3-D Rendering of beta-amyloid peptide, a hallmark pathology in Alzheimer's disease

Scientists with Framingham, Massachusetts-based Alzheon identified a substance in the human brain that inhibits the formation of beta-amyloid (Aβ), the primary driver of Alzheimer’s disease. The substance is 3-sulfopropanoic acid (3-SPA).

The company indicates that tramiprosate and its prodrug ALZ-801 are consistently metabolized in humans to a single major metabolite, 3-SPA. 3-SPA inhibits the formation of beta-amyloid oligomers, comparable to the effects of tramiprosate.

In their research, the company found that levels of 3-SPA were up to 12 times greater in Alzheimer’s patients who received oral tramiprosate than in drug-naïve patients or patients being treated with placebo. The data adds to what is already known about the mechanism of the company’s ALZ-801, which is a Phase III-ready drug candidate.

It also hints at the possibility of a protective endogenous anti-beta-amyloid oligomer pathway, which it’s dubbing an “Aβ oligomer brake pathway” within the human central nervous system. And, potentially, this pathway could prevent or delay the onset of Alzheimer’s disease, or offset or modulate the neurotoxic effects of abnormal beta-amyloid accumulation in the aging human brain. Which sounds like an awful lot of “ifs” and “maybes,” but at least is more information in support of the beta-amyloid theory of Alzheimer’s disease, which has come under a shadow from many failed Alzheimer’s drugs.

The beta-amyloid theory is based on the belief that the primary driver of Alzheimer’s disease is the accumulation of beta-amyloid plaques in the brain, which results in the memory loss and cognitive deficits seen in Alzheimer’s patients. However, there have been a number of high-level Phase III drug trial failures in antibodies that do prevent or clear beta-amyloid successfully, but do not result in improved cognition. Some believe this means the beta-amyloid theory is wrong, while most believe it means the brain damage has already been done and can’t be reversed, so clinical trials of drugs that prevent or clear beta-amyloid are taking place earlier and earlier in the disease.

“We are excited to contribute to a better understanding of the pathogenic and therapeutic mechanisms in Alzheimer’s disease,” said Martin Tolar, Alzheon’s founder, president and chief executive officer, in a statement. “The results from this publication suggest a potential protective role of endogenous 3-SPA in normal human brains, guarding against the formation of beta-amyloid oligomers that cause neurodegenerative disorders such as Alzheimer’s.”

Tolar goes on to say, “In addition, our results suggest a potential contribution of 3-SPA to the clinical efficacy of ALZ-801 and connect it more closely to the protective effects against neurotoxic amyloid oligomers. While targeting soluble amyloid aggregates is the only therapeutic approach to date that has shown a disease-modifying effect in Alzheimer’s patients, no drugs have been approved yet that can slow or stop the disease. This new discovery and mechanistic data strongly support our therapeutic approach and strengthen Alzheon’s commitment to confirm the efficacy of ALZ-801 in APOE4 carriers, a genetically-defined subset of Alzheimer’s patients.”

The research was published in the journal CNS Drug and is titled, “Discovery and Identification of An Endogenous Metabolite of Tramiprosate and its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in Human Brain.”