From new data released at AAIC 2023, here's what's different about Alzheon’s experimental Alzheimer's pill, ALZ-801.
Drugmaker Alzheon is currently running clinical trials on a new disease-modifying Alzheimer’s treatment: valiltramiprosate, or ALZ-801. While, like the new buzzy new Alzheimer’s monoclonal antibodies Leqembi and Aduhelm, it’s also designed to target amyloid proteins in the brain, it’s a little bit different — in some very important ways. And the drugmakers predict it may be just two years before it becomes widely available to people living with Alzheimer’s disease.
It’s delivery method way more user-friendly than anything else like it
A new class of Alzheimer’s drugs has entered the scene in the past two years. They’re “disease-modifying” drugs meaning that, unlike every other Alzheimer’s treatment that preceded them, they don’t just put a band-aid on symptoms — they actually treat the root pathology of the disease itself. One of the drawbacks of the first two of these drugs to achieve some degree of FDA approval, however, is that they’re administered by infusion. That means a patient must travel to a special healthcare facility to get their dose of the drug monthly, and that can pose a serious barrier to access.
The new Alzheon drug, on the other hand, comes in the form of a pill. If the drug proves out, in its further journey through clinical trials and the FDA evaluation process, patients may one day be able to pick their prescription up at the pharmacy counter like any other pill — it would be just that easy.
It takes a slightly different approach to treating Alzheimer’s disease
Another key difference between ALZ-801 and the newly FDA-approved disease-modifying Alzheimer’s drugs to date — Leqembi and Aduhelm — is that Alzheon’s drug isn’t designed to attack the problematic beta-amyloid protein plaques that build up in the the brains of people with Alzheimer’s. Rather, it comes at the problem from a different direction, prevents good forms of beta-amyloid from turning into toxic plaques.
(In February 2024, Biogen took Aduhelm off the market indefinitely.)
It may be a safer bet for carriers of the “Alzheimer’s gene”
Creating buzz at the Alzheimer’s Association International Conference 2023, the drugmakers shared that, based on early trial data from two ongoing clinical trials, the Alzheimer’s pill may be safe and effective for a very specific audience: carriers of the “Alzheimer’s gene,” ApoE4 — though more data is needed.
As of summer 2023, Leqembi is the first fully FDA-approved and Medicare-covered drug designed to slow the progression of Alzheimer’s. After the drug is infused intravenously, it sticks to and clears out beta-amyloid protein plaques in the brain.
But, one in five patients using Leqembi tend to experience the side effect of brain swelling (ARIA-E) or brain bleeds (ARIA-H). Often, these side effects are so mild, they may never even be noticed. But increasingly, the clinical community is on watch for these side effects and they’ve learned too that they are more common in people who carry a certain gene variant called ApoE4 — known as the “Alzheimer’s gene” because it’s associated with a higher risk of developing the disease.
These ARIA side effects are also common for Leqembi’s predecessor, Aduhelm — also an anti-amyloid infusion. But they do not appear to be as common in people who carry Apoe4 in the Alzheon clinical trial. Data from the clinical trials so far shows the drug appears safe for people who carry one or both copies of the ApoE gene variant ApoE4, and that the pill may slow the rate of cell death and cognitive decline in the early stages of the disease.
What else do we know about the Alzheimer’s pill so far?
The first of the two clinical trials discussed at AAIC tracked 84 patients with mild cognitive impairment or early-stage Alzheimer’s taking ALZ-801 over the course of two years. The company presented data gathered from 75 of the patients who had been taking the drug for a year. The researchers found that the drug lowered the levels of amyloid and tau proteins in the blood.
The patients in the study also underwent brain imaging which showed less cell death and shrinkage of the hippocampus — the part of the brain important for memory. On tests assessing their cognitive abilities, the patients staved off symptoms like forgetfulness, trouble with problem solving, and other issues related to attention and concentration. Importantly, there were no serious side effects or cases of ARIA so far in the trial.
“Phase 2 study results provide compelling support for the disease modifying effect of ALZ-801 tablet,” Dr. John Hey, the chief scientific officer said. He added that the results “highlight the potential for efficacy of ALZ-801 in ApoE4 carriers, who represent two thirds of Alzheimer’s patients.” The results from the full two-year trial are expected by the end of the year. Note that this study does not compare patients to a placebo group.
The second trial is a Phase 3 trial of the drug called APOLLOE4 which aims to treat people carrying two copies of the APOE4 gene with ALZ-801.
The company presented brain imaging data from patients before they even took ALZ-801 or a placebo. Early Alzheimer’s patients who carried two copies of the APOE4 gene were very likely to have a condition called cerebral amyloid-angiopathy (CAA). This occurs when beta amyloid plaques start lining the blood vessels and increases the risk of brain bleeds and brain swelling. In fact, one in three patients enrolled in this study showed evidence of at least one brain bleed.
This also puts them at high risk if they take drugs like Leqembi which target beta-amyloid plaques themselves. Binding to and removing the plaques that line these blood vessels can damage them (think of waxing off hair with duct tape).
“High prevalence of CAA-related lesions in APOE4/4 Alzheimer’s patients is consistent with the emerging safety risks of plaque-clearing antibodies in large pivotal AD trials, showing how helpful oral ALZ-801 treatment could be even just from the safety standpoint in APOE4 patients, who represent 65-70% of Alzheimer’s population,” said Dr. Susan Abushakra, chief medical officer of Alzheon.
What’s next for the Alzheimer’s pill?
“ALZ-801 is potentially two years from a U.S. commercial launch as 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 founder and CEO Martin Tolar said in a press release.
The company aims to finish the rest of their small two-year biomarker study by the end of 2023 Tolar said. Their larger study — APOLLOE4 — which includes 300 participants will run for the next two years.
Patients with two copies of the ApoE4 gene who have developed mild cognitive impairment or early-stage Alzheimer’s will take either two tablets of ALZ-801 or placebo everyday. The trial is set to finish by June 2024.
UPDATED: 3 March 2024, 8:44 P.M. ET. In February 2024, Biogen took Aduhelm off the market, citing financial concerns. Although the drug did receive accelerated, conditional FDA approval for the treatment of early Alzheimer’s disease in 2021, it is no longer available to new patients. The company announced it would sunset trials in May 2024 and cease supplying the drug to current patients in November 2024.
