Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of LXR‐623, a Novel Liver X‐Receptor Agonist, in Healthy Participants

Abstract

Liver X-receptor (LXR) agonists have been postulated to enhance reverse cholesterol transport (RCT), a process believed to shuttle cholesterol from the periphery back to the liver. Enhancing RCT via the upregulation of cholesterol transporters such as the adenosine triphosphate-binding cassettes ABCA1 and ABCG1 could therefore inhibit the progression of atherosclerosis. LXR-623 is a synthetic ligand for LXRs alpha and beta that has shown promise in animal models of atherosclerosis. The authors present results from a single ascending-dose study of the safety, pharmacokinetics, and pharmacodynamics of LXR-623 in healthy participants. LXR-623 was absorbed rapidly with peak concentrations (C(max)) achieved at approximately 2 hours. The C(max) and area under the concentration-time curve increased in a dose-proportional manner. The mean terminal disposition half-life was between 41 and 43 hours independently of dose. LXR activation resulted in a dose-dependent increase in ABCA1 and ABCG1 expression. The effect of LXR-623 concentration on ABCA1 and ABCG1 expression was further characterized via a population pharmacokinetic-pharmacodynamic analysis, yielding EC(50) estimates of 526 ng/mL and 729 ng/mL, respectively. Central nervous system-related adverse events were observed at the 2 top doses tested. The pharmacodynamic effects described here are the first demonstration of "target engagement" by an LXR agonist in humans.

Nuclear Receptors and Their Selective Pharmacologic Modulators

“…Along with the natural function in lowering plasma cholesterol, it did not appear to have the adverse side effects seen with other LXR agonists. LXR-623 (2-[(2-chloro-4-fluorophenyl) methyl]-3-(4-fluorophenyl)-7-(trifluoromethyl)indazole), an indazole, was also tested in the first reported phase 1 clinical trials; it had adverse CNS side effects, so the study was terminated (DiBlasio-Smith et al, 2008;Katz et al, 2009).…”

“…WAY-252623 (LXR-623) (Fig. 13) is one such indazole-based selective LXR modulator with an IC 50 of 179 and 24 nM for LXRa and LXRb, respectively (Katz et al, 2009). The X-ray structure of LXR-623 bound to LXRb revealed that N-1 indazole nitrogen forms a hydrogen bond with His435, while the 7-trifluoromethyl group makes electrostatic interactions with the same residue; this makes it different from GW3965 and explains its good in vivo efficacy .…”

Nuclear Receptor Signaling Inhibits HIV-1 Replication in Macrophages through Multipletrans-Repression Mechanisms

“…LXR agonists, on the other hand, are not approved for clinical use in humans. The LXR agonist TO-901317 was tested in a clinical trial for the treatment of atherosclerosis and hyperlipidemia; however, the trial was discontinued due to unexpected neurotoxicity after systemic administration (33,74). In a topical preparation, however, the systemic adverse effects associated with NR ligand administration might be limited.…”

Cinnamamides, Novel Liver X Receptor Antagonists that Inhibit Ligand-Induced Lipogenesis and Fatty Liver

“…LXR-623, a tissue-specific ligand that activates LXR with limited hepatic liability, was also disappointing; central nervous system-related adverse events were observed in the first-in-humans clinical trial (Katz et al, 2009). Therefore, it is essential to identify selective LXR agonists or antagonists that have beneficial effects on the target tissue with minimal unwanted effects on off-target tissues.…”