By Mary Welch

If Esperion Therapeutics Inc. sees the future correctly, people will go to a doctor's office a couple times a year to have their cholesterol deposits cleared from their arteries — just like they get their teeth cleaned.

"The process would not involve just one vessel but the whole circulation system," said Roger Newton, the president and CEO of the Ann Arbor, Mich., company. "Treatment would not only promote regression of atherosclerosis but also alleviate symptoms associated with other metabolic diseases."

The start-up firm, which just raised $15.5 million, was co-founded by Oak Investment Partners, of Westport, Conn., and Scheer & Co. Inc., of Branford, Conn. They recruited Newton and three associates, who were researchers with Parke-Davis Pharmaceutical Research, a division of Warner-Lambert Co., of Morris Plains, N.J.

The team, which includes Charles Bisgaier, Michael Pape and Thomas Rea, pioneered the current generation of highly successful lipid-lowering drugs such as gemfibrozil (or Lopid) and atorvastatin (Lipitor) while at Warner-Lambert. Lipitor had one of the most successful product launches in the industry. Some analysts have said the drug, which hit the market in February 1997, will reach sales of $6 billion by 2002.

Funding To Support Preclinical, Clinical Studies

Oak Partners led the venture capital financing, which also included TL Ventures, of Wayne, Pa., and HealthCap AB, of Stockholm, Sweden.

"That was our first entry into venture capital," said Newton, "and it is an incredible amount for any start-up company. It allows us to set up our infrastructure in the right way and to perform preclinical and clinical studies on our technology over the next year-and-a-half."

Esperion's goal is to exploit the high-density lipoprotein (HDL) pathway to remove excessive, disease-causing lipids, a process called reverse cholesterol transport. Lipoproteins are blood-borne particles that transport lipids (or fat-solubles) throughout the body and contain a blend of cholesterol, proteins, triglycerides and phospholipids.

High levels of HDL — also known as good cholesterol — reduce the risk of heart disease by countering the body's level of low-density lipoprotein (LDL) and the very low-density lipoproteins (VLDL). Both LDL and VLDL — referred to as bad and very bad cholesterol, respectively — contribute to the risk of heart attacks by promoting atherosclerosis.

"HDLs and LDLs are the yin and yang in cholesterol metabolism," Newton explained. "LDL brings cholesterol to vascular cells and stores it; HDL antagonizes it by promoting removal of cholesterol from the cell. In a number of patients with metabolic disorders, they not only have too much LDL in their blood, but too little HDL. This limits the body's capability to counterbalance the delivery of LDL cholesterol and remove it from cells."

The medical and health fields have concentrated on lowering LDL cholesterol with little focus on developing agents that modify HDL and promote reverse cholesterol transport.

"The research community unrealistically had abandoned looking at HDL and its role as a potential therapeutic target," Newton said. "Instead, it worked at overcoming the adverse effects of LDL. HDL and its potential benefits just weren't in vogue. But to us, it made a lot of sense to look into them."

Esperion wants to reverse vascular disease by removing lipids from potentially unstable plaques in blood vessels called atherosclerotic lesions. Its initial area of focus will be on ApoA-I Milano, a component of HDL.

The ApoA-I Milano, a variant of normal apolipoprotein A-L, was discovered by researchers at the University of Milan (Italy), who studied the local population, who, despite other risk factors, have a low incidence of cardiovascular disease.

Licensed P&U Product Targets Lipid Removal

A lipid-based formulation of ApoA-I Milano has shown significant anti-atherogenic activity in preclinical studies.

Esperion, which has six employees, acquired worldwide rights to the recombinant human ApoA-I Milano from Pharmacia & Upjohn, of London, which retains an exclusive option for codevelopment and marketing outside the U.S. and Canada.

"We plan to use these technologies to develop therapies to remove harmful lipids, including cholesterol derived from LDL, from tissues and from blood vessels for delivery to the liver for disposal from the body," Newton said. "There are a number of areas in which this would be beneficial, including the millions of people who suffer from heart disease, stroke, obesity, diabetes and Alzheimer's disease. These disorders share the problem of abnormal lipid metabolism, which contributes to the severity and progression of complications."

Initially, Esperion will develop ApoA-I Milano for the treatment of atherosclerosis, with a goal of eliminating or reducing the need for angioplasty or bypass surgery.

The company anticipates reaching clinical trials within three years.

As part of its agreement with Pharmacia & Upjohn, which has facilities in Stockholm, Esperion also has an office there and plans to conduct clinical trials in Sweden. *