Abstract 680: KC706, an Oral p38 MAP Kinase Inhibitor, Increases HDL-C
Introduction: KC706 is a novel p38 MAP kinase inhibitor with anti-inflammatory properties. In rats and monkeys, KC706 administration was associated with a 50 – 60% ↑ in HDL-C. Because HDL-C is an important target for the treatment of CV disease a Phase 2a study was designed to determine whether KC706 administration would elevate HDL-C levels in patients with dyslipidemia.
Methods: A double-blind, placebo-controlled, 6-week study was conducted in patients with ↓ HDL-C and ↑ triglyceride (TG) levels. Patients (N = 115) were randomized to placebo or to KC706 (150 or 300 mg po qd). Standard chemistry and hematology parameters and lipid, metabolic, inflammatory, and thrombotic markers were monitored. The primary end point was an increase in HDL-C in treatment v. placebo groups.
Results: Patients were primarily male (59%) and white (97%). At baseline, 35% were receiving statins, 44% were hypertensive, 15% had CV disease, 70% fulfilled ATPIII criteria for metabolic syndrome, and 43% had CRP > 3 mg/L. The primary endpoint of the study was met at both dose levels. Compared to baseline, HDL-C ↓ 2.9% in the placebo group, ↑ 18.6% in the 150 mg group (p < 0.0001 v. placebo) and ↑ 11.6% in the 300 mg group (p = 0.0003 v. placebo) after 6 wks of treatment. Effects were noted in men and women, whether patients were receiving statins or not, and whether CRP was elevated or not at baseline. ApoAI ↑ significantly in the 150 mg group (p = 0.0056 v. placebo). TG, LDL-C, and VLDL-C were unchanged. CRP levels trended downward in patients with ↑ baseline CRP levels. HDL/Total cholesterol (+22%), ApoA1/ApoB100 (+14%), and HDL/LDL (+31%) increased in the KC706 150 mg group. Mean HDL particle size (measured in a subset of patients) increased from 8.4 to 8.7 nm in the KC706 150 mg group (p = 0.04), from 8.5 to 8.7 nm in the KC706 300 mg group (p = 0.01) but not in the placebo group (8.3 v. 8.4 nm, p = 0.66). No increases in either systolic or diastolic blood pressures were observed in any group. One patient in the 150 mg group and 4 in the 300 mg group had a reversible elevation in either AST and/or ALT of > 3X ULN. Adverse events were similar in the 3 treatment groups.
Conclusions: KC706, an oral p38 MAP kinase inhibitor with anti-inflammatory properties, increased HDL and ApoA1 in patients with dyslipidemia and was well tolerated.