CombinatoRx, Incorporated (CAMBRIDGE, Massachusetts) announced positive preliminary results of its phase II clinical trial of CRx-102, an oral synergistic combination drug candidate containing the generic cardiovascular agent dipyridamole and an unconventionally low dose (3mg, below the effective human dose) of the generic steroid prednisolone, in rheumatoid arthritis (RA). The trial compared CRx-102 plus a disease-modifying antirheumatic drug (DMARD), such as methotrexate or sulfasalazine, to placebo plus DMARD (control) in subjects with RA. In this trial, CRx-102 demonstrated statistically significant reduction in C-reactive protein (CRP), the primary endpoint; and statistically significant ACR 20 responses (American College of Rheumatology, patients are classified as ACR20 responders if they demonstrate a 20% improvement from baseline in tender and swollen joint count and at least three  of five other symptom-related criteria) and DAS28 scores (Disease Activity Score using 28 joint count scores), the currently analyzed secondary endpoints.

This trial was a multicenter, blinded, placebo-controlled, randomized study comparing the effect of a 6-week treatment of CRx-102 plus a DMARD therapy to placebo plus DMARD therapy in a 1:1 ratio in 59 subjects with established RA and moderate disease activity, as determined by DAS28 scores of greater than 4.5 and CRP levels of greater than 2.2 mg/L. Patients had to be on a DMARD therapy for at least 3 months and be on a stable dose of DMARD therapy for a minimum of 28 days prior to enrollment. CRx-102 was dosed in this trial using 3 mg of prednisolone and two different doses of dipyridamole (200 mg and 400 mg). Patients received the first ratio for the first week of treatment and the second ratio for the following 5 weeks. A 50% median reduction in CRP was achieved from baseline to day 42 compared to 19% with control (P = .024). A 63% ACR20 response was demonstrated at day 42 compared to 30% with control (P = .025), and the DAS28 score measured a -1.6 mean change from baseline to day 42 compared to -0.7 with control (P = .016). CRx-102 was generally well tolerated, and there were no serious adverse events reported for subjects treated with CRx-102. Data provided are per the protocol; statistical significance remains consistent in the intent-to-treat population. Other secondary endpoints are being analyzed and will be presented at a later time.

CRx-102 works through a novel mechanism of action in which dipyridamole selectively amplifies prednisolone's anti-inflammatory and immunomodulatory activities without replicating its side effects. A modified-release commercial formulation of CRx-102 for the treatment of multiple immuno-inflammatory diseases is expected to be completed in 2007.

CRx-102 has now demonstrated positive results in three clinical settings. Earlier in 2006, the company announced positive preliminary results of its multi-center, randomized, blinded, placebo-controlled phase IIa clinical trial of CRx-102 in patients with osteoarthritis (OA) of the hand. This trial enrolled 83 subjects at four Norwegian study centers and evaluated the effect of a 6-week treatment of CRx-102 compared to placebo in a 1:1 ratio with a primary endpoint of pain relief. The study met its primary endpoint of improvement in the AUSCAN visual analogue pain scale. Analysis of the primary endpoint shows that mean change from baseline in the CRx-102 group was -102.4mm (a 33% improvement in pain) compared to the mean change from baseline in the placebo group of -30.9mm (a 10% improvement). This improvement in pain was statistically significant with P = .006. The company plans to initiate a phase IIb study with CRx-102 in OA.

The poster "CRx-102: Molecular Insight into Steroid Dissociation for CRx-102, a Clinically Active Immunomodulatory Agent", ER Price, et al. (Abstract #3263), will be presented on Tuesday, November 14, at 9 to 11:00 am ET at the ACR meeting, which is being held on November 10–15, 2006, in Washington, DC.

—A. Techman