A Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease

A Phase 1/2, Open-Label, Multicenter, Single-Arm Study to Assess the Safety, Tolerability, and Efficacy of BIVV003 for Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Sickle Cell Disease

This is an open label, multicenter, Phase 1/2 study in approximately eight adults with severe Sickle Cell Disease (SCD). The study will evaluate the safety, tolerability, and efficacy of autologous hematopoietic stem cell transplantation using BIVV003.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Biological: Plerixafor; Drug: Busulfan; Genetic: BIVV003

Detailed Description

Subject participation in this study will be approximately 136 weeks. Enrolled subjects will be asked to participate in a separate long-term follow-up study to monitor the safety and efficacy of BIVV003 treatment for a total of 15 years post-transplant.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Oakland, California, United States, 94609
      • UCSF Benioff Children's Hospital
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Children's Healthcare of Atlanta
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Investigational Site Number 101
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 36 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

• Ages 18 to 40
• Confirmation of sickle cell disease (SCD) diagnosis (HbSS or HbS[beta]0 genotype)
• Severe SCD, defined as having 1 or more of the following manifestations: Clinically significant neurologic event (example [e.g.], stroke) or any neurological deficit lasting more than 24 hours; History of 2 or more episodes or Acute Chest Syndrome (ACS) in 2 years prior to informed consent (despite adequate supportive therapies such as asthma therapy); Six or more pain crises per year in 2 years prior to informed consent (requiring intravenous [IV] pain management in the outpatient or inpatient hospital setting); History of 2 or more cases or priapism with participant seeking medical care in the 2-years prior to informed consent; Regular RBC transfusion therapy in the year prior to informed consent (having received 8 or more transfusions to prevent vaso-occlusive clinical complications); and Echocardiographic finding of tricuspid valve regurgitant jet (TRJ) velocity of greater than or equal to 2.5 meter per second (m/s)
• Clinically stable to undergo stem cell mobilization and myeloablative hematopoietic stem cell transplantation (HSCT)
• Adequate physiological function, defined as the following: Karnofsky/Lansky Performance of greater than or equal to 60; Acceptable cardiac function as defined in protocol; Acceptable pulmonary function as defined in protocol; Acceptable renal function as defined in protocol; and Acceptable hepatic function as defined in protocol
• Ability to understand purpose and risks of study, provide Informed Consent Form (ICF) and authorization to use protected health information
• Completion of age-appropriate cancer screening
• Willingness to use double-barrier method of contraception through entire study period (for participants of childbearing potential)
• Willingness to receive blood transfusions
• Willingness to discontinue hydroxyurea (HU) at least 30 days prior to stem cell mobilization through Day 100 post-transplantation

Exclusion Criteria:

• Previous receipt of an autologous or allogeneic HSCT or solid organ transplantation
• Previous treatment with gene therapy
• Current enrollment in an interventional study or having received an investigational drug within 30 days of study enrollment
• Pregnant or breastfeeding female
• Female or male who plans to become pregnant or impregnate a partner, respectively, during the anticipated study period
• Contraindication to plerixafor, apheresis, or busulfan
• Treatment with prohibited medication in previous 30 days
• Known allergy or hypersensitivity to plerixafor, busulfan, or investigational product excipients
• History of active malignancy within past 5 years, any history of hematologic malignancy, or a family history of a cancer predisposition syndrome (without negative result of candidate)
• Current diagnosis of uncontrolled seizures
• History of significant bleeding disorder
• Clinically significant infection
• Any major organ dysfunction involving brain, kidney, liver, lung, or heart (e.g., congestive heart failure, pulmonary hypertension)
• Corrected QT interval of more than 500 millisecond (ms) based on screening electrocardiogram (ECG)
• Positive for human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV)
• Known to have a gamma-globin variant associated with altered oxygen affinity
• Hereditary persistence of fetal hemoglobin (HPFH) or HbF concentration of more than or equal to 20 percent (%) at screening
• Absolute Neutrophil Count (ANC) of less than or equal to 1,000 per microliter
• Platelet count of less than 100,000 per microliter
• History of platelet alloimmunization (precluding ability to provide transfusion support)
• Extensive Red Blood Cell (RBC) alloimmunization (precluding ability to provide transfusion support)
• Judged unsuitable for participation by investigator and/or sponsor

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BIVV003; Participants will receive plerixafor as subcutaneous (SQ) administration followed by myeloablative conditioning therapy with intravenous (IV) busulfan. BIVV003 will then be administered as a 1-time IV infusion of autologous Cluster of Differentiation 34 + Hematopoietic Stem/Progenitor Cell (CD34+HSPC) transfected ex vivo with zinc finger nuclease (ZFN) messenger ribonucleic acid (mRNAs) targeting the B-cell lymphoma/leukemia 11A (BCL11A) locus.

Biological: Plerixafor; Plerixafor subcutaneous injection will be administered prior to apheresis.; Drug: Busulfan; Busulfan IV infusion will be administered as myeloablative conditioning therapy.; Genetic: BIVV003; BIVV003 will be administered as an IV infusion following myeloablative conditioning with busulfan.; Other Names: Autologous CD34 + hematopoietic stem cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants who are Alive at Post-transplantation Day 100	The percentage of participants who are alive at post-transplantation Day 100 will be calculated using the Kaplan-Meier estimate.	Day 100
Percentage of Participants who are Alive at Post-transplantation Week 52	The percentage of participants who are alive at post-transplantation Week 52 will be calculated using the Kaplan-Meier estimate.	Week 52
Percentage of Participants who are Alive at Post-transplantation Week 104	The percentage of participants who are alive at post-transplantation Week 104 will be calculated using the Kaplan-Meier estimate.	Week 104
Percentage of Participants With Successful Engraftment	Successful engraftment is defined by absolute neutrophil count (ANC) greater than or equal to >=500 cells/microliter (mL) for 3 consecutive days.	Up to Day 42
Number of Participants With Adverse Events (AEs)	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.	Up to Week 104
Number of Participants With Serious Adverse Events (SAEs)	An SAE is any untoward medical occurrence that at any dose: Results in death, in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); however, this does not include an event that, had it occurred in a more severe form, might have caused death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or is a medically important event.	Up to Week 104

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD34 + HSPC Yield from Plerixafor Stem Cell Mobilization		Approximately 12 weeks
Proportion of Participants with Sufficient Stem Cell Mobilization for Rescue Aliquot and BIVV003 Production		Approximately 12 weeks
Yield of Zinc Finger Nuclease (ZFN)-edited Investigational Product		Approximately 12 weeks
Time to Initial Neutrophil Recovery Following BIVV003 Infusion		Up to Week 104
Time to Platelet Recovery Following BIVV003 Infusion		Up to Week 104
Percentage of Participants With Maintenance of Absolute Neutrophil Count (ANC) of >=500/mcL to last Participant Visit	Percentage of participants maintaining ANC of >=500/mcL to last Participant Visit (Week 104) will be calculated.	Up to Week 104
Percentage of Participants With Maintenance of Platelet count of >=50,000/mcL to last Participant Visit	The percentage of participants attaining a post-transplant platelet count of >=50,000/mcL and maintaining this level through last Participant Visit (Week 104) will be calculated.	Up to Week 104
Change From Baseline in Peripheral Blood Fetal Hemoglobin (HbF) Levels	Change from baseline in HbF up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Peripheral Blood Percent (%)F cells	Change from baseline in %F cells up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Peripheral Blood Sickle Hemoglobin (HbS) Levels	Change from baseline in peripheral blood HbS levels up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Peripheral blood total hemoglobin (Hb) concentration	Change From baseline in peripheral blood total hemoglobin (Hb) concentration up to week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Reticulocyte Count	Change from baseline in reticulocyte count up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Lactate Dehydrogenase (LDH) Levels	Change from baseline in LDH levels up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Haptoglobin Levels	Change from baseline in haptoglobin levels up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Serum Bilirubin Levels	Change from baseline in serum bilirubin levels up to Week 104 will be assessed.	Baseline up to Week 104
Change From Baseline in Patient-Reported Outcomes Measurement Information System 57 (PROMIS-57) Scale Score	Quality of life (QoL) measures including fatigue will be assessed using PROMIS-57 scale. This is a 57-item questionnaire with 8 questions per domain for assessing physical and mental well-being in participants with SCD. 57 questions are summed into a total score, which is transformed into an age specific normalized t-score with 50 representing normal, and lower scores representing increasing disability.	Baseline up to Week 104
Number of Participants With Sickle Cell Disease (SCD)-related Clinical Events	Number of participants with SCD-related clinical events (including vaso-occlusive crisis [VOC], pain episodes etc.) will be reported.	Baseline up to Week 104
Number of SCD Related Clinical Events by Severity	Severity will be categorized by toxicity grade according to CTCAE Version 5.0. AEs not listed in the CTCAE Version 5.0 will be evaluated by: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe or medically significant but not immediately life threatening, Grade 4=Life-threatening consequences; Grade 5=Death.	Baseline up to Week 104
Participants lymphocyte Counts	Lymphocyte counts will be measured to assess reconstitution of immune function post-BIVV003 transplantation.	At Weeks 13 and 52
Participants Immunoglobulin levels	Immunoglobulin levels will be measured to assess reconstitution of immune function post-BIVV003 transplantation.	At Weeks 13 and 52
Number of Red Blood Cell (RBC) Transfusions Received During the Post-transplantation Study Period	The number of RBC transfusions received during the Post-Transplantation study period will be reported.	Up to Week 104
Total Volume of RBC Transfused	Total volume of RBC transfused during the Post-Transplantation study period will be reported.	Up to Week 104

Collaborators and Investigators

• Sponsor: Sangamo Therapeutics
• Investigators: Study Director: Medical Monitor, Sangamo Therapeutics

Publications and helpful links

General Publications

• Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.

Study record dates

Study Major Dates

• Study Start (Actual): March 6, 2019
• Primary Completion (Actual): July 17, 2025
• Study Completion (Actual): July 17, 2025

Study Registration Dates

• First Submitted: August 10, 2018
• First Submitted That Met QC Criteria: August 28, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Estimated): September 12, 2025
• Last Update Submitted That Met QC Criteria: September 5, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Intervention: Genetic: BIVV003; Drug: Busulfan; Biological: Plerixafor; Phase: Phase 1/2
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Anemia, Sickle Cell; Sulfur Compounds; Organic Chemicals; Hydrocarbons, Acyclic; Hydrocarbons; Alkanes; Alcohols; Butylene Glycols; Glycols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Sulfonic Acids; Sulfur Acids; Busulfan; plerixafor
• Other Study ID Numbers: 003SCD101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No