Biology:ApoA-1 Milano

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Apolipoprotein A-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]

Discovery

The ApoA-1 Milano mutation was found by University of Milan researchers after their 1974 investigation of a low HDL / high triglyceride phenotype exhibited by Valerio Dagnoli of Limone sul Garda, a small village in northern Italy.[2]:163 Limone had only 1,000 inhabitants at the time and when blood tests were run on the entire population of the village, the mutation was found to be present in about 3.5% of the local population.[2]:163 The mutation was traced to one man, Giovanni Pomarelli,[3] who was born in the village in 1780 and passed it on to his offspring.[4][2]:163[5] It is characterised by the replacement of arginine by cysteine at position 173 (197 for UniProt).[6] The mutation is known in single nucleotide polymorphism (SNP) nomenclature as rs28931573.[7]

In the 1990s, researchers at the Cedars-Sinai Medical Center showed that injection of a synthetic version of the mutant ApoA-1 into rabbits and mice could reverse vascular plaque buildup.[2]:164

Efficacy in Apo A-I/Apo E null mice

Apo A-I Milano has been shown to reduce atherosclerosis in animal models and in a small phase 2 human trial. Recombinant adeno-associated virus 8 (AAV8) mediated Apo A-I Milano gene therapy in combination with low-cholesterol diet induces rapid and significant regression of atherosclerosis in mice.[8][9]

Efficacy in humans

The first examination of using the mutant ApoA-1 in humans was conducted through a three way collaboration between the University of Milan and the companies Pharmacia and Upjohn in 1996, focusing on treatment of atherosclerosis.[2]:164

The ApoA-1 Milano Trial, published in JAMA in 2003,[10] 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. This trial was initiated by Steven Nissen of the Cleveland Clinic after prompting by Roger Newton of Esperion to examine the effects of the mutant protein using intravascular ultrasound imaging.[2]:164 Esperion provided the protein, code named ETC-216, for the duration of the trial.[10]:2293

Use as treatment

Due to its potential efficacy, it was speculated that development of synthetic ApoA-1 Milano might be a key factor in eradicating coronary heart disease.[11]

Esperion Therapeutics, a high tech venture capital start-up, demonstrated 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).[10]

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.[citation needed]

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.[12][13]

Subsequent Development

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,[14] is back in business and continue to work on HDL mimetic therapies.[15] The company established an agreement with TransGenRx as a protein source.[16]

Calgary-based SemBioSys Genetics Inc. was a biotechnology company that was using Safflower to develop commercial quantities of ApoA-1 Milano.[citation needed] 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.[17]

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.[18][19]

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.[20] After a trial study failed to produce significant enough results compared to other drugs being tested, in 2016 The Medicines Company discontinued development of MDCO-216.[21]

Cardigant Medical is a Los Angeles-based biotech company that worked to commercialize ApoA-1 Milano to treat various vascular diseases. As of 2021, no new trials or commercialisation have been reported, and the web domain of the company website (http://www.cardigant.com ) has expired.

References

  1. ↑ "A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family". J. Clin. Invest. 66 (5): 892–900. 1980. doi:10.1172/JCI109956. PMID 7430351. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Li, Jie Jack (2009). Triumph of the Heart: The Story of Statins. Oxford University Press. ISBN 9780195323573. 
  3. ↑ Maugh II, Thomas H. (November 5, 2003). "Drug for Heart Disease Called Breakthrough". Los Angeles Times. http://articles.latimes.com/2003/nov/05/science/sci-heart5. 
  4. ↑ "Italian Gene Holds Hope for Unclogging Arteries". October 17, 1994. http://articles.latimes.com/1994-10-17/news/mn-51362_1_artery-disease. 
  5. ↑ "AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission". Am. J. Hum. Genet. 37 (6): 1083–97. 1985. PMID 3936350. 
  6. ↑ "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. 25 February 1983. doi:10.1016/S0021-9258(18)32955-7. PMID 6401735. http://www.jbc.org/cgi/reprint/258/4/2508. 
  7. ↑ "rs28931573 RefSNP Report". https://www.ncbi.nlm.nih.gov/snp/rs28931573. 
  8. ↑ Wang L., Tian F., Arias A., Yang M., Sharifi B. G., Shah P. K. (2015). "Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo AI Milano Gene Therapy on Regression of Atherosclerosis". Journal of Cardiovascular Pharmacology and Therapeutics 21 (3): 320–328. doi:10.1177/1074248415610216. PMID 26499098. 
  9. ↑ Wang L, Tian F, Arias A, Yang M, Sharifi BG, Shah PK (2016). "Comparative Effects of Diet-Induced Lipid Lowering Versus Lipid Lowering Along With Apo A-I Milano Gene Therapy on Regression of Atherosclerosis". J Cardiovasc Pharmacol Ther 21 (3): 320–328. doi:10.1177/1074248415610216. PMID 26499098. 
  10. ↑ 10.0 10.1 10.2 Nissen, Steven E.; Tsunoda, Taro et al. (November 5, 2003). "Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes". JAMA 290 (17): 2292–300. doi:10.1001/jama.290.17.2292. PMID 14600188. open access
  11. ↑ "What's the Deal With the New Plaque Dissolver?". http://heartdisease.about.com/cs/coronarydisease/a/plaquebuster.htm. 
  12. ↑ ERASE: New HDL Mimetic Shows Promise, S Hughes, 2007, Heartwire
  13. ↑ http://www.drugdevelopment-technology.com/projects/etc/ ETC-216 - Phospholipid Therapy for Coronary Heart Disease (CHD) Patients
  14. ↑ url=http://www.ace-event.org/RNewtonAcePresentation.pdf[yes|permanent dead link|dead link}}]
  15. ↑ "Esperion Product Candidates". http://www.esperion.com/products-research/product-candidates.php. 
  16. ↑ "TransGenRx Protein Therapeutics Technology to Support Research Related to Protein-Based HDL Therapies at Esperion". http://www.esperion.com/modules/xnews/article.php?storyid=4. 
  17. ↑ "SemBioSys Announces First Quarter Results and Provides Update on Activities". 15 May 2012. http://www.newswire.ca/en/story/975453/sembiosys-announces-first-quarter-results-and-provides-update-on-activities. 
  18. ↑ "The Medicines Company | Development Pipeline | MDCO216". http://www.themedicinescompany.com/products_MDCO216.shtml. 
  19. ↑ "The Medicines Company Acquires ApoA-I Milano From Pfizer". 22 December 2009. http://investors.themedicinescompany.com/phoenix.zhtml?c=122204&p=irol-newsArticle&ID=1369038&highlight=. 
  20. ↑ "The Medicines Company signs agreement with OctoPlus for MDCO-216 | TradingMarkets.com". http://www.tradingmarkets.com/news/stock-alert/mdco_the-medicines-company-signs-agreement-with-octoplus-for-mdco-216-1035307.html. 
  21. ↑ "The Medicines Company Discontinues Development of MDCO-216, its Investigational Cholesterol Efflux Promoter | The Medicines Company" (in en). http://www.themedicinescompany.com/investors/news/medicines-company-discontinues-development-mdco-216-its-investigational-cholesterol. 

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