CombinatoRx, Incorporated announced preliminary results of its randomized, blinded, placebo-controlled clinical trial of CRx-150 in patients with rheumatoid arthritis (RA). The trial compared CRx-150 plus a disease-modifying anti-rheumatic drug (DMARD) to placebo plus DMARD (control) in subjects with active RA. In the preliminary analysis of this trial, CRx-150 demonstrated statistically significant effects on DAS28 and pain, a trend on ACR20 and no effect on CRP.
For CRx-150 treated subjects, median baseline pain as measured on a visual analogue scale (VAS), went from 63.0mm to 37.0mm at day 42, with a median change of -11.5mm, whereas placebo went from 64.5mm at baseline to 59.5mm at day 42, with a median change of -2.0mm (p=0.04).
CRx-150 was generally well tolerated. The most common adverse events in the CRx-150-treated group included headache, nausea, and the anti-cholinergic side effects typically associated with tricyclic anti-depressants such as amoxapine.
"While we're pleased to see that this novel synergistic combination has demonstrated some clinical effect, it does not meet our target product profile and has been discontinued as a development program," commented Alexis Borisy, President and CEO of CombinatoRx. "The level of activity observed with CRx-150 would not be competitive within the CombinatoRx product portfolio or the RA marketplace, as our lead RA product candidate, CRx-102, has demonstrated a much stronger clinical profile to date. We look forward to providing an update on the CombinatoRx pipeline including CRx-102, CRx-191 and CRx-401 among others at our R&D Day event in Cambridge on July 24th."
CRx-150 is a novel synergistic cytokine modulator comprised of the antidepressant amoxapine and the cardiovascular drug dipyridamole, neither of which is indicated for the treatment of immuno-inflammatory disease on its own, but which have been shown in both preclinical and human inflammatory biomarker studies to act synergistically to modulate cytokine production.
This trial was a multi-centre, blinded, randomized study evaluating the effectiveness of CRx-150 plus DMARD therapy compared to placebo plus DMARD in a 2:1 ratio in subjects with RA. The primary endpoint was reduction in CRP levels comparing CRx-150 plus DMARD to placebo plus DMARD from baseline at day 42. Secondary endpoints of the study included DAS28 scores, ACR 20 responses and changes in inflammatory cytokines from baseline to day 42.
64 subjects with established RA and moderate disease activity with greater than or equal to 6 tender and greater than or equal to 5 swollen joints were enrolled in this study. Patients had to be on DMARD therapy (such as methotrexate or sulfasalazine) for at least 3 months and be on a stable dose of DMARD therapy for a minimum of 28 days prior to enrollment. CRx-150 was dosed in this trial using 200mg of dipyridamole and two different doses of amoxapine (50mg titrating to 100mg after the first 2 weeks of treatment).
The Disease Activity Score using 28 joint counts (DAS28) is a composite score used to monitor disease activity in RA patients. The ACR20 score is a standard measure developed by the American College of Rheumatology to rate RA disease improvement. Patients are classified as ACR20 responders if they demonstrate a 20% improvement from baseline in tender and swollen joint count and at least 3 of 5 other symptom related criteria. C-reactive protein (CRP) is an acute phase protein and marker of systemic inflammation. A relationship between inflammatory processes and elevation of CRP has been established in a number of immuno-inflammatory diseases, including RA.
CombinatoRx, Incorporated (CRXX) is pioneering the new field of synergistic combination pharmaceuticals and has a broad product portfolio in phase 2 clinical development. Going beyond traditional combinations, CombinatoRx creates product candidates with novel mechanisms of action striking at the biological complexities of human disease.