Denosumab Offers New Approach to Treating Bone Erosions in People with Rheumatoid Arthritis

Newswise — Denosumab treatment every six months can reduce bone erosions in patients with rheumatoid arthritis, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Boston, Mass.

Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 2.1 million Americans have RA, most of them women.

Denosumab is a fully human monoclonal antibody which attaches to, and inhibits, a molecule in the bone called RANK ligand. RANK ligand is important in the function of osteoclasts, the cells responsible for bone resportion. If overproduced in the body, RANK ligand can cause bone loss, including bone erosions in rheumatoid arthritis.

Researchers conducted a study to determine if denosumab treatment could reduce the progression of bone erosions in patients with rheumatoid arthritis taking methotrexate.

A total of 227 patients were randomly assigned in this double-blind, placebo-controlled study and received subcutaneous injections of 60 or 180 mg of denosumab or placebo every six months.

To assess progress, X-rays were taken of hands and feet at the beginning of the study and at six months and 12 months into the study. By using a standard scoring system to measure damage to joints by x-ray, erosions and joint space narrowing were evaluated and monitored throughout the study.

Eighty-nine percent of the participants completed the 12 month study. Participants taking denosumab (at both 60 and 180 mg) showed decreased progression of bone erosions compared with the placebo group; this effect was already discernable by six months for the higher dose group. However, there was no detectable difference in joint space narrowing between the groups, and the data for cartilage turnover suggested that the dose and frequency used in the study may not have been sufficient to preserve cartilage.

The erosion scores after six months from the standard x-rays were consistent with erosion scores seen by magnetic resonance imaging studies. Adverse events were similar across all three treatment groups.

"These data show the significant potential of denosumab, revealing that patients receiving denosumab experienced a reduced progression of erosions compared to control," said Désirée van der Heijde, MD, PhD; professor of rheumatology; dept of rheumatology; Leiden University Medical Center; The Netherlands. "Most significant was the difference observed between the control group and the group receiving denosumab 180mg. The reduction in progression of erosions was already present in this group as early as six months after only one injection."

http://www.rheumatology.org/annual

Editor's Notes: Dr. van der Heijde will present this research during the ACR Annual Scientific Meeting at the Boston Convention and Exhibition Center from 2:30 " 4:00 pm ET on Thursday, November 8, 2007, in Grand Ballroom East. Dr. van der Heijde will be available for media questions and briefing at 8:30 am ET on Saturday, November 10 in the on-site press conference room, Room 251. Presentation Number: 698

Denosumab Inhibits RANKL, Reducing Progression of the Total Sharp Score and Bone Erosions in Patients With Rheumatoid Arthritis: 12-month X-Ray Results

Désirée van der Heijde1, Stanley Cohen2, John T. Sharp3, Peter Ory3, Lifen Zhou4, Wayne Tsuji4, Richard Newmark4. 1Leiden University Medical Center, Leiden, The Netherlands; 2Metroplex Center for Clinical Research, Dallas, TX; 3University of Washington, Seattle, WA; 4Amgen, Inc., Thousand Oaks, CA

Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL, a key mediator of osteoclast formation, function, and survival. RANKL-driven osteoclast activity has been implicated in the bone erosions that are characteristic of rheumatoid arthritis (RA).

This ongoing, double-blind, placebo-controlled, phase 2 study was conducted to determine if denosumab treatment could reduce the progression of bone erosions in patients with RA on background methotrexate (MTX).

A total of 227 patients were randomly assigned to receive subcutaneous injections of denosumab 60 mg (n=73) or 180 mg (n=76) or placebo (n=78) every 6 months. Radiographs of hands and feet were taken at baseline, 6, and 12 months. In exploratory analyses, changes from baseline in the radiographic assessments using the van der Heijde-modified total Sharp score (TSS) and its components (erosion score and joint space narrowing [JSN] score) were evaluated at month 6 and month 12. Safety was monitored throughout the study. Increasing scores reflect increased damage.

A total of 202 patients (89%) completed 12 months of study. A smaller increase in mean TSS from baseline was observed in the 60-mg dose group than in the placebo group at month 12 (table; P=.03). The increase in mean TSS was also smaller in the 180-mg group than in the placebo group (table; P=.18). The increase from baseline in the mean erosion score was smaller than placebo for both the denosumab 60-mg and 180-mg groups (table; P<.05) at month 12 (mean reduction, 75% and 86%, respectively). For changes in JSN, no detectable difference was observed between the denosumab and placebo groups (table). Modeling of data for collagen C-telopeptide Type II (CTX-II, a biomarker of cartilage turnover) suggests that the dose/frequency used in this study may not have been sufficient to preserve cartilage. The radiographic erosion scores were consistent with MRI erosion scores analyzed as the primary endpoint of the study. Adverse events were similar across the 3 treatment groups.

Change in Score at 12 MonthsMeasurement: Mean (SD) PlaceboN = 71 Denosumab 60 mgN = 69 Denosumab 180 mgN = 69Total Sharp Score 1.87 (5.06) 0.85 (2.52)a 0.97 (2.70)bErosion Score 1.34 (4.40) 0.33 (1.22)c 0.19 (1.61)cJoint Space Narrowing 0.53 (1.49) 0.51 (1.63) 0.78 (1.72) a P = .03 vs. placebo b P = .18 vs. placebo c P < .05 vs. placebo

Denosumab treatment (60 mg and 180 mg) every 6 months reduced progression of TSS and bone erosions compared with placebo, with an adverse event profile similar to placebo.

Disclosure Block: D. van der Heijde, Abbott Laboratories, 5; Amgen, Inc., 5; Bristol-Myers Squibb, 5; Centocor, 5; Chugai, 5; Merck, 5; Schering-Plough, 5; UCB, 5; Wyeth, 5; S. Cohen, Amgen, Inc., 2; Genentech, 2; Biogen Idec, 2; Merck & Co., 2; Sanofi-Aventis, 2; Procter & Gamble, 2; Pfizer, 2; Centocor, 2; Scios, 2; Bristol-Myers Squibb, 2; Wyeth-Ayerst, 2; Amgen, Inc., 5; Sanofi-Aventis, 5; Procter & Gamble, 5; Scios, 5; Wyeth-Ayerst, 5; Genentech, 5; Genentech, 8; Sanofi-Aventis, 8; Procter & Gamble, 8; Amgen, Inc., 8; Scios, 8; Wyeth-Ayerst, 8; J.T. Sharp, Amgen, Inc., 5; Abbott Laboratories, 5; Biogen Idec, 5; P. Ory, Abbott Laboratories, 5; Amgen, Inc., 5; Targeted Genetics, 5; Tanabe, 5; Fujisawa, 5; L. Zhou, Amgen, Inc., 1; Amgen, Inc., 3; W. Tsuji, Amgen, Inc., 1; Amgen, Inc., 3; R. Newmark, Amgen, Inc., 1; Amgen, Inc., 3.