Alzheimer Gene Therapy LX1001 Demonstrates Dose-Dependent Increase in APOE2 Expression

Sandi See Tai

New interim data from a phase 1/2, open-label study (NCT03634007) showed that treatment with LX1001 (Lexeo Therapeutics), an adeno-associated viral vector (AAV) investigational gene therapy, resulted in a dose- and time-dependent effect on apolipoprotein (APOE)2 expression among patients with APOE4 homozygote Alzheimer disease (AD). These findings, coupled with a decrease in several cerebrospinal fluid (CSF) AD tau biomarkers and changes on tau PET, further support the development of LX1001 in the treatment of AD.¹

Presented as a late-breaker at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, the study featured 15 participants who were dosed across 3 ascending single-dose cohorts: 1.4E10 gc/ml (C1; n = 5), 4.4E10 gc/ml (C2; n = 4), 1.4E11 gc/ml (C3; n = 3), and one fixed-dose cohort of 1.4E14 gc (C4; n = 3). The study was a 52-week trial, with participants receiving prednisone for 8 weeks following initial LX1001 dosing. To be included, patients must have APOE4 homozygous status, aged at least 50 years, positive amyloid PET, CSF biomarkers consistent with AD, and mild cognitive impairment or mild to moderate dementia due to AD.

Overall, LX1001 was considered safe and well tolerated, with no events of amyloid-related imaging abnormalities (ARIA) observed. All participants included expressed APOE2 in the CSF, with a dose- and time-dependent increase in APOE2e4 expression. While the interim data did not reveal a directional trend in CSF amyloid-ß42/40 or amyloid PET, the data did show a decrease in CSF t-tau and phosphorylated-tau181 in 9 of the 13 participants. Notably, these patients also demonstrated a decrease in CSF p-tau217 and p-tau231.

"In light of the rapid progression of Alzheimer’s disease in this population, these data highlight the therapeutic potential of delivering APOE2, which can impact multiple mechanisms of Alzheimer’s disease upstream of any specific pathway and thereby meaningfully alter the devastating course of this complex disease," Sandi See Tai, chief development officer at Lexeo, said in a statement. "These data are highly encouraging and provide clinical evidence of the unique and targeted mechanism of LX1001 to potentially treat Alzheimer’s disease."

Coming into the study, literature has shown that APOE4 homozygotes face a 14.5-fold higher risk of late-onset AD than APOE3 homozygotes, and that APOE2/E4 heterozygotes have a 2.6-fold increased risk, indicating a potential protective role for APOE2. LX1001, an investigational medicine, is designed to deliver the APOE2 gene into the central nervous system of patients with APOE4 homozygous AD, potentially converting their profile to APOE2/E4 and slowing disease progression. To date, there are no approved therapies that focus specifically on treating the APOE4 homozygous population.

READ MORE: Intranasal Insulin and Empagliflozin Demonstrate Therapeutic Potential as Combination Treatment for Alzheimer Disease

The analysis presented at CTAD 2024 included 12-month data from patients in cohorts C1-C3 and 6-month data for those in C4. In the study, investigators observed transient CSF pleocytosis (>5 cells/ul), predominantly lymphocytic, in 12 patients, with no significant associated adverse events. In addition, tau PET evaluated in C3 and C4 demonstrated a decrease in global update in 5 of the 6 participants assessed.

"With research, we know that people with APOE2 have less rates of getting Alzheimer disease. If they do get Alzheimer disease, but with APOE2/4, the disease progresses slower," Kim G. Johnson, MD, primary investigator of the trial, told NeurologyLive^®. "Introducing an [APOE] 2 factor gives participants who are APOE4 [carriers] hope. That was really important."

Johnson, who serves as the division chief of memory disorders at Duke University, added that, "one of the things I took away from this trial was that this treatment could offer people hope. It’s important that we did a trial in only 15 people to see if it was safe. That was the primary reason to do the trial, and we found that [LX1001] was safe."

Lexeo originally released topline results from the lowest-dose group of the study in March 2022. All told, the APOEe2 protein was detectable in CSF after 3 months in all 4 participants in the cohort, and after 1 year in the 2 who reached that time point. In these 2, total tau and p-tau reportedly declined from baseline at 1 year with no serious adverse events reported.³

During CTAD 2024, Johnson, Tai, and R. Nolan Townsend, chief executive officer at Lexeo, sat down to discuss the data, including some of the key safety findings from the trial. In the video below, the trio talked about how the APOE2 gene delivery impacted amyloid and tau biomarkers in trial participants, as well as the significance of targeting APOE4 homozygotes with gene therapy in the AD treatment landscape.

Click here for more CTAD 2024 coverage.

REFERENCES
1. Lexeo Therapeutics Announces Positive Interim Data for LX1001, First-Ever Gene Therapy to Impact the Underlying Genetic Cause of APOE4-Associated Alzheimer’s Disease, at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference. Lexeo Therapeutics. October 30, 2024. Accessed October 31, 2024.
2. Johnson K, Kaplitt M, Kaminsky S, et al. Safety and preliminary efficacy of AAV gene therapy (LX1001) in patients with APOE4 homozygote Alzheimer disease – interim data from a phase 1/2, open-label, 52-week, multicenter study. Presented at: Clinical Trials on Alzheimer’s Disease conference; October 29-November 1, 2024; Madrid, Spain. ABSTRACT LB04
3. LEXEO Therapeutics Announces Positive Initial Data from Ongoing Phase 1/2 Clinical Trial of AAV-based Gene Therapy Candidate LX1001 in Patients with Alzheimer’s Disease. News Release. Published March 2, 2022. Accessed October 31, 2024. https://www.lexeotx.com/post/lexeo-therapeutics-announces-positive-initial-data-from-ongoing-phase-1-2-clinical-trial-of-aav-based-gene-therapy-candidate-lx1001-in-patients-with-alzheimers-disease/