New Drug Approval Could Be on Horizon for Alzheimer’s after 17-Year Drought

A drug to halt the progression of Alzheimer’s disease will likely be approved within the next three years, and Alzheon’s ALZ-801 might be the leading candidate.

No new Alzheimer’s drugs have been approved in the past 17 years. Now, “After decades of little to no progress, there’s a clear path forward in targeting the toxic amyloid aggregates,” Martin Tolar, M.D., Ph.D., founder, president, and CEO of Alzheon, told BioSpace.

Alzheon’s lead compound, ALZ-801, received Fast Track designation from the U.S. Food and Drug Administration in 2017. It will begin the Phase III APOLLOE4 trial in the second quarter of this year to halt disease progression among early Alzheimer’s disease patients who have two copies of the apolipoprotein E4 gene (APOE4/4).

The ALZ-801 program may be expanded in the future to healthy individuals to prevent Alzheimer’s disease onset, and to early Alzheimer’s patients who carry only one copy of the APOE4 gene.  

APOE4 genotype is the most important risk factor after age and is strongly implicated in Alzheimer’s disease. More than 65% of Alzheimer’s patients carry at least one copy of the APOE4 gene and 15% are APOE4/4 homozygous.

“Patients with the APOE4 gene don’t clear amyloid well – in particular, the most toxic amyloid aggregates called oligomers,” Tolar explained.

In fact, their levels of oligomers in the brain are three times higher than in patients without that gene. They also tend to be diagnosed at a younger age so, relevant to this study, they are less likely to have other illnesses.

ALZ-801 is an oral, amyloid anti-oligomer agent that blocks formation of neurotoxic oligomers in the brain. Its active ingredient, tramiprosate, reduces aggregation of brain amyloid and, thereby, inhibits the formation of amyloid oligomers and their downstream effects, which kill brain cells and destroy their connections.

Tramiprosate alone, however, has variable oral absorption and can lead to nausea as a side effect. ALZ-801 overcomes those limitations with its prodrug formulation, resulting in an oral therapy that is well-absorbed, has excellent brain entry and is well-tolerated.

ALZ-801 also avoids the side effects of anti-amyloid antibodies, in particular, brain edema and microhemorrhages.

Using an enveloping mechanism of action, several ALZ-801 molecules surround and interact with beta amyloid monomers, stabilizing their shape and blocking the formation of neurotoxic oligomers. This inhibits the atrophy of the hippocampus that is associated with disease onset and progression.

“In addition to slowing progression on clinical measures, we can completely stop the loss of this brain tissue, which gives us confidence our treatment will work, especially for those with a very aggressive course of the disease,” Tolar said.

Throughout the biopharma industry, only four anti-amyloid disease-modifying therapies are in Phase III trials. Alzheon’s therapy ALZ-801 is the only highly selective amyloid anti-oligomer agent and the only one that can be administered orally.

The remaining three are antibody-based and are administered by injection or infusion.

“Those programs show you can slow the progression of symptoms,” Tolar said. “With ALZ-801, we believe we can stop and even prevent the disease.”

Comparison of studies with anti-amyloid agents show that, of the Alzheimer’s drugs in Phase III trials, ALZ-801 has the best brain penetration capability – 40% versus 1.5% or less for the antibodies, according to data presented during the recent Neurodegenerative Drug Development Summit.

Clinical trials also indicate that ALZ-801 has no major serious side-effects. Whereas 10% to 35% of patients in competitors’ programs exhibit brain edema and hemorrhage, “None of the patients in the Alzheon program had brain bleeds,” Tolar said. “This gives us the opportunity to treat patients much earlier in the disease, for a long time and without safety monitoring by brain imaging.”

Enrollment in the 300-person APOLLOE4 trial, in collaboration with – and supported by a grant from – the National Institute on Aging, is set to begin soon, with the first dosing anticipated in May.

The final readout from the APOLLOE4 trial is expected the first half of 2024, measuring cognition, as well as functional and global impairments.

All subjects enrolled in Phase III will be tested for Alzheimer’s blood biomarkers and brain volume measures. A substudy will also measure biomarkers of Alzheimer’s disease in the cerebrospinal fluid (CSF), including phosphorylated tau (p-tau), and biomarkers of neurodegeneration and neuroinflammation. Another substudy will measure tau pathology in the brain by positron emission tomography.

The two substudies are expected to confirm p-tau in blood and CSF, and aggregated tau on brain imaging as biomarkers of drug effects. “Phosphorylated tau only appears in Alzheimer’s patients in response to the presence of toxic amyloid aggregates,” Tolar said.

Alzheon is also conducting a Phase II study focused on the CSF and blood biomarkers of Alzheimer’s disease. The interim readout is expected before year’s end and the final data in the first half of 2023.

“ALZ-801 has the potential to be used as a disease-modifying monotherapy or in combination with anti-amyloid antibodies,” Tolar said. “That’s a big breakthrough. There is unprecedented support to bring treatments to patients as early as 2025.”

Eventually, presymptomatic patients may be able to begin treatment for Alzheimer’s disease during middle age, long before symptoms emerge, thereby – perhaps – preventing the disease from disrupting their lives.

Currently, some 35 million patients suffer from Alzheimer’s disease world-wide. Nearly 6 million of them are in the US. By 2050, global numbers are projected to reach 100 million patients, of which nearly 14 million will be in the U.S. That represents potential health care costs of $1.1 trillion.

Now, there is hope.

“We’re standing on the edge of terra incognita, on the cusp of finally having at least one approach that allows us to understand and treat Alzheimer’s disease,” Tolar said. “And that’s incredible.”