NeuroVoices: John Hey, PhD, on ALZ-801’s Impact on Alzheimer Biomarkers, P-Tau181

John Hey, PhD

In recent years, there has been an explosion in therapeutics for Alzheimer disease (AD), led by 2 major approvals of antiamyloid agents designed to clear amyloid plaques in the brain. ALZ-801, developed by Alzheon, is an orally administered prodrug of tramiprosate that is designed to inhibit amyloid oligomer formation, a key driver of AD. Developed to improve gastrointestinal tolerability through absorption in the gut, ALZ-801 could be among the first disease-modifying therapies for AD.

In September 2020, the company began a phase 2, open-label biomarker study (NCT04693520) enrolling 84 individuals with early-stage AD dementia and 1 or 2 copies of apolipoprotein e4, the most common genetically at-risk group for this disease. Participants received 265 mg of the therapy twice daily for 2 years, with primary outcomes being change from baseline in cerebrospinal fluid phosphorylated tau (p-tau)181 and adverse events (AEs). After presenting preliminary data at the 2022 Clinical Trials on Alzheimer’s Disease (CTAD) conference, the company followed up with interim data from the study at the 2023 American Academy of Neurology (AAN) Annual Meeting, held April 22-27, in Boston, Massachusetts.

Presented by John Hey, PhD, 12-month findings showed that plasma p-tau181, a marker of amyloid-induced neuronal injury in AD, was reduced by 41% by week 52 (P = .016), with reductions seen as early as 13 weeks. Furthermore, these reductions correlated with significant reduction in plasma amyloid-ß42 and Aß40 at the same time point (–5%; P = .002 and P = .005). As part of a new iteration of NeuroVoices, Hey, chief scientific officer of Alzheon, sat down at the meeting to discuss the findings, along with the significance of reductions in p-tau181 and other potential AD-related biomarkers.

Can you provide some background on the 1-year data presented for ALZ-801?

We presented the 1-year results from our 2-year open label, single arm, biomarker study, We had a primary focus on fluid biomarkers, specifically, the primary endpoint of plasma p-tau181, as well as primary imaging biomarkers at the 1-year time point. We also did comparisons with regards to the some of the key data to an external match control group, the ADNI database, matched to our trial. With that analysis, we showed improvements in hippocampal volume and lateral ventricle enlargement relative to patients of the same matched stage of the disease and with regards to the 1-year time point decline of hippocampal atrophy.

Data at 1 year also showed a very substantial and sustained reduction in plasma p-tau181 with about a 41% reduction. This was substantial and robust. For those that follow the therapeutic very closely, the annualized rate antiamyloid antibodies produced anywhere between 20-25% and maxed out at 78 weeks. We have a very robust effect. We're excited where we are at for the 1-year time point and we're moving to complete the trial by the middle of this year.

What is the significance of effect on p-tau181? How does this biomarker differ from other Alzheimer-related biomarkers?

We’re looking at other biomarkers, some of those we’ll be delving into at the end of the study. But as a prime biomarker, we focused on p-tau181, a biomarker that is proximal to neuronal injury in the brain. We are positing a working hypothesis in which the damage in the brain that comes from the toxic oligomers leads to neuronal injury, the neurons release p-tau181 that is clear from the brain when they're injured, and we can measure it in the plasma. That’s why that's significant.

We believe that this is a surrogate for target engagement, and a benefit to the patient relative to the progression of the disease. It's important to note that p-tau181 or the other phosphorylated taus do not occur naturally in the in the peripheral circulation. Any increase in plasma, p-tau181, 217, or the others is a result of what's happening centrally. For that reason, it's a very promising biomarker for target engagement, disease progression and seeing how the patients are responding to your therapy.

Besides ALZ-801, what excites you in the Alzheimer space?

There are exciting developments with regards to fluid biomarkers. We looked at [p-tau]181, but there are others that are coming down the pike, including p-tau217, which may be a little bit more sensitive. Maybe they start showing movement earlier in the disease, and possibly tapping into those for prevention trials as markers of disease progression early on so we can make these trials more efficient, improve our ability to sort of hit the potential efficacy in those populations.

The other thing that's very exciting is the potential for drugs, like ALZ-801, that appear to decrease ventricular atrophy, hippocampal, and volume atrophy. The markers of those we're going to start looking at correlation to clinical outcomes. Those also afford opportunities to evaluate as potential endpoints in these diseases, because they are some of the hallmarks of the disease.

Using these biomarkers as surrogate for clinical efficacy we believe has important benefits ultimately to patients, but in the near term, how we conduct trials and get better precision therapeutics to patients that need it. We'll be actively looking at some [of these biomarkers], maybe secondary inflammatory markers that give us insights on where the methodology is going and some heterogeneity in the population. We believe that to tackle the disease from a disease modification standpoint, you want to hit the origins of the disease. But with regards to some of these other pathways, it’s important to understand the phenotypic impact on the patient.

Transcript edited for clarity. Click here for more coverage of AAN 2023.

REFERENCE
1. Hey J, Abushakra S, Blennow K, et al. Effects of ALZ-801, an oral amyloid oligomer inhibitor, on biomarkers of Alzheimer’s disease (AD): 12-month results of phase 2 biomarker study in early AD. Presented at: 2023 AAN Annual Meeting; April 22-27; Boston, MA. Abstract 003243