Thomas Dayspring recommended this bit of research description from New Amsterdam Pharmaceuticals which provides an overview of their CETP inhibitor Obicetrapib.
To save you a trip to their fancy web site, here is the content:
Blocking Cholesterol Transfer for Alzheimer’s Disease
Alzheimer’s disease is the most prevalent form of dementia and is the fifth leading cause of death in adults in the U.S. older than age 65. As populations age worldwide, the global burden of dementia including Alzheimer’s disease is expected to triple by 2050.⁷ The global cost of dementia care was estimated to be $1 trillion in 2018 will increase to an estimated $2 trillion by 2030.⁸
Alzheimer’s disease is characterized by:
- Extracellular plaques
- Amyloid-beta (Aβ) peptides
- Intracellular neurofibrillary tangles
- Hyperphosphorylated tau and microtubules
Robust genetic and preclinical mechanism. Moreover, recent genetic findings are now elucidating this story. Approximately 60% of Alzheimer’s patients carry a defective copy of the gene encoding for apoliprotein E (ApoE). In healthy individuals, the ApoE gene is responsible for regulating excess cholesterol levels and Aβ plaques in the central nervous system (CNS). However, the protein encoded by the ApoE4 variant is significantly hampered in performing this job, and thus these patients are hampered in their ability to clear cholesterol or Aβ plaques effectively, leading to cholesterol and eventually amyloid beta accumulation in CNS. We now know that patients with loss-of-function mutations in the CETP gene are protected from the increased Alzheimer’s risk associated with also carrying an ApoE4 mutation, and we are armed with preclinical evidence showing that CETP inhibition can indeed reverse cholesterol accumulation and associated cognitive impairment in mice. Armed with this exciting data, NewAmsterdam has initiated a Phase 1 program to test obicetrapib’s effect on the lipid profile of the brain and its corresponding ability to appropriately clear cholesterol from cells in the brain.
[Obligatory pretty picture]
ApoE plays a central role in the transport of Aβ from the brain
CNS ApoE redistributes cholesterol and lipids to neurons and other brain cells for repair and remodeling of membranes, organelle biogenesis, and synaptogenesis. ApoE in addition to transporting lipids across organs in the periphery, also regulates Aβ aggregation and clearance. In Alzheimer’s disease animal models, increasing ApoE lipidation by genetic or pharmacological methods improves Aβ clearance, reduces brain inflammation, and improves cognition.
How does CETP inhibition fit into the Alzheimer’s story?
- People with CETP loss-of-function mutations mutations appear significantly protected from Alzheimer’s, especially in patients who carry a copy of the ApoE ε4 gene.
- It is believed that increasing ApoA1 levels in the blood increases the amount of ApoA1 that crosses the blood brain barrier.
- ApoA1 in the brain also clears cholesterol via the same mechanism as healthy ApoE proteins.
- Obicetrapib has been shown to substantially increase ApoA1 levels in the body, and we are now initiating a proof-of-concept study intended to show that this also drives increase in ApoA1 levels in the brain.
- We believe that by increasing ApoA1 in the brain via CETP inhibition with obicetrapib we can restore healthy clearance of cholesterol out of the brain so that it can be cleared by the liver.
I'll add some additional non-Aβ CETP pictures from Dayspring in a follow-up comment.