Background/Purpose:

PF-04171327, a pro drug of PF-00251802, is under investigation as a potential dissociated agonist of the glucocorticoid receptor (DAGR). PF-00251802 is a selective high-affinity partial agonist of the glucocorticoid receptor (GR). It manifests potent anti-inflammatory activity in preclinical in vivo models, at exposures that provide lower adverse effects on bone and glucose metabolism relative to prednisolone, a full GR agonist. If this dissociation is present clinically, PF-04171327 represents a therapeutic improvement relative to current glucocorticoids (GC). The purpose of this study was to evaluate efficacy and safety of PF-04171327, relative to placebo (PBO) and low-dose prednisone, in subjects with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

Methods:

Adult subjects (>18 years) with active RA and receiving concomitant MTX were randomized to receive oral doses of either PF-04171327 10 mg (n=21) or 25 mg (n=22), prednisone 5 mg (n=21), or PBO (n=22) once daily for 2 weeks in a blinded fashion. Diagnosis of active RA was based on the ACR 1987 Revised Criteria (including at least 6 tender and 6 swollen joints plus elevated CRP of 0.7 mg/dL or higher). Subjects with prior use of GC within six weeks of baseline were excluded. The primary efficacy endpoint was the change from baseline on DAS28-4 (CRP) at Week 2. Secondary efficacy variables included: ACR20/50/70 response rates; individual components of ACR response; DAS28‑3 (CRP) and DAS28‑4 (CRP), and SF-36. Adverse events (AEs) and safety laboratory tests were recorded throughout. Blood samples were collected for pharmacokinetic and biomarker analyses.

Results:

At Week 2, PF-04171327 10 mg and 25 mg showed a statistically significantly greater improvement in the mean change from baseline in DAS28 over PBO by ‑0.73 (p=0.0141) and ‑1.26 (p<0.0001), respectively. In addition, both doses of PF-04171327 demonstrated a greater reduction in DAS28 than prednisone 5 mg at Week 2. Prednisone did not show statistically significant differences in the mean change from baseline in DAS28 over PBO. The effects of PF-04171327 on secondary efficacy variables were generally consistent with those observed for the primary endpoint. Treatment-emergent all causality AEs were reported for 8 (38%), 3 (14%), 11 (19%), and 12 (55%) subjects in the PF-04171327 10 mg, 25 mg, prednisone 5 mg, and PBO groups, respectively. The majority of AEs were mild in severity, with headache the most frequently reported. Four subjects discontinued the study due to an AE (two subjects from the PF-04171327 10 mg group and 2 subjects from the PBO group). There were no SAEs during the study.

Conclusion:

PF-04171327 10 mg and 25 mg demonstrated robust and rapid onset of efficacy relative to PBO and prednisone. Both doses were well tolerated. These results support ongoing evaluation of PF-04171327 as a treatment for RA.  

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/phase-2-evaluation-of-pf-04171327-a-dissociated-agonist-of-the-glucocorticoid-receptor-for-the-treatment-of-rheumatoid-arthritis-in-patients-with-an-inadequate-response-to-methotrexate/