Phosphagenics Limited ("Phosphagenics") (ASX:POH, AIM:PSG, OTCQX:PPGNY) today announced results of a pre-clinical study demonstrating that the combination of its APA-01 product candidate and the statin atorvastatin (Lipitor™) significantly reduced serum lipids and inflammatory proteins involved in the development of atherosclerosis.
Study Design
The purpose of the study was to determine whether a combination of the statin drug atorvastatin and APA-01 could reduce serum lipids, inhibit atherosclerotic lesion progression and reduce proinflammatory cytokines and other biomarkers of inflammatory disease more effectively than the statin alone.
Studies were performed in ApoE mice, animals that spontaneously form atherosclerotic plaques and represent a well-established model of human atherogenic hyperchosterolemia.
During the first 16-weeks of this 24-week study, all animals in the experimental group were maintained on a standard diet, followed by an eight week treatment period in which this diet was supplemented with 21 percent fat and 0.15 percent cholesterol, an atherogenic diet expected to accelerate atherosclerotic progression. All animals in the experimental groups received drug treatment in both their normal and high-fat diets at various dosing regiments throughout the 24-week study. Control group animals received no drug treatment and were maintained on either the same diet as the treatment groups or on a standard diet.
Study Results
Effects on Serum Lipids
The study results indicated that among the animals treated with the APA-01 and atorvastatin combination, total cholesterol levels fell by up to an additional 12% compared to those animals treated with atorvastatin alone. Total HDL-C (good cholesterol) levels increased by up to 37% in combination drug-treated animals, while LDL-C (bad cholesterol) levels were further reduced by up to 24% with the combination, as opposed to atorvastatin alone. The combination also caused a decrease of 92% in triglycerides levels compared to 72% with atorvastatin alone.
Effects on Biomarkers of Inflammation
APA-01, combined with atorvastatin, enhanced the statin’s effects on lowering inflammation that contributes to the development of atherosclerotic plaques. Reductions occurred in final plasma levels of 23 cytokines that were measured. Following 24 weeks of treatment with various doses of APA-01 and atorvastatin a statistically significant reduction occurred in a number of cytokines including IL-1β, IL-10, G-CSF, GM-CSF, IFN-γ,MCP-1, and RANTES compared to control and these decreases were greater than with either compound alone and appeared to be somewhat dose-dependent.
Effects on Atherosclerotic Plaque progression
Atherosclerotic lesions were significantly elevated following incorporation of the high-fat high-cholesterol diet in all animals compared to animals maintained on the regular, rodent diet for the 24-week study period. The effect of the combination treatment of APA-01 combined with atorvastatin appeared to cause a trend toward decreased aortic lesions, but these were not statistically significant.
Commenting on the study results, Dr Esra Ogru, Executive Vice President of Research and Development at Phosphagenics, said, “Current therapies for atherosclerosis focus on drugs that lower serum cholesterol levels. Experimental and clinical evidence suggests that the efficacy of these drugs may also be related to their ability to reduce oxidative stress and inflammation in the endothelium, or blood vessel lining, where atherosclerotic plaques develop. We believe that APA-01’s apparent enhancement of a statin’s anti-inflammatory functions could potentially provide a novel therapeutic approach to treating atherosclerosis.”
Atorvastatin is the world’s largest selling drug with sales of US$13.6 billion annually and is the major contributor to the US$35.2 billion market for statin drugs globally.
“In particular there is an unmet need for a more effective treatment for elevated triglycerides and APA-01 has demonstrated efficacy in this area in this pre-clinical study.
“We are now assessing the impact of these results before determining our future strategy. However, the insulin, oxycodone and Phospha E® clinical programs will remain our priority for this year,” Dr Ogru said.
