NeuroVoices: Susan Abushakra, MD, on the Potential Role of ALZ-801 Within the Alzheimer Treatment Landscape

Susan Abushakra, MD

With the approval of aducanumab (Aduhelm; Biogen) in June 2021, and the regulatory decision of lecanemab (Eisai; Biogen) coming next spring, there has been substantial movement within the Alzheimer disease (AD) space for anti-amyloid therapies. Another investigational agent, ALZ-801 (Alzheon), has shown potential to be the first oral disease-modifying treatment for AD. A prodrug of homotaurine, a modified amino acid, ALZ-801 is currently being assessed in a phase 2, open-label biomarker study (NCT04693520), and a phase 3 trial, dubbed APOLLOE4 (NCT04770220), which began in May 2021.

One-year interim data from the biomarker study was presented at the recently concluded 2022 Clinical Trials on Alzheimer Disease (CTAD) conference, November 29 to December 2, in San Francisco, California, by lead investigator Susan Abushakra, MD. The study was unique in that it featured patients with early AD who have either apolipoprotein (APOE) e4/4 or APOE e3/4 genotype and prior positive amyloid-PET. Participants received 265 mg of the agent twice daily for 2 years, with primary outcomes being change from baseline in cerebrospinal fluid (CSF) phospho tau (p-tau)181 and adverse events.

At the 52-week mark, investigators observed a statistically significant reduction of 41% in p-tau181 from treatment with ALZ-801 (P = .016). Additionally, ALZ-801-treated patients saw significant elevation in plasma amyloid-ß (Aß)42 and plasma Aß40 at weeks 13 and 26, followed by significant reduction at 52 weeks. In comparison with individuals from the Alzheimer Disease Neuroimaging Initiative, the agent reduced bilateral hippocampal brain volume by 25% at the 1-year treatment period.

Abushakra, chief medical officer of Alzheon, sat down with NeurologyLive® at CTAD 2022 to discuss the phase 2 findings, and the topline data being presented. In the first half of the interview, as part of a new iteration of NeuroVoices, Abushakra discussed the significance of the positive data in high-risk individuals, the safety profile of the therapy, including its amyloid-related imaging abnormality (ARIA) risk, and the future plans going forward.

NeurologyLive®: How significant is it that the agent showed positive results in high-risk individuals?

Susan Abushakra, MD: Our idea was if we find good results in the phase 2 study, then it would give us a very solid rationale to expand our studies from just homozygous—about 15% of all patients with AD—to carriers, meaning homo- and heterozygous, then you'll cover 65% to 70% of all AD. It's the majority of the population. And of course, that's good because they also require good treatment. The APOE carriers are the population that's at somewhat increased risk of vasogenic edema, or the complications with amyloid immunotherapy with antibodies. It was important to expand the population. The way we interpret the data is that everything is consistent to the previous data with the old formulation, which is important to show the reproducibility.

All the outcomes we saw fit together very well with our basic mechanism of action, which is the following: you're able to inhibit the formation of the soluble amyloid oligomers, which are the most toxic species. By that, we're able to reduce p-tau, early, significantly, and robust, because it's not enough to just have any p-tau reduction. Even if it's significant at 10%, it may not be meaningful, [whereas] we have multiples of that. 41% is a large effect, it start early, and it's consistent over a year. That's an important point because patients with AD can decline quite a bit. We think of it as a race between our drug effect and the natural history of the disease. If you wait a year or a year and a half to achieve efficacious concentrations, like with some of the antibodies, this disease is already progressing, and it may be harder to show benefit.

In contrast, we have probable efficacy on the biomarkers as early as 3 months. And indeed, at the 6-month and 12-month endpoint, we actually show significant benefits on cognition in this study, which replicates the old placebo control data. We’re able to show robust effects on these biomarkers, and we’re able to change brain volume. That's really changing brain structure, which is what we call disease modification. You're able to change the core pathologies of the disease amyloid and phospho tau, and able to show preservation of hippocampal volume and cognitive benefit.

What does the safety profile of the agent look like?

In Alzheimer disease trials, we usually select the least at-risk patients because you want to be able to understand the efficacy of the drug without confounding variables. They tend to be a selected population. Of course, if a drug is approved, and you start treating a wider range of patients, the risks might increase or they may be different because people are on multiple medications like anticoagulants, or they might have other cerebrovascular disease. Having a clean safety profile in the pivotal trials is really important. As a drug goes into the market, you start treating a wider population. We will do post marketing trials.

The old formulation of the drug actually had included about 2000 patients with AD and we had a very favorable safety profile. Nausea was the most common adverse event, which we knew how to manage. Otherwise, we had not seen any effects on any ARIA (amyloid-related imaging abnormalities) side effects in about 400 with patients who had MRIs in the old study with the old formulation. Now, with the new formulation, we do more frequent MRI monitoring, because our drug targets amyloid. The good news is, between our phase 2 study and our ongoing phase 3 study, we already have more than 450 patients exposed to drug. In the open label study, we understand the safety every week, we review it, and we have not had a single case of ARIA-E. Of the 84 patients, 75 have completed imaging at 1 year, and most of them are now on a year and a half of treatment.

The safety profile remains very consistent with all the prior data. The most common adverse events are nausea. The rate of vomiting has decreased quite a bit compared to the old formulation because it's absorbed better and has better tolerability in the gastrointestinal tract. We have a quite favorable safety profile. Of course, we continue to monitor all these very carefully. Our phase 3 trial has an independent data safety monitoring board that oversees the study quite carefully. We haven't had to make any changes. By the end of our phase 3, we would have more than 200-250 patients treated with the drug for at least a year and a half because we're also going to do extension studies. And it looks like the ARIA rates so far look minimal to none.

What is next for the drug? Where do we go from here?

Our phase 3 trial will probably report out in about a year and a half. In parallel, we're very confident now with the phase 2 data in hand to expand to a carrier population that includes both homozygotes and heterozygotes. Similar study design, it's been quite standard and successful with lecanemab, and some other aducanumab (Aduhelm; Biogen) trials. We have clinical endpoints, a lot of functional endpoints. It’s very important to know the value of the treatment, including on imaging. We want to look at hippocampal volume and many of the fluid biomarkers. In addition to what we have in hand now, clearly you see at this meeting [CTAD 2022], there are so many biomarkers that tell us more about early stages of the disease. What is the most predictive of the earliest effects? There is a lot more specificity. We have a lot of plasma biomarkers that we can test going forward, and we'll include them in all our future trials. The short answer is, we're looking forward to starting a phase 3 trial in APOE e4 carriers so we can cover the whole population of carriers. In the future, it would be nice to even enroll non carriers, as long as we select them with the right levels of amyloid and tau pathology. Alzheimer disease, by definition, have to have amyloid and tau pathology, and so if they are enriched in amyloid and tau, they should respond to ALZ-801 as well.

Transcript edited for clarity. Click here for more iterations of NeuroVoices.

REFERENCE
1. Abushakra S, Hey J, Bennow K, et al. Significant effects of oral ALZ-801 on plasma biomarkers of Alzheimer’s disease: 12-month interim analysis of phase 2 biomarker study in APOE4 carriers with early AD. Presented at: 2022 CTAD Conference; November 29-December 2; San Francisco, CA. Abstract OC27