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11 - Milano: Luci della Citta' - News/Events Dic 2002-Gen 2003,... citylightsnews.com |
ApoA-1 Milano is a naturally occurring mutated variant of the apolipoprotein A1 protein found in human HDL, the lipoprotein particle that carries cholesterol from tissues to the liver and is associated with protection against cardiovascular disease. ApoA1 Milano was first identified by Dr Cesare Sirtori in Milan, who also demonstrated that its presence significantly reduced cardiovascular disease, even though it caused a reduction in HDL levels and an increase in triglyceride levels.[1]
[edit] DiscoveryDiscovered by accident, the mutation was found to be present in about 3.5% of the population of Limone sul Garda, a small village in northern Italy. It has been traced to a mutation in a single man who had lived in the village in the 1700s and passed it on to his offspring.[2] It is characterized by the replacement of a single amino acid at R173C.[3] [edit] Efficacy in HumansThe ApoA1 Milan Trial, published in JAMA in 2003[4] was the first published placebo controlled, 2 dose level, trial in humans. This was a secondary prevention trial in that those included were individuals who presented to a participating hospital with unstable angina and agreed to consent to a rigorous trial, well beyond usual clinical practice testing and treatment, to test whether this HDL protein variant, which was so effective in animals, would also work in humans. [edit] Use as treatment
Due to its enormous apparent efficacy, some have speculated that development of synthetic apoA-1 Milano may be a key factor in eradicating coronary heart disease. Proof of efficacy in both animals and humans was performed by the Esperion company, a high tech venture capital start-up, which spent many millions of dollars over several years culminating in a single human trial which showed impressively rapid efficacy by IVUS of coronary arteries, but managed to produce only enough of the apoA-1 protein over several years of effort to partially treat 30 out of the 45 people in the randomized trial, once weekly for a total of 5 weeks. The trial results were published in JAMA and multiple references are available on the net: the ApoA-1 Milano trial. From a business standpoint, producing an expensive protein which has to be administered IV to be effective and has to be given repeatedly and indefinitely is not a good business model. However, it did provide some proof of concept and the impetus to develop a mass market HDL improving product. Given the ground breaking work and promising future product concepts Esperion was working on, Pfizer purchased and internalized the Esperion company shortly before the Apo A-1 Milano trial was published in hopes of developing a more effective treatments than their current product Lipitor. No drugs are currently commercially available based on apoA-1 Milano. Rights to apoA-1 Milano were acquired in 2003 by Pfizer. Clinically known as ETC-216, Pfizer has not moved trials forward, probably because the protein is complex and very expensive to produce and must be administered intravenously, thus limiting its application as compared to oral medications [5]. [edit] Subsequent DevelopmentPfizer, after the CETP agent torcetrapib (which Pfizer had committed to advanced development funding) failed miserably in a large human safety trial, Pfizer (apparently for business and developmental complexity reasons) decided to exit the entire cardiovascular market in 2008, though they continue to aggressively market Lipitor. Roger S. Newton, PhD, FAHA[6], who many credit with the eventual developmental success of Lipitor within Pfizer, and who later abandoned Pfizer in order to devote his research skills and risk his net work on developing ApoA1 Milano under the company name Esperion, managed to buy back patent rights to much of his work and continues to work on developing small-molecule HDL function enhancing agents. Esperion, now named Esperion Therapeutics[7], May 2008, is back in business and publicly stating they have agent ETC-1002[8] in development work. As part of the buy back agreement, Pfizer continues to hold an undisclosed share of Esperion's net worth. Calgary-based SemBioSys Genetics Inc. is a biotechnology company that is using its plant-based production system to develop ApoA-1 Milano to reduce and stabilize vascular plaques associated with Acute Coronary Syndrome (ACS) and stroke indications. [edit] References
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