presented at ASH and published in the New England Journal of Medicine distinctively demonstrates the impact of lovo-cel on biologic and clinical outcomes, as well as to patient-reported outcomes that indicate a meaningful difference in the daily lives of people with sickle cell disease,” said Richard Colvin, chief medical officer, Bluebird Bio. “The ability to trace how lovo-cel integrates on a genetic level is a distinguishing characteristic of LVV gene therapy and confers a unique understanding of how the proposed mechanism of action of the drug product is correlated to safety and clinical outcomes.”

There have been no reports of graft versus host disease (GvHD), graft failure, replication-competent lentivirus, or vector-mediated insertional oncogenesis in subjects from Group C or any subject treated in HGB-206.

The safety data from Group C patients in HGB-206 remain generally consistent with the known side effects of autologous hematopoietic stem cell collection and myeloablative single-agent busulfan conditioning, as well as underlying SCD. One non-serious, Grade 2 adverse event (AE) of febrile neutropenia was considered related to lovo-cel; additionally, one non-serious, Grade 2 AE of leukopenia and one Grade 1 AE of decreased diastolic blood pressure were considered possibly related to lovo-cel. There were no serious AEs related to lovo-cel.

As previously reported, one patient with significant baseline SCD-related cardiopulmonary disease died 20 months post-treatment; the treating physician and an independent monitoring committee agreed his death was unlikely related to lovo-cel and that SCD-related cardiac and pulmonary disease contributed.

In the initial cohort (Group A) of the HGB-206 study, two patients treated with lovo-cel developed acute myeloid leukemia (AML). After thorough investigations into the cases Bluebird Bio determined that these were unlikely related to the insertion of bluebird’s lentiviral vector (LVV) gene therapy for SCD.

Photo: Richard Colvin, chief medical officer, Bluebird Bio

Author: Rare Daily Staff