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

Genetix Biotherapeutics Inc.35 enrolled

Overview

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 in the long-term follow-up Study LTF-304 (NCT02698579).

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Cerebral Adrenoleukodystrophy (CALD)

Interventions

Eligibility

Sex: MALEMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. 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. 2. Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent. 3. Active CALD as defined by: 1. Elevated very long chain fatty acids (VLCFA) values, and 2. 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) Gadolinium enhancement (GdE) on MRI of demyelinating lesions. 4. NFS \< or = 1. Exclusion Criteria: 1. Prior receipt of an allogeneic transplant or gene therapy. 2. 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. 3. 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. 4. Any conditions that make it impossible to perform MRI studies (including allergies to anesthetics or contrast agents). 5. Hematological compromise as evidenced by: 1. Peripheral blood absolute neutrophil count (ANC) count \<1500 cells/ cubic millimeter (mm\^3), and either 2. Platelet count \<100,000 cells/mm\^3, or 3. Hemoglobin \<10 gram per deciliter (g/dL). 6. Hepatic compromise as evidenced by: 1. Aspartate transaminase (AST) value greater than (\>) 2.5 × upper limit of normal (ULN) 2. Alanine transaminase (ALT) value \>2.5 × ULN 3. 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 7. Baseline estimated glomerular filtration rate \<70 milliliter per minute (mL/min)/1.73 square meter (m\^2). 8. Cardiac compromise as evidenced by left ventricular ejection fraction \<40 percent (%). 9. Immediate family member with a known or suspected Familial Cancer Syndrome. 10. Clinically significant uncontrolled, active bacterial, viral, fungal, parasitic, or prion associated infection. 11. 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). 12. Any clinically significant cardiovascular, hematological, or pulmonary disease, or other disease or condition that would be contraindicated for any of the other study procedures. 13. Absence of adequate contraception for fertile participants. 14. 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. 15. Known hypersensitivity to protamine sulfate.

Locations (8)

Lucile Packard Children's Hospital

Palo Alto, California, United States

Boston Children's Hospital/Massachusetts General Hospital

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Hôpital Robert Debré

Paris, France

Universitätsklinikum Leipzig AöR

Leipzig, Germany

Ospedale Pediatrico Bambino Gesù

Rome, Italy

Prinses Maxima Center

Utrecht, Netherlands

UCL-ICH/Great Ormond Street Hospital

London, United Kingdom

Outcomes

Primary Outcomes

Percentage of Participants Who Were Alive and Have None of the 6 Major Functional Disabilities (MFDs) at Month 24

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

Percentage of Participants Who Achieved Neutrophil Engraftment After Drug Product 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).

Time frame: By 42 days post-drug infusion

Secondary Outcomes

Percentage of Participants Without Gadolinium Enhancement (i.e. GdE-) on Magnetic Resonance Imaging (MRI) at Month 24

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

Time frame: At Month 24

Number of Participants With Change in Neurologic Function Score (NFS) From Baseline to Month 24

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

Number of Participants Who Achieved Stable NFS at Month 24

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

Major Functional Disability (MFD)-Free Survival Rate

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

Overall Survival Rate

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

Median Detectable Vector Copy Number (VCN) in Peripheral Blood Cells by Month 6

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

Time to Neutrophil Engraftment (NE) After Drug Product Infusion

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

Percentage of Participants With Platelet Engraftment by Month 24

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

Time to Platelet Engraftment Post-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

Percentage of Participants With Loss of Neutrophil Engraftment Post-drug Product Infusion by Month 24

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

Percentage of Participants Who Underwent a Subsequent Allo- Hematopoietic Stem Cell Transplantation (HSCT) Infusion by Month 24

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

Time frame: By Month 24

Percentage of Participants Who Experienced Either Acute (>= Grade 2) or Chronic Graft Versus Host Disease (GVHD) at Month 24

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

Percentage of Participants Who Experienced >= Grade 2 Acute Graft Versus Host Disease (GVHD) by Month 24

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

Percentage of Participants Who Experienced Chronic GVHD by Month 24

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

Percentage of Participants Who Experienced Transplant-related Mortality Through 100 and 365 Days Post-drug Product Infusion

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

Percentage of Participants With Clinical >= Grade 3 Adverse Events (AEs), All Investigational Medicinal Product-related AEs, All Serious Adverse Events (SAEs), and >= Grade 3 Infections

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

Number of Participants With >= Grade 3 Prolonged Cytopenia on or After Rel Day 60 And Rel Day 100

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

Percentage of Participants With Potentially Clinically Significant Changes in Laboratory Parameters by Month 24

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

Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24

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

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

Median Number of Emergency Room Visits (Post-Neutrophil Engraftment) by Month 24

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

Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24

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

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

Median Number of In-patient Hospitalizations (Post-Neutrophil Engraftment) by Month 24

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

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

Duration of In-patient Hospitalizations (Post-Neutrophil Engraftment) up to Month 24

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

Number of Intensive Care Units (ICU) Stays (Post-neutrophil Engraftment) by Month 24

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

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

Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24

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

Number of Participants Who Tested Positive and Negative for Vector-Derived Replication Competent Lentivirus (RCL) Detected by Month 24

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

Number of Participants With Insertional Oncogenesis by Month 24

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