Tolerability, safety, and pharmacokinetics of the novel cathepsin A inhibitor SAR164653 in healthy subjects
Abstract
Cathepsin A (CathA) is a lysosomal protein where it forms a stable complex with neuraminidase and ß‐galactosidase. CathA also has enzymatic activity and is involved in the degradation of many peptides. CathA was recently discovered as a target for heart failure, fostering the development of CathA inhibitors with SAR164653 as a frontrunner. The first‐in‐man study investigated single oral doses from 20 to 800 mg of SAR164653 followed by repeat dose studies at doses up to 800 mg in healthy young and elderly subjects. SAR164653 was safe and well tolerated at doses up to 800 mg in healthy subjects, and a maximum tolerated dose could not be determined from the study. Activity of ß‐galactosidase measured in leukocytes did not show any abnormalities. The t max was 1.0 to 2.5 hours, and the t 1/2 was ∼5–11 after single dosing; exposure increased less than dose proportional. Following multiple dosing, accumulation was not observed, C max and AUC 0–24 increased in a dose‐proportional manner, and t 1/2 was around 14–20 hours. The novel CathA inhibitor SAR164653 was found to have a favorable safety profile in these early phase 1 studies, but further studies are required to confirm if SAR164653 is equally safe in patients undergoing long‐term treatment.
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SAR164653 (CTSAi) is a selective small-molecule inhibitor of CTSA.
“We next evaluated the effect of CTSA inhibition using the selective small-molecule inhibitor SAR164653 (CTSAi) 35,36 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [36]
Phase I clinical studies of the CTSA inhibitor SAR164653 in healthy individuals showed a promising safety profile and supported proposed studies for ischaemic cardiomyopathy.
“Phase I clinical studies of the CTSA inhibitor SAR164653 in healthy individuals showed a promising safety profile and supported proposed studies for ischaemic cardiomyopathy 35,36 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [36]
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Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
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- Authors
- Tillner, J., Lehmann, A., Paehler, T., Lukacs, Z., Ruf, S., Sadowski, T., Pinquier, J., & Ruetten, H.
- Affiliations
- Sanofi (Germany) (DE)
- Hamburg University Medical Center Metabolic Laboratory Hamburg Germany
- Sanofi (France) (FR)
- Corresponding author
- Tillner, Joachim
- Venue
- Clinical Pharmacology in Drug Development
- Publisher
- Wiley
- Published
- 2015-09-24
- Volume
- 5
- Issue
- 1
- Pages
- 57-68
- ISSN
- 2160-763X (ISSN-L)
- 2160-7648
- OpenAlex
- W1952933997
- Cited by
- 14
- References
- 24
- Citations by year
- 2026: 5 · 2022: 1 · 2020: 1 · 2019: 3 · 2018: 1 · 2017: 1 · 2016: 2
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology in Drug Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sanofi
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- cathepsin A, heart failure, pharmacokinetics, tolerability, safety, dose proportionality, beta-galactosidase, leukocytes, healthy volunteers, repeated dosing
- MeSH terms
- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, Double-Blind Method, Female, Half-Life, Humans, Male, Middle Aged, Area Under Curve, Cathepsin A, Young Adult
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