A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

This trial assessed the efficacy and safety of autologous cluster of differentiation 34 (CD34+) hematopoietic stem cells, transduced ex-vivo with Lenti-D lentiviral vector (also called elivaldogene autotemcel or eli-cel), for the treatment of cerebral adrenoleukodystrophy (CALD). A participant's blood stem cells were 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 were transplanted back into the participant following myeloablative conditioning. Participants in this study will be continuously followed in study LTF-304.

For study ALD-102 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) were identical.

Inclusion Criteria:

1. Informed consent was 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).

2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.

3. Active cerebral adrenoleukodystrophy (ALD) as defined by:

   1. Elevated very long chain fatty acids (VLCFA) values, and
   2. Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating:
   3. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
   4. Gadolinium enhancement on MRI of demyelinating lesions.

4. NFS less than or equal to (<or=) 1.

Exclusion Criteria:

1. Receipt of an allogeneic transplant or gene therapy.

2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes).

3. Use of statins, Lorenzo's Oil, or dietary regimens used to lower very long chain fatty acids (VLCFA) levels. Note: participants must discontinue use of these medications at time of consent.

4. 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.

5. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents).

6. Hematological compromise as evidenced by:

   • Peripheral blood absolute neutrophil count (ANC) count < 1500 cells/ cubic milli meter (mm3),
   • Platelet count < 100,000 cells/mm3, or
   • Hemoglobin < 10 gram per deciliter (g/dL).
   • Uncorrected bleeding disorder.

7. Hepatic compromise as evidenced by:

   • Aspartate transaminase (AST) value > 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

8. Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance < 50 milliliter per minute [mL/min])

9. Cardiac compromise as evidenced by left ventricular ejection fraction <40 percent (%)

10. Immediate family member with a known or suspected Familial Cancer Syndrome (including but not limited to hereditary breast and ovarian cancer syndrome, hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous polyposis).

11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection

12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B; hepatitis C; human T lymphotrophic virus 1 (HTLV-1). (Note that participants who have been vaccinated against hepatitis B [hepatitis B surface antibody-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B core antibody (Ab)] are eligible. Participants with past exposure to hepatitis B virus (HBV [HBcAb positive and/or 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 antibody are eligible as long as they have a negative hepatitis C viral load.

13. Any clinically significant cardiovascular or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures.

14. Absence of adequate contraception for fertile participants. Male participants and their female partners are required to use two different effective methods of contraception from Screening through at least 6 months after drug product infusion. If subjects are truly sexually abstinent (where true sexual abstinence is defined as being in line with the preferred and usual lifestyle of the subject), no second method is required.

15. Any contraindications to the use of granulocyte colony stimulating (G-CSF) during the mobilization of HSCs, and any contraindications to the use of busulfan or cyclophosphamide, including known hypersensitivity to the active substances or to any of the excipients in their formulations.