The RANKL Inhibitor Denosumab

OP0120 - The RANKL Inhibitor Denosumab reduces progression of the total Sharp Score and bone erosions in patients with Rheumatoid Arthritis: X-Ray results at 12 months

Authors: D. van der Heijde, S.B. Cohen, J.T. Sharp, P. Ory, L. Zhou, W. Tsuji, R. Newmark

OP0226 - Inhibiting RANKL with Denosumab reduces progression of bone erosions in patients with Rheumatoid Arthritis: 6-Month MRI results from a randomized, Placebo-Controlled Study

Authors: S.B. Cohen, P.A. Valen, C. Ritchlin, J. Schechtman, C.G. Peterfy, D. van der Heijde, L. Zhou, R. Newmark, W. Tsuji

Background:

Denosumab (previously AMG 162) 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) and in other forms of erosive arthritis such as psoriatic arthritis, as well as in the bone resorption of osteoporosis, and metastatic bone disease. We have previously reported on the results from this study presented at ACR 2006 showing a significant reduction in bone erosions by MRI at 6 months with a single dose of denosumab 180 mg (http://www.hopkins-arthritis.org/physician-corner/education/acr2006/RA/Other-Agents/RA-Other-Agents-Abstract-2120.html). At EULAR 2007 additional data were presented from this ongoing study including 12 month plain radiographic results.

Methods:

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. Increasing scores reflect increased damage. Safety was monitored throughout the study.

Results:

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 Months
Measurement (Mean (SD))	Placebo	Denosumab 60 mg	Denosumab 180 mg
	n = 71	n = 69	n = 69
Total Sharp Score	1.87 (5.06)	0.85 (2.52)*	0.97 (2.70)†
Erosion Score	1.34 (4.40)	0.33 (1.22)#	0.19 (1.61)#
Joint Space Narrowing	0.53 (1.49)	0.51 (1.63)	0.78 (1.72)

*P = 0.03 vs. placebo, †P = 0.18 vs. placebo #P < 0.05 vs. placebo.

Conclusion:

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.

Editorial Comment:

The results from these denosumab studies in RA are very encouraging in terms of the role of a potent osteoclast inhibitor as a component of treatment for patients. These results support the earlier studies demonstrating slowing of MRI-detectable erosions, and importantly show that a shorter term MRI outcome may serve as an early surrogate for plain radiographically detectable changes. As previously noted, the ultimate place for this compound in the treatment armamentarium is unclear as there is still no indication of an effect on signs and symptoms, or effects on cartilage. Nonetheless the idea that a medication (with few side effects so far) could lead to a marked reduction in erosions is encouraging. There may also be a significant role for this medication in helping to prevent steroid-induced osteoporosis, given the concomitant steroids used by many patients; however, while studies have been reported for postmenopausal osteoporosis showing improved BMD compared to a placebo, there are not yet studies to demonstrate its effects in steroid-induced osteoporosis.