CTAD 2022 – Lexeo takes baby steps towards Alzheimer’s gene therapy

In targeting a genetic cause of the disease, Lexeo reckons it could outdo anti-amyloid antibodies, but has a long way to go.

While Eisai’s lecanemab stole the headlines at this year’s CTAD meeting there were also early data on an intriguing gene therapy being developed by the private group Lexeo.

The company is not targeting amyloid, as such, but rather a genetic risk factor for the disease, namely ApoE4. Lexeo only presented safety and biomarker results from a handful of patients, so it is impossible to gauge its chances; even if the group prevails, eventual uptake of its therapy would depend on the availability of ApoE4 testing.

Still, given that this is the first Alzheimer’s gene therapy to reach the clinic, its progress will no doubt be watched with interest.

And ApoE4 testing is something that Lexeo’s chief executive, Nolan Townsend, believes will become more widespread if and when more anti-amyloid antibodies make it to market. ApoE4 carriers have been shown to have a higher risk than non-carriers of the troubling Aria-E side effect, with the highest incidence seen in those with two copies of this allele. It has also been hypothesised that ApoE4 carriers might derive more benefit from anti-amyloid antibodies than non-carriers, but the recent lecanemab data did not support this.

Mr Townsend notes that ApoE4 testing is already available, for example from the genomics company 23andme, and says: “Our expectation is that understanding a patient’s genetic profile will be part of treating them with an antibody.”

But he adds: “If we don't see that developing, we'll have to create our own plans.”

ApoE2 for ApoE4

There are three major alleles of the ApoE gene: ApoE2, ApoE3 and ApoE4. ApoE3 is the most common; relative to this genotype, the rare ApoE2 allele is associated with a decreased risk, while ApoE4 is linked with an increased risk of Alzheimer’s. The ApoE4 allele is seen in around 14% of the general population, and in roughly 40% of Alzheimer’s patients.

However, “if you're an E2/E4 heterozygote, the existence of E2 removes most of the E4 risk”, Mr Townsend notes.

Lexeo’s contender, LX1001, does not hit ApoE4 directly, but instead is designed to increase levels of the ApoE2 protein, essentially to cancel out the deleterious effects of ApoE4. 

The chief exec concedes that the exact mechanism by which ApoE4 increases the risk of Alzheimer’s is “hotly debated”, but it is thought to involve cholesterol dysregulation, which in turn could lead to features of Alzheimer’s like amyloid plaques and tau tangles. Mr Townsend believes that, by going upstream and hitting more than just amyloid deposition, LX1001 could be more effective than the anti-amyloid antibodies.

Lexeo is a long way off proving this. Its CTAD presentation on Friday involved five patients in a phase 1 study – all ApoE4 homozygotes – receiving the lowest dose of LX1001, 5x1010gc/ml. Among the three patients with 12 months’ follow-up, there were decreases in cerebrospinal fluid total tau and phosphorylated tau. Two of three patients saw reductions in CSF amyloid-beta 42 levels, while the other had stable levels.

Going higher

The company is dosing higher: it has completed enrolment in a cohort evaluating 1.6x1011gc/ml, and has started enrolling into an arm testing 5x1011gc/ml. Mid-dose data are set for next year, with high-dose results due in 2024.

There will be some clinical outcomes data from this trial, but Mr Townsend stresses: “The study is not powered to show an effect on cognitive decline.”

As for future plans, if all goes well he says the next trial should look “more like a typical phase 2 Alzheimer's study than a typical rare disease gene therapy trial”.

Gene therapies have so far been notoriously pricey, so how does Lexeo square this with targeting a relatively common disease like Alzheimer’s? “We've done a lot of work on the manufacturing side to develop a process that we believe can produce vector at a cost of goods that's similar to biologics,” Mr Townsend replies.

These are questions for the future. First, Lexeo has to prove LX1001's worth in the clinic. 

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