Lexeo Therapeutics' Gene Therapy LX1001 Increases APOE2 Expression in Patients With Alzheimer Disease
LX1001's safety profile was characterized as well-tolerated with no amyloid-related imaging abnormalities reported.
This article originally appeared on our sister site, NeurologyLive®.
Lexeo Therapeutics' LX1001, an investigational adeno-associated virus (AAV) vector-based gene therapy, has demonstrated a dose- and time-dependent impact on apolipoprotein (APOE2) expression in patients with APOE4 homozygote Alzheimer disease (AD) in interim data from a phase 1/2, open-label clinical trial (NCT03634007).1 In addition, a decrease in several cerebrospinal fluid (CSF) AD tau biomarkers and changes on tau PET were reported.
The data were announced in a late-breaking presentation at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain. Fifteen patients were dosed in the trial across 3 ascending single-dose cohorts: 1.4x1010 gc/ml (C1; n = 5), 4.4x1010 gc/ml (C2; n = 4), 1.4x1011 gc/ml (C3; n = 3). A single fixed-dose cohort was also included, treating patients at a dose of 1.4x1014 gc (C4; n = 3). Participants in the 52-week study were administered prednisone for 8 weeks after treatment with LX1001. APOE4 homozygous status, an age of at least 50 years, positive amyloid PET, CSF biomarkers consistent with AD, and mild cognitive impairment or mild to moderate dementia due to AD were requirements for inclusion in the study.
In terms of safety, the gene therapy was deemed safe and well-tolerated, with no cases of amyloid-related imaging abnormalities (ARIA) reported. Expression of APOE2 in the CSF was observed in all of the patients, with a dose- and time-dependent increase in APOE2e4 expression noted. A decrease in CSF t-tau and phosphorylated-tau181 in 9 of the 13 participants was observed, although no directional trend in CSF amyloid-ß42/40 or amyloid PET was recorded. Notably, a decrease in CSF p-tau217 and p-tau231 was also seen in the 9 aforementioned patients.
"In light of the rapid progression of AD in this population, these data highlight the therapeutic potential of delivering APOE2, which can impact multiple mechanisms of AD upstream of any specific pathway and thereby meaningfully alter the devastating course of this complex disease," Sandi See Tai, MD, the chief development officer at Lexeo, said in a statement.1 "These data are highly encouraging and provide clinical evidence of the unique and targeted mechanism of LX1001 to potentially treat AD."
Previous research has revealed that people who are homozygous for APOE4 have a 14.5-fold higher risk of late-onset AD than people homozygous for APOE3, and that patients heterozygous for APOE2/E4 face a 2.6-fold increased risk, suggesting that APOE2 may play a protective role. LX1001 is intended to deliver the APOE2 gene into the central nervous system of patients with AD who are homozygous for APOE4, with the aim of converting the profile of their cells to APOE2/E4 heterozygosity and thus potentially slowing progression of the disease. No therapies that targeted specifically at treating the population of patients with AD who are homozygous for APOE4 are currently approved by the FDA.
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 AD," Kim G. Johnson, MD, primary investigator of the trial, told NeurologyLive®. "If they do get AD, but with APOE2/4, the disease progresses slower. 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 with NeurologyLive 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 patients homozygous for APOE4 with gene therapy in the AD treatment landscape.
