FRAMINGHAM, Mass.—Beta amyloid plaques, sticky aggregates of the beta amyloid peptide that are a primary driver of disease progression, are the best-known culprit of Alzheimer's disease. As noted by biopharmaceutical company Alzheon Inc., beta amyloid (Aβ) oligomers have a variety of neurotoxic effects in the brain, including synaptic damage, oxidative stress, neuronal death and abnormal tau phosphorylation, among others. As such, a primary approach in attempting to develop treatments against this neurodegenerative disease is to focus on the clearance of Aβ oligomers from the brain. Alzheon has found that the primary metabolite from of tramiprosate and its prodrug ALZ-801, 3-sulfopropanoic acid (3-SPA), is an endogenous substance that inhibits the formation of neurotoxic Aβ oligomers. Alzheon is developing ALZ-801 as a treatment for Alzheimer's disease, and received Fast Track designation for it from the FDA in October 2017.
A recent study showed that 3-SPA blocks the formation of toxic soluble Aβ oligomers in a comparable manner to the effects of tramiprosate. Alzheimer's patients who were administered tramiprosate presented with levels of 3-SPA that were up to 12 times greater than those in patients who were drug-naïve or treated with placebo. The results were published in a paper titled “Discovery and Identification of an Endogenous Metabolite of Tramiprosate and Its Prodrug ALZ-801 that Inhibits Beta Amyloid Oligomer Formation in the Human Brain,” which appeared in CNS Drugs.
As noted in that work, “[W]e showed that 3-SPA has potent anti-Aβ oligomer activity, inhibiting aggregation of Aβ42 into small oligomers with efficacy comparable to that of tramiprosate. 3-SPA displays excellent oral availability and brain penetration in rats, suggesting that the higher CSF concentrations of 3-SPA in the human brain after oral administration of ALZ-801 or tramiprosate (and subsequent conversion to 3-SPA) result from the penetration of the metabolite into the central nervous system. These data suggest that 3-SPA is an endogenous agent with potential activity stabilizing the conformational flexibility of Aβ monomers that, in turn, inhibit Aβ misfolding and formation of soluble toxic Aβ oligomers in humans, thereby preventing the initial pathogenic step in the progression of AD.”
Beyond the promise of 3-SPA itself, Alzheon points out that its presence “suggests the possibility of a protective endogenous anti-Aβ oligomer pathway (“Aβ oligomer brake pathway”) within the human central nervous system, with the potential to prevent or delay the onset of AD. Such physiological anti-Aβ oligomer pathway could modulate the neurotoxic effects of abnormal Aβ aggregation in the aging human brain.”
ALZ-801 has been engineered for a better pharmacokinetic profile and better gastrointestinal tolerability, according to Alzheon's website, as it can be “absorbed through the gut wall in a prodrug inactive form and metabolized into active tramiprosate after absorption into the bloodstream.” Compared to the original formulation of tramiprosate—which Alzheon noted featured poor oral absorption and a high rate of nausea/vomiting—in the Phase 1 program for ALZ-801, the compound saw increased gastrointestinal tolerability (especially with food), 50-percent less pharmacokinetic variability in plasma and increased brain penetration to the tune of a roughly 40 percent brain to plasma ratio.
“We are excited to contribute to a better understanding of the pathogenic and therapeutic mechanisms in Alzheimer’s disease. 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,” Dr. Martin Tolar, founder, president and CEO of Alzheon, remarked in a press release. “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.”
Patients who present with the APOE4 allele, which confers a higher genetic risk for developing Alzheimer's disease, also tend to have higher levels of Aβ oligomers. Patients of this subtype were able to reach “brain concentrations associated with prevention of Aβ42 oligomer formation and clinical outcome benefit” in a Phase 3 study of tramiprosate, the paper reported. The study also found that in study participants with memory deficits (resulting from a variety of neurodegenerative diseases) that were drug-naïve, 3-SPA was “present endogenously in cerebrospinal fluid and plasma samples, suggesting that this substance may be a physiological protective mechanism in aging brain that counteracts amyloid aggregation leading to AD.”
“Our published findings suggest that an endogenous substance, 3-SPA, may protect the human brain against Alzheimer’s, and contribute to the clinical efficacy of ALZ-801 by inhibiting the formation of toxic soluble amyloid oligomers at therapeutic concentrations,” said Dr. John Hey, chief scientific officer of Alzheon. “Our data support the central role of amyloid oligomers in the initiation of the pathogenic cascade of Alzheimer’s disease, as well as the potential preventive and therapeutic approaches that could be applied to counteract these neurotoxic oligomers. Based on the emerging scientific and clinical trial data from Alzheon, as well as independent studies which highlight amyloid oligomers as key drivers of Alzheimer’s, we have developed ALZ-801 as a pioneering small molecule which directly blocks the formation of amyloid oligomers and may slow or stop Alzheimer’s disease progression.”