The next wave of amyloid-targeting projects approaches

Acumen is the latest player to take aim at amyloid, but competition is fierce.

Monday’s approval of Biogen’s Alzheimer’s drug Aduhelm raised the possibility that old amyloid-targeting agents might be resurrected. But there are plenty of young companies also trying to get into this space – and one, Acumen Pharmaceuticals, disclosed plans for a $100m flotation yesterday.

Acumen’s supposed unique selling point is that its lead project, ACU193, targets amyloid-beta oligomers, rather than monomers or plaques, something the company believes could lead to improved efficacy and safety over other candidates. But a look at the pipeline shows that there are several more advanced projects that also hit oligomers.

ARIA avoiding?

As the clearance of plaques is associated with brain oedema, Acumen hopes that ACU193 can avoid the side effect of Aria-E that has hit other anti-amyloid antibodies. This will be put to the test in the group’s phase I study, which began this quarter, with data due by the fourth quarter of 2022.

Still, a greater affinity for oligomers over plaques did not allow Biogen/Eisai’s lecanemab, previously known as BAN2401, to avoid this issue. The groups pushed lecanemab into phase 3 despite disappointing mid-stage results, with the best responders at the highest dose being at greatest risk of brain swelling.

Lecanemab does have some impact on plaques, however, while Acumen claims that ACU193, which was originally developed in collaboration with Merck & Co, has “limited or no binding”.

In this respect ACU193 is similar to Alzheon’s ALZ-801, a small molecule designed to inhibit oligomer formation by enveloping amyloid-beta monomers and preventing their aggregation. Alzheon's asset, which does not hit plaques, recently started its phase 3 trial in early Alzheimer’s patients with two copies of the ε4 allele of the apolipoprotein E gene.

Selected amyloid-targeting projects in development for Alzheimer's
Project Company Description Disease setting Note, clinical trial
Phase III
Gantenerumab Roche Anti-amyloid-beta antibody, preferentially targets plaques Prodromal/mild Graduate 1, ends Sep 2022
Graduate 2, ends May 2022
BAN2401 (lecanemab) Biogen/Eisai Anti-amyloid-beta antibody, preferentially targets oligomers Early Clarity AD, ends Jun 2022
Solanezumab Lilly Anti-amyloid-beta antibody, targets monomers At-risk asymptomatic A4, ends Dec 2022
Donanemab (LY3002813) Lilly Anti-amyloid-beta antibody, targets plaques Early symptomatic Trailblazer-Alz 2, ends Feb 2023
ALZ-801 Alzheon Small molecule targeting amyloid-beta oligomers Early disease with APOE4/4 genotype ApolloE4, ends Apr 2024
Phase II
ACI-24 AC Immune Vaccine targeting amyloid-beta Mild EudraCT: 2018-000445-39, 18mth interim recently reported
Elayta (CT1812) Cognition Therapeutics Sigma-2 inhibitor, targets amyloid-beta oligomers Mild to moderate NCT04735536, ends Jul 2021
ABvac40 Araclon/Grifols Vaccine targeting amyloid-beta40 Mild NCT03461276, ends Dec 2021
Crenezumab Roche/AC Immune Anti-amyloid-beta antibody, targets various forms of amyloid, inc oligomers Preclinical PSEN1 E280A mutation carriers NCT01998841, ends Feb 2022
("brain shuttle" gantenerumab)
Roche Brain-penetrating antibody fragment, targets amyloid plaques Prodromal or mild to moderate Ph1/2, NCT04639050, ends Oct 2024
Phase I
(N3pG-Aβ mAb)
Lilly Anti-amyloid-beta antibody Mild NCT04451408, ends Apr 2022
ACU193 Acumen Pharmaceuticals Anti-amyloid-beta antibody, targets oligomers Mild Ph1 began Q2'21, data due Q4'22
Source: Evaluate Pharma, company releases,

Cognition Therapeutics also has a small molecule in phase 2, Elayta, targeting oligomers in a different way. The asset binds to sigma-2, a receptor on neurons that regulates the cellular damage response; the theory is that Elayta displaces amyloid-beta oligomers from these receptors and allows the cell’s damage response to return to normal.

Other oliogomer-targeting projects are at the preclinical stage, and Acumen lists the likes of Alzinova, Promis Neurosciences, Kalgene Pharmaceuticals and Wren Therapeutics among its potential rivals. The last two groups are privately held – maybe a resurgence of interest in amyloid-beta could prompt them to follow Acumen onto the public markets.

Perhaps the most remarkable thing about the table above is that so many companies have kept faith with amyloid-targeting agents despite repeated failures in the space. Following Aduhelm’s approval, more are sure to join the fray.

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