Fosdagrocorat (PF-04171327) versus prednisone or placebo in rheumatoid arthritis: a randomised, double-blind, multicentre, phase IIb study

Abstract

Objectives: Glucocorticoids have anti-inflammatory, transrepression-mediated effects, although adverse events (AEs; transactivation-mediated effects) limit long-term use in patients with rheumatoid arthritis (RA). We evaluated the efficacy and safety of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, versus prednisone or placebo.

Methods: In this 12-week, phase II, randomised controlled trial, 323 patients with moderate to severe RA were randomised 1:1:1:1:1:1:1 to fosdagrocorat (1 mg, 5 mg, 10 mg or 15 mg), prednisone (5 mg or 10 mg) or placebo, once daily. The primary endpoints (week 8) were American College of Rheumatology 20% improvement criteria (ACR20) responses, and percentage changes from baseline in biomarkers of bone formation (procollagen type 1 N-terminal peptide [P1NP]) and resorption (urinary N-telopeptide to urinary creatinine ratio [uNTx:uCr]). Safety was assessed.

Results: ACR20 responses with fosdagrocorat 10 mg and 15 mg were superior to placebo, and fosdagrocorat 15 mg was non-inferior to prednisone 10 mg (week 8 model-predicted ACR20 responses: 47%, 61%, 69% and 73% vs 51%, 71% and 37% with fosdagrocorat 1 mg, 5 mg, 10 mg and 15 mg vs prednisone 5 mg, 10 mg and placebo, respectively). Percentage changes from baseline in P1NP with fosdagrocorat 1 mg, 5 mg and 10 mg met non-inferiority criteria to prednisone 5 mg. Corresponding changes in uNTx:uCr varied considerably. All fosdagrocorat doses reduced glycosylated haemoglobin levels. AEs were similar between groups; 63 (19.5%) patients reported treatment-related AEs; 9 (2.8%) patients reported serious AEs. No patients had adrenal insufficiency, treatment-related significant infections or laboratory abnormalities. No deaths were reported.

Conclusion: In patients with RA, fosdagrocorat 10 mg and 15 mg demonstrated efficacy similar to prednisone 10 mg and safety similar to prednisone 5 mg.

Trial registration number: NCT01393639.

Keywords: disease activity; rheumatoid arthritis; treatment.

Conflict of interest statement

Competing interests: FB has received consultancy fees, honoraria and travel expenses from Pfizer Inc. VS is a consultant for Pfizer Inc. EBL has acted as a consultant for Pfizer Inc. BT, RR, AG and JH-H are employees of Pfizer Inc. DM was an employee of Pfizer Inc at the time the trial was conducted.

Figures

Figure 1

(A) ACR20, ACR50 and ACR70 sample proportions at week 8, and (B) ACR20, (C) ACR50 and (D) ACR70 responses over time (Fas, NRI). All study treatments were administered once daily. ACR20/50/70, American College of Rheumatology response criteria; Fas, full analysis set; NRI, non-responder imputation.

Figure 2

Mean change from baseline in (A) P1NP and (B)uNTx:uCr over time (active treatment and taper periods). All study treatments were administered once daily. All statistical values are derived from a repeated measures mixed model with fixed effects for treatment and visit, treatment-by-visit interaction and baseline value. P1NP, procollagen type 1 N-terminal telopeptide; uNTx:uCr, urinary N-terminal telopeptide to urinary creatinine ratio.

Figure 3

(A) Change from screening in glucose metabolism biomarker HbA1c at week 8. (B) Change from baseline in cortisol over time (active treatment and taper periods). *Estimates are from an ANCOVA model with baseline as a covariate. All study treatments were administered once daily. ANCOVA, analysis of covariance; HbA1c, glycosylated haemoglobin; LS, least squares.