New Alzheimer’s treatment buoyed by US Fast Track Designation

By Rachel Arthur

- Last updated on GMT


Related tags Alzheimer's disease Aducanumab Aduhelm Biogen Clinical trials Dementia

Acumen Pharmaceuticals believes ACU193 – the first clinical-stage monoclonal antibody that selectively targets toxic soluble amyloid beta oligomers (AβO) – offers the promise of an effective treatment with a better safety profile than other Alzheimer's drugs.

The monoclonal antibody has the potential to deliver cognitive improvement as well as disease slowing, according to the company. In addition, the drug promises a low risk of amyloid-related imaging abnormalities (ARIA) – a concern that has plagued other Alzheimer’s Disease (AD) drugs.

The announcement of Fast Track Designation for the treatment of early Alzheimer's from the US Food and Drug Administration (FDA) – alongside recent positive Phase 3 data for Eisai/Biogen’s lecanemab – has buoyed Acumen’s hopes for the Phase 1 drug.

New target: AβOs

In Alzheimer’s patients, three dominant pools of amyloid-beta (Aβ) species have been identified: Aβ monomers, Aβ oligomers (AβOs) and fibrillar Aβ aggregates that deposit into amyloid plaques. The most abundant species, Aβ monomers, as well as Aβ plaques, have been the main focus of Alzheimer’s drug development efforts throughout the past decade.

However, Acumen's ACU193 is a humanized monoclonal antibody that was discovered and developed based on its selectivity for soluble AβOs. And it's these AβOs that appear to be the most toxic and pathogenic form of Aβ (Some types of toxic soluble AβOs have been found to interact within synapses which leads to altered neuronal function, and can initiate and perpetuate the process of neurodegeneration, ultimately leading to cell death).

By selectively targeting toxic soluble AβOs, ACU193 aims to ‘directly address what a growing body of evidence indicates is a primary underlying cause of the neurodegenerative process in AD’.

But aside from its potential in tackling AD, a key point of interest in the drug is that it comes with a low risk of amyloid-related imaging abnormalities (ARIA), because ACU193 blocks the toxic effects of AβOs without directly targeting amyloid plaques.

The risk of ARIA has proved to be a tricky point for other Alzheimer’s treatments: most notably in Biogen's Aduhelm's US launch where it is included as a warning in prescribing information.

ARIA risk

ARIA is an adverse event of amyloid-lowering therapies. This can be amyloid related imaging abnormalities-edema (ARIA-E), which can be observed on MRI as brain edema or sulcal effusions, and amyloid related imaging abnormalities hemosiderin deposition (ARIA-H), which includes microhemorrhage and superficial siderosis.

Biogen's long-term study is assessing cases of ARIA found ​in Phase 3 trials: ensuring 'ARIA is further characterized & the risk well understood​' (in refusing the EU application in 2021, the EMA highlighted 'brain scans of some patients showing abnormalities suggestive of swelling or bleeding, which could potentially cause harm​') 

Eisai & Biogen's lecanemab also recorded a risk of ARIA in Phase 3 trials, although highlighted this was 'within expectations'.

Eli Lilly’s Phase 2 trial for donanemab​ also noted incidents of ARIA-E & AREA-H.  

Eric Siemers, MD, who is the Chief Medical Officer for Charlottesville, VA-headquartered Acumen Pharmaceuticals, says non-clinical studies suggest ACU193 may have ‘significantly lower’ rates of ARIA.

“The monoclonal antibodies that target amyloid plaques, aducanumab and donanemab, have the highest rates of ARIA,” ​he told us.

“This is likely because the majority of people with AD not only have plaques within the brain, but also around blood vessels.

"Binding of these antibodies to plaques surrounding bloods vessels is thought to cause the blood vessels to become “leaky,” leading to ARIA. 

“Not all monoclonal antibodies lead to ARIA, for example solanezumab binds abeta monomers but not plaque, and does not cause ARIA.

"Lecanemab binds to “protofibrils” and may have some binding to plaques around blood vessels; it appears to have an intermediate rate of ARIA. 

“ACU193 appears to have little or no binding to plaques based on animal studies and autopsy studies of humans with AD. For that reason, we are optimistic that little or no ARIA will develop, similar to the situation with solanezumab.” 

Aside from the clear benefit to patients, good news on ARIA would help the drug clear other hurdles, Siemers continued.

“A lack of ARIA would be a clear advantage for a treatment, since the risk of ARIA will likely lead to the need for surveillance MRIs and a need for additional MRIs if symptoms suggestive of ARIA (such as headache) develop. 

“Regulators are generally more likely to approve drugs even with a risk of ARIA, but payor reimbursement is less clear.

"And the development of drugs with less ARIA and greater or equal efficacy will continue to be an investment opportunity for the foreseeable future.” 

'It's an exciting time for AD research'

Biogen’s disappointing experience with Aduhelm​ – and subsequent emphasis on proven clinical benefit​ set out by CMS policies – proves the road to success for Alzheimer’s drugs is not an easy one.

ACU193 is the result of an 8 year research collaboration between Acumen & Merck (Acumen holds exclusive rights). 

In 2017, the National Institute of Aging awarded a $3.6m grant for preclinical & early clinical development.

But Siemers is optimistic that the company – and indeed wider industry – is ready to overcome the obstacles.

“Many challenges will continue to exist for AD trials, but we feel that advances in the field make this an exciting time for AD research. 

"In particular, study designs have evolved substantially in the last 5-10 years, and we intend to incorporate those advances into our clinical development plan. 

“Clinical trial recruitment is always a challenge, but many new strategies, some involving digital technologies, are being developed to aid recruitment.

"Increasing diversity in clinical trial populations for AD is clearly a challenge, but various efforts are underway to address this concern.” 

Phase 1 Intercept-AD trial

Approximately 62 individuals with early AD (mild cognitive impairment or mild dementia due to AD) are expected to be randomized into this double-blind, placebo-controlled, first-in-human study of ACU193.

Intercept-AD is designed to establish safety and proof of mechanism. It consists of single-ascending-dose (SAD) and multiple-ascending-dose (MAD) cohorts and is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and target engagement of intravenous doses of ACU193. The study​ is enrolling at multiple investigative sites in the US.

Acumen expects to disclose top line Intercept-AD results in the first half of 2023. Under the FDA Fast Track program – designated to facilitate the development and expedite review of new drugs – Acumen will benefit from frequent engagement with the FDA to progress the drug through to a Biologics License Application with the FDA and other regulatory agencies - although it has not disclosed a timeline on expected development past Phase 1.

'Combination therapy will ultimately be development for AD'

As a new drug in the field, Siemers sees the potential for it to open up new avenues of development. 

"By targeting oligomers selectively, ACU193 demonstrates that the “amyloid hypothesis” should not be viewed as monolithic.

“Consistent with this concept, lecanemab targets protofibrils, solanezumab targets abeta monomers and aducanumab and donanemab target amyloid plaques. Numerous studies suggest that abeta monomers or amyloid plaque alone are not toxic. Other soluble abeta species do appear to be toxic based on several years of research. These soluble species include protofibrils and the forms of oligomers (Amyloid Derived Diffusible Ligands, ADDLs) that are targeted by ACU193. 

“Since ACU193 and lecanemab both target toxic soluble abeta species, the recent announcement of a statistically significant benefit from lecanemab in a Phase 3 study we believe improves the probability of success for ACU193. Beyond targeting abeta species and amyloid plaques, other targets such as tau and targets unrelated to either abeta/amyloid or tau are being investigated.

"There is a broad consensus that combination therapy with multiple drugs, similar to HIV, will ultimately be developed for AD.”

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