Trial Outcomes & Findings for A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD) (NCT NCT03852498)

This study was conducted at 8 study centers in France, Italy, Germany, the Netherlands, United Kingdom, and United States of America from 24 January 2019 to 24 July 2023.

A total of 35 male participants were enrolled. All underwent mobilization and were treated with Lenti-D Drug Product also referred to as eli-cel (elivaldogene autotemcel) in this study. For study ALD-104 the Transplant Population (TP), Neutrophil Engraftment Population (NEP), and Intent-to-Treat Population (ITT) are identical.

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

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cell administration or allo-hematopoietic stem cell transplantation (HSCT) by 24 months post infusion; and have not withdrawn from the study or have not been lost to follow-up by 24 months post infusion.

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).

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

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.

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.

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.

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.

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).

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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

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

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

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.

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

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.

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.

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