BOSTON – A nonsteroidal investigational drug that acts on the glucocorticoid receptor was superior to placebo and noninferior to higher-dose prednisone in adults with rheumatoid arthritis, investigators report.
The drug, prosaically labeled PF-04171327, is a dissociated agonist of the glucocorticoid receptor, lending it the handy acronym DAGR (pronounced “dagger.”). In a phase II safety and efficacy trial, 10-mg and 15-mg daily doses of DAGR were superior in efficacy to placebo at improving rheumatoid arthritis (RA) disease activity scores, and the drug was comparable in efficacy to prednisone at a 10-mg daily dose but with effects similar to 5 mg prednisone on bone formation and glucose markers, said Dr. Vibeke Strand, a rheumatologist and biopharmaceutical consultant based in Portola Valley, Calif.
Dr. Vibeke Strand
“Suppression of plasma cortisol was observed with DAGR 5, 10, and 15 mg versus partial suppression with prednisone 5 and 10 mg. No clinical symptoms of adrenal insufficiency were reported at any time, and rapid recovery of suppression of the HPA [hypothalamic-pituitary-adrenal] axis was evident by week 13 after taper,” she said at a late-breaking abstract session at the annual meeting of the American College of Rheumatology.
In preclinical studies, DAGR was shown to have potent anti-inflammatory activity similar to glucocorticoids such as prednisone but with fewer potential adverse events, and phase I trials in healthy volunteers indicated that it was safe. The drug was also shown to have efficacy against RA in a phase IIa trial, Dr. Strand said.
A seven-arm study
In the current study, 323 patients were randomly assigned to receive DAGR in doses of 1 mg (45 patients), 5 mg (47), 10 mg (45), 15 mg (48); prednisone in doses of 5 mg (45) or 10 mg (46); or placebo (47). The study measured efficacy by ACR 20 criteria in which patients must have at least 20% fewer tender joints and at least 20% fewer swollen joints, plus at least a 20% improvement in at least three of five areas: patient and physician rated global assessment of RA, patient pain and physical functioning self-assessments, and erythrocyte sedimentation rate or C-reactive protein results.
At 8 weeks, ACR 20 responses by nonresponder imputation were seen in 78% of patients on the 10 mg DAGR dose, compared with 72% on 10 mg prednisone, 68% on 15 mg DAGR, 60% on 5 mg DAGR, 44% on 1 mg DAGR, 51% on 5 mg prednisone, and 38% on placebo. Similarly proportioned but smaller responses were seen for ACR 50 and ACR 70 measures.
Effects on bone formation biomarkers
An analysis of the effects of DAGR and prednisone on bone formation biomarkers showed that the experimental agent at doses of 1, 5, and 10 mg was noninferior to 5 mg prednisone as measured by procollagen type 1 N-terminal propeptide (P1NP), and that DAGR at all four dose levels tested was noninferior to 5 mg prednisone as measured by osteocalcin.
DAGR at the three lowest dose levels was also noninferior to 5 mg prednisone, according to the bone resorption biomarker type I collagen N-telopeptide related to creatinine (uNTX/uCr), and 5 mg DAGR was noninferior to the comparable prednisone dose for the resorption biomarker serum C-terminal cross-linking telopeptide of type I collagen (sCTX).
DAGR effect on blood glucose and cortisol
DAGR at all four dose levels was also comparable to 5 mg prednisone in the mean change from baseline to week 8 in hemoglobin A1C in the study population, which was largely comprised of patients without diabetes.
Where DAGR differed from prednisone at both the 5- and 10-mg doses, however, was in its effect on cortisol suppression. The experimental drug at 5-, 10-, and 15-mg doses was found to suppress cortisol significantly more than did both doses of prednisone, which were associated with only partial cortisol suppression. An adrenocorticotropic hormone (ACTH) stimulation test at week 13 showed rapid recovery of HPA axis suppression in more than 95% of all patients, with the remaining patients recovering by week 15, except for two patients who were lost to follow-up.
Treatment adverse events occurred in 20%, 19%, 22%, and 18% of patients on DAGR (from lowest to highest dose), compared with 16% on 5 mg prednisone, 19% on 10 mg prednisone, and 17% of patients on placebo. There were five serious adverse events among all patients on DAGR, three among patients on prednisone, and two among placebo controls.
The findings warrant further evaluation of DAGR as an alternative to prednisone in the treatment of patients with autoimmune disease, Dr. Strand said.
The study was funded by Pfizer. Dr. Strand disclosed serving as a consultant and advisory board member to Pfizer and several other companies.