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Gene Therapy for APOE4 Homozygote of Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03634007
Recruitment Status : Recruiting
First Posted : August 16, 2018
Last Update Posted : May 12, 2023
Sponsor:
Collaborators:
Alzheimer's Drug Discovery Foundation
Weill Medical College of Cornell University
Information provided by (Responsible Party):
Lexeo Therapeutics

Study Description
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Brief Summary:
This clinical trial is an open label, dose-ranging study designed to evaluate gene therapy to treat patients who are APOE4 homozygotes with clinical diagnosis varying from mild cognitive impairment due to Alzheimer's, mild dementia due to Alzheimer's disease, and moderate dementia due to Alzheimer's disease.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Early Onset Alzheimer Disease Biological: LX1001 Phase 1 Phase 2

Detailed Description:
The study will assess the safety and toxicity of intrathecal administration of AAVrh.10hAPOE2 (LX1001), serotype rh.10 adeno-associated virus (AAV) gene transfer vector expressing the complementary deoxyribonucleic acid (cDNA) coding for human apolipoprotein E2 (APOE2), directly to the central nervous system (CNS)/ CSF of APOE4 homozygotes with Alzheimer's disease. All subjects will have evidence of cerebrospinal fluid (CSF) biomarkers consistent with Alzheimer's disease. The study will establish a maximum tolerable dose and generate preliminary evidence regarding whether direct administration of LX1001 to the CNS of those Alzheimer's patients will lead to conversion of the APOE protein isoforms in the CSF of APOE4 homozygotes from APOE4 to APOE2-APOE4.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A 52-Week, Multicenter, Phase 1/2 Open-label Study to Evaluate the Safety of LX1001 in Participants With APOE4 Homozygote Alzheimer's Disease
Actual Study Start Date : November 6, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1: 1.4 x 10^10 gc/mL CSF
Participants will receive 1.4 x 10^10 gc/mL CSF of LX1001.
 Biological: LX1001
LX1001 is a serotype rh.10 AAV gene transfer vector expressing the cDNA coding for human APOE2.
Other Name: AAVrh.10hAPOE2
Experimental: Cohort 2: 4.4 x 10^10 gc/mL CSF
Participants will receive 4.4 x 10^10 gc/mL CSF of LX1001.
 Biological: LX1001
LX1001 is a serotype rh.10 AAV gene transfer vector expressing the cDNA coding for human APOE2.
Other Name: AAVrh.10hAPOE2
Experimental: Cohort 3: 1.4 x 10^11 gc/mL CSF
Participants will receive 1.4 x 10^11 gc/mL CSF of LX1001.
 Biological: LX1001
LX1001 is a serotype rh.10 AAV gene transfer vector expressing the cDNA coding for human APOE2.
Other Name: AAVrh.10hAPOE2
Experimental: Cohort 4: 1.4 x 10^14 gc (fixed dose)
Participants will receive 1.4 x 10^14 gc (fixed dose; approximately 3.4 × 10^11 gc/mL CSF based on an average CSF volume of 409 mL) of LX1001.
 Biological: LX1001
LX1001 is a serotype rh.10 AAV gene transfer vector expressing the cDNA coding for human APOE2.
Other Name: AAVrh.10hAPOE2


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of participants with treatment-emergent adverse events and serious adverse events [ Time Frame: 1 year ]
    Adverse events categorized and graded

  2. The proportion of participants with treatment-emergent adverse events and serious adverse events at each dosage [ Time Frame: 1 year ]
    Adverse events categorized and graded per study drug dose


Eligibility Criteria
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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • APOE4 homozygotes
  • Willing and able to provide informed consent (or consent provided by a legally authorized representative)
  • Clinical diagnosis of mild cognitive impairment due to Alzheimer's disease or mild to moderate dementia due to Alzheimer's disease
  • Evidence of CSF biomarkers consistent with Alzheimer's disease
  • Serum neutralizing anti-AAVrh10 titer <1:100
  • No evidence of active infection of any type, including hepatitis virus (A, B, or C) or human immunodeficiency virus (HIV-1 and HIV-2)
  • Fertile or infertile individuals; it will be recommended that fertile individuals utilize barrier birth control measures to prevent pregnancy for the duration of the study
  • Individuals not receiving experimental medications or participating in another experimental protocol for at least 4 weeks prior to entry into the study
  • Participants who agree not to post their personal data related to the study on social media.

Exclusion Criteria:

  • Individuals receiving systemic immunosuppressant or corticosteroid therapy other than protocol-specified, are receiving a monoclonal anti-amyloid therapy (example, Aduhelm™ (aducanumab), Leqembi™ (lecanemab-irmb) or unable to wash out from anti-coagulant medications.
  • Individuals who do not fit the American Journal of Neuroradiology recommendations for image-guided spinal procedures
  • Presence of other significant medical, psychiatric, or neurological conditions may disqualify the participant from participation in this study, particularly those which would create an unacceptable risk of receiving the LX1001-01 vector, for example, malignancy, heart failure, liver or renal failure, or HIV positive.
  • Elevated white blood cell count, temperature >38.5° C, infiltrate on chest x-ray. Note: Repeat of these examinations during the screening period is permitted to confirm eligibility
  • Prior or concurrent participation in any gene and/or cell therapy
  • Any condition, disorder, or abnormal laboratory test findings at screening which, in the judgment of the investigator, would interfere with the individual's ability to comply with all study requirements or would require the administration of treatment during the study that could potentially affect the interpretation of the study data, or would place the individual at unacceptable risk by his/her participation in the study
  • Individuals who cannot participate in magnetic resonance imaging, amyloid and tau PET scans, and CSF studies
  • Individuals who cannot undergo study-related procedures without general anesthesia (other than who need general anesthesia for the gene therapy administration)
  • More than 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or evidence of a prior macro hemorrhage on screening MRI
  • Individuals with a history of clinically significant hypersensitivity or contraindication as judged by the investigator, to any component of the study drug formulation or to any drugs used in this study (examples are corticosteroids and proton-pump inhibitors)
  • Are pregnant or nursing
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03634007


Contacts
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Contact: Lexeo Clinical Trials +1 212-547-9879 clinicaltrials@lexeotx.com
Contact: Lexeo Clinical Trials

Locations
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United States, Florida
K2 Medical Research Recruiting
Maitland, Florida, United States, 32751
Contact: Jawad Alqerem    407-815-2505    jawad.alqerem@k2med.com)   
PPD Development Recruiting
Orlando, Florida, United States, 32806
Contact: Sarah Poissant    689-216-3179    Sarah.Poissant@ppdi.com   
United States, New York
Weill Cornell Medicine Recruiting
New York, New York, United States, 10065-4870
Contact: Haley Bowe    646-962-2672    hab40007@med.cornell.edu   
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27708
Contact: Sidney Wright    919-681-9249    sidney.fitz@duke.edu   
Sponsors and Collaborators
Lexeo Therapeutics
Alzheimer's Drug Discovery Foundation
Weill Medical College of Cornell University
Investigators
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Study Director: Lexeo Clinical Trials Lexeo Therapeutics
More Information
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Responsible Party: Lexeo Therapeutics
ClinicalTrials.gov Identifier: NCT03634007    
Other Study ID Numbers: LX1001-01
First Posted: August 16, 2018    Key Record Dates
Last Update Posted: May 12, 2023
Last Verified: May 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Lexeo Therapeutics:
Alzheimer Disease
APOE4 homozygotes
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
 Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders