Lexeo shares dip on early data with Alzheimer's gene therapy

Lexeo Therapeutics' gene therapy for Alzheimer's has shown that it can reduce biomarkers of the disease in a small study, including reductions in disease biomarkers.

The data comes from a phase 1/2 trial – presented at the Clinical Trials on Alzheimer's Disease (CTAD) conference in Madrid, Spain – looking at the effect of the LX001 gene therapy in patients with Alzheimer's who have two copies of the APOE4 gene variant.

Studies have suggested that APOE4-associated Alzheimer's is a distinct genetic form of the disease, characterised by early onset and rapid progression, with around 900,000 people homozygous, i.e., carrying two copies of the gene.

The new data comes from 15 patients with mild cognitive impairment (MCI) or mild or moderate dementia who received one of four one-off, intrathecal doses of LX001, an adeno-associated virus (AAV) gene therapy candidate designed to deliver the gene for APOE2.

APOE2 is thought to have a protective effect, as people expressing the gene tend to have a significantly lower risk of Alzheimer's onset, as well as slower disease progression, so it is hoped that converting patients to expression of that isoform will deliver clinical benefits.

LX001 was found to lead to APOE2 expression in all of the subjects for at least a year, with improvements in various tau protein biomarkers associated with cognitive improvements. While Lexeo pointed to "positive" effects for the candidate, investors seemed a bit unimpressed and shares in the company lost around 20% of their value after the data drop.

That could relate to the lack of any effect on amyloid – another biomarker for disease progression – with minimal change from baseline in Aß42/40 ratio and amyloid PET – although, Lexeo said that the gene therapy appeared to "stabilise" levels in a majority of patients.

Doubts have also been voiced about how the relatively modest APOE2 expression shown in the trial could have an impact on patients with a highly progressive form of the disease.

On a more positive note, analysts at Baird called the data "early but interesting," adding that, if the effect on tau can be "clearly and consistently" shown in further testing, they "could see an accelerated approval pathway for this programme, down the road."

"In light of the rapid progression of Alzheimer’s disease in this population, [this] data highlight[s] 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 Dr Sandi See Tai, Lexeo's chief development officer.

The results in Alzheimer's come a few months after Lexeo also reported encouraging data with its gene therapy for Friedreich's ataxia (FA) cardiomyopathy in the phase 1/2 SUNRISE-FA trial, which is considered to be the company's most promising asset.