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.
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, who lived in the village in the 18th century and passed it on to his offspring.
Efficacy in Humans
The ApoA-1 Milano Trial, published in JAMA in 2003, 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.
Use as treatment
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).
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.
Calgary-based SemBioSys Genetics Inc. was a biotechnology company that was using Safflower to develop commercial quantities of ApoA-1 Milano. On October 11, 2011 SemBioSys Genetics signed a multi-product commercialization and platform collaboration agreement with Tasly Pharmaceuticals of Tianjin China. In May 2012, SemBioSys terminated its operations and announced that Tasly had terminated their agreement.
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. The Medicines Company expects to commence clinical studies sometime in 2011. 
Cardigant Medical is a Los Angeles based biotech company currently working to commercialize ApoA-1 Milano to treat various vascular diseases.
- Franceschini G, Sirtori CR, Capurso A, Weisgraber KH, Mahley RW (1980). "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family" (PDF). J. Clin. Invest. 66 (5): 892–900. doi:10.1172/JCI109956. PMC 371523. PMID 7430351.
- Drug for Heart Disease Called Breakthrough, "Los Angeles Times", November 5, 2003
- Gualandri V, Franceschini G, Sirtori CR, et al. (1985). "AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission". Am. J. Hum. Genet. 37 (6): 1083–97. PMC 1684746. PMID 3936350.
- Weisgraber KH, Rall SC, Bersot TP, Mahley RW, Franceschini G, Sirtori CR (25 February 1983). "Apolipoprotein A-IMilano. Detection of normal A-I in affected subjects and evidence for a cysteine for arginine substitution in the variant A-I" (PDF). J. Biol. Chem. 258 (4): 2508–13. PMID 6401735.
- "Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes".
- "What's the Deal With the New Plaque Dissolver?".
- Nissen et al (2003). "Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes".
- Sue Hughes, ERASE: New HDL Mimetic Shows Promise, Heartwire
- http://www.drugdevelopment-technology.com/projects/etc/ ETC-216 - Phospholipid Therapy for Coronary Heart Disease (CHD) Patients
- "Esperion Product Candidates".
- "TransGenRx Protein Therapeutics Technology to Support Research Related to Protein-Based HDL Therapies at Esperion".
- "SemBioSys Announces First Quarter Results and Provides Update on Activities". 15 May 2012.
- "The Medicines Company Acquires ApoA-I Milano From Pfizer". 22 December 2009.