Cholesterol Champions

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-08-01-2004,

We had a vision that this project deserved a company with a focus on HDL as the next frontier in the cardiovascular area.

Roger Newton and David Scheer were the co-founders of Esperion. Newton now leads Esperion as a unit of Pfizer’s global R&D. Scheer is president of Scheer & Co., a venture capital consultancy.

Every year, 1.5 million people cross a threshold into a dangerous disease. The plaque lining the inside of their arteries becomes thick or unstable enough to put them at risk for a heart attack. Known as atherosclerosis, the condition affects 12–15 million people worldwide and has a high mortality rate. In addition, hundreds of millions of patients suffer from high cholesterol levels, which cause that plaque to form. The pharmaceutical industry has produced a group of statins—all with blockbuster sales—to lower cholesterol levels, but so far, a medicine that reverses the buildup of plaque has been elusive.

Such a product may now be in sight. Several of the scientists who developed Lipitor (atorvastatin), an anti-cholesterol drug that became the best-selling prescription product in the world at $9 billion a year—have wowed clinicians with their next breakthrough. The new therapy, which includes a recombinant form of apolipoprotein A-I, known as Apo-I Milano, has demonstrated in a small Phase II clinical trial that it can reverse plaque buildup by an average of 4 percent in five weeks.

"The results were as spectacular as any I have ever seen," says Steve Nissen, MD, of the Cleveland Clinic, who designed, conducted, and reported the trial. "They've set the research world on fire. People will be talking about this for a long time."

Cholesterol Cycle. High-density lipoprotein (HDL), otherwise known as "good cholesterol," enters the arteries where it converts cholesterol to a new form, then carries it away from the arteries to the liver, where it is processed for disposal. Low-density lipoprotein (LDL) or "bad cholesterol," on the other hand, delivers cholesterol to the arteries, where it can build up in the form of plaque. Esperions pipeline candidates mimic the action of HDL, and Apo-I Milano takes it a step further by reducing the volume of plaque that has already built up.

Before the Apo-I Milano champions could bring the protein to that point, they had to license the compound and start their own company, Esperion. But this story really begins long before that in a small town in Italy.

Protein Journey

Limone sul Garda sits high in the mountains of Northern Italy on the western shore of Lake Garda. In the 1970s, two scientists from the University of Milano, Guido Franceschini and Cesare Sirtori, discovered that 44 of its inhabitants had dangerously low levels of high-density lipoprotein (HDL), also known as "good cholesterol."

What's good about HDL is that it converts and carries cholesterol away from the arteries to the liver, where it is processed for disposal. Low-density lipoprotein (LDL) or "bad cholesterol," on the other hand, delivers cholesterol to the arteries, where it can build up in the from of plaque. (See "Cholesterol Cycle.")

The Arsenal. Esperion has a full line of cholesterol-regulating candidates in development to beat the war on plaque.

But despite their lack of HDL, these Italians—and their ancestors before them—lived long, healthy lives and had few heart attacks: the type of contradiction that makes researchers say "hmm." So Franceschini and Sirtori looked closely at the subjects' HDL and discovered that it was a little different from the norm, that it was, in fact, extremely efficient at its job, so very little of it was necessary. The researchers recognized a drug in the making, bonded the protein to a phospholipid, patented the combination, named it Milano, and in 1985, licensed it to Pharmacia (which was still based in Sweden).

Then in the late 1990s, a round of acquisitions and restructuring shook loose both the protein and the people with the skills to develop it. Pharmacia merged with Upjohn, and the Milano protein, which had been largely ignored for a decade, was targeted for divestiture. David Scheer of Scheer & Co., a venture capitalist firm and consultancy, was hired during the Pharmacia Upjohn merger to evaluate those back-burner projects.

"We looked at 14 and came to the conclusion that the Apo-I Milano protein was the most interesting," Scheer recalls. But at the time, Pharmacia wanted to focus on small molecules, not proteins, which are more difficult to develop and manufacture. Says Scheer, "They were interested in developing pills in a bottle."

HDL Startup

Scheer and his company had grander plans: "We had vision that this project deserved a platform, a company that had as its focus HDL as the next frontier in the cardiovascular arena." So they developed two scenarios to present to Pharmacia. Both had Apo-I Milano as a core candidate with other HDL therapies to be acquired or discovered, but one was designed as a Pharmacia management buyout or spin-off, and the other was a separate company founded by Scheer and a team of independent HDL experts, who would license the compound.

"We essentially had a bake-off at the 11th hour," Scheer recalls. "The fact that Roger Newton was half Swedish worked in our favor."

The independent scenario won out. Around the same time, Warner-Lambert initiated a restructuring that limited the research activities of the team that had developed Lipitor, which was led by Newton. Scheer contacted Newton, who he saw not only as a expert in the field of dyslipidemia, but as an "entrepreneur, someone with charismatic leadership qualities who was under-appreciated by Warner-Lambert." Newton, with a PhD in nutrition with an emphasis on lipid metabolism, had headed the Parke-Davis/Warner-Lambert Atherosclerosis Drug Discovery Program for 12 years, including championing the discovery and development of Lipitor. He was ready for a change.

"The experience I gained prepared me, at the Lipitor chapter close, to consider options outside of a large pharmaceutical company," Newton recalls. "At that time, genomics was very much a focus of preclinical research, and I wanted to be able to do what I did with Lipitor, but instead of focusing on LDL, I wanted to focus on HDL. And it became obvious that the better way of doing that would be to work in a smaller, specialized, company."

Knowing he would need a great team of scientists, Newton persuaded three of his colleagues from Warner-Lambert's atherosclerosis program to join him. In May 1998, he and Thomas Rea, Charles Bisgaier, and Michael Pape left Warner-Lambert, and in July, the group launched Esperion in their hometown of Ann Arbor, Michigan. "We were all introduced to our entrepreneurial spirit," Newton says. "It's a different way of living your life, no question about it, but a very exciting one."

To fund the company, Scheer (who until recently was Esperion's chairman) raised $15.5 million in venture capital from groups such as Oak Investment Partners, Healthcap, and TL Ventures. The Swedish government, which had supported Sirtori's initial research on the protein, kicked in $6.5 million in the form of a "forgivable loan." Additional financing from venture capital included $22 million in Series C and $5 million in Series D funding. In August 2000, Esperion went public and raised $62 million in its IPO. After that, the company raised almost another $100 million in equity financing.

Some of the money was used to license and develop other HDL-based compounds. And some of the scientists who had been developing those projects followed the molecules to Esperion. "With each of these programs, there were people who were so excited by what Esperion was doing that they wanted to join with their feet and head up the discovery and research in the program," says Scheer.

Holy Grail

In the body, HDL circulates through the walls of the arteries to scavenge surplus LDL, converts it to a new form, then transports it to the liver for elimination. The process, know as reverse lipid transport (RLT), is more efficient in some people than in others. If LDL levels are too high, plaque eventually forms within artery walls. When these plaque formations rupture, heart attacks can result.

Apo-I Milano (ETC-216) mimics HDL, but is in fact so efficient that it actually removes cholesterol that is clinging to the artery wall. Scientists discovered its effectiveness early in animal testing. "In one study where they used IVUS [intravascular ultrasound], the arteries in the rabbits showed changes in 45 minutes," says Mary Ann Andreach, Esperion's vice-president of marketing and product planning. "So we knew that we had a very special product candidate on our hands." For the human trials, they contacted Nissen, who specialized in cardiovascular medicine and intravascular ultrasound. Not only was he an expert at going inside the arteries to measure plaque, he had also conducted his share of clinical trials for anti-cholesterol therapy, including some for Lipitor.

Andreach, who worked with Nissen to design the study, describes its protocol: "We decided to take a risk and do our multiple-dose study in patients with heart disease. We identified people within two weeks of either having a heart attack or being hospitalized for unstable angina. It was a double-blind, placebo-controlled trial, and we administered five treatments over four weeks. We did an IVUS of one of their coronary arteries at the beginning of the study, and we did an IVUS at the exact same spot at the end of the study."

The study was a long shot. "I expected nothing," Nissen says. "They had very little drug and the trial was very short." But in that short time and much to Nissen's surprise, the Milano protein reduced patients' plaque by an average of 4 percent. That may not sound like much, but patients taking anti-cholesterol medicines see their plaque volume increase by half that much each year.

"What we showed for the first time is that you can take this disease process and actually reverse it," says Andreach. As yet, the excitement is based on only one small study. But Nissen assures, "This will be evaluated in multiple clinical trials."

So the biggest hurdles are still to come. "Our goal in Phase III studies would be to treat 1,500 or 2,000 patients, per treatment arm," Newton says, "and show the aggregate reduction of overall mortality, nonfatal MI [myocardial infarction], and revascularization procedures that often are a component of people who have acute coronary syndromes."

HDL Portfolio

"One thing we didn't want to be from the get-go was a 'one-trick pony' company," says Newton. So early on, Esperion licensed several complementary anti-cholesterol molecules. The first came from Canada's Imex. Now in Phase II, ETC-588 is a naturally occurring lipid that helps HDL remove cholesterol from arteries and other tissues. (See "The Arsenal.") Known as large unilamellar vesicles (LUVs), these "cholesterol sponges" are being tested in patients with cardiovascular disease and in patients with acute coronary syndrome.

Newton describes the LUV mechanism of action: "It's a phospholipid bilayer that has an incredible capability of sequestering cholesterol. From a physical–chemical point of view, cholesterol loves to be in such a bilayer. This infusion product is too large to get into the arterial wall itself. But the HDL particle is small enough to enter the arterial wall, pull the cholesterol out of the plaque, and then it gives up the cholesterol very readily to the LUV. For every gram of LUV that is infused, a half gram of cholesterol can be sequestered. So there is a very high capacity process here for sequestering cholesterol out of arterial walls and particularly out of atherosclerotic plaques."

A third pipeline candidate about to enter Phase II is another cholesterol mimetic. ETC-642 is a small peptide phospholipid complex that has properties similar to Apo-I Milano. In Phase I trials, it was shown to increase HDL levels and enhance the mobilization of cholesterol.

Although only one-tenth the size of Apo-I Milano, ETC-642 is also an infusion product, as is ETC-588. But Newton doesn't believe that administration route will hinder sales. "Of the patients who have ACS [acute coronary syndrome], up to 25 percent will come back within the year having experienced another event," he explains. "And then there are the people who have stable atherosclerosis—which may be 12–15 million patients in the US alone who have already had a heart attack and are at high risk for having another one. So there is a large potential market out there for these periodic, weekly infusions."

Further down in the pipeline (preclinical and Phase I) is a group of small molecules that act as lipid regulators. In other words, they have the potential to be formulated as tablets that can be taken by a broad range of patients with high cholesterol and heart disease. These candidates are seen as those with the most potential to someday be combined with Pfizer's oral anti-cholesterol medicines.

Pfizer Fold

But Esperion's pipeline is no longer under Newton's control. Not long after the Apo-I Milano study was published, Pfizer—which had already acquired two of the earlier players in the Milano protein shuffle, Warner-Lambert and Pharmacia—made an offer to buy the startup for $1.3 billion. Esperion's board of directors accepted it.

They've kept the name, but the company now exists only in spirit—which is, ironically, what Esperion means. The R&D direction and funding are under Pfizer's governance. With a projected $200–$500 million in annual sales, the Milano protein is likely to receive the resources it needs. However, there is no certainty that all of Esperion's projects will move forward.

"Obviously in the near term, because they are the furthest along, the large-molecule product candidates are of greatest interest to Pfizer," Newton says. "And they also have an interest in what we've been doing at the small-molecule level. But [to move forward] these product candidates must be complementary to the Pfizer strategy for their overall cardiovascular portfolio."

Newton is optimistic about joining the fold: "It's actually very exciting, because we are a division of Pfizer. I report to John LaMattina, the president of Pfizer Global R&D, and I oversee the operations of the Esperion division. We will continue on our road to bringing HDL therapies to the marketplace. Based on our discussions so far, it looks like we will be able to continue to advance the science that we originally started six years ago."

Staying with the project is important to Newton. "I like to finish what I start," he says. "I get a lot of pleasure out of working on the discovery and development of new medicines with talented people. To me, it's the journey and the personal relationships that are most meaningful, not getting to the end. So my commitment has not wavered a single bit since this acquisition. I was an entrepreneur when I was at Parke-Davis. I was also an entrepreneur doing what I did in Esperion. And I think I can do the same within Pfizer."