Central Role of Amyloid Oligomers in Alzheimer’s
Although the precise events that trigger Alzheimer’s are unknown, there is a large body of scientific evidence suggesting that amyloid peptides, particularly soluble aggregated forms, or amyloid oligomers, cause neuronal damage and cell death leading to the disease. Pathologically, Alzheimer’s disease is defined by the presence in the brain of insoluble extracellular amyloid plaques and intracellular neurofibrillary tangles that are composed primarily of tau protein.
Soluble amyloid oligomers = the key driver of Alzheimer’s
In the aging brain, decreased clearance of amyloid monomers & their aggregation into toxic oligomers initiate Alzheimer’s pathology1
Amyloid peptides are derived from the amyloid precursor protein, or APP, an integral membrane protein, in neurons and astrocytes in the brain. Through the enzymatic cleavage of APP, amyloid monomers are produced normally at low levels and cleared from the brain via cerebrospinal fluid. One view of Alzheimer’s disease is that APP is cleaved at an accelerated rate, producing increased amounts of soluble amyloid monomers. These monomers then aggregate to form larger soluble amyloid oligomers, that are neurotoxic and, over time, lead to loss of neuronal synapses, nerve cell dysfunction and, ultimately, nerve cell death.
The consequences of this progressive cascade include the formation of amyloid plaques, loss of brain volume, particularly in the hippocampus, and a progressive decline in cognition and the ability to function.
Recent research and clinical trials support the importance of targeting amyloid oligomers early in disease progression, including the following findings:
- Amyloid oligomer formation begins in Alzheimer’s patients years before clinical signs of the disease appear.
- Accumulation of amyloid oligomers in the brain correlates with Alzheimer’s disease progression.
- Patients with APOE4 have higher levels of amyloid oligomers compared to non-carriers, which predisposes them to increased risk and early onset of Alzheimer’s.
- Results from a recent clinical trial of BAN2401, an injectable monoclonal antibody that targets amyloid oligomers, showed reduced amyloid plaque in the brain and slowing of cognitive decline in mild Alzheimer’s patients.
We have discovered that the brain has an endogenous molecule, 3-SPA, which has potent anti-amyloid oligomer activity. 3-SPA is also the primary metabolite of tramiprosate, the active agent of ALZ-801, and, we found that its levels in the brain increased with the administration of tramiprosate in clinical trials. The endogenous nature of this major metabolite of tramiprosate may help explain the safety, excellent brain penetration and potential efficacy of ALZ-801
Amyloid oligomers play a central role in Alzheimer’s
Our lead product candidate, ALZ-801, is a patented, orally administered prodrug of tramiprosate that is designed to inhibit amyloid oligomer formation, a key driver of Alzheimer’s disease. We believe ALZ-801 has the potential to be differentiated from other emerging therapies targeting Alzheimer’s disease pathology due to its novel mechanism of action, oral mode of administration, potential efficacy in a genetically-targeted population. If our development program is successful and ALZ-801 is approved, we believe it has the potential to be among the first drugs to intervene in an underlying mechanism of Alzheimer’s disease.
The formation of neurotoxic soluble amyloid oligomers is inhibited by ALZ-801
ALZ-801 blocks amyloid oligomer formation
Conformational modulation of Aβ42 amyloid prevents oligomer formation1
1Alzheon publications: Kocis (2017) CNS Drugs; Hey (2018) CNS Drugs
2Liang (2019) Chem Theory Comput
ALZ-801 protects native state of beta amyloid protein
Multiple molecules of ALZ-801 form an enveloping cloud around Aβ42 amyloid monomer that maintains amyloid in its native shape, thereby preventing aggregation into toxic oligomers
Amyloid conformation enforced by ALZ-801
Influenced by surrounding cloud of excess ALZ-801 molecules, Aβ42 amyloid monomer adopts shape that blocks formation of oligomers