title: Predicting the probability of successful efficacy of a dissociated agonist of the glucocorticoid receptor from dose-response analysis.
abstract: PF-04171327 is a dissociated agonist of the glucocorticoid receptor (DAGR) being developed to retain anti-inflammatory efficacy while reducing unwanted effects. Our aim was to conduct a longitudinal dose-response analysis to identify the DAGR doses with efficacy similar to or greater than prednisone 10 mg once daily (QD). The data included were from a Phase 2, randomized, double-blind, parallel-group study in 323 subjects with active rheumatoid arthritis on a background of methotrexate. Subjects received DAGR 1, 5, 10 or 15 mg, prednisone 5 or 10 mg, or placebo QD for 8 weeks. The Disease Activity Score 28-4 calculated using C-Reactive Protein (DAS28-4 CRP) was the efficacy endpoint utilized in this dose-response model. For DAGR, the maximum effect (Emax) on DAS28-4 CRP was estimated to be -1.2 points (95 % CI -1.7, -0.84), and the evaluated dose range provided 31-87 % of the Emax; for prednisone 5 and 10 mg, the estimated effects were -0.27 (95 % CI -0.55, 0.006) and -0.94 point (95 % CI -1.3, -0.59), respectively. Stochastic simulations indicated that the DAGR 1, 5, 10 and 15 mg have probabilities of 0.9, 29, 54 and 62 %, respectively, to achieve efficacy greater than prednisone 10 mg at week 8. DAGR 9 mg estimated probability was 50 % suggesting that DAGR ≥9 mg QD has an effect on DAS28-4 CRP comparable to or greater than prednisone 10 mg QD. This work informs dose selection for late-stage confirmatory trials.
authors.affiliation: Pfizer Global Innovative Pharma Business, Groton, CT, USA.|Metrum Research Group LLC, 36 Washington Street, Suite 245, Wellesley, MA, 02481, USA.
authors.forename: Daniela J
authors.initials: DJ
authors.lastname: Conrado
authors.affiliation: Pfizer Global Innovative Pharma Business, Groton, CT, USA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.affiliation: Pfizer Japan Inc. Development Japan, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shoji
authors.affiliation: Pfizer Global Innovative Pharma Business, Pfizer, NY, USA.
authors.forename: Sheela
authors.initials: S
authors.lastname: Kolluri
authors.affiliation: Pfizer Global Innovative Pharma Business, Pfizer, NY, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Hey-Hadavi
authors.affiliation: Pfizer Global Innovative Pharma Business, Pfizer, NY, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: McCabe
authors.affiliation: Pfizer Global Innovative Pharma Business, Groton, CT, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rojo
authors.affiliation: Pfizer Global Innovative Pharma Business, Collegeville, PA, USA. brinda.tammara@pfizer.com.
authors.forename: Brinda K
authors.initials: BK
authors.lastname: Tammara
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000032:analysis; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010755:Organophosphates / Q000008:administration & dosage* / Q000627:therapeutic use*; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000627:therapeutic use*; D011336:Probability; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D012720:Severity of Illness Index; D013269:Stochastic Processes; D016896:Treatment Outcome; D055815:Young Adult; D001549:Benzamides
chemical_list: D000893:Anti-Inflammatory Agents; D002097:C-Reactive Protein; D010755:Organophosphates; D010616:Phenanthrenes; D011965:Receptors, Glucocorticoid; C000615597:fosdagrocorat; D001549:Benzamides
keywords: Disease activity score 28-4 C-reactive protein (DAS28-4 CRP); Dissociated agonist of glucocorticoid receptor (DAGR); Longitudinal dose–response; Phase 2 randomized double-blind clinical trial; Rheumatoid arthritis (RA); Stochastic simulations