About Cholesteryl Ester Transfer Protein (CETP) Inhibition

Overview

Cholesterol in the body is stored in different types of large particle complexes that are packed up by proteins called lipoproteins. Two of the most important types of cholesterol particles are high-density lipoprotein (HDL) particles (also known as “good cholesterol”) and low-density lipoprotein (LDL) particles (also known as “bad cholesterol”). Too much LDL in the blood results in the buildup of cholesterol in the walls of arteries, resulting in cardiovascular disease. Insufficient HDL in the body is also linked to pathologies including diabetes and Alzheimer’s.

Cholesteryl ester transfer protein (CETP) is a protein that connects to form a tunnel between HDL particles and LDL particles, and it is through the CETP protein that cholesterol esters are transported from the ”good” HDL particles to the ”bad” LDL particles, which can drive cholesterol imbalances underlying a range of health conditions. NewAmsterdam is developing obicetrapib, which blocks the CETP protein from permitting this transfer of cholesterol from ”good” to ”bad.”

 

CETP inhibition has multiple actions that are beneficial for CHD risk:

  • Circulation

    CETP inhibition blocks transportation of cholesterol esters from HDL > LDL, lowering LDL and increasing HDL

  • Liver

    CETP inhibition upregulates LDL catabolism in the liver by causing an increase in LDL receptors, resulting in drop in LDL levels in circulation

  • Pancreas

    CETP inhibition protects vital pancreatic B-cells by increasing small functional HDLs, supporting islet cell survival and increasing insulin production in the pancreas

  • Brain

    CETP inhibition promotes cholesterol clearance from the brain by increasing small functional HDLs that can cross the blood-brain barrier to clear out excess cholesterol, a precedent step to amyloid beta and tau accumulation

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CETP Inhibition and Cardiovascular Disease

CVD remains a significant unmet need, despite the availability of statins. NewAmsterdam Pharma’s mission is to offer a potent LDL-lowering treatment that is safe and convenient.

 
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NewAmsterdam Pharma strongly considered the following factors when selecting its CETP inhibitor therapy:

Cardiovascular disease (CVD) remains a significant unmet need, despite the availability of statins. NewAmsterdam Pharma’s mission is to offer a potent LDL-lowering treatment that is safe and convenient. NewAmsterdam Pharma strongly considered the following factors when selecting its CETP inhibitor therapy:

  • LDL Impact - The primary goal is to achieve strong LDL-C reduction in patients

  • Convenience of Administration - An oral, once daily treatment is relatively hassle-free compared to an injection or more frequent dose regimen

  • Minimal Side Effects - A safe treatment is essential for patients, and we aim to avoid the significant side effects observed in alternative treatment regimens.

CETP inhibition has been proven genetically to reduce LDL-C. People with loss-of-function mutations in the CETP gene are at significantly lower risk for cardiovascular disease. The reduction in genetic risk for cardiovascular disease associated with CETP mutations is identical to the genetic validation for statins, PCSK9 modulators, and ezetimibe, respectively. This consistency of benefit across genotypes in all 4 target genes indicates a very high predictability and probability of success for how clinically efficacious CEPTi-induced LDL-C lowering will be.


CETP inhibition has been proven clinically to reduce cardiovascular events. A 2.3-year follow-up of the REVEAL trial (Phase 3) with anacetrapib showed that CETP inhibition drove a major cardiovascular adverse event (MACE) reduction of 20% compared to placebo, which is higher than the MACE benefit reported for existing PCSK9 inhibitors. We believe that given obicetrapib’s superior potency to anacetrapib, CETP inhibition with obicetrapib is likely to result in significant improvements to cardiovascular risk for patients.

 

CETP Inhibition and Diabetes

Comprehensive pre-specified analysis confirms CETP inhibition reduces diabetes risk both genetically and clinically. While statins increase diabetes risk by 11% to 15%, CETP inhibition is clinically demonstrated to reverse existing diabetes, decrease new-onset diabetes, and improve glucose control. Genetic CETP deficiency lowers glucose levels:

  • Dalcetrapib reduced the risk of developing diabetes by 26% and increased the conversion of diabetes to nondiabetes in high-risk cardiovascular patients

  • CETP inhibitor therapy associated with a significant 12% reduction in incidence of diabetes

CETP Inhibition in the Pancreas

  • Pancreas

    CETP inhibition also protects vital pancreatic β cells

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CETP Inhibition and Alzheimer’s Disease

Current insights into Alzheimer’s disease indicate that cholesterol in membranes facilitates aggregation of amyloid β protein at physiologically low concentrations. Both the number of Aβ42 oligomers and their sizes grow when cholesterol is present. Importantly, the aggregation process is dynamic, so the aggregates assembled on the membrane can dissociate from the bilayer surface. Obicetrapib TULIP trial showed significant increase in HDL-C, apoA-1, and apoE up to 10mg.

 

 

Excess cholesterol and Ab plaque removal facilitated by increasing ApoA1 levels in the CNS

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ApoE plays a central role in the transport of Aβ from the brain

CNS ApoE redistribute 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 amyloid-β (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.

A marked (~80%) reduction in insoluble Aβ 1e42 in the hippocampus after intrahippocampal administration of APP.PS1/TRE4 mice 8 weeks after injection of the AAVrh.10-APOE2 vector. These data suggest that APOE2 can essentially counteract or reverse the ability of APOE4 to promote brain Ab accumulation and deposition/fibrillization

 

How does CETP inhibition fit into the Alzheimer’s story?

  • CETP activity is detected in cerebrospinal fluid especially in astrocytes

  • Close to senile plaques, intense staining of reactive astrocytes in gray matter was observed

  • CETP polymorphism modifies the AD risk associated with ApoE ε4 allele

  • It is hypothesized that CETP leads to delipidation of apoE-HDL with diminished function of the particle

  • High brain CETP concentration would result in low levels of HDL associated with high levels of neuronal cholesterol and an increased risk of AD

  • 10 mg of obicetrapib significantly increases beneficial HDL indices