Emerging Alzheimer's disease therapies target amyloid protein

By Carol Nathan | Medically reviewed by Brigid Dwyer, MD

Published January 31, 2023

Key Takeaways

Amyloid-targeting treatments for Alzheimer's disease (AD) are at the forefront of AD research.
There are five amyloid-targeting drugs that are either already FDA-approved or in development.
Physicians should stay apprised of these treatments, as they have the potential to make a significant clinical impact in patients with AD.

Existing Alzheimer's disease treatments may help boost memory performance but are not disease-modifying. Now, a series of Alzheimer's disease (AD) treatments that target the amyloid beta protein in the brain are in development.

These options mainly apply to patients at specific stages of disease with specific clinical profiles, and could potentially become game-changers in AD treatment.

Vast amount of trials

As of December 2022, there were 488 ongoing clinical trials looking at improving quality of life in patients with AD.

In 2020, nearly 5.8 million people in the US had AD, and the number is projected to triple to 14 million in 2060, with a global prevalence of 152.8 million cases in 2050.^[]^[]

Since AD is believed to be the leading cause of dementia, this is a global public health crisis and priority.

Some treatments for AD are targeting the amyloid beta protein in the brain because its abnormal accumulation is believed to be the start of the AD process.^[] The accumulation begins at least 15 to 20 years before clinical symptoms develop, so removing the amyloid plaques is hypothesized to provide a disease–modifying clinical benefit if this accumulation can be slowed or stopped. However, there are safety and efficacy issues associated with each of the treatments that have to be weighed regarding risks and benefits for each patient.

According to Mohammad Kassem, MD, a neurologist practicing in Ohio, amyloid–targeting treatments that are FDA–approved or in development are aducanumab (Aduhelm) from Biogen, AZ-801 (valiltramiprosate) from Alzheon, donanemab from Eli Lilly, gantenerumab from Genentech and Roche, and lecanemab (Leqembi) from Eisai and Biogen.

Aduhelm (aducanumab)

Aducanumab was approved by the FDA in June 2021 under the Accelerated Approval Program, which is utilized for serious conditions with an unmet need.^[] It is indicated for patients with early AD and administered by IV infusion over time.^[]

Although approved, there has been controversy about its data, approval process, cost, and side effects, and there have been numerous articles written that urge patients and HCPs to use caution in prescribing.

ALZ-801 (valiltramiprosate)

According to a December 2022 press release from Alzheon, ALZ-801 (valiltramiprosate) is an investigational oral small molecule that targets neurotoxic amyloid oligomers.^[] As of February 2023, it is in phase 3 development (trial name APOLLOE4) as a potentially disease-modifying treatment for AD.

The phase 3 study is focused on evaluating ALZ-801’s effect on early AD patients with the APOE4/4 genotype. Clinical data indicates a favorable safety profile, with no evidence of vasogenic brain edema, and the drug received Fast Track designation from the FDA in 2017. It is positioned to become one of the first approved disease-modifying AD treatments designed to slow and even prevent cognitive decline in early Alzheimer’s patients.

Donanemab

Another emerging drug targeting amyloid is donanemab, which is also for early-stage AD and given by IV.

Ely Lilly announced promising new late-stage trial results May 3, 2023, showing that donanemab slowed cognitive decline by 35% compared to placebo, while also significantly reducing brain plaque. The study builds on earlier studies, including:

A 2021 phase 2 study found that donanemab resulted in a better composite score at 76 weeks compared to placebo for cognition and the ability to perform activities of daily living, although results for secondary outcomes were mixed.^[]
A phase 3 trial (TRAILBLAZER-ALZ 4) is comparing the effectiveness of donanemab with aducanumab in early AD. Early data from this trial announced in November 2022, showed that 37.9% of donanemab-treated participants experienced brain amyloid clearance compared with 1.6% of Aduhelm-treated patients at 6 months.^[]

While Lilly had been pursuing an accelerated FDA approval for donanemab, the company announced in a January 19, 2023 press release that the FDA had requested additional information.

With its new trial results, Lilly said it now plans to file for traditional US approval by the end of June, and with regulators from other countries shortly thereafter. A company spokesman said a US approval decision could come by year-end or early 2024.^[]

Gantenerumab

“Gantenerumab is also for early-stage AD, and is given by SQ injection, but this drug did not have as robust outcomes as expected and is currently being tweaked by the manufacturer to allow better [central nervous system] penetrance,” Dr. Kassem said.

In addition, the Alzheimer's’s Association issued a statement that it was disappointed in the topline phase 3 data from the GRADUATE study for gantenerumab.^[]

Leqembi (lecanemab)

The FDA approved lecanemab on January 6, 2023, using the Accelerated Approval pathway.^[]

Results thus far are encouraging—research showed that lecanemab reduced markers of amyloid in early AD and resulted in moderately less decline on measures of cognition and function than placebo at 18 months. However, there are a range of adverse effects that need to be considered.^[]

Also, lecanemab is administered via IV infusion for one hour every two weeks, so there is a considerable time commitment to receiving this treatment. The presence of amyloid beta pathology must be confirmed prior to treatment. A brain MRI also needs to be obtained prior to treatment, and must be repeated at defined stages.