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

NCT03852498 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: ALD-1042018-001145-14
• Study Type: interventional
• Target: 35
• Locations: 6 countries
• Sites: 8

Brief Summary

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).

Conditions

Cerebral Adrenoleukodystrophy (CALD)

Keywords

Adrenoleukodystrophy; X-linked adrenoleukodystrophy; Gene therapy; Hematopoietic stem cell

Outcome Measures

Primary Outcomes (2)

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cell administration or allo-hematopoietic stem cell transplantation (HSCT) by 24 months post infusion; and have not withdrawn from the study or have not been lost to follow-up by 24 months post infusion.

  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).

  By 42 days post-drug infusion

Secondary Outcomes (27)

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

  At Month 24

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

  Baseline up to Month 24

• Number of Participants Who Achieved Stable NFS at Month 24

  At Month 24

• Major Functional Disability (MFD)-Free Survival Rate

  At 24 months after Lenti-D drug infusion

• Overall Survival Rate

  At 24 months after Lenti-D drug infusion

Study Arms (1)

Lenti-D Drug Product

EXPERIMENTAL

Participants received a single intravenous (IV) infusion of eli-cel (also referred to as Lenti-D Drug Product) on Day 1 at a dose of \> or = 5.0\*10\^6 CD34+ cells/kilogram (kg). All participants received myeloablative conditioning with busulfan and fludarabine over a number of days prior to drug product infusion.

Genetic: Lenti-D

Interventions

Lenti-D GENETIC

Participants received a single IV infusion of Lenti-D Drug Product.

Also known as: elivaldogene autotemcel, eli-cel

Lenti-D Drug Product

Eligibility Criteria

• Age: Up to 17 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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) Gadolinium enhancement (GdE) on MRI of demyelinating lesions.
• NFS \< or = 1.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genetix Biotherapeutics Inc.: lead

Study Sites (8)

Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

Boston Children's Hospital/Massachusetts General Hospital

Boston, Massachusetts, 02215, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Hôpital Robert Debré

Paris, 75019, France

Location

Universitätsklinikum Leipzig AöR

Leipzig, 04103, Germany

Location

Ospedale Pediatrico Bambino Gesù

Rome, 00165, Italy

Location

Prinses Maxima Center

Utrecht, 3508AB, Netherlands

Location

UCL-ICH/Great Ormond Street Hospital

London, WC1N3JH, United Kingdom

Location

Related Publications (1)

• Duncan CN, Bledsoe JR, Grzywacz B, Beckman A, Bonner M, Eichler FS, Kuhl JS, Harris MH, Slauson S, Colvin RA, Prasad VK, Downey GF, Pierciey FJ, Kinney MA, Foos M, Lodaya A, Floro N, Parsons G, Dietz AC, Gupta AO, Orchard PJ, Thakar HL, Williams DA. Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2024 Oct 10;391(14):1287-1301. doi: 10.1056/NEJMoa2405541.

  PMID: 39383458 DERIVED

MeSH Terms

Conditions

Adrenoleukodystrophy

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Study Medical Director
• Organization: bluebird bio, Inc

clinicaltrials@bluebirdbio.com

+1-833-999-6378

Study Officials

• Himal Lal Thakar, MD

  bluebird bio, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2019
• First Posted: February 25, 2019
• Study Start: January 24, 2019
• Primary Completion: July 24, 2023
• Study Completion: July 24, 2023
• Last Updated: May 24, 2024
• Results First Posted: May 24, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); GB (1); US (3); FR (1); NL (1); DE (1)