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Tuesday, October 20, 2009: 5:15 PM
108 B (Pennsylvania Convention Center)
Presentation Number: 1943
Purpose: High-dose intra-articular GC is used commonly to treat OA, but oral GC is not used due to safety concerns in this patient population. CRx-102 is a combination of very low-dose prednisolone (Pd 2.7 mg/d) and dipyridamole (Dp), demonstrating synergistic enhanced anti-inflammatory GC effects in vitro and in vivo, without amplification of the GC adverse effects, approaching GC dissociation through a multi-target mechanism rather than medicinal chemistry. In previous RA and hand OA studies, CRx-102 exhibited clinically meaningful anti-inflammatory activity and was generally well-tolerated.
Methods: COMET-1 was a 14-week Ph2, double-blind, placebo-controlled, knee OA trial, with a 1-y follow-on safety extension. Subjects had screening WOMAC knee pain Q#1 VAS score of 30-80 mm with at least 10 mm flare following NSAID/Coxib discontinuation. Three CRx-102 doses (Pd 2.7 mg/d with Dp 90, 180 or 360 mg/d) were compared with Pd (2.7 mg/d) and placebo on knee OA and hand OA efficacy measurements. In the safety extension, all subjects received 1 of the 2 higher doses of CRx-102 and were monitored for long-term GC tolerability and durability of response. Intensive monitoring of weight, lipids, glucose homeostasis, HPA axis, bone density, intraocular pressure and cataract development with FDA-approved intervention rules makes this the first large, prospective, controlled study of the safety of very low-dose GC.
Results: COMET-1 enrolled 279 subjects and 141 continued in the safety extension (74% of eligible completers). With NSAID/Coxib therapy withdrawn, the CRx-102 (2.7/360) group had sustained, significant reductions in median WOMAC pain, function and stiffness scores vs. placebo, greater at D98 than the placebo and Pd groups by 17.2-19.5 mm and 5.5-8.6 mm, respectively. Accordingly, WOMAC 70% response rates were significantly greater for CRx-102 (2.7/360) vs. placebo on all three subscales at D98. Similar trends in hand pain reduction were seen in the subset of OA subjects with baseline hand pain >= 30 mm. The most commonly-reported AE was headache, with 4-5% drop-out in each active treatment arm. CRx-102 at the maximally effective dose (Pd + the vasodilator Dp at 360 mg/d) reduced both SBP and hypertension frequency vs. placebo and Pd alone. Analysis of bone metabolism demonstrated a small but significant decrease in bone formation markers in the Pd group, contrasting with a more balanced effect on formation and resorption with CRx-102 exposure accompanied by a trend to higher mean hip and femoral neck BMD.
Conclusion: COMET-1 is the first prospective RCT to demonstrate the efficacy of the dissociated glucocorticoid CRx-102 and very low-dose oral Pd in the treatment of knee OA. These effects are comparable to those of current OA therapies, including NSAIDs and Coxibs, and in conjunction with the good tolerability and long-term safety support the investigation of CRx-102 as an alternative anti-inflammatory therapy in OA.
Methods: COMET-1 was a 14-week Ph2, double-blind, placebo-controlled, knee OA trial, with a 1-y follow-on safety extension. Subjects had screening WOMAC knee pain Q#1 VAS score of 30-80 mm with at least 10 mm flare following NSAID/Coxib discontinuation. Three CRx-102 doses (Pd 2.7 mg/d with Dp 90, 180 or 360 mg/d) were compared with Pd (2.7 mg/d) and placebo on knee OA and hand OA efficacy measurements. In the safety extension, all subjects received 1 of the 2 higher doses of CRx-102 and were monitored for long-term GC tolerability and durability of response. Intensive monitoring of weight, lipids, glucose homeostasis, HPA axis, bone density, intraocular pressure and cataract development with FDA-approved intervention rules makes this the first large, prospective, controlled study of the safety of very low-dose GC.
Results: COMET-1 enrolled 279 subjects and 141 continued in the safety extension (74% of eligible completers). With NSAID/Coxib therapy withdrawn, the CRx-102 (2.7/360) group had sustained, significant reductions in median WOMAC pain, function and stiffness scores vs. placebo, greater at D98 than the placebo and Pd groups by 17.2-19.5 mm and 5.5-8.6 mm, respectively. Accordingly, WOMAC 70% response rates were significantly greater for CRx-102 (2.7/360) vs. placebo on all three subscales at D98. Similar trends in hand pain reduction were seen in the subset of OA subjects with baseline hand pain >= 30 mm. The most commonly-reported AE was headache, with 4-5% drop-out in each active treatment arm. CRx-102 at the maximally effective dose (Pd + the vasodilator Dp at 360 mg/d) reduced both SBP and hypertension frequency vs. placebo and Pd alone. Analysis of bone metabolism demonstrated a small but significant decrease in bone formation markers in the Pd group, contrasting with a more balanced effect on formation and resorption with CRx-102 exposure accompanied by a trend to higher mean hip and femoral neck BMD.
Conclusion: COMET-1 is the first prospective RCT to demonstrate the efficacy of the dissociated glucocorticoid CRx-102 and very low-dose oral Pd in the treatment of knee OA. These effects are comparable to those of current OA therapies, including NSAIDs and Coxibs, and in conjunction with the good tolerability and long-term safety support the investigation of CRx-102 as an alternative anti-inflammatory therapy in OA.
Keywords: corticosteroids and osteoarthritis
Disclosure: K. Huttner, Combinatorx, Inc., 3 ; W. J. Shergy, None; C. Romney, None; J. C. R. Randle, Combinatorx Incorporated, 5 .