A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

A Phase 3 Study of Lenti-D Drug Product After Myeloablative Conditioning Using Busulfan and Fludarabine in Subjects ≤17 Years of Age With Cerebral Adrenoleukodystrophy (CALD)

The purpose of this study is to evaluate the efficacy and safety of Lenti-D Drug Product (also known as elivaldogene autotemcel or Skysona, hereafter referred to as eli-cel) after myeloablative conditioning with busulfan and fludarabine in participants with CALD. A participant's blood stem cells will be collected and modified (transduced) using the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein. After modification (transduction) with the Lenti-D lentiviral vector, the cells will be transplanted back into the participant following myeloablative conditioning. Enrollment and treatment in Study ALD-104 have been completed and further enrollment in this study is not expected, although participants follow-up remains ongoing.

Participants received a single intravenous (IV) infusion of Lenti-D Drug Product at a dose of > or = 5.0*10^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contains cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) following myeloablative conditioning with busulfan and fludarabine on Day 1.

Percentage of participants who are alive and have none of the 6 major functional disabilities (MFDs) at Month 24

The MFDs are loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement.

Percentage of participants without gadolinium enhancement (that is [i.e.,] negative for GdE-) on Magnetic Resonance Imaging (MRI).

The NFS is a 25-point score used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms (functional domains) across 6 categories. Listed here are the 15 symptoms followed by their maximal score out of 25 points: a) Hearing / auditory processing problems-1, b) Aphasia / apraxia-1, c) Loss of communication-3, d) Vision impairment /field cut-1, e) Cortical blindness-2, f) Swallowing / other CNS dysfunctions-2, g) Tube feeding-2, h) Running difficulties / hyperreflexia-1, i) Walking difficulties / spasticity / spastic gait (no assistance)-1, j) Spastic gait (needs assistance)-2, k) Wheelchair dependence-2, l) Complete loss of voluntary movement-3, m) Episodes of incontinence -1, n) Total incontinence-2, o) Nonfebrile seizures-1. A score of "0" denotes absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain.

MFD-free survival over time is defined as time from drug product infusion to either a rescue cell administration or second transplant, MFD, or death due to any cause, whichever occurs first.

Percentage of participants who experience either acute (greater than or equal to [> or =] Grade II) or chronic graft versus host disease (GVHD) at Month 24

Percentage of participants with loss of neutrophil engraftment post-drug product infusion by Month 24

Percentage of participants who undergo a subsequent hematopoietic stem cell (HSC) infusion by Month 24

Percentage of participants who experience transplant-related mortality through 100 and 365 days post-drug product infusion

Percentage of participants with clinical > or = Grade 3 AEs, drug product -related AEs, all serious adverse events (SAEs), AEs > or = Grade 3 infections by Month 24.

Percentage of participants with potentially clinically significant changes in laboratory parameters by Month 24

Percentage of participants who experience greater than or equal to (> or =) Grade II acute GVHD by Month 24

Number of participants in which vector-derived replication competent lentivirus (RCL) is detected by Month 24

Inclusion Criteria: Informed consent is obtained from a competent custodial parent or guardian with legal capacity to execute a local Institutional Review Board (IRB)/independent ethics committee (IEC) approved consent. Informed assent will be sought from capable participants, in accordance with the directive of the IRB/IEC and with local requirements. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent. Active CALD as defined by: Elevated very long chain fatty acids (VLCFA) values, and Active central nervous system (CNS) disease established by central radiographic review of brain MRI demonstrating i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and ii. GdE on MRI of demyelinating lesions. NFS < or = 1. Exclusion Criteria: Prior receipt of an allogeneic transplant or gene therapy. Use of statins, Lorenzo's Oil, or dietary regimens used to lower VLCFA levels. Note: participants must discontinue use of these medications at time of consent. Receipt of an investigational study drug or procedure within 3 months before Screening that might confound study outcomes. Use of investigational study drugs is prohibited throughout the course of the study. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents). Hematological compromise as evidenced by: Peripheral blood absolute neutrophil count (ANC) count <1500 cells/ cubic millimeter (mm^3), and either Platelet count <100,000 cells/mm^3, or Hemoglobin <10 gram per deciliter (g/dL). Hepatic compromise as evidenced by: Aspartate transaminase (AST) value greater than (>) 2.5 × upper limit of normal (ULN) Alanine transaminase (ALT) value >2.5 × ULN Total bilirubin value >3.0 milligram per deciliter (mg/dL), except if there is a diagnosis of Gilbert's Syndrome and the participant is otherwise stable Baseline estimated glomerular filtration rate <70 milliliter per minute (mL/min)/1.73 square meter (m^2). Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%). Immediate family member with a known or suspected Familial Cancer Syndrome. Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B virus (HBV); hepatitis C virus (HCV); human T lymphotrophic virus 1 (HTLV-1). (Note that participants who have been vaccinated against HBV [positive for HBV surface antibodies] who are negative for other markers of prior HBV infection [e.g., negative for HBV core Ab] are eligible. Participants with past exposure to HBV [hepatitis B core antibody [HBcAb] -positive and/or hepatitis B e-antigen antibody [HBeAb]-positive] are also eligible for the study provided they have a negative test for HBV DNA. Also note that participants who are positive for anti-hepatitis C Ab are eligible as long as they have a negative hepatitis C viral load). Any clinically significant cardiovascular, hematological, or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures. Absence of adequate contraception for fertile participants. Any contraindications to the use of Granulocyte colony-stimulating factor (G-CSF) or plerixafor during the mobilization of HSCs, and any contraindications to the use of busulfan or fludarabine, including known hypersensitivity to the active substances or to any of the excipients in their formulations. Known hypersensitivity to protamine sulfate.

Bluebird bio is committed to transparency and appropriately de-identified patient-level datasets and supporting documents may be shared 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.