And an update from one of the main competitors:
>>Atherosclerosis 2001 Jul;157(1):97-105
The combined effect of inhibiting both ACAT and HMG-CoA reductase may directly induce atherosclerotic lesion regression.
Bocan TM, Krause BR, Rosebury WS, Lu X, Dagle C, Bak Mueller S, Auerbach B, Sliskovic DR.
Department of Cardiovascular Therapeutics, Pfizer Global Research and Development, Ann Arbor Laboratories, Pfizer Inc., 2800 Plymouth Road, Ann Arbor, MI 48105, USA. thomas.bocan@pfizer.com
We hypothesized that coadministration of avasimibe and simvastatin would limit size, composition and extent of atherosclerotic lesions and potentially promote lesion regression, since bioavailable ACAT inhibitors decrease monocyte-macrophage enrichment and HMG-CoA reductase inhibitors limit smooth muscle cell migration and proliferation. Male New Zealand white rabbits were sequentially fed a 0.5% cholesterol, 3% peanut oil, 3% coconut oil diet for 9 weeks and a chow-fat diet for 6 weeks prior to drug administration. A time zero control group was necropsied prior to drug administration and the progression control was fed various diets but untreated. Avasimibe (10 mg/kg), simvastatin (2.5 mg/kg) or combination of avasimibe (10 mg/kg) with simvastatin (2.5 mg/kg) were administered in the chow-fat diet for 8 weeks. Plasma total cholesterol exposure was unchanged by avasimibe but was reduced 21% by both simvastatin alone and in combination with avasimibe. Combination of avasimibe and simvastatin decreased VLDL-cholesterol exposure by 56%. VLDL+IDL lipid composition was similar in the progression control and simvastatin-treated animals. Administration of avasimibe alone or in combination with simvastatin reduced the cholesteryl ester fraction and increased the triglyceride fraction to comparable extents. Relative to the progression control, avasimibe plus simvastatin markedly decreased thoracic aortic cholesteryl ester content and lesion coverage by 50% and aortic arch lesion size and macrophage area by 75 and 73%, respectively. With respect to lesion regression, avasimibe+simvastatin decreased aortic arch lesion size by 64% and monocyte-macrophage area by 73% when compared to time zero. Based on these data, we conclude that despite changes in plasma total and lipoprotein cholesterol exposure and lipoprotein composition comparable to monotherapy, inhibition of both ACAT and HMG-CoA reductase may not only directly blunt lesion progression but also promote regression of pre-established atherosclerotic lesions.<<
Interestingly, Krause was a co-author two months later on a study on APO A-1 Milano, but the abstract wasn't available.
ESPR is interesting to me because their approach seems to present fewer safety problems than KOSP's Advicor/Niaspan combo, and because I'm flirting with cholesterol problems myself and may be allergic to statins (my Mom is definitely allergic to statins). Pfizer's CETP program, though controversial, seems to have good animal data behind it. I think they are in pivotal trials, so we should get a good indication of how well it works in a few months.
Cheers, Tuck |
