Response rates with an investigational dissociated agonist of the glucocorticoid receptor (DAGR) were comparable with response rates with prednisone in patients with rheumatoid arthritis (RA). Results of a phase 2 trial were presented by Vibeke Strand, MD, Stanford University, Stanford, California, USA.

The glucocorticoid receptor (GR) regulates genes that control development and metabolism and the immune response [Buttgereit F et al. Lancet. 2005; Arthritis Rheum. 2004]. A DAGR is a nonsteroidal ligand of the GR that has both partial agonist and antagonistic properties [De Bosscher K et al. Brain Behav Immun. 2010].

Preclinical and phase 1 and phase 2a clinical data had demonstrated that PF-04171327, a selective high-affinity partial agonist of the GR, possesses potent anti-inflammatory activity at doses that produce potentially fewer adverse effects commonly associated with glucocorticoids, namely adverse bone and glucose metabolism [Hu X et al. Endocrinology. 2011].

The phase 2 trial was undertaken to determine the efficacy and safety of 4 doses of DAGR after 8 weeks of treatment compared with placebo and prednisone. It was conducted in 323 patients who had moderate to severe RA despite treatment with methotrexate. Patients were randomized to receive once-daily doses of the DAGR at 1, 5, 10, or 15 mg; prednisone, 5 or 10 mg; or placebo for 8 weeks, followed by a 4-week taper.

The primary end points at week 8 were American College of Rheumatology 20% improvement response criteria (ACR20) and assessment of the dissociation bone biomarkers total procollagen type 1 N-terminal propeptide (P1NP) and osteocalcin, markers of bone formation, and urine N-telopeptide/urine creatinine (uNTX/uCr) and serum C-telopeptide, markers of bone resorption.

ACR20 responses were achieved by 78% of patients randomized to 10 mg/d of DAGR. The proportion of responders to other doses of DAGR ranged from 44% (1 mg) to 68% (15 mg). Among patients randomized to prednisone, 51% achieved an ACR20 response with 5 mg and 72% with 10 mg. Thirty-eight percent of the placebo group had an ACR20 response. The rates of ACR50 and ACR70 responses were also similar between DAGR and prednisone (Figure 1). DAGR 10 and 15 mg were significantly superior to placebo, and DAGR 15 mg was noninferior to prednisone 10 mg.

Compared with prednisone 5 mg, the 1-, 5-, and 10-mg doses of DAGR were noninferior on P1NP values, and all doses of DAGR were noninferior on the osteocalcin end point. Compared with prednisone 5 mg, DAGR at 1, 5, and 10 mg was noninferior on the uNTX/uCr end point, and 5 mg of DAGR was noninferior on serum C-telopeptide. All doses of DAGR and 5 mg of prednisone resulted in similarly small decreases in HbA_1c values from screening to week 8.

The safety profile of DAGR was comparable with placebo and prednisone. The rates of treatment-emergent adverse events (AEs) were similar across all groups. Serious AEs occurred in 2% to 4% of patients in each randomized group. No significant laboratory abnormalities were observed. Suppression of plasma cortisol was observed with 5, 10, and 15 mg of DAGR compared with partial suppression with prednisone at 5 and 10 mg. No clinical symptoms of adrenal insufficiency were reported at any time. Prompt recovery of the hypothalamic-pituitary-adrenal axis was evident at week 13 in all patients.

The totality of the data demonstrates superior efficacy of DAGR 10 and 15 mg compared with placebo and comparable efficacy compared with prednisone 10 mg, concluded Dr Strand. All DAGR doses were noninferior to prednisone 5 mg on bone formation biomarkers.