Pharmacodynamics, Pharmacokinetics, and Safety of AM211: A Novel and Potent Antagonist of the Prostaglandin D₂ Receptor Type 2

Abstract

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Pharmacokinetics, Safety, and Tolerability of Fevipiprant (QAW039), a Novel CRTh2 Receptor Antagonist: Results From 2 Randomized, Phase 1, Placebo‐Controlled Studies in Healthy Volunteers

“…Multiple CRTh2 receptor antagonists are under clinical investigation, and there has also been a significant degree of turnover of CRTh2 antagonists in clinical development (AZD1981, setipiprant, AZD5985, RG7185), the main reasons disclosed being low clinical efficacy (setipiprant) or undesirable PK profiles . For example, MK7246 was discontinued because of high intersubject variability, and studies on AM211 also reported high intersubject variability and enterohepatic recirculation . In contrast, fevipiprant has demonstrated efficacy in phase 2 studies in patients with asthma and is now proceeding toward development phase 3.…”

“…In contrast, fevipiprant has demonstrated efficacy in phase 2 studies in patients with asthma and is now proceeding toward development phase 3. Clinical efficacy was observed as well as strong mechanistic effects, including a reduction in lung eosinophils that was demonstrated in a recently published mechanistic study …”

Retinoic Acid Modulates PTGDR Promoter Activity

“…Moreover, we identified RARE elements in this promoter region, and found that differential allelic occupancy at different positions determines modifications in transcription factor binding that could explain differential promoter activation. All these results provide new insights into the effects of RA and treatments based on PTGDR modulators [36], although more studies are needed to assess the relevance of these results to allergic diseases.…”

Pharmacological Therapy of Bronchial Asthma: The Role of Biologicals

“…The two CRTH2 antagonists in phase I clinical trials are AM211 [(2′-[3-benzyl-1-ethyl-ureidomethyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid sodium salt] [86] and RG7185. To the date of reporting, three CRTH2 antagonists have been tested in phase II trials, i.e.…”