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

Neutrophil engraftment is defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of \>= 0.5x10\^9 cells/liter (L) (after initial post-infusion nadir) obtained on different days by 42 days postinfusion of eli-cel (Rel Day 43).

Time frame: By 42 days post-drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants for NE if they achieved neutrophil engraftment by Rel Day 43, or had discontinued or were lost to follow-up before Rel Day 43 without achieving NE, or had been followed to at least Rel Day 43 but had not achieved NE. Participants who discontinued or were lost to follow-up before Rel Day 43 without achieving NE were considered failures for NE.

The MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month-24 MFD-Free survival criteria defined as: alive at 24 months post infusion; have not developed any of the MFDs by 24 months post infusion; have not received rescue cell administration or allo-hematopoietic stem cell transplantation (HSCT) by 24 months post infusion; and have not withdrawn from the study or have not been lost to follow-up by 24 months post infusion.

Time frame: At Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as participants who have been followed for 24 months (i.e. Rel Day of last contact \>=730) or have completed the Month 24 Visit, or discontinued from the study but would have been followed for 24 months if still on the study (i.e. Rel Day of data cut \>=730), at the time of the data cut.

Duration of ICU Stays was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24 was reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure. No participant had ICU stay, hence data could not be estimated.

Duration of in-patient hospitalizations was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 was reported. The range of in-patient hospitalizations is influenced by hospital stays for participants who received allogeneic stem cell transplants.

Time frame: From post-neutrophil engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure.

MFD-free survival rate was defined as percentage of participants from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first. MFD-free survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after Lenti-D drug infusion was reported.

Time frame: At 24 months after Lenti-D drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Deaths, MFDs, and rescue cell administration or allo-HSCT are considered events. If a participant did not experience any event, he was to be censored at the Date of Last Contact.

Presence of vector sequences in the genome of cells derived from the originally transduced HSC indicates the presence of transduced cells amongst the HSC precursors. The presence of vector sequences was evaluated throughout the study in whole blood, in selected subpopulations of blood cells (including CD14+ cells), and in bone marrow when indicated. The presence of vector sequences in the genomic DNA of cells was detected using quantitative polymerase chain reaction (qPCR), and results were expressed as vector copy number (VCN; vector copies per diploid genome, c/dg).

Time frame: By Month 6 post-transplant

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.

Median number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.

Time frame: From Post-Neutrophil Engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure.

Median number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure.

Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.

Time frame: From Post-Neutrophil Engraftment up to Month 24

Population: Successful Neutrophil Engraftment Population (NEP) consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.

Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.

Time frame: From Post-Neutrophil Engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.

Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: Successful NEP consisted of participants who achieved neutrophil engraftment defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by Rel Day 43.

Stable NFS was defined as maintaining an NFS \<=4 without an increase of \>3 from Baseline. Number of participants who achieved stable NFS at Month 24 were reported.

Time frame: At Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as participants who have non-missing Baseline and have completed the Month 24 NFS assessment.

Number of participants who tested positive and negative for vector-derived RCL detected at Month 24 were reported. Screening of participant's blood samples for RCL at Month 24 following Lenti-D Drug infusion was performed, with the more rigorous co-culture assays used to distinguish any false positives as applicable.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Participants were evaluable if they have at least 1 RCL assessment.

NFS was a 25-point score used to evaluate the severity of gross neurologic dysfunction in cerebral adrenoleukodystrophy (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 central nervous system (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= absence of clinical signs of cerebral disease.

Time frame: Baseline up to Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as participants who have non-missing Baseline and have completed the Month 24 NFS assessment.

Number of participants with \>= Grade 3 prolonged cytopenia (i.e., decreased platelet counts, decreased neutrophil counts, and/or decreased hemoglobin counts) on or after Rel Day 60 and Rel Day 100 were reported.

Time frame: Prolonged cytopenias occurring on or after Rel Day 60 and Rel Day 100 following drug product infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Insertional oncogenesis included myelodysplastic syndrome, leukemia, lymphoma. Number of participants with insertional oncogenesis at Month 24 were reported.

Time frame: By Month 24 post-transplant

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Overall survival rate was defined as percentage of participants alive from date of Lenti-D drug product infusion (Day 1) to date of death of all causes. Overall survival rate was censored at the date of last visit if the subject were alive. Participants who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis.

Time frame: At 24 months after Lenti-D drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Chronic GVHD graded on the Chronic GVHD Grading Scale as limited or extensive. Chronic GVHD was determined by the Investigator. No chronic GVHD was observed in any participants. Acute GVHD was seen after an eli-cel participant received a subsequent allogeneic hematopoietic stem cell transplant. No GVHD was seen in participants who did not receive allogeneic stem cell transplants. Grade 2 non-serious GVHD was reported in a participant who received allogeneic transplant post eli-cel infusion. Percentage of participants who experienced chronic GVHD by Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as those who had chronic GVHD by Month 24 (Rel Day 730), or have been followed for at least 12 months (Rel Day of last contact \>= 365) if no events yet.

Acute GVHD graded on the Acute GVHD Grading Scale (1-4): Grade 1 is characterized as mild disease, Grade 2 as moderate, Grade 3 as severe (involvement of any organ system), and Grade 4 as life-threatening; chronic GVHD was determined by the Investigator. GVHD was seen after an eli-cel participant received a subsequent allogeneic hematopoietic stem cell transplant. No GVHD was seen in participants who did not receive allogeneic stem cell transplants. Grade 2 non-serious GVHD was reported in a participant who received allogeneic transplant post eli-cel infusion. Percentage of participants who experienced either acute (\>= Grade 2) or chronic GVHD at Month 24 were reported.

Time frame: At Month 24

Population: TP consisted of participants who received Lenti- D Drug Product infusion. Evaluable participants are defined as those who have either experienced the event by Month 24 (Rel Day 730) or have been followed for at least 12 months (Rel Day of last contact \>= 365) if no events yet.

Acute GVHD graded on the Acute GVHD Grading Scale (1-4): Grade 1 is characterized as mild disease, Grade 2 as moderate, Grade 3 as severe (involvement of any organ system), and Grade 4 as life-threatening; Acute GVHD was determined by the Investigator. GVHD was seen after an eli-cel participant received a subsequent allogeneic hematopoietic stem cell transplant. No GVHD was seen in participants who did not receive allogeneic stem cell transplants. Grade 2 non-serious GVHD was reported in a participant who received allogeneic transplant post eli-cel infusion. Percentage of participants who experienced \>= Grade 2 Acute GVHD at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as those who had \>= Grade 2 acute GVHD by Month 24 (Rel Day 730), or have been followed for at least 12 months (Rel Day of last contact \>= 365) if no events yet. The case of GVHD was experienced by a participant after receiving allo-HSCT.

Transplant-related mortality was determined by the investigator and summarized for the following intervals: from Rel Day 1 through 100 days post-drug product infusion (Rel Day 101) and from Rel Day 1 through 365 days post-drug product infusion (Rel Day 366). Percentage of participants who experienced transplant-related mortality through 100 and 365 days post-drug product infusion were reported.

Time frame: From time of drug product infusion through 100 and 365 days post-drug product infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants include participants who have died from transplant-related causes by Rel Day 101 or 366 respectively or have been followed to at least Rel Day 101 or 366 respectively if no events yet.

Percentage of participants who have undergone a subsequent allo-HSCT infusion by Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as those who received subsequent allo-HSCT, or participants who have been followed for at least 24 months (Rel Day of last contact \>= 730 or completed Month 24 visit) if no events. Three participants had Subsequent allo-HSCT by Month 24.

Adverse event was defined as any untoward medical occurrence associated with the use of a drug product in participants, whether or not considered drug related. SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the subject and may require medical or surgical intervention to prevent an outcome listed previously. Percentage of participants with clinical \>= Grade 3 AEs, all investigational medicinal product-related AEs, all serious adverse events (SAEs), and \>= Grade 3 infections were reported.

Time frame: From date of informed consent up to Month 24

Population: Intent-to-treat (ITT) population consisted of participants who initiated any study procedures, beginning with mobilization by granulocyte colony stimulating factor (G-CSF).

Participants were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A participant was considered to have secondary engraftment failure if they achieved and then subsequently lost NE by the Month 24, i.e., if they met both the conditions; Achieved NE by Relative Day 43 as defined above and had sustained decline in ANC to \< 0.5 x 10\^9 cells/L for 3 consecutive measurements on different days after Relative Day 43, without alternate etiology. First day of the 3 consecutive ANC decline to \< 0.5 x 10\^9 cells/L was considered the day of secondary engraftment failure. Percentage of participants with both primary or secondary loss of neutrophil engraftment at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants include participants who, had either primary engraftment failure or secondary engraftment failure by Month 24, or have been followed for at least 24 months if no events.

Percentage of participants without Gadolinium Enhancement (i.e. GdE-) on MRI at Month 24 were reported.

Time frame: At Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants are defined as participants who have completed the Month 24 GdE assessment.

Platelet engraftment was defined as achieving 3 consecutive unsupported platelet counts of \>=20 x 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first Day of 3 consecutive platelet counts \>=20 x 10\^9 cells/L was considered the Day of platelet engraftment.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Participants are evaluable for platelet engraftment if they achieved PE by Month 24, or have been followed for at least 24 months if no platelet engraftment.

Laboratory parameters included Hematology (Leukocytes \[with a threshold range \<4.0 x 10\^9/L, \>=18 x 10\^9/L\], Neutrophils \[\<1.0 x 10\^9/L\], Erythrocytes \[\<=3.0 x 10\^12/L\], Platelets \[\<=75 x 10\^9/L\]); Clinical chemistry (Sodium \[\<=126 millimoles per liter (mmol/L), \>=156 mmol/L\], Potassium \[\<=3 mmol/L, \>=6 mmol/L\], Glucose \[\<=3.0 mmol/L\]), Renal (Urea Nitrogen \[\>=10.7 mmol/L\], Creatinine \[\>=150 umol/L\]) and liver (Alanine Aminotransferase \[ALA\]. Aspartate Aminotransferase \[ASA\], Alkaline Phosphatase \[AP\] with threshold range of \>=3 x upper limit of normal (ULN), Bilirubin \[\>=34.2 micromoles per liter (umol/L)\]). Clinical significance was decided by investigator.

Time frame: From Day 1 to Month 24

Population: ITT population consisted of participants who initiated any study procedures, beginning with mobilization by G-CSF.

Neutrophil engraftment is defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of \>= 0.5 x 10\^9 cells/liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of eli-cel (Rel Day 43). Time to neutrophil engraftment after drug product infusion was reported.

Time frame: By 42 days post-drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of \> or =20 x 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts \>=20 x 10\^9 cells/L was the day of PE. Time to platelet engraftment post-drug product infusion by Month 24 was reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion.