New Review Article in ESC’s Cardiovascular Research Examines Cholesteryl Ester Transfer Protein (CETP) Inhibition’s Role in Reducing Cardiovascular Disease Risk

Blocking CETP can have two major effects on a patients’ lipid profile depending on the characteristics of the CETP inhibitor: it can lower LDL-c and ApoB, and increase HDL-c. First generation CETP inhibitors focused on increasing HDL-c to reduce MACE. It is now well-understood in the cardiovascular medicine community that increasing HDL-c levels does not reduce MACE risk, but rather lowering LDL-c is the axiom for MACE reduction.

A recently published analysis of the long-term follow up of the Phase 3 cardiovascular outcome trial, REVEAL, showed that LDL-c and ApoB reduction by a CETP inhibitor results in MACE risk reduction to the same degree as any other LDL-lowering therapy, including statins.¹ This observed outcome confirms findings shown in recent large Mendelian randomization studies that people with CETP loss-of-function genes have the same decreased cardiovascular outcome risk as people with mutations in the genes targeted by currently used LDL-lowering drugs.² NewAmsterdam’s next generation CETP inhibitor, obicetrapib, is intended to lower LDL-c and ApoB, showing a 51% LDL-c reduction in patients treated with high intensity statin dosages in its Phase 2 trial, ROSE.³ Obicetrapib could become a simple, low-dose, cost-effective treatment for reducing MACE by optimizing the lipid profile of patients with atherosclerosis.

“NewAmsterdam Pharma has been working diligently to deliver an LDL-c lowering therapy that is low-dose, cost effective, once daily, and more targeted to reducing LDL-c, ApoB and the significant health risks associated with ASCVD,” said NewAmsterdam’s chief scientific officer and founder Dr. John Kastelein. “CETP loss-of-function is considered a longevity gene, and those with CETP loss-of-function are significantly less likely to develop cardiometabolic diseases, and are at less of a risk for major adverse cardiac events (MACE). This genetic validation is at the core of our research into obicetrapib, and, we believe, is one of the main reasons for its effectiveness in clinical trials.”

More than 100 million people globally are not achieving LDL-c goals despite the current available standard of care. Current lipid lowering therapies come in the form of statin therapy, ezetimibe and proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9). PCSK9 and statin therapies also come with statin intolerance and discontinuation, as well as showing a likelihood of developing new-onset diabetes in patients. CETP inhibitors, however, have proven to be effective in lowering the risk of new-onset diabetes, and improve glucose tolerance and insulin sensitivity. These reasons highlight why there continues to be a significant unmet need for future lipid-lowering therapies.

This paper examines how a CETP inhibitor like obicetrapib, which is now entering Phase 3 trials, has the potential to provide an effective, simple, low dose, once daily, cost-effective treatment for lowering cholesterol and reducing the risk for cardiovascular events.

About Obicetrapib
Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor in development for lowering low-density lipoprotein cholesterol (LDL-c) and preventing major adverse cardiovascular events. More than 100 million people globally cannot achieve LDL-c goals despite current standard of care. Obicetrapib was previously tested in ROSE and TULIP (published in The Lancet), randomized double-blind, placebo-controlled Phase 2 trials. The latest data, from the ROSE trial presented in November 2021 at the AHA Scientific Sessions, showed that both obicetrapib 5 mg and 10 mg dosed as a once daily oral treatment reduced median LDL-c levels by 42% and 51% from baseline, respectively, in patients on high-intensity statin therapy and were well tolerated, with no serious adverse effects in the two cohorts and two serious AEs in the placebo arm.

About NewAmsterdam Pharma
Founded in 2019 by the venture capital firm Forbion and John Kastelein, NewAmsterdam Pharma is a privately held, clinical-stage company focused on the research and development of transformative therapies for metabolic diseases. Its mission is to improve patient care in populations. In April 2020, NewAmsterdam acquired Dezima Pharma from Amgen, including all rights for obicetrapib (formerly AMG 899, now TA-8995) a selective cholesteryl ester transfer protein (CETP) inhibitor. In January 2021, NewAmsterdam Pharma closed a $196M (€161M) Series A financing led by Morningside Ventures and Ascendant BioCapital with participation from Forbion, Kaiser Foundation Hospitals, BVF Partners L.P., Population Health Partners, LSP Dementia Fund, Peter Thiel, Janus Henderson Investors, Medpace, GL Capital, JVC Investment Partners, and Presight Capital. The Company is investigating obicetrapib as the preferred LDL-c lowering therapy for patients with ASCVD/FH on maximally tolerated statin therapy as well as for the treatment of Alzheimer’s disease and diabetes. NewAmsterdam Pharma is headquartered in Naarden, The Netherlands. For more information, please visit: www.newamsterdampharma.com

¹ Sammons, E., Hopewell, J. C., Chen, F., Stevens, W., Wallendszus, K., Valdes-Marquez, E., Dayanandan, R., Knott, C., Murphy, K., Wincott, E., Baxter, A., Goodenough, R., Lay, M., Hill, M., Macdonnell, S., Fabbri, G., Lucci, D., Fajardo-Moser, M., Brenner, S., … Landray, M. (2021). Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease. European Heart Journal. https://doi.org/10.1093/eurheartj/ehab863
² HPS3/TIMI55-REVEAL: Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. 2019. https://www.revealtrial.org/ (10 September 2020, date last accessed).
³ Late-breaking science abstracts and featured Science abstracts from the American Heart Association’s Scientific sessions 2021 and late-breaking abstracts in resuscitation science from the resuscitation science symposium 2021. (2021). Circulation, 144(25). https://doi.org/10.1161/cir.0000000000001041