Asthma and lower airway disease
Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients

https://doi.org/10.1016/j.jaci.2012.10.013Get rights and content

Background

The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2.

Objective

We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma.

Methods

Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV1, symptom scores, rescue short-acting β-agonist use, and exacerbations.

Results

Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, −0.492; range for AMG 853 groups [n = 317], −0.444 to −0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator.

Conclusion

AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma.

Section snippets

Patients

Eligible patients were aged 18 to 65 years, had moderate-to-severe asthma, and were receiving stable inhaled corticosteroids (ICSs; ≥200 and ≤1000 μg/d fluticasone or equivalent) for 30 or more days, with consecutive use for at least the prior 3 months before screening. Patients were recruited from each clinical site’s pool of patients or from referral and selected based on key inclusion criteria, which included ongoing asthma symptoms with Asthma Control Questionnaire (ACQ) scores of 1.5 or

Disposition

A total of 397 patients were randomized (placebo, n = 79; 5 mg of AMG 853 BID, n = 80; 25 mg of AMG 853 BID, n = 79; 100 mg of AMG 853 BID, n = 79; and 200 mg of AMG 853 QD, n = 80), and 396 received investigational product. One patient enrolled into the 5-mg AMG 853 BID group but did not meet eligibility requirements and therefore did not receive investigational product. Of all patients randomized, 351 (88.4%) completed the study. Forty-six patients prematurely discontinued the study, with 7

Discussion

This study provides the first clinical data to date examining the effects of a CRTH2 and DP dual antagonist as add-on treatment to ICS therapy in asthma. The findings from this study suggest that AMG 853, when evaluated as add-on treatment to ICSs in patients with moderate-to-severe persistent asthma whose symptoms are not fully controlled with ICSs, demonstrated no improvement in control of asthma or modifying biomarkers. The adverse events observed after AMG 853 treatment would not preclude

References (24)

  • A. Arimura et al.

    Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751

    J Pharmacol Exp Ther

    (2001)
  • M. Shichijo et al.

    A prostaglandin D2 receptor antagonist modifies experimental asthma in sheep

    Clin Exp Allergy

    (2009)
  • Cited by (0)

    Supported by Amgen.

    Disclosure of potential conflict of interest: W. W. Busse has served on the advisory board for Merck; has consultant arrangements with Amgen, AstraZeneca, Novartis, GlaxoSmithKline, MedImmune, and Genentech; has received research support from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases and the NIH/National Heart, Lung, and Blood Institute. S. E. Wenzel has received research support from Amgen. E. M. Kerwin has received research support from Amgen; has served on advisory boards or speakers' panels for Astra Zeneca (MAP Pharma), Dey Laboratories, Ironwood Pharmaceuticals, Pfizer, Sanofi Aventis, Sunovion (Sepracor), and Targacept; has received travel reimbursement from Merck (Schering-Plough), Forest Labs, and Novartis; has conducted clinical research trials for Abbott, Actelion, Adams, Alcon, ALK-Abelló, Allergy Therapeutics, Almirall, Amgen, Amphastar, Astellas, Astra Zeneca (MAP Pharma), Asubio, Biota, Boehringer Ingelheim, Cephalon (Centocor, Ception), Chiesi, Critical Therapeutics, Daiichi Sankyo, Dey Labs, Elevation Pharma, Elixir, Exelixis, Forest, Genentech, GlaxoSmithKline, Incyte, Inflazyme, Johnson & Johnson, Lilly, Meda, Medicinova, MedImmune, Med Pointe, Merck (Schering-Plough), Mpex, Novartis, Novo Nordisk, Otsuka, Pearl, Pfizer (Wyeth), Phenomix, Replidyne, Roche, Sanofi-Aventis, Skye Pharma, Stallergenes, Sunovion (Altana, Sepracor), TAP, Takeda, Targacept, Teva (Ivax), UCB Pharma, and Wellstat. M. C. Liu has received research support from GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Amgen and has served on the Data Safety Monitoring Board for Cephalon. N. Zhang, A. L. Budelsky, J. Lin, and S.-L. Lin are employed by Amgen. Y. Chon is employed by and holds stock in Amgen. The rest of the authors declare that they have no relevant conflicts of interest.

    View full text