Roger Newton never claimed to be the smartest person in the room. “These guys are obviously a lot smarter in their specific areas than I am,” he told the Observer in 1998, referring to his scientific colleagues at the time. Newton calls himself a builder and relishes the teamwork integral to science, especially in his profession, drug development.

Newton built the Ann Arbor-based team that developed Lipitor, which became the world’s best-selling prescription drug. Then he founded two different local biotech companies, both named Esperion and both extremely successful. The second Esperion achieved a rare milestone in late February when the FDA approved its first two drugs, Nexletol and Nexlizet, for lowering LDL (bad) cholesterol. Annual sales forecasts exceed $1 billion.

“It all started with Roger,” says Esperion CEO Tim Mayleben. “Roger had the original vision.”

A career biochemist, Newton didn’t become an entrepreneur until age forty-eight, when he left Warner-Lambert/Parke-Davis’s Ann Arbor research labs to found the first Esperion. Speaking at the time with the Observer at his then-brand-new company (employees were still unloading boxes of lab equipment), Newton reflected on his gamble.

“It’s a huge risk,” he said. “We obviously aren’t thinking failure … but the reality is, is that companies fail.”

But he also had a mission. Newton trained as a nutritional biochemist at the University of Connecticut, and came to realize that diet only goes so far to reverse atherosclerosis–the buildup of cholesterol and other substances in arteries that leads to blockages, heart attacks, and strokes. He recalled sitting at his lab desk at 11 p.m. on a Saturday in 1974, “reading a book on atherosclerosis. And it was one of those rare times in life that things were so very clear.

“And the clarity was, ‘Why don’t you try finding something that could alleviate this disease?'”

Though new to running a company, he was willing to learn. And, colleagues say, he has traits that can’t be taught.

“His insights and intuition are really strong,” says Esperion biologist Clay Cramer. “He’s not worried about being wrong, and he’s persistent.”

Newton’s impact on Ann Arbor includes the medical benefits of the drugs he developed, the companies he built, the wealth they generated, and the people they employed. But it didn’t stop there. Lipitor, the blockbuster drug he co-discovered and developed, changed the city forever.

When Newton arrived in Ann Arbor in 1981 to work for Parke-Davis, the drug research division of health-care conglomerate Warner-Lambert, the company had gone three decades without getting a major drug approved by the FDA. Newton took charge of a small team tasked with discovering a cholesterol-lowering drug in the emerging class known as statins.

They first synthesized the drug that became Lipitor in 1985. But it had many doubters within the company.

At different points Warner-Lambert managers and marketing executives at the New Jersey headquarters sought to kill the program. There were already three statins on the market, they reasoned, so who needed another one? But Newton and key allies in Ann Arbor managed to keep it alive.

The FDA approved Lipitor for sale in 1997, and it went on to become the biggest prescription drug in history. It brought in $13 billion a year at its peak, vindicating the team’s belief in it. And Lipitor’s vast profits fueled a building boom at Parke-Davis’s Plymouth Road labs.

Before Lipitor, Warner-Lambert’s failure to develop profitable drugs had left it vulnerable to a takeover. The drug made the company rich and apparently safe from predators. But paradoxically, Lipitor was too successful.

With so many other statins already on the market, Warner-Lambert knew it would have to capture sales from competitors. To add marketing muscle, the company agreed to share Lipitor’s marketing rights and profits with Pfizer, which had a massive sales force.

But then Lipitor sales exploded–and the New York-based drug giant coveted all of the drug. Twenty years ago, Pfizer ruthlessly swallowed Warner-Lambert in a hostile takeover.

For Pfizer, though, the prize was Lipitor–not the facility that developed it. That became clear seven years later, when Pfizer needed to slash its costs. Lipitor’s patent was approaching expiration, and Pfizer had been forced to abandon its own great cholesterol drug hope–in a massive, late-stage trial, people taking it died at a much higher rate.

Rather than spread the cuts among its three drug-development sites, Pfizer simply axed the entire Ann Arbor research campus. The closing eliminated 3,100 well-paid jobs on the cusp of the Great Recession of 2008 and collapsed the local housing market. The U-M later bought the site, now known as the North Campus Research Complex, but the city’s biggest private employer and taxpayer was no more.

Newton left Warner-Lambert before Pfizer took over. Convinced that he could better develop drugs on his own, he founded the first Esperion in 1998. The main goal was to find drugs that raise HDL (good) cholesterol. But Newton also assigned two chemists, Jean-Louis Dasseux and Daniela Carmen Oniciu, to design a pill to lower LDL–like Lipitor.

“He encouraged us to be creative,” says Oniciu, now living in France and working as an advisor to biotech start-ups. She and Dasseux started with molecules that mimicked certain lipids (the molecules that make up fat), hoping to find one that would trick the body into stopping lipid production. They made hundreds of different compounds, varying their length and attaching different groups of atoms [functional groups of atoms], searching for the most potent version.

And potency alone wasn’t enough. To work, the drug would have to be absorbed into the bloodstream, penetrate body tissues, and not break down prematurely. It couldn’t antagonize other drugs. And it had to be safely removed from the body.

The chances of finding a compound that hit all those marks were slim. “At a certain point it’s serendipity and luck,” says Oniciu. “Everything has to fall into place.”

And then everything did. In 2001 Oniciu synthesized ETC-1002–the molecule that, nineteen years later, would win FDA approval as Nexletol.

Only later did Esperion’s researchers discover how ETC-1002 worked. By a stroke of luck, the molecule is inert until it makes it to the liver, where a liver enzyme converts it to an active form. There it interferes with another enzyme that’s crucial for building cholesterol molecules. That reduces cholesterol production in the liver.

“We’ve tricked the [liver cell] into believing that it doesn’t have enough cholesterol,” Cramer explains. “The cell says, ‘Oh, I don’t have enough cholesterol, I’m going to take cholesterol from the environment.'”

The liver pulls LDL from the bloodstream, which prevents plaque from building up in arteries and causing atherosclerosis. And because the drug is only active in the liver, there are few side effects.

As Esperion progressed, Pfizer seized control of Warner-Lambert and the Ann Arbor labs. In 2004 it added to its Ann Arbor empire by buying Esperion and its drug pipeline, including ETC-1002, for $1.3 billion.

Newton stayed on, but Pfizer disbanded the Esperion organization and shelved ETC-1002, leaving it for dead. And when Pfizer abandoned the Ann Arbor labs, Newton was left with no research future at the company. That’s when he decided to launch a new Esperion–and resume development of ETC-1002.

“Roger Newton actually asked me to go out to dinner and said, ‘We need to get this compound back from Pfizer so we can develop it as a drug,'” recalls Cramer. “Had he not pulled it out of Pfizer it wouldn’t be here today, period.” After a year negotiating, Newton had to pay Pfizer only $5 million, a pittance in the pharma world.

In 2008, Newton’s new Esperion was in business. But the money he paid for ETC-1002 was just a down payment. Getting it approved would take a dozen years of laboratory work and human trials, and those are enormously expensive.

Newton raised the initial money by convincing several venture capital funds and individuals to buy into his vision. His track record with Lipitor certainly helped, says Cramer, “but at the end of the day he still went up there and put his name on the line.”

Newton raised $57 million for Esperion between 2008 and its initial public stock offering in 2013. The company to date has raised and spent more than $700 million.

Pfizer could have shared in the rewards. Small biotechs like Esperion typically partner with larger companies to mount the huge trials necessary for FDA approval. In 2011 Newton approached Pfizer with a collaboration offer–but the pharma giant turned him down. “They did not have an interest,” says Mayleben.

So Newton and Esperion forged on alone. In 2012, Newton brought on Mayleben as CEO and transitioned to executive chairman and then to board member. Meanwhile, ETC-1002 moved slowly but steadily forward, along with Nexlizet, which combines the Nexletol molecule with an older cholesterol drug into a single pill. The drugs are designed for the minority of people who either can’t tolerate statins like Lipitor (mainly because of muscle pain) or who need to lower their cholesterol level more than statins alone can achieve.

Esperion sponsored five different “phase-three” trials to prove the drugs worked, enrolling more than 4,000 people. Nexletol, added to a statin, lowered LDL cholesterol an average of 18 percent compared to a statin plus a placebo pill, and did so with only minor side effects. Nexlizet, given alone, lowered LDL 38 percent compared to a placebo. These results virtually guaranteed FDA approval, says Derek Archila, a biotech analyst at the investment bank Stifel in Boston.

Most biotechs live and die without getting a drug approved, and the vast majority of clinical trials fail. Esperion scored with its first two shots on goal. “I don’t think it’s fully sunk in,” says Mayleben. “Given all the time that’s passed and … how rare it is to get a drug approved. Or, for that matter, to get two drugs approved in a week.” Mayleben expects another milestone, full European approval, this month.

How big could Nexletol and Nexlizet get? Based on interviews with doctors and key opinion leaders, Archila forecasts peak sales of about $3 billion in 2029. (Anything over $1 billion is considered a blockbuster drug.) He expects Nexlizet especially to be the first thing cardiologists prescribe to patients who can’t take statins, or who must limit their statin dose. “You have this combination product that’s relatively cheap, easy to prescribe,” Archila says.

Now Esperion is working on a new pill combining Nexletol and Lipitor. If it works, that 100 percent Roger Newton and Ann Arbor product could be the most powerful cholesterol-lowering drug known.

Newton, meanwhile, is finally stepping back: he retired last May and moved up north.

“He’s living his best life,” Mayleben says. “I think he’s even doing a little bit of farming.”