Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist

Abstract

ACT-774312 is an antagonist of the chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type-2 inflammatory diseases. Placebo, single doses of 1-1000 mg, or multiple doses of 30-500 mg either once or twice daily for 4 days of ACT-774312 were administered orally to healthy subjects. The single-and multiple-dose pharmacokinetics (PK) of ACT-774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half-life of about 12 hours In the presence of food, t max was delayed by 1 hour and exposure to ACT-774312 slightly decreased. Full blockade (>90% of the maximum effect, E max ) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT-774312 twice daily and lasted for at least 9 hours The relationship between ACT-774312 concentration and CRTH2 blockade was described by a E max model. The estimated twicedaily dose of ACT-774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT-774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT-774312. K E Y W O R D SACT-774312, CRTH2, entry-into-man study, pharmacokinectics, receptor internalization

Design, Synthesis, and Optimization of Indole Acetic Acid Derivatives as Potent and Selective CRTH2 Receptor Antagonists: Discovery of ACT‐774312

“…Based on that data, (S)‐72 ( ACT‐774312 ) was selected as a follow‐up of setipiprant ( ACT‐129968 ). The compound was safe and well tolerated in phase 1 clinical studies after single‐ and multiple‐dose administrations [48] …”

“…This highly potent CRTH2 antagonist with an excellent overall biological profile together with good pharmacokinetic properties in animals and a low potential to inhibit or induce cytochrome P450 enzymes, was selected as a follow‐up of setipiprant ( ACT‐129968 ) for clinical development. Compound (S)‐72 ( ACT‐774312 ) was safe and well tolerated in phase 1 clinical studies [48] . Following initial exploratory results in nasal polyposis in a phase 2 clinical trial, the company decided not to pursue this indication any further.…”

The randomized, single‐ and multiple‐ ascending dose studies of the safety, tolerability, pharmacokinetics of CSPCHA115 in healthy Chinese subjects

“…25,26 Several CRTH2 antagonists have been studied in recent years but have shown limited efficacy. 15,16,[27][28][29][30] After the failure of the LUSTER-1 and LUSTER-2 trials of fevipiprant, many clinical developments of CRTH2 antagonists halted. One explanation for these negative results…”

“…PGD2‐CRTH2 signaling produces a powerful chemotactic effect on eosinophils, leading to Th2‐type inflammation, such as asthma and allergic rhinitis 25,26 . Several CRTH2 antagonists have been studied in recent years but have shown limited efficacy 15,16,27–30 . After the failure of the LUSTER‐1 and LUSTER‐2 trials of fevipiprant, many clinical developments of CRTH2 antagonists halted.…”

The Case for an Unblinded Modeler in Early Clinical Development

“…Model‐guided dose escalation allows extending the classical approach. The targeted dose can be defined as a specific biomarker target such as receptor antagonism or, classically, the determination of the MTD. On a PK level, modeling can guide the implementation of an uptitration regimen by assessing the achievement of approximately 90% of the steady‐state concentration before increasing the dose to assess safety at the current dose for repeated dosing…”