ApoA-1 Milano (also ETC-216, now MDCO-216) 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]
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Discovered 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, Giovanni Pomarelli[2], who lived in the village in the 18th century and passed it on to his offspring.[3]
It is characterized by the replacement of a single amino acid at R173C.[4]
The ApoA-1 Milano Trial, published in JAMA in 2003[5], 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, testing whether this HDL protein variant, which was so effective in animals, would also work in humans.
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.[6]
Esperion Therapeutics, a high tech venture capital start-up, demonstrated proof of efficacy in both animals and humans, spending many millions of dollars over several years to conduct a single human trial which showed impressive and rapid efficacy by IVUS of coronary arteries. However, over the course of the project they produced only enough ApoA-1 Milano to partially treat thirty out of the forty-five people in the randomized trial, giving them one weekly dose each for five weeks. The results of the trial were published in JAMA (November 5, 2003).[7]
Hoping to develop a more effective treatment than their current product Lipitor, Pfizer purchased and internalized Esperion shortly before JAMA published the results of the Apo A-1 Milano trial.
Currently, no drugs based on ApoA-1 Milano are commercially available. Rights to ApoA-1 Milano were acquired in 2003 by Pfizer. Clinically known as ETC-216, Pfizer did not move trials forward, probably because the complex protein is very expensive to produce and must be administered intravenously, limiting its application compared to oral medications[8][9].
Pfizer, after the CETP agent torcetrapib failed in a large human safety trial, decided to exit the cardiovascular market in 2008, though they continue to market Lipitor aggressively.
Esperion, divested by Pfizer in 2008[10], is back in business and publicly state they have agent ETC-1002[11] in development work. Roger S. Newton, PhD, FAHA[12], who many credit with the eventual developmental success of Lipitor within Pfizer, and who abandoned Pfizer, risking his net worth to found Esperion Therapeutics and devote his research skills to developing ApoA-1 Milano, managed to buy back Esperion and patent rights to much of his work. He continues to work on developing small-molecule HDL function enhancing agents. As part of the repurchase 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 commercial quantities of ApoA-1 Milano to reduce and stabilize vascular plaques associated with Acute Coronary Syndrome (ACS) and stroke indications.
On 22 December 2009 The Medicines Company [1] announced it had entered into an exclusive worldwide licensing agreement with Pfizer Inc. for ApoA-I Milano which it then renamed MDCO-216.[13]
On the 12th of July 2010 The Medicines Company signed a pharmaceutical development and manufacturing contract with OctoPlus (Netherlands-based drug delivery and drug development company) to perform process development and clinical manufacturing of MDCO-216[14]. The Medicines Company expects to commence clinical studies sometime in 2011[15].