ALZ-801 trial results announced: A breakthrough in Alzheimer's treatment?

By Naveed Saleh, MD, MS | Medically reviewed by Amanda Zeglis, DO, MBA
Published September 20, 2022

Key Takeaways

  • ALZ-801 phase 2 results in patients with the APOE4/4 or APOE3/4 genotype indicate that the drug not only treats but may also prevent Alzheimer's disease (AD).

  • This oral agent has multipronged efficacy: According to trial results, it decreases p-tau181 levels, reduces brain atrophy, and improves cognitive skills. It has a good safety profile, with no vasogenic edema demonstrated.

  • A phase 3 trial is underway to further investigate its potential benefits, and will examine ALZ-801 outcomes in early AD patients with the APOE4/4.

The age of precision medicine in treatment of Alzheimer's disease (AD) is one step closer to reality.

On September 20, 2022, Alzheon Inc. announced promising results from its phase 2 trial of oral ALZ-801 (valiltramiprosate) in patients with early AD.

Backed by a $47 million grant from the National Institute on Aging, Alzheon’s drug candidate is poised to become one of the first disease-modifying treatments to mitigate—or even possibly prevent—cognitive decline in patients with AD, according to Alzheon.[]


Patients with AD who harbor one or two copies of the ε4 allele of apolipoprotein E gene (ie, APOE3/4 heterozygotes and APOE4/4 homozygotes, respectively) constitute two-thirds of people with AD. After aging, APOE4 genotype is the main risk factor for developing AD, and is linked to a much greater accumulation of neurotoxic amyloid oligomers in the brain.

Phosphorylated tau (p-tau) levels are a sensitive, specific biomarker of neuronal stress and brain injury in patients with AD.

Neurons form this biomarker after exposure to toxic beta amyloid oligomers, the principal culprits in the pathology and neurodegeneration in AD.

Both p-tau181 and Ab42 are key biomarkers in core AD, and phase 2 trial results indicate a disease-modifying effect of ALZ-801 in patients with AD.

Phase 2 trial results

Alzheon reported promising results on plasma biomarker reduction, preservation of brain volume, and positive memory effects in Alzheimer's patients after 12 months of treatment with the investigational drug.

In the trial, 84 patients with early AD harboring the APOE4/4 or APOE3/4 genotype were given oral ALZ-801 (265 mg) twice a day.

A total 75 patients took the drug through week 52 and were included in the analysis. Participants taking ALZ-801 exhibited a 41% decrease in plasma p-tau181 concentrations (P = 0.016) and a 37% decrease in the plasma p-tau181/Ab42 ratio (P = 0.032).

Serum p-tau181 concentrations heighten with the progression of AD, as does clinical deterioration. In contrast, levels fall secondary to effective treatment with disease-modifying AD drugs.

Reduction in p-tau181 levels were demonstrated at 13, 26, and 52 weeks alongside identifying preservation of hippocampal volume and improved memory tests. ALZ-801 yielded a 40% brain penetration versus a 1% brain penetration with plaque-clearing antibodies.

ALZ-801 resulted in a manifold decrease in levels of p-tau181 biomarker in plasma versus plaque-clearing anti-amyloid antibodies. The significant decrease of p-tau181 due to ALZ-801 therapy reflects precise targeting and activity against AD.

In addition to decreasing levels of p-tau181, ALZ-801 preserved hippocampal volume and had an advantageous safety profile sans vasogenic edema. ALZ-801 is the first (and to date, only) agent to demonstrate a decrease in brain atrophy.

Furthermore, like anti-amyloid antibodies, ALZ-801 exerts an effect upstream on the pathway preventing the generation of neurotoxic soluble amyloid oligomers. ALZ-801, however, does not interfere with the deposition of insoluble plaques in the brain and small vessels.

Partner Content Provided by Alzheon Inc.

A New Hope for Patients with Alzheimer’s Disease: Video takes a look at a Phase 3 biotech’s novel approach. Learn more here.

ALZ-801 potential

“Importantly, rather than slowing the cognitive decline of patients as seen in trials with other agents, subjects treated with ALZ-801 demonstrated cognitive gain from baseline status on memory tests and maintained their cognitive skills over 1 year,” said Alzheon founder and CEO Martin Tolar, MD, PhD.

"These well-differentiated results position ALZ-801 to potentially become the first oral agent that can slow or even stop and prevent Alzheimer’s pathology in patients and healthy individuals at risk for the disease."

Alzheon CEO Martin Tolar, MD, PhD

Results of the current trial are supported by other findings made by Alzheon investigators during the past 9 years.

“The significant effect on plasma p-tau181, combined with hippocampus volume preservation and clinical stabilization after 12 months of treatment, support the anti-amyloid oligomer action of ALZ-801 in brains of patients with Alzheimer’s disease,” said Alzheon Chief Medical Officer Susan Abushakra, MD.

"Consistency across these three outcomes, including structural effects, is very encouraging and supports the disease-modifying profile of ALZ-801 in Alzheimer’s patients."

Alzheon CMO Susan Abushakra, MD

Looking forward

In addition to the ongoing phase 2 trial, a phase 3 trial is underway. It is examining ALZ-801 outcomes in early patients with AD with the APOE4/4, who represent 15% of this patient population. Expansion of the cohort to include treatment/prevention in individuals harboring only one copy of the APOE4 gene, as well as noncarriers, is anticipated.

Outcomes of the phase 3 trial will be safety, efficacy, biomarker effects, and imaging results in patients taking 265 mg by mouth twice a day for more than 78 weeks. This double-blind, randomized trial will include a control group taking placebo.

What this means for you

Results from ongoing phase 2 trials of ALZ-801 may portend a safe, effective, and preventive treatment of Alzheimer's disease. This drug works on three fronts: clinical features (ie, memory); hippocampal volume preservation; and p-tau181 reduction. In addition to homozygous and heterozygous carriers, this drug will be tested in patients without the APOE4 gene. Clinicians should stay apprised of ongoing developments from these trials.

Read Next: The latest advances in Alzheimer's research
Share with emailShare to FacebookShare to LinkedInShare to Twitter