ApoA-1 Milano
Encyclopedia
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.
, 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.
It is characterized by the replacement of a single amino acid
at R173C.
.
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.
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, is back in business and publicly state they have agent ETC-1002 in development work. Roger S. Newton, PhD, FAHA, 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 http://www.themedicinescompany.com/ announced it had entered into an exclusive worldwide licensing agreement with Pfizer Inc. for ApoA-I Milano which it then renamed MDCO-216.
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.
Apolipoprotein A1
Apolipoprotein A-I is a protein that in humans is encoded by the APOA1 gene. It has a specific role in lipid metabolism.Apolipoprotein A-I is the major protein component of high density lipoprotein in plasma. Chylomicrons secreted from the intestinal enterocyte also contain ApoA1 but it is quickly...
protein found in human HDL
High density lipoprotein
High-density lipoprotein is one of the five major groups of lipoproteins, which, in order of sizes, largest to smallest, are chylomicrons, VLDL, IDL, LDL, and HDL, which enable lipids like cholesterol and triglycerides to be transported within the water-based bloodstream...
, the lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
particle that carries cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from tissues to the liver and is associated with protection against cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. ApoA1 Milano was first identified by Dr. Cesare Sirtori in Milan
Milan
Milan is the second-largest city in Italy and the capital city of the region of Lombardy and of the province of Milan. The city proper has a population of about 1.3 million, while its urban area, roughly coinciding with its administrative province and the bordering Province of Monza and Brianza ,...
, who also demonstrated that its presence significantly reduced cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, even though it caused a reduction in HDL levels and an increase in triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
levels.
Discovery
Discovered by accident, the mutation was found to be present in about 3.5% of the population of Limone sul GardaLimone sul Garda
Limone sul Garda is a town and comune in the province of Brescia, in Lombardy , on the shore of Lake Garda.-History:Despite the presence of famous cultivations of lemons , the town's name is probably derived from the ancient lemos or limes Limone sul Garda is a town and comune in the province of...
, a small village in northern Italy
Italy
Italy , officially the Italian Republic languages]] under the European Charter for Regional or Minority Languages. In each of these, Italy's official name is as follows:;;;;;;;;), is a unitary parliamentary republic in South-Central Europe. To the north it borders France, Switzerland, Austria and...
. 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.
It is characterized by the replacement of a single amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
at R173C.
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
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 diseaseCoronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
.
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
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
. 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.
Subsequent Development
Pfizer, after the CETP agent torcetrapibTorcetrapib
Torcetrapib was a drug being developed to treat hypercholesterolemia and prevent cardiovascular disease...
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, is back in business and publicly state they have agent ETC-1002 in development work. Roger S. Newton, PhD, FAHA, 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 http://www.themedicinescompany.com/ announced it had entered into an exclusive worldwide licensing agreement with Pfizer Inc. for ApoA-I Milano which it then renamed MDCO-216.
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.