Dosing Starts in Phase 3 Trial of ALZ-801 in Patients With APOE Variant

A first patient has been dosed in APOLLOE4, a Phase 3 trial testing the efficacy and safety of ALZ-801, an investigational oral treatment by Alzheon for people carrying a specific genetic variant linked to early onset, rapidly progressive Alzheimer’s disease.

ALZ-801 is a small molecule designed to prevent the formation and clustering of harmful proteins that play a role in the development of Alzheimer’s. It does this by releasing tramiprosate, a compound that protects nerve cells by blocking the formation of soluble amyloid oligomers — or small protein fragments — that damage those cells and are associated with the onset of Alzheimer’s cognitive symptoms and progression.

“Because ALZ-801 is an oral treatment that has been shown to fully block formation of neurotoxic amyloid oligomers, it could be used as a monotherapy or as a long-term maintenance treatment in combination with, or following, a treatment with monoclonal antibodies, which remove amyloid plaques from the brain,” Anton Porsteinsson, MD, director of the Alzheimer’s Disease Care, Research and Education Program at the University of Rochester School of Medicine and Dentistry, said in a press release. Porsteinsson is also  a member of Alzheon’s clinical steering committee.

This investigative treatment is for patients who carry a specific variant in the apolipoprotein E gene (APOE), linked to an earlier age of disease onset and an increased risk of rapid progression. It is thought that people with two copies of that variant, called APOE4 or APOE4/4 — estimated to be about 15% of all Alzheimer’s patients — may benefit most from an anti-amyloid therapy like ALZ-801.

APOLLOE4 (NCT04770220) aims to enroll 300 people, ages 50 to 80, with early Alzheimer’s and carrying two copies of APOE4 across about 85 sites in the U.S., Canada, and Europe. Patients will receive either 265 mg of ALZ-801 or a placebo tablet twice a day for 78 weeks (about one and a half years). More information can be found here; information on non-U.S. sites is not yet available, but may be gained by emailing [email protected].

The study’s primary objective is to measure the effect of ALZ-801 on cognition, using the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog). Potential side effects will also be evaluated.

Other objectives include assessments of function, ability to go about daily activities, and neuropsychiatric symptoms. Blood plasma and imaging biomarkers shown to be sensitive early markers of disease progression and neuroinflammation will also be evaluated.

“We have designed this confirmatory Phase 3 trial in an unprecedented way by applying a precision medicine approach, focusing initially on high-risk patients with the APOE4/4 genotype shown to respond to anti-amyloid agents,” said Martin Tolar, MD, PhD, Alzheon’s founder, president, and CEO.

A successful trial could “open a path to treatment for the remaining Alzheimer’s populations, as well as healthy people at high risk for the disease,” Tolar added.

An ongoing Phase 2 trial of ALZ-801 (NCT04693520) is investigating the effect of treatment on the levels of Alzheimer’s-related biomarkers in people with early stage disease and one or two copies of APOE4. It main goal is to measure changes with treatment on the levels of Alzheimer’s-related biomarkers, including the proteins beta amyloid and p-tau.

“Tramiprosate, the active agent in ALZ-801, showed favorable safety in more than 3,000 patients, with no cases of vasogenic edema [swelling of blood vessels in the brain] … This profile provides an advantage over other late-stage amyloid antibodies, which are associated with increased risks of brain edema and small bleeds and are administered as intravenous infusions,” said Susan Abushakra, MD, Alzheon’s chief medical officer.

The APOLLOE4 study is being supported by a National Institute of Aging grant worth $47 million.

ALZ-801 was given fast track status by the U.S. Food and Drugs Administration (FDA) in 2017 to speed its development, potentially making it available to patients more quickly.