Central Role of Amyloid Oligomers in Alzheimer’s
Although the precise events that trigger AD are unknown, there is a large body of scientific evidence suggesting that Aβ peptides, particularly soluble aggregated forms, or Aβ oligomers, cause neuronal damage and cell death leading to the disease. Pathologically, AD is defined by the presence in the brain of insoluble extracellular Aβ plaques and intracellular neurofibrillary tangles that are composed primarily of tau protein.
Soluble Amyloid Oligomers = Key Driver of AD
Genetic Data Point to Primary Toxic Role of Amyloid in Alzheimer’s
Aβ 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, Aβ monomers are produced normally at low levels and cleared from the brain via cerebrospinal fluid. One view of AD is that APP is cleaved at an accelerated rate, producing increased amounts of soluble Aβ monomers. These monomers then aggregate to form larger soluble Aβ oligomers, which 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:
- Aβ oligomer formation begins in AD patients years before clinical signs of the disease appear.
- Accumulation of Aβ oligomers in the brain correlates with AD progression.
- Patients with APOE4 have higher levels of Aβ oligomers compared to non-carriers, which predisposes them to increased risk and early onset of AD.
- Results from clinical trials of aducanumab and BAN2401, both injectable monoclonal antibodies that targets Aβ oligomers, showed reduced amyloid plaque in the brain and slowing of cognitive decline in mild AD patients.
We have discovered that the brain has an endogenous molecule, 3-SPA, that has potent anti-Aß 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 administration of tramiprosate in clinical trials. We believe that these findings further support the favorable safety, brain penetration and potential efficacy of ALZ-801 in AD patients early in the disease course.
ALZ-801 Pill Inhibits Formation of Amyloid Oligomers
Amyloid Oligomers Play Central Role in AD
Our lead product candidate, ALZ-801, is a patented, orally administered prodrug of tramiprosate that is designed to inhibit Aβ oligomer formation, a key driver of AD. We believe ALZ-801 has the potential to be differentiated from other emerging therapies targeting AD pathology due to its novel mechanism of action, oral mode of administration, potential efficacy in a genetically-targeted population and observed favorable safety profile. 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 AD.
Formation of Toxic Soluble Aβ Oligomers Inhibited by ALZ-801
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, Aß42 amyloid monomer adopts shape that blocks formation of oligomers