Amlogenyx Reports Preclinical Data for AM805, an AAV9 Gene Therapy Designed to Degrade Amyloid in Alzheimer's Disease
Amlogenyx Inc., a Novato, California-based biotechnology subsidiary of Ultragenyx, disclosed preclinical results for AM805, an investigational AAV9 gene therapy encoding protective protein cathepsin A (PPCA), a lysosomal carboxypeptidase, for the treatment of Alzheimer's disease. The data, presented at the AD/PD 2026 International Conference on Alzheimer's and Parkinson's Diseases in Copenhagen, showed dose-dependent amyloid reduction in mouse models of the disease, with the company stating that the magnitude of reduction was comparable to, and in some cases exceeded, that reported for approved anti-amyloid monoclonal antibodies.
AM805 represents a mechanistically distinct approach to amyloid plaque clearance. Rather than deploying antibodies to tag amyloid for immune-mediated removal, the therapy delivers a gene encoding PPCA via an AAV9 vector directly to the central nervous system. Once expressed, PPCA functions as an amyloid-degrading protease, catalytically breaking down amyloid-beta peptides within the lysosomal compartment of neurons. The company describes this as catalytic amyloid degradation, a process intended to clear both intracellular amyloid accumulations and extracellular plaques. The work was conducted in collaboration with researchers at St. Jude Children's Research Hospital, who identified PPCA as an enzyme capable of degrading amyloid with high efficiency.
According to the data disclosed by Amlogenyx, studies were conducted in mouse models representing both severe and moderate Alzheimer's disease pathology, in young and aged animals. All routes of administration tested resulted in increased PPCA enzymatic activity in the brain and reduced amyloid-positive brain area in a dose-dependent manner. Aβ peptide levels, measured by 4G8-positive signal, were lowered in both intracellular and extracellular compartments. The company also reported that PPCA was delivered safely to the brains of non-human primates and achieved enzyme expression levels consistent with the therapeutic effect observed in the mouse models. The company did not disclose specific quantitative endpoints, statistical analyses, or detailed safety data from these studies.
No clinical trial for AM805 has been registered on ClinicalTrials.gov, and the program remains in the preclinical stage. Amlogenyx stated that AM805 is currently in IND-enabling studies and that the company plans to submit an Investigational New Drug application to the US FDA in 2027. The company did not disclose the intended route of administration for human dosing, the target patient population for first-in-human studies, or the anticipated clinical trial design.
The Alzheimer's disease treatment landscape has shifted considerably in recent years with the approval of two anti-amyloid monoclonal antibodies. Lecanemab (Leqembi), developed by Eisai and Biogen, received traditional US FDA approval in July 2023 for early Alzheimer's disease, based on the CLARITY AD trial showing a 27% slowing of cognitive decline over 18 months compared with placebo. Donanemab (Kisunla), developed by Eli Lilly, was approved in July 2024 based on the TRAILBLAZER-ALZ 2 trial, which demonstrated a 35% slowing of decline in a combined tau and clinical endpoint population. Both therapies require chronic intravenous infusions and carry the risk of amyloid-related imaging abnormalities (ARIA), including brain edema and microhemorrhages, necessitating regular MRI monitoring.