A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT04293185
• Recruitment Status: Recruiting
• First Posted: March 3, 2020
• Last Update Posted: March 24, 2023
• Sponsor: bluebird bio
• Information provided by (Responsible Party): bluebird bio

Tracking Information

• First Submitted Date: February 12, 2020
• First Posted Date: March 3, 2020
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: February 14, 2020
• Estimated Primary Completion Date: October 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2022)

VOE-CR [ Time Frame: 6-18 months post-transplant ]

Proportion of subjects achieving complete resolution of VOEs between 6 months and 18 months after drug product infusion

Original Primary Outcome Measures (submitted: February 28, 2020)

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:

1. Weighted average HbAT87Q percentage of total Hb* ≥30% AND
2. 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

Current Secondary Outcome Measures (submitted: July 15, 2022)

• sVOE-CR [ Time Frame: 6-18 months post-transplant ]
  Proportion of subjects achieving complete resolution of severe vaso-occlusive events, between 6 months and 18 months after drug product infusion
• Proportion of subjects achieving Globin Response [ Time Frame: 6-24 months post-transplant ]
  Globin Response, defined as meeting the following criteria for a continuous period of at least 6 months after drug product infusion:

  1. Weighted average HbAT87Q percentage of non-transfused total Hb* ≥30% AND
  2. Weighted average non-transfused total Hb* increase of ≥3 g/dL compared to baseline total Hb* OR weighted average non-transfused total Hb* ≥10 g/dL
     • non-transfused total Hb is the total g/dL of HbS + HbF + HbA2 + HbAT87Q
• Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent [ Time Frame: 1-24 months post-transplant ]
• Change in the annualized number of severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
• VOE-CR24 [ Time Frame: 6-24 months post-transplant ]
  Proportion of subjects achieving complete resolution of VOEs between 6 months and 24 months after drug product infusion
• sVOE-CR24 [ Time Frame: 6-24 months post-transplant ]
  Proportion of subjects achieving complete resolution of severe VOEs between 6 months and 24 months after drug product infusion
• sVOE-75 [ Time Frame: 1-24 months post-transplant ]
  Proportion of subjects achieving at least a 75% reduction in annualized severe VOEs in the 24 months after drug product administration compared to the 24 months prior to Informed Consent.
• Weighted average non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbAT87Q percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average non-HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Average and median of non-transfused total Hb [ Time Frame: 1-24 months post-transplant ]
• Average and median of HbS percentage of non-transfused total Hb [ Time Frame: 1-24 months post-transplant ]
• Average and median of HbAT87Q percentage of non-transfused total Hb [ Time Frame: 1-24 months post-transplant ]
• Average and median of non-HbS percentage of non-transfused total Hb [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in absolute reticulocyte count [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in percent reticulocytes [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in percent erythrocytes [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in total bilirubin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in haptoglobin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in lactate dehydrogenase [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in ferritin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in liver iron content [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in cardiac iron content (if assessed at baseline) [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in erythropoietin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in serum transferrin receptor [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in annualized frequency of packed red blood cell (pRBC) transfusions [ Time Frame: 6-24 months post-transplant ]
• Change from baseline in annualized volume of pRBC transfusions [ Time Frame: 6-24 months post-transplant ]
• Change from baseline in TCD velocity at Month 12 and Month 24 (for subjects ≤ 16 years old at Informed Consent) [ Time Frame: Month 12 and Month 24 post-transplant ]
• Change from baseline in meters walked during the 6-minute walk test [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in annualized number of SCD-related hospital admissions [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in annualized number of total days hospitalized [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in patient-reported quality of life, as measured by PROMIS-57 Version 2.1 for subjects ≥ 18 years of age and PROMIS Pediatric Profile/Parent Proxy Profile 49 Version 2.0 for subjects < 18 years of age [ Time Frame: 1 - 24 months post-transplant ]

Original Secondary Outcome Measures (submitted: February 28, 2020)

• Percent of subjects reaching a 75% reduction in annualized severe vaso-occlusive events (sVOE-75) in the 24 months after drug product administration compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
• Weighted average non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbS percentage of non-transfused total Hb ≤70%, ≤60%, ≤50% [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average HbAT87Q percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Weighted average non-HbS percentage of non-transfused total Hb [ Time Frame: Month 6, 12, 18 and 24 post-transplant ]
• Average and median of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
• Average and median of HbS percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
• Average and median of HbAT87Q percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
• Average and median of non-HbS percentage of non-transfused total Hb over time [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in absolute reticulocyte count [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in percent reticulocytes [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in percent erythrocytes [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in total bilirubin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in haptoglobin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in lactate dehydrogenase [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in iron [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in ferritin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in transferrin saturation [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in liver iron content [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in cardiac iron content (if assessed at baseline) [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in erythropoietin [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in serum transferrin receptor [ Time Frame: 1 - 24 months post-transplant ]
• Change in the annualized number of severe VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
• Change in the annualized number of VOEs in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent [ Time Frame: 1-24 months post-transplant ]
• Proportion of subjects achieving severe VOE-complete resolution (sVOE-CR) [ Time Frame: 6-24 months post-transplant ]
  Defined as complete resolution of severe VOEs between 6 months and 24 months after drug product administration
• Proportion of subjects achieving reduction in the annualized number of severe VOEs of at least 90% in the 24 months after drug product infusion compared to the 24 months prior to Informed Consent. [ Time Frame: 1-24 months post-transplant ]
• Change from baseline in annualized frequency transfusions [ Time Frame: 6-24 months post-transplant ]
• Change from baseline in volume of packed red blood cell (pRBC) transfusions [ Time Frame: 6-24 months post-transplant ]
• Change from baseline in cerebral vasculature and prior brain parenchymal injury [ Time Frame: Months 12 and 24 post-transplant ]
  As measured by cerebral MRA/MRI in all subjects, and transcranial doppler (TCD) for subjects ≤16 years old at Informed Consent
• Change from baseline in bone mineral density (BMD) evaluation using dual x-ray (DXA) absorptiometry [ Time Frame: 24 months post-transplant ]
• Proportion of subjects with the development of osteonecrosis in new joints needing any specific therapeutic procedure [ Time Frame: 1 - 24 months post-transplant ]
• Proportion of subjects with new or worsening retinopathy complications needing any specific therapeutic procedure [ Time Frame: Months 12 and 24 post-transplant ]
• Proportion of subjects with new or worsening severe leg ulcers needing wound care specialized follow-up [ Time Frame: Months 12 and 24 post-transplant ]
• Change from baseline in proteinuria [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in microalbuminuria [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in estimated glomerular filtration rate (eGFR) [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in cardiac-pulmonary function via echocardiogram [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in cardiac-pulmonary function via pulmonary function test [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in cardiac-pulmonary function via brain natriuretic peptide [NT-proBNP] [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in meters walked during 6-minute walk test [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in annualized number of hospital admissions [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in annualized number of total days hospitalized [ Time Frame: 1 - 24 months post-transplant ]
• Change from baseline in patient-reported quality of life, as measured by Patient Reported Outcomes Measurement Information System-57 (PROMIS-57) [ Time Frame: 1 - 24 months post-transplant ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study Evaluating Gene Therapy With BB305 Lentiviral Vector in Sickle Cell Disease
• Official Title: A Phase 3 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the BB305 Lentiviral Vector in Subjects With Sickle Cell Disease
• Brief Summary: 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) using bb1111 (also known as LentiGlobin BB305 Drug Product for SCD).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Sickle Cell Disease

Intervention

Genetic: bb1111

Drug Product is administered by IV infusion following myeloablative conditioning with busulfan.

Other Names:

• lovotibeglogene autotemcel
• lovo-cel
• LentiGlobin BB305 Drug Product for SCD
• autologous CD34+ cell-enriched population from patients with SCD that contains HSCs transduced with BB305 LVV encoding the βA-T87Q-globin gene, suspended in cryopreservation solution

Study Arms

Experimental: bb1111

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 collection of rescue cells.

Intervention: Genetic: bb1111

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 28, 2020): 35
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: April 2027
• Estimated Primary Completion Date: October 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Have a diagnosis of SCD, with either βS/βS, βS/β0, or βS/β+ genotype.
• Be ≥2 and ≤50 years of age at time of consent.
• Weigh a minimum of 6 kg.
• Have a Karnofsky performance status of ≥60 (≥16 years of age) or a Lansky performance status of ≥60 (<16 years of age).
• Be treated and followed for at least the past 24 months prior to Informed Consent in medical center(s) that maintained detailed records on sickle cell disease history.
• In the setting of appropriate supportive care measures (e.g., pain management plan), have experienced at least 4 protocol-defined VOEs in the 24 months prior to informed consent.
• Have either experienced HU failure at any point in the past or must have intolerance to HU (intolerance is defined as the patient being unable to continue to take HU per PI judgment).
• Female and male subjects of childbearing potential agree to use 1 method of highly effective contraception from Screening to at least 6 months after drug product infusion.
• Provision of written informed consent for this study by subject, or as applicable, subject's parent(s)/legal guardian(s).

Exclusion Criteria:

• Subjects for whom allogeneic hematopoietic stem cell transplantation (allo-HSCT) is medically appropriate per PI judgment and a willing, human leukocyte antigen (HLA)-matched related hematopoietic stem cell donor is available.
• Severe cerebral vasculopathy, defined by any history of overt ischemic or hemorrhagic stroke, a history of abnormal transcranial Doppler (TCD) or TCD imaging (TCDI) for subjects ≤ 16 years of age (e.g. TCD velocity >200 cm/sec) requiring ongoing chronic transfusions, a Screening TCD or TCDI velocity > 200 cm/sec (central read), a Screening MRA showing > 50% stenosis or occlusion in the circle of Willis (central read), or a Screening MRA showing the presence of Moyamoya (central read).
• Positive for presence of human immunodeficiency virus type 1 or 2 (HIV-1 or HIV-2), hepatitis B, hepatitis C, human T-lymphotropic virus-1 (HTLV-1), active syphilis.
• Clinically significant, active bacterial, viral, fungal, or parasitic infection

• Advanced liver disease, such as

  1. clear evidence of liver cirrhosis, active hepatitis or significant fibrosis (based on MRI or liver biopsy)
  2. liver iron concentration ≥15 mg/g unless liver biopsy shows no evidence of cirrhosis, active hepatitis or significant fibrosis
• Inadequate bone marrow function, as defined by an absolute neutrophil count of <1×10^9/L (<0.5×10^9/L for subjects on hydroxyurea treatment) or a platelet count <100×10^9/L.
• Any contraindications to the use of plerixafor during the mobilization of hematopoietic stem cells and any contraindications to the use of busulfan and any other medicinal products required during the myeloablative conditioning, including hypersensitivity to the active substances or to any of the excipients.
• Patients needing therapeutic anticoagulation treatment during the period of conditioning through platelet engraftment
• Unable to receive pRBC transfusion.
• Prior receipt of an allogeneic transplant.
• Prior receipt of gene therapy.
• Any prior or current malignancy or immunodeficiency disorder, except previously treated, non-life threatening, cured tumors such as squamous cell carcinoma of the skin.
• Immediate family member with a known or suspected Familial Cancer Syndrome.
• Female subject is breastfeeding, pregnant or will attempt to become pregnant from Screening to at least 6 months after drug product infusion.
• Any other condition that would render the subject ineligible for HSCT.
• Participation in another clinical study with an investigational drug within 30 days of screening.
• Presence of a chromosomal abnormality or genetic mutation that may put the subject at an increased risk of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) per Investigator's judgment.
• Presence of genetic mutations that result in the inactivation of 2 or more α-globin genes

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 2 Years to 50 Years (Child, Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: bluebird bio; +1-339-499-9300; clinicaltrials@bluebirdbio.com

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04293185
• Other Study ID Numbers: HGB-210
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Bluebird bio is committed to transparency and appropriately de-identified patient-level datasets and supporting documents may be shared upon completion of study participation and following attainment of applicable marketing approvals associated with this study and consistent with criteria established by bluebird bio and/or industry best practices to maintain the privacy of study participants. For enquiries, please contact us at datasharing@bluebirdbio.com.

• Current Responsible Party: bluebird bio
• Original Responsible Party: Same as current
• Current Study Sponsor: bluebird bio
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Anjulika Chawla, MD, FAAP; bluebird bio, Inc.

• PRS Account: bluebird bio
• Verification Date: March 2023