A new research paper published by Alzheon suggests the inhibition of amyloid toxicity is the only clinically validated strategy for slowing Alzheimer’s disease progression.
A new research paper published by Alzheon suggests the inhibition of amyloid toxicity is the only clinically validated strategy for slowing Alzheimer’s disease (AD) progression. The company indicates longitudinal clinical data show only agents targeting soluble amyloid oligomers have clinical efficacy in AD, while those that only target amyloid monomers or plaque have shown little to no clinical success.
The paper, published in the International Journal of Molecular Sciences, also points to evidence showing complete removal of plaques in the brain is not necessarily associated with clinical efficacy. Several data points from newer positive clinical trials, however, demonstrate amyloid neurotoxicity inhibition can lead to a reduction in tau pathology, a hallmark of AD. These trials also demonstrate amyloid toxicity flue increased tau phosphorylation as well as tau deposition in neurofibrillary tangles.
Alzheon is currently developing ALZ-801, a potentially disease-modifying treatment for AD. The candidate, which is undergoing Phase III trials, may fully inhibit neurotoxic soluble amyloid oligomer formation when given at its currently studied dose.
In the new research paper, Alzheon highlights data showing ALZ-801 demonstrates “superior selectivity” for amyloid oligomers in APOE4/4 homozygous patients with AD. The company explained in a statement that Biogen’s accelerated approval of aducanumab, an anti-amyloid therapy, confirms ALZ-801’s mechanism of action and validates “a regulatory path for a clinical study that provides strong biomarker data to support clinical outcomes.”
Alzheon’s founder, president and chief executive officer, Martin Tolar, M.D., Ph.D., said that the approval of aducanumab has allowed the industry to enter a new era of AD drug development. “The degree of amyloid oligomer selectivity appears to be the key factor that, together with pharmacokinetic properties, determines the magnitude of the benefit and risk profile for each anti-amyloid agent,” said Tolar, who was a lead author in the paper.
Tolar added that the accelerated approval of aducanumab based on biomarker data further validates the company’s Phase II biomarker study alongside with its Phase III ALZ-801 trial. “This positions ALZ-801 to potentially become the first oral disease-modifying agent for patients and healthy people at high risk for Alzheimer’s disease,” he said.
The Phase II biomarker study recently completed patient enrollment. This study is set to assess biomarker evidence of disease modification in carriers of the APOE4 gene, who comprise up to two-thirds of all patients with AD.
“Our analysis shows that the biomarker that best correlates with clinical benefit is reduction of phosphorylated tau in cerebral spinal fluid, and tau hyperphosphorylation is driven by soluble toxic amyloid oligomers rather than plaque,” added senior author Susan Abushakra, M.D., who serves as Alzheon’s chief medical officer. “We believe that plaque reduction is an indirect association since its correlation with clinical efficacy seems to be mediated by drug effects on phosphorylated tau biomarker.”
To date, anti-amyloid antibody therapies carry with them several logistical challenges, primarily because these are given via intravenous infusions. Additionally, these treatments require several magnetic resonance imaging scans for monitoring hemorrhage and brain edema.
John Hey, Ph.D., Alzheon’s chief scientific officer and co-author of the new research paper, stated ALZ-801 is “much more accessible to patients,” given it “does not interact with amyloid plaque and, therefore, is not associated with the risk of vasogenic edema.” He noted that if ultimately approved for an indication in patients with AD and two copies of the APOE4 gene, the Alzheon candidate could “serve 1.35 million patients, which can scale up to 15 million patients in additional indications.”
