Gene Therapy for APOE4 Homozygous Alzheimer Disease

Sandi See Tai, MD

Interim safety and efficacy data regarding Lexeo Therapeutics' LX1001, an investigational adeno-associated virus (AAV) vector-based gene therapy, were recently gathered in a phase 1/2, open-label clinical trial (NCT03634007) in patients with APOE4 homozygote Alzheimer disease (AD). The data were presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain.

Shortly before the presentation, CGTLive®'s sister site NeurologyLive® interviewed R. Nolan Townsend, chief executive officer at Lexeo, coauthor Sandi See Tai, MD, chief development officer at Lexeo, and lead author Kim G. Johnson, MD, the division chief of memory disorders at Duke University, to get some more background about the gene therapy and the trial. The 3 experts explained the rationale behind the approach and discussed the early findings.

Can you speak about the presentation from your perspectives?

R. Nolan Townsend: Lexeo is a clinical stage gene therapy company focused in genetic cardiac disease and AD. The program that we'll be discussing in the presentation tomorrow is LX1001, it's the company's most advanced clinical stage program focused on APOE4 homozygous AD, where we're delivering the APOE2 gene to the CNS of APOE4 homozygotes. Taking a step back, we looked at the overall AD treatment landscape and found that there were not sufficient treatment options for E4 homozygotes—in a disease with very complex biology, the thinking from a gene therapy company is to go upstream—treat the genetics of the disease, which we would expect to have a downstream impact on multiple different pathogenic mechanisms simultaneously. This is the study which we've advanced over the last couple of years and this is a data which we'll be reporting at this conference. We think it's exciting that a gene therapy has been introduced to the AD population and we're excited to present the results from the study in the conference.

Sandi See Tai, MD: I can give a brief overview of the study. We included APOE4 homozygotes with mild cognitive impairment and also mild to moderate dementia due to AD. We enrolled 15 patients across 4 dose escalation cohorts. The vector we're using is an AAVrh10, and we administer the APOE2 gene, as Nolan mentioned. We administer that intrathecally, or intracisternal. We followed the patients out through 1 year initially, and then they can move over to long-term follow up study. Across the 15 patients, what we've been able to demonstrate and we were really happy to see is whether you can actually achieve transduction and expression of the protein. We've been able to show APOE2 protein expression in the CSF across all the patients that were dosed. That has translated to seeing some stabilization in terms of amyloid biomarkers, and then also we're particularly encouraged at seeing reductions across multiple tau biomarkers—whether it's t tau, p tau, but also on our tau PET—and so we look at that in combination with the safety profile that we've observed, which is one that has shown LX1001 to be generally well-tolerated. We had some CSF pleocytosis that was observed, but it was transient and not associated with any adverse events. Most importantly, we did not see any events of amyloid related imaging abnormalities, which was to us a key concern, given that we were going specifically into E4 homozygotes. We felt confident in terms of looking at what we're seeing so far in terms of a benefit risk profile here.

Kim G. Johnson, MD: I'll speak a little bit about the participant experience, since that's the population that I have the most interaction with as one of the primary investigators. I would say that APOE4/APOE4s have no good treatment options right now and this trial is a potential treatment option for this population that they're very hopeful about. I found that working with participants, participants not only wanted to do this trial for themselves and see how the disease affects them, but also for their children and their grandchildren, because they know that there's a genetic variant to the disease. They also know that recent research shows that all E4/4s will develop amyloid pathology by about 65 years of age, and if they end up developing cognitive symptoms, they often have the fastest progression in the disease. I think that for an E4/4, knowing that can be a little hopeless.

We do know also with research that people with APOE2 have less rates of AD. If they do get AD (for example, if they are an APOE2/4) the disease progresses slower. So I think introducing an APOE2 as a protective factor gives participants who are E4/4s hope. That was really important and one of the things that I took away from the trial working with people: that this treatment could offer people hope. I think, as Sandy was saying, it's really important that we did a trial in only 15 people to just see if it was safe. That was the primary reason to do the trial, and we found out that it was basically safe. Out of the 15 people it was well-tolerated in the patient population, with 3 serious adverse events and 1 serious adverse event that involved some mild to moderate hearing loss. So it was pretty well-tolerated in the patient population and as Sandy mentioned, also affected key biomarkers of tau.

This transcript has been edited for clarity.

REFERENCES
1. Johnson K, et al. 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. Presented at: 2024 CTAD; October 29-November 1; Madrid, Spain. Abstract 486.
2. 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. News Release. Lexeo Therapeutics. Published October 30, 2024. Accessed October 20, 2024.