bluebird bio, Inc.bluebird bio, Inc. (NASDAQ:BLUE) today announced updated results from its Phase 1/2 HGB-206 study of lovotibeglogene autotemcel (lovo-cel; formerly LentiGlobin® for SCD, bb1111) gene therapy for sickle cell disease, including further analyses from its pivotal cohort, HGB-206 Group C, following enhancements to the manufacturing protocols and treatment process. In addition to continued complete resolution of severe vaso-occlusive events (VOEs), patients in Group C achieved near normal levels of key hemolysis markers and experienced sustained improvements in patient-reported quality of life following treatment. Data were presented in two oral sessions at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition, taking place December 11-14, 2021, at the Georgia World Congress Center in Atlanta and virtually; select data from the Group C cohort of the HGB-206 study were simultaneously published in The New England Journal of Medicine (NEJM).

“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 F. Tisdale, MD, Chief, Cellular and Molecular Therapeutics Branch, NHLBI, Bethesda, Md. “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 (n=3), HGB-206 (n=44) and HGB-210 (n=2) clinical studies, representing more than 109 total patient-years of data. The Phase 1/2 HGB-206 trial includes Groups A (n=7), B (n=2) and C (n=35), 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 (ACS), 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, MD, PhD, 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.”

Data published in The New England Journal of Medicine is titled Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell Disease Gene Therapy.

Updated HGB-206 Group C Efficacy & Safety Data

As of February 2021, the 35 Group C patients had up to 37.6 months of follow-up (median of 17.3; min-max: 3.7-37.6 months), for a total of 54.8 patient-years of experience.


Following engraftment, median total hemoglobin increased from 8.5 g/dL at baseline to ≥11 g/dL from six through up to 36 months post-infusion in all patients; notably, sickle hemoglobin (HbS) in all patients was less than 60% of total hemoglobin, and gene therapy-derived anti-sickling hemoglobin, HbAT87Q, contributed at least 40% of total hemoglobin.

These decreased levels of sickle hemoglobin (HbS) after lovo-cel infusion were comparable to individuals living with sickle trait (βS/βA), not in the study—in general, people with sickle cell trait enjoy normal life spans with no medical problems related to sickle cell trait.

All evaluable patients (n=25) continued to experience complete resolution of severe VOEs through up to 36 months of follow-up, compared with a median of 3.5 per year (min-max: 2.0-13.5) in the 24 months before enrollment.

Hemolysis Markers

Red blood cells normally break down in the body through a naturally occurring process called hemolysis. In sickle cell disease, hemolysis happens too quickly due to the fragility of sickled RBCs, resulting in hemolytic anemia. In findings published in NEJM, key hemolysis markers for sickle cell patients treated with lovo-cel in Group C approached normal levels.

From six months post-infusion through the last visit, several indicators of the health of red blood cells suggest that treatment with lovo-cel improved biological markers for SCD to near-normal levels. Lactate dehydrogenase and indirect bilirubin levels normalized, reticulocyte counts approached normal levels, and haptoglobin levels were positive at last visit, which suggests a reduction in hemolysis.


Exploratory assay data evaluated HbAT87Q and HbS protein in individual RBCs to assess if HbAT87Q was pancellular, meaning present throughout all of a patient’s RBCs.

In 10 patients with at least 24 months of follow-up, a mean of 85% of RBCs contained βA-T87Q, suggesting near-pancellular HbAT87Q distribution and with pancellularity further increasing over time. This indicates that there were very few circulating non-gene therapy-modified RBCs containing a majority of HbS and prone to sickling. Within HbAT87Q-containing RBCs, the median HbAT87Q was estimated to be 15.3 pg per RBCs (range, 11.7 to 22.7), a finding that was similar to the range of 13 to 18 pg per cell of adult hemoglobin reported in persons with sickle cell trait.


Lentiviral vector (LVV) gene therapy is uniquely traceable at the genetic level. Traceability is possible through the utilization of sophisticated and precise integration site analysis (ISA), which enables the active identification and tracking of LVV-modified cells after delivery to a patient, thereby improving the ability to further evaluate biological effects.

Based on manufacturing improvements reflected in the Group C cohort of HGB-206, greater diversity was detected in LVV insertion sites, which was associated with increased pancellularity, a reduced sickling rate, and reduced proliferative and hematopoietic stress.


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.

Patient-Reported Quality of Life

Sickle cell disease is characterized by high morbidity and early mortality. The management of such a complex disease with many sequalae has a profound impact on all aspects of patient quality of life—physical, mental and socioemotional.

Health-related quality of life (HRQoL) findings in Group C patients were generated using the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), a validated instrument in SCD. Generally, improvements reported previously at Month 12 post infusion were sustained through Month 24. Specifically, 67% (n=10/15) reported a significant decrease in pain intensity at Month 12, which was sustained for 56% (n=5/9) of evaluable patients at Month 24. Similarly, 56% (n=9/16) reported clinically meaningful reductions in pain interference on daily life at Month 12, which was sustained at Month 24 (56%, 5/9). The majority of patients at Months 12 (69%, n=11/16) and Month 24 (63%, n=5/8) reported clinically meaningful improvements in physical functioning, and half of patients at Months 12 (50%, n=8/16 and 24 (56%, n=5/9) reported clinically meaningful reductions in fatigue following treatment with lovo-cel. The remaining domains reported trends toward improvement in other aspects of quality of life, including mental and social health.

These findings provide a broader understanding of the impact to patient life over time following treatment with lovo-cel and are the strongest HRQoL improvements reported to-date in the SCD treatment landscape.