A Phase I/II study of Lexeo Therapeutics’ gene therapy to treat patients with Alzheimer’s associated with the APOE4 genetic variant has achieved good interim results according to the company.
If approved, this therapy (currently known as LX1001) would be ground-breaking as the first gene therapy for Alzheimer’s disease in a high-risk population with limited treatment options.
There are many genes that can influence the risk for Alzheimer’s disease, but one of the most well-known is apolipoprotein E (APOE). The most common allele of the gene is APOE3, which is carried by more than half the population. People with two copies of this allele have a neutral or average risk for Alzheimer’s.
However, those with one or more copies of the APOE4 (15–25% of people have one copy) allele are at increased risk and those with one or more copies of APOE2 (5–10% of people have one copy) are at decreased risk of developing the neurodegenerative condition.
Since the approval of Biogen’s and Eisai’s Leqembi (lecanemab) in 2023 and Lilly’s Kisunla (donanemab) earlier this year, treatment options for Alzheimer’s are improving. But people with the APOE4 mutation are not eligible for these antibody treatments due to a very high risk of experiencing amyloid-related imaging abnormalities (ARIA) in this patient group.
“APOE4 homozygotes are approximately 15 times more likely to develop Alzheimer’s disease than the general population, have faster disease progression, and have an increased risk of ARIA with currently available therapies that can cause serious complications,” said principal study investigator Kim Johnson, MD, division chief, memory disorders at the department of neurology of Duke University School of Medicine, in a press statement.
To try and help people carrying the APOE4 allele, Lexeo has created a gene therapy to deliver the a copy of the protective APOE2 allele into the brain and nervous system of Alzheimer’s patients with two copies of the APOE4 allele.
The idea is that the APOE2 protein will help slow or even stop disease progression in these patients. Overall, 15 patients with mild to moderate symptoms were treated with LX1001 in four dose-ascending cohorts.
The interim results show only one possible mild-moderate treatment associated adverse event of mild-moderate sensorineural hearing loss at 12 months. APOE2 was found in cerebrospinal fluid in all patients and amyloid pathology stabilized in most participants. Reductions in tau protein were also seen in most patients.
“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,” said Sandi See Tai, chief development officer of Lexeo Therapeutics.
“These data are highly encouraging and provide clinical evidence of the unique and targeted mechanism of LX1001 to potentially treat Alzheimer’s disease.”
The company is also developing a similar gene therapy (LX1021) containing APOE2 with an additional mutation thought to be protective against the disease and a more complex gene therapy (LX1020) to provide protective APOE2 while simultaneously suppressing APOE4, but both these programs are at very early stages.
