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Review
. 2024 Dec;12(6):e70010.
doi: 10.1002/prp2.70010.

Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials

Stephen J Nicholls  1 , Adam J Nelson  1 , John J P Kastelein  2 , Marc Ditmarsch  2 , Andrew Hsieh  2 , Judith Johnson  2 , Danielle Curcio  2 , Douglas Kling  2 , Carol F Kirkpatrick  3 , Michael H Davidson  2
Affiliations
Review

Obicetrapib exhibits favorable physiochemical and pharmacokinetic properties compared to previous cholesteryl ester transfer protein inhibitors: An integrated summary of results from non-human primate studies and clinical trials

Stephen J Nicholls et al. Pharmacol Res Perspect. 2024 Dec.

Abstract

Anacetrapib, a cholesteryl ester transfer protein (CETP) inhibitor previously under development, exhibited an usually extended terminal half-life and large food effect and accumulated in adipose tissue. Other CETP inhibitors have not shown such effects. Obicetrapib, a potent selective CETP inhibitor, is undergoing Phase III clinical development. Dedicated assessments were conducted in pre-clinical and Phase I and II clinical studies of obicetrapib to examine the pharmacokinetic issues observed with anacetrapib. After 9 months of dosing up to 50 mg/kg/day in cynomolgus monkeys, obicetrapib was completely eliminated from systemic circulation and not detected in adipose tissue after a 13-week recovery period. In healthy humans receiving 1-25 mg of obicetrapib, the mean terminal half-life of obicetrapib was 148, 131, and 121 h at 5, 10, and 25 mg, respectively, and food increased plasma levels by ~1.6-fold with a 10 mg dose. At the end of treatment in Phase II trials, mean plasma levels of obicetrapib ranged from 194.5 ng/mL with 2.5 mg to 506.3 ng/mL with 10 mg. Plasma levels of obicetrapib decreased by 92.2% and 98.5% at four and 15 weeks post-treatment, respectively. Obicetrapib shows no clinically relevant accumulation, is minimally affected by food, and has a mean terminal half-life of 131 h for the 10 mg dose. These data support once daily, chronic dosing of obicetrapib in Phase III trials for dyslipidemia management.

Keywords: accumulation; anacetrapib; cholesteryl ester transfer protein; elimination; obicetrapib; pharmacokinetics; toxicokinetic.

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Conflict of interest statement

Stephen J. Nicholls received grant/research support from AstraZeneca, NewAmsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi‐Regeneron, and LipoScience; and was a consultant for AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi‐Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, and Vaxxinity. Adam J. Nelson received personal fees from Boehringer Ingelheim, AstraZeneca, Amgen, Novartis, and Sanofi. John J.P. Kastelein is Chief Scientific Officer for NewAmsterdam Pharma and Emeritus Professor of Medicine at the University of Amsterdam, The Netherlands. Marc Ditmarsch is Chief Development Officer for NewAmsterdam Pharma. Andrew Hsieh is Vice President of Medical Affairs for NewAmsterdam Pharma. Judith Johnson is Executive Director of Clinical Operations for NewAmsterdam Pharma. Danielle Curcio is Executive Director of Clinical Operations for NewAmsterdam Pharma. Douglas Kling is Chief Operating Officer for NewAmsterdam Pharma. Carol F. Kirkpatrick is an employee of Midwest Biomedical Research, which has received consulting fees and/or grant funding from Acasti Pharma, Beren Therapeutics, Eli Lilly and Company, Indiana University and Foundation, Matinas BioPharma, NewAmsterdam Pharma, NorthSea Therapeutics, and 89Bio. Michael H. Davidson is Chief Executive Officer for NewAmsterdam Pharma.

Figures

FIGURE 1
FIGURE 1
Metabolism of obicetrapib (TA‐8995) in the cynomolgus monkey (n, 3). M, metabolite; UM, urinary metabolite.
FIGURE 2
FIGURE 2
Obicetrapib (TA‐8995) metabolites detected above LLOQ (>1% radioactivity) in human plasma expressed as the percent radioactivity profiled† (TA‐8995‐07 CSR, NewAmsterdam Pharma). †Data from n = 6 individuals from 24 h AUC pools. AUC, area under the curve; LLOQ, lower limit of quantification; M, metabolite; P, secondary metabolite.
FIGURE 3
FIGURE 3
Chemical structures and lipophilicity of CETP inhibitors., , ,
See this image and copyright information in PMC

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