LX1001 / Weill Cornell Medical College, Lexeo Therap - LARVOL DELTA

LONG-TERM FOLLOW-UP OF AAV GENE THERAPY (LX1001) IN APOE4 HOMOZYGOTES WITH ALZHEIMER'S DISEASE (ADPD 2026) - P1, P1/2 | "LX1001 is the first investigational gene therapy for APOE4 homozygotes. Preliminary LTFU data suggest LX1001 is generally safe and well tolerated with cognitive outcomes stable up to 3 years. These findings suggest LX1001 may be a potential treatment option for APOE4 homozygotes."

Gene therapy • Alzheimer's Disease • CNS Disorders • Gene Therapies

Drug Development. (PubMed, Alzheimers Dement) - P1/2 | "LX1001 is the first investigational gene therapy for APOE4 homozygotes. Data suggest LX1001 is generally safe and well tolerated with reduction in CSF tau biomarkers and Tau PET, measures that are highly correlated with cognitive decline."

Biomarker • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gene Therapies • Aβ42 • CSF Aβ42 • CSF T-tau

AAV-mediated Delivery of Human APOE2 Variant APOE2-Christchurch Protects Against Neuronal Loss and Preserves Myelin Integrity in Humanized Tau Model of Alzheimer’s Disease (ESGCT 2024) - P1/2 | "This concept was supported by preclinical data in a murine humanized APOE4 model of AD demonstrating efficacy of CNS administration of AAVrh.10hAPOE2, an adenoassociated virus (AAV) serotype rh.10 coding for human APOE2 and led to LEXEO Therapeutics ongoing clinical trial of CNS administration of AAVrh.10hAPOE2 to APOE4 homozygotes with early AD (NCT03634007)...In the AAVrh.10hAPOE2Ch treated group, tissue qPCR analysis also confirmed a significant reduction in pro-inflammatory markers (p<0.01) and increase in anti-inflammatory markers (p<0.01). In summary, addition of the Ch variant to the APOE2 variant was more effective than the APOE2 variant alone in correcting the AD Tau-related pathology, supporting the concept that AAVrh.10hAPOE2Ch represents a 2nd generation candidate to treat homozygous APOE4-associated AD."

Alzheimer's Disease • CNS Disorders • Gene Therapies • Solid Tumor • APOE • OLIG2

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=10 | Active, not recruiting | Sponsor: Lexeo Therapeutics | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • Gene Therapies

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=10 | Enrolling by invitation | Sponsor: Lexeo Therapeutics | Active, not recruiting ➔ Enrolling by invitation

Enrollment open • Alzheimer's Disease • CNS Disorders • Gene Therapies

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=9 | Active, not recruiting | Sponsor: Lexeo Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Alzheimer's Disease • CNS Disorders • Gene Therapies

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: Lexeo Therapeutics | N=15 ➔ 9

Enrollment change • Alzheimer's Disease • CNS Disorders • Gene Therapies

LX1001-01: Gene Therapy for APOE4 Homozygote of Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=15 | Completed | Sponsor: Lexeo Therapeutics | Active, not recruiting ➔ Completed

Gene therapy • Trial completion • Alzheimer's Disease • CNS Disorders • Gene Therapies

Lexeo Therapeutics to Present New Interim Data from Phase 1/2 Trial of LX1001 at the Clinical Trials on Alzheimer’s Disease (CTAD) 2024 Conference (GlobeNewswire) - "Lexeo Therapeutics...announced that interim data from the ongoing Phase 1/2 trial (NCT03634007) of LX1001 have been selected as a late-breaking oral presentation at the Clinical Trials on Alzheimer’s Disease (CTAD) conference....The presentation will include new safety and biomarker data from four dose cohorts of LX1001, an AAVrh10-based gene therapy candidate designed to deliver the protective APOE2 gene into the central nervous systems of APOE4 homozygotes with Alzheimer’s disease....The presentation will review safety as well as multiple measures of efficacy, including protein expression and tau and amyloid biomarkers. 12-month data will be presented for all patients in Cohorts 1-3, and 6-month data for Cohort 4."

Late-breaking abstract • P1/2 data • Alzheimer's Disease

Safety and Preliminary Efficacy of AAV Gene Therapy (LX1001) in Patients with APOE4 Homozygote Alzheimer's Disease – Interim Data from a Phase 1/2, Open-Label, 52-Week, Multicenter Study (CTAD 2024) - No abstract available

Clinical • Gene therapy • Late-breaking abstract • P1/2 data • Alzheimer's Disease • CNS Disorders • Gene Therapies

New Considerations for Accelerating Combination Therapy Trials to be Showcased at 2024 Clinical Trials on Alzheimer’s Disease Conference (PRNewswire) - "The Alzheimer's Drug Discovery Foundation (ADDF) will be leading a roundtable, 'Advancing Combination Therapy: Discussion on Key Considerations, Perspectives, and Promising Avenues for the Future of Alzheimer's Treatments,' at the 2024 Clinical Trials on Alzheimer's Disease (CTAD) conference, which will be held October 29th through November 1st in Madrid, Spain...CTAD will feature several key sessions from ADDF-funded investigators, whose work in drug development and biomarkers is shaping and leading the field towards the holy grail of Alzheimer's treatments—combination therapy and precision medicine, similar to cancer care."

P1/2 data • P2 data • P2a data • Alzheimer's Disease • CNS Disorders

Lexeo Therapeutics Reports Second Quarter 2024 Financial Results and Operational Highlights (GlobeNewswire) - "Expected Upcoming Milestones: LX2006 for the treatment of Friedreich ataxia cardiomyopathy: Previously disclosed data, and one additional cardiac biopsy from Cohort 2, will be shared at a scientific conference in Fall 2024; Update on ongoing regulatory engagements expected by end of 2024; LX2020 for the treatment of PKP2-ACM: Interim data readout (Cohort 1) in 2H 2024; LX1001 for the treatment of APOE4-associated Alzheimer’s disease: Interim Phase 1/2 data readout (all cohorts) in 2H 2024; LX2021 for the treatment of DSP cardiomyopathy: Initiate IND-enabling studies in 2024."

P1/2 data • Preclinical • Regulatory • Alzheimer's Disease • Cardiomyopathy • CNS Disorders • Friedreich ataxia

AAVrh.10 delivery of the combined E2 and Christchurch gain‐of‐function variants of the human APOE gene effectively suppresses both amyloid and Tau pathology in the CNS of murine models of APOE4 homozygote Alzheimer's Disease (ESGCT 2023) - "We tested the hypothesis that AAVrh.10-mediated CNS delivery of the combined human APOE2 allele with the Christchurch mutation (AAVrh.10hAPOE2Ch, referred to as "E2Ch"), will provide superior protection against development of AD-related pathology compared to the unmodified APOE2 allele (AAVrh.10hAPOE2, referred to as "E2")...In the amyloid mice, the E2 and E2Ch vectors had similar function, but in the tau mice, the E2Ch vector outperformed the E2 vector, with E2Ch improvement in all 4 behavioral assays compared to E2. In summary, while the E2 vector is effective, the combined Christchurch and APOE2 variant is a "hyper" gain-of-function APOE variant that more effectively treats both the amyloid and tau pathology of murine models of APOE4 homozygous Alzheimer's disease."

Preclinical • Alzheimer's Disease • CNS Disorders • Gene Therapies • Genetic Disorders • Hemophilia • APOE • Aβ42 • GFAP

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Lexeo Therapeutics

Gene therapy • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Gene Therapies

Gene Therapy for APOE4 Homozygote of Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=15 | Active, not recruiting | Sponsor: Lexeo Therapeutics

Gene therapy • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Gene Therapies

Lexeo Therapeutics Reports Third Quarter 2023 Financial Results and Operational Highlights (GlobeNewswire) - "Completed enrollment of all four cohorts in the LEAD Phase 1/2 clinical trial of LX1001 for the treatment of APOE4-associated Alzheimer’s disease. Additionally, Lexeo presented murine data on LX1021, a preclinical gene therapy candidate designed to deliver a Christchurch mutation modified APOE2 gene, at the 2023 Clinical Trials in Alzheimer's Disease (CTAD) conference in October 2023. The data demonstrated impact to both amyloid and tau pathology as measured in two distinct murine models of Alzheimer’s disease and suggest a potentially enhanced tau pathology treatment effect compared to LX1001....Interim Phase 1/2 data readout (all cohorts) in 2H 2024..."

Enrollment closed • P1/2 data • Preclinical • Alzheimer's Disease • CNS Disorders

Gene Therapy for APOE4 Homozygote of Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=15 | Active, not recruiting | Sponsor: Lexeo Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Gene therapy • Alzheimer's Disease • CNS Disorders • Gene Therapies

Combined E2 and Christchurch Gain-of-Function Variants of the Human APOE Gene Delivered by AAVrh.10 Effectively Suppresses Both Amyloid and Tau Pathology in the CNS of Murine Models of APOE4 Homozygous Alzheimer's Disease (CTAD 2023) - "We tested the hypothesis that AAVrh.10-mediated CNS delivery of the combined human APOE2 allele with the Christchurch mutation (AAVrh.10hAPOE2Ch, referred to as “E2Ch”), will provide greater protection against development of APOE4-associated AD-related pathology compared to the unmodified APOE2 allele (AAVrh.10hAPOE2, referred to as “E2”)... In summary, while the E2 vector is effective in suppressing APOE4-associated amyloid pathology, only the combined Christchurch and APOE2 variant provided a “hyper” gain-offunction APOE variant that effectively treats both the amyloid and tau pathology of murine models of APOE4 homozygous AD, supporting the development of AAVrh.10APOE2Ch as a therapy for APOE4-associated AD."

Preclinical • Alzheimer's Disease • CNS Disorders • APOE • Aβ42 • GFAP

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=15 | Recruiting | Sponsor: Lexeo Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Gene therapy • Alzheimer's Disease • CNS Disorders • Gene Therapies

Gene Therapy for APOE4 Homozygote of Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=15 | Recruiting | Sponsor: Lexeo Therapeutics | Trial completion date: Jun 2024 ➔ Dec 2024 | Trial primary completion date: Jun 2023 ➔ Dec 2023

Gene therapy • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Gene Therapies

A Phase 1, Open-Label, 52-Week, Multicenter Study to Evaluate the Safety and Biochemical Efficacy of AAV Gene Therapy (LX1001) in Patients with APOE4 Homozygote Alzheimer’s Disease – Interim Data (CTAD 2022) - "LX1001 is the first investigational gene therapy to directly address APOE, a well-recognized genetic risk factor of AD. Initial data in the low-dose cohort supports technical feasibility of conferring APOE2 expression in the CNS of human APOE4 homozygotes and indicates that there were no serious adverse events from either CSF delivery of LX1001 or from documented expression of APOE2 in these subjects. These data support further exploration of APOE2 gene therapy as a potential therapeutic for APOE4 homozygous AD patients."

Clinical • P1 data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gene Therapies • APOE • CSF P-tau • CSF T-tau

Gene Therapy for APOE4 Homozygote of Alzheimer's Disease (clinicaltrials.gov) - P1/2 | N=15 | Recruiting | Sponsor: Lexeo Therapeutics | Phase classification: P1 ➔ P1/2 | Trial completion date: Sep 2024 ➔ Apr 2024 | Trial primary completion date: Sep 2023 ➔ Apr 2023

Phase classification • Trial completion date • Trial primary completion date • Alzheimer's Disease • CNS Disorders • Gene Therapies

LEXEO Therapeutics to Present New Clinical Data from its Investigational Gene Therapy LX1001 for APOE4-Associated Alzheimer’s Disease at the 29th European Society of Gene & Cell Therapy Annual Meeting (GlobeNewswire) - “LEXEO Therapeutics, Inc…announced new clinical data from its ongoing study of LX1001 for APOE4-associated Alzheimer’s disease will be presented at the 29th European Society of Gene and Cell Therapy Annual Meeting (ESGCT), which is being held live in Edinburgh, Scotland and virtually from October 11-14, 2022. In an oral presentation, LEXEO will present clinical data from the ongoing study of LX1001 for APOE4-associated Alzheimer’s disease.”

Clinical data • Alzheimer's Disease • CNS Disorders

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Lexeo Therapeutics | Initiation date: Jun 2022 ➔ Sep 2022

Trial initiation date • Alzheimer's Disease • CNS Disorders • Gene Therapies

LEADLTFU: Long-Term Follow-up of Gene Therapy for APOE4 Homozygote Alzheimer's Disease (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: Lexeo Therapeutics

New P1 trial • Alzheimer's Disease • CNS Disorders • Gene Therapies