Therapeutics

Obicetrapib

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Overview

Name: Obicetrapib
Synonyms: TA-8995
Therapy Type: Small Molecule (timeline)
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: NewAmsterdam Pharma

Background

This cholesteryl ester transfer protein (CETP) inhibitor is being developed primarily as a cholesterol-targeted therapy to reduce cardiovascular disease. CETP inhibitors block the transfer of cholesteryl esters from high-density lipoprotein (HDL) into other lipoproteins, and thus promote removal of cholesterol by HDL. Drugs of this class were initially developed to increase “good” high-density lipoprotein (HDL) cholesterol, and were shown to also reduce “bad” low-density lipoprotein (LDL) cholesterol in people. Previous CETP inhibitors were discontinued when they showed little or no improvement in cardiovascular outcomes, or even increased deaths, despite raising HDL (see review by Nurmohamed et al., 2022; also Oct 2021 news). Obicetrapib is claimed to be more potent and specific than these failed candidates.

The rationale for testing this CETP inhibitor for Alzheimer’s disease stems from work linking high levels of HDL to longer life and preserved cognition (Barzilai et al., 2006; Lewis et al., 2010). By its ability to elevate HDL, obicetrapib increases cholesterol efflux from cells, a process which may mitigate the risk of AD due to ApoE4, and help clear Aβ from brain (van Capelleveen et al., 2016; Van Valkenburgh et al., 2021). However, low-activity CETP gene variants that mimic inhibition do not decrease the risk of AD (Nordestgaard et al., 2022; Peloso et al., 2018). In one study, genetic variants associated with higher HDL actually raised AD risk (May 2023 news). High HDL is also linked to an elevated risk of age-related macular degeneration (Burgess and Davey Smith, 2017).

No preclinical work is published on obicetrapib in Alzheimer’s models. Mice lack a CETP gene, but a recently produced transgenic animal may be useful for such studies (Oestereich et al., 2022).

Findings

In Phase 1 evaluation in healthy subjects, single and multiple oral doses of obicetrapib from 2.5 to 25 mg daily were well-tolerated and nearly completely inhibited CETP (Ford et al., 2014). The treatment increased high-density lipoprotein-cholesterol (HDL-C) by 96 to 140 percent and decreased low-density lipoprotein-cholesterol (LDL-C) by 40 to 53 percent. No significant effects of age, gender, ethnicity, or food were found. There was no evidence of off-target effects seen with earlier inhibitors, such as changes in blood pressure, serum electrolytes, or aldosterone.

In January 2022, NewAmsterdam Pharma began a Phase 2, open-label proof-of-concept study in 13 patients with a clinical diagnosis of Alzheimer's disease who carried one or two ApoE4 alleles. Treatment consisted of 10 mg obicetrapib daily for 24 weeks. Primary outcomes were concentration of apolipoproteins and high-density lipoprotein particles in plasma and CSF. Other outcomes were pharmacokinetics including CSF levels of drug. The study was completed in June 2023. In September, the company announced top-line data, saying that obicetrapib had been well-tolerated (company press release). No data on lipoprotein levels was reported; instead, the company claimed 10 and 11 percent reductions in CSF 24- and 27-hydroxycholesterol, respectively. This was interpreted as evidence of normalization of cholesterol metabolism in the brain. The treatment nudged up the CSF Aβ42/40 ratio by 8 percent.

Three large, worldwide Phase 3 trials of obicetrapib are ongoing, testing it as an add-on to statins to further lower cholesterol and improve cardiovascular outcomes in people with familial high cholesterol or atherosclerotic cardiovascular disease. In a Phase 2 study, 10 mg obicetrapib added to high-intensity statin treatment decreased LDL and increased HDL (Nicholls et al., 2022). Obicetrapib additively lowered cholesterol when given with statins and ezetimbe, a drug that blocks intestinal cholesterol absorption (Ballantyne et al., 2023). Even though CETP inhibitors raise HDL, their cardiovascular benefits are now attributed to their ability to lower LDL and apolipoprotein B (see Nelson et al., 2022; Mehta et al., 2023).

For details on this study, see clinicaltrials.gov.

Last Updated: 07 Nov 2023

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References

News Citations

  1. Target or Decoy: Are Drug Developers Chasing the Right Thing?
  2. Does “Good” Cholesterol Increase Your Risk of Alzheimer’s?

Paper Citations

  1. Ford J, Lawson M, Fowler D, Maruyama N, Mito S, Tomiyasu K, Kinoshita S, Suzuki C, Kawaguchi A, Round P, Boyce M, Warrington S, Weber W, van Deventer S, Kastelein JJ. Tolerability, pharmacokinetics and pharmacodynamics of TA-8995, a selective cholesteryl ester transfer protein (CETP) inhibitor, in healthy subjects. Br J Clin Pharmacol. 2014 Sep;78(3):498-508. PubMed.
  2. Nicholls SJ, Ditmarsch M, Kastelein JJ, Rigby SP, Kling D, Curcio DL, Alp NJ, Davidson MH. Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nat Med. 2022 Aug;28(8):1672-1678. Epub 2022 Aug 11 PubMed.
  3. Ballantyne CM, Ditmarsch M, Kastelein JJ, Nelson AJ, Kling D, Hsieh A, Curcio DL, Maki KC, Davidson MH, Nicholls SJ. Obicetrapib plus ezetimibe as an adjunct to high-intensity statin therapy: A randomized phase 2 trial. J Clin Lipidol. 2023;17(4):491-503. Epub 2023 Jun 3 PubMed.
  4. Nelson AJ, Sniderman AD, Ditmarsch M, Dicklin MR, Nicholls SJ, Davidson MH, Kastelein JJ. Cholesteryl Ester Transfer Protein Inhibition Reduces Major Adverse Cardiovascular Events by Lowering Apolipoprotein B Levels. Int J Mol Sci. 2022 Aug 20;23(16) PubMed.
  5. Mehta N, Dangas K, Ditmarsch M, Rensen PC, Dicklin MR, Kastelein JJ. The evolving role of cholesteryl ester transfer protein inhibition beyond cardiovascular disease. Pharmacol Res. 2023 Nov;197:106972. Epub 2023 Oct 28 PubMed.
  6. Nurmohamed NS, Ditmarsch M, Kastelein JJ. Cholesteryl ester transfer protein inhibitors: from high-density lipoprotein cholesterol to low-density lipoprotein cholesterol lowering agents?. Cardiovasc Res. 2022 Nov 10;118(14):2919-2931. PubMed.
  7. Barzilai N, Atzmon G, Derby CA, Bauman JM, Lipton RB. A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 2006 Dec 26;67(12):2170-5. PubMed.
  8. Lewis TL, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, LaDu MJ, Li L. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010 Nov 19;285(47):36958-68. Epub 2010 Sep 16 PubMed.
  9. van Capelleveen JC, Kastelein JJ, Zwinderman AH, van Deventer SJ, Collins HL, Adelman SJ, Round P, Ford J, Rader DJ, Hovingh GK. Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses. J Clin Lipidol. 2016;10(5):1137-1144.e3. Epub 2016 Jun 25 PubMed.
  10. Van Valkenburgh J, Meuret C, Martinez AE, Kodancha V, Solomon V, Chen K, Yassine HN. Understanding the Exchange of Systemic HDL Particles Into the Brain and Vascular Cells Has Diagnostic and Therapeutic Implications for Neurodegenerative Diseases. Front Physiol. 2021;12:700847. Epub 2021 Sep 6 PubMed.
  11. Nordestgaard LT, Christoffersen M, Lauridsen BK, Afzal S, Nordestgaard BG, Frikke-Schmidt R, Tybjærg-Hansen A. Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population. JAMA Cardiol. 2022 Jan 1;7(1):55-64. PubMed.
  12. Peloso GM, van der Lee SJ, International Genomics of Alzheimer's Project (IGAP), Destefano AL, Seshardi S. Genetically elevated high-density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease. Alzheimers Dement (Amst). 2018;10:595-598. Epub 2018 Sep 22 PubMed.
  13. Burgess S, Davey Smith G. Mendelian Randomization Implicates High-Density Lipoprotein Cholesterol-Associated Mechanisms in Etiology of Age-Related Macular Degeneration. Ophthalmology. 2017 Aug;124(8):1165-1174. Epub 2017 Apr 26 PubMed.
  14. Oestereich F, Yousefpour N, Yang E, Phénix J, Nezhad ZS, Nitu A, Vázquez Cobá A, Ribeiro-da-Silva A, Chaurand P, Munter LM. The cholesteryl ester transfer protein (CETP) raises cholesterol levels in the brain. J Lipid Res. 2022 Sep;63(9):100260. Epub 2022 Jul 31 PubMed.

External Citations

  1. company press release
  2. clinicaltrials.gov

Further Reading

Learn More

  1. Symposium on Lipids in Brain Diseases - 2nd