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

NCT01896102 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ALD-1022011-001953-10
• Study Type: interventional
• Target: 32
• Locations: 6 countries
• Sites: 8

Brief Summary

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.

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 and Without Allo-HSCT or Rescue Cell Administration

  The 6 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 was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 were reported.

  At Month 24

• Proportion of Participants Who Had Experienced Either Acute ([>or=] Grade II) or Chronic Graft Versus Host Disease (GVHD) by Month 24

  Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (\>= Grade II) or chronic GVHD at Month 24 were reported.

  By Month 24

Secondary Outcomes (21)

• Percentage of Participants Who Demonstrated Resolution of Gadolinium Positivity on Magnetic Resonance Imaging (MRI) at Month 24

  At Month 24

• Time to Sustained Resolution of Gadolinium Positivity on MRI

  Up to Month 24

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

  Baseline up to 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 Lenti-D Drug Product at a dose of greater than or equal to (\>=) 5.0 × 10\^6 CD34+ cells/kilogram (kg) (autologous CD34+ cell-enriched population that contained cells transduced with lentiviral vector encoding ABCD1 cDNA for human adrenoleukodystrophy protein, suspended in a cryopreservative solution) on Day 0.

Genetic: Lenti-D Drug Product (eli-cel)

Interventions

Lenti-D Drug Product (eli-cel) 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 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).
• Males aged 17 years and younger, at the time of parental/guardian consent and, where appropriate, participant assent.
• Active cerebral adrenoleukodystrophy (ALD) as defined by:
• Elevated very long chain fatty acids (VLCFA) values, and
• Active CNS disease established by central radiographic review of brain magnetic resonance imaging (MRI) demonstrating:
• Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and
• Gadolinium enhancement on MRI of demyelinating lesions.
• NFS less than or equal to (\<or=) 1.

You may not qualify if:

• Receipt of an allogeneic transplant or gene therapy.
• Availability of a willing 10/10 HLA-matched sibling donor (excluding female heterozygotes).
• 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.
• 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 milli meter (mm3),
• Platelet count \< 100,000 cells/mm3, or
• Hemoglobin \< 10 gram per deciliter (g/dL).
• Uncorrected bleeding disorder.
• 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
• Renal compromise as evidenced by abnormal renal function (actual or calculated creatinine clearance \< 50 milliliter per minute \[mL/min\])

Sponsors & Collaborators

• Genetix Biotherapeutics Inc.: lead

Study Sites (8)

Mattel Children's Hospital UCLA/Ronald Reagan UCLA Medical Center

Los Angeles, California, 90095, United States

Location

Boston Children's Hospital/Massachusetts General Hospital

Boston, Massachusetts, 02115, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Medeos SRL

Buenos Aires, C1022, Argentina

Location

Women and Children's Hospital

North Adelaide, South Australia, 5006, Australia

Location

Hôpital Bicêtre

Le Kremlin-Bicêtre, 94275, France

Location

University of Leipzig

Leipzig, 04103, Germany

Location

Great Ormond Street Hospital for Children NHS Foundation Trust

London, WC1N3JH, United Kingdom

Location

Related Publications (3)

• Eichler F, Duncan CN, Musolino PL, Lund TC, Gupta AO, De Oliveira S, Thrasher AJ, Aubourg P, Kuhl JS, Loes DJ, Amartino H, Smith N, Folloni Fernandes J, Sevin C, Sankar R, Hussain SA, Gissen P, Dalle JH, Platzbecker U, Downey GF, McNeil E, Demopoulos L, Dietz AC, Thakar HL, Orchard PJ, Williams DA. Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2024 Oct 10;391(14):1302-1312. doi: 10.1056/NEJMoa2400442.

  PMID: 39383459 DERIVED

• 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

• Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA. Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638. doi: 10.1056/NEJMoa1700554. Epub 2017 Oct 4.

  PMID: 28976817 DERIVED

Related Links

• ALD-102 is parent study for LTF-304 study

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

medinfo@bluebirdbio.com

339-499-9300

Study Officials

• Jakob Sieker, MD.

  bluebird bio, Inc.

  STUDY DIRECTOR

• David Williams, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

• Christine Duncan, MD

  Boston Children's Hospital

  PRINCIPAL INVESTIGATOR

• Florian Eichler, MD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

• Satiro de Oliveira, MD

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

• Paul Orchard, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

• Adrian Thrasher, MD, PhD

  Great Ormond Street Hospital for Chidren NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

• Patrick Aubourg, MD, PhD

  Hôpital Bicêtre

  PRINCIPAL INVESTIGATOR

• Jorn-Sven Kuhl, MD

  University of Leipzig

  PRINCIPAL INVESTIGATOR

• Nicholas Smith, MD

  Women and Children's Hospital

  PRINCIPAL INVESTIGATOR

• Hernan Amartino, MD

  Medeos SRL

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 22, 2013
• First Posted: July 11, 2013
• Study Start: August 21, 2013
• Primary Completion: March 26, 2021
• Study Completion: March 26, 2021
• Last Updated: April 25, 2022
• Results First Posted: April 25, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will share

Locations

US (3); DE (1); AR (1); AU (1); FR (1); GB (1)