Therapeutic Areas

Cholesteryl ester transfer protein (CETP) inhibition has many actions and effects we believe are beneficial across multiple therapeutic areas, including some of the world’s most prevalent and devastating diseases. Learn more about our therapeutic areas:

With this broad application in mind, there are several key advantages of CETP inhibition versus other mechanisms of action:

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 a more frequent dose regimen.

Minimal adverse effects – A principal tenet of our mission is delivering safe and tolerable treatments for patients.

Blocking Lipid Transfer for Cardiovascular Disease

Cardiovascular disease (CVD) is the leading cause of death among adults worldwide. People with hyperlipidemia experience nearly double the risk of developing CVD compared to those with normal total cholesterol levels. Elevated levels of low-density lipoprotein (LDL) cholesterol particles are the root cause of atherosclerosis, the process that leads to heart 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.

In the United States, Europe, and Japan combined:

  • An estimated 235 million patients are or may be eligible for statin therapy.¹

  • It is estimated that 118 million of these patients are not on therapy.²

  • Another 73 million are on statin therapy but are not reaching their treatment goals.³

Left untreated, elevated levels of LDL cholesterol can cause heart disease:

  • LDL cholesterol builds up in the walls of arteries.

  • Deposits prevent normal blood flow and render the vessels stiffer.

  • These deposits can suddenly break and form a clot that causes a heart attack or stroke.

CETP inhibition has been shown genetically to reduce LDL-C: 

  • Cutting-edge recent genetic research has elucidated how important CETP biology is for cardiovascular disease, demonstrating people with loss-of-function mutations in the CETP gene are at significantly lower risk for cardiovascular disease and exhibited significant decreases of CVD risk.

  • Similarly, carrying a gain-of-function mutation in this gene substantially increases the risk of coronary artery disease and adverse cardiovascular outcomes. The reduction in genetic risk for cardiovascular disease associated with CETP mutations is just as powerful as the genetic mechanism underpinning currently successful therapies that are used to reduce LDL levels in cardiovascular patients — statins, PCSK9 modulators, and ezetimibe.

  • Based on the powerful consistency across this genetic and clinical data, we believe there is a strong predictability through the CETP inhibitor, obicetrapib, will ultimately help reduce adverse cardiovascular outcomes for patients.

CETP inhibition has been shown clinically to reduce cardiovascular events:

  • Obicetrapib’s mechanism of action has been observed in clinical trials to decrease the risk of adverse cardiovascular outcomes.

  • In the REVEAL trial of 30,000 hyperlipidemia patients, anacetrapib demonstrated LDL-lowering with a CETP inhibitor reduced cardiovascular outcomes in patients by 9% after 4.1 years and 20% after 6.4 years (in each case compared to placebo). This is a degree consistent with expectations based on magnitude of LDL decrease.

  • We believe, given obicetrapib’s high potency paired with intelligent clinical design to select for the patients most likely to benefit from treatment, NewAmsterdam will be able to demonstrate significant reductions in cardiovascular risk for patients beyond those achieved by current lipid-lowering therapies.

Blocking Cholesterol Transfer for Diabetes

The global prevalence and mortality of diabetes have rapidly increased in recent decades:

  • Between 1980 and 2014, the number of people living with diabetes nearly quadrupled globally, from 108 million in 1980 to 422 million in 2014.⁴

  • An estimated 1.5 million people died due to diabetes in 2019.⁴

  • By 2045, projections show this number rising to 700 million diabetics globally.⁴

Genetic predisposition to low high-density lipoprotein (HDL) cholesterol or high triglycerides is related to elevated type 2 diabetes risk.⁵ Specifically, the increased activity of CETP results in lower HDL cholesterol levels and thus causes prediabetic effects.⁶

In a comprehensive prespecified analysis, CETP inhibition reduced diabetes risk both genetically and clinically.

While statins increase diabetes risk by 11% to 15%, CETP inhibition has been observed in clinical trials to reverse existing diabetes, decrease new cases of type 2 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 was associated with a significant 12% reduction in incidence of diabetes.

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 aged 65 years and older in the United States. 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 and is expected to increase to roughly $2 trillion by 2030.⁸

Alzheimer’s disease is characterized by:

  • Extracellular plaques

  • Amyloid-beta (Aβ) peptides

  • Intracellular neurofibrillary tangles

  • Hyperphosphorylated tau and microtubules

Elevated cholesterol levels have been linked to increased risk of Alzheimer's disease later in life. New biology shows us cholesterol accumulation in the brain precedes disease onset and may cause amyloid protein cleavage leading to Aβ plaque deposition.

Robust genetic and preclinical mechanism. Moreover, recent genetic findings are now elucidating this story. Approximately 60% of Alzheimer’s disease 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 Aβ accumulation in CNS.  We now know patients with loss-of-function mutations in the CETP gene are protected from the increased Alzheimer’s disease risk associated with also carrying an ApoE4 mutation, and we are armed with preclinical evidence showing that CETP inhibition can 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.

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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 disease story?

  • People with CETP loss-of-function mutations appear significantly protected from Alzheimer’s disease, 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 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.

1. Primary and secondary prevention combined; assumes similar statin eligibility in EU and US (based on Ueda et al. Br J Gen Pract. 2017 and Lee et al. JAMA Cardiology 2017) and a population of 335M adults in the EU and 94.5M in Japan.

2. U.S. Centers for Disease Control and Prevention (2015). Prevalence of Cholesterol Treatment Eligibility and Medication Use Among Adults — United States, 2005–2012. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6447a1.htm

3. Ray, K. et al. (2020). EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. European Journal of Preventive Cardiology. https://doi.org/10.1093/eurjpc/zwaa047. Last accessed 1 September 2021.

4. World Health Organization (2021). Diabetes [fact sheet]. https://www.who.int/news-room/fact-sheets/detail/diabetes.

5. Qi, Q (2012). Genetic Predisposition to Dyslipidemia and Type 2 Diabetes Risk in Two Prospective Cohorts. Diabetes. 2012 Mar; 61(3): 745–752.

6. López-Ríos et al (2011). Interaction between Cholesteryl Ester Transfer Protein and Hepatic Lipase Encoding Genes and the Risk of Type 2 Diabetes: Results from the Telde Study. PLOS One. https://doi.org/10.1371/journal.pone.0027208.

7. Nichols, E. et al (2019). The estimation of the global prevalence of dementia from 1990-2019 and forecasted prevalence through 2050: An analysis for the Global Burden of Disease (GBD) study

8. Prince, M. et al (2015). World Alzheimer’s Report 2015, The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. Alzheimer’s Disease International.