Before Mike Sofia became a big name in the world of drug discovery, he and his team wrestled with a challenge common to many businesses: How do we take a great idea to a bigger scale?
How would they take a molecule from working well in one cell to a whole patient, and have it kill the hepatitis C virus without damaging the body? And then, how would they produce enough of it to make medicine for millions?
"There appeared to be no path forward, and the project could have been stopped in its tracks," Sofia said. "Yet we were able to innovate out of the hole."
The innovations led to what experts call one of the greatest advances in public health in the 21st century. The drug cures 90 percent of patients with hepatitis C, a disease prevalent among baby boomers that can lead to liver cancer and death. And it represents big money for companies involved in producing the drug, sofosbuvir, sold under the brand name Sovaldi.
Sofia, who works in Doylestown, was the principal inventor of the drug, which generated $10.3 billion in first-year revenue for Gilead Sciences in 2014, representing the biggest drug launch to that point.
A grandson of Italian immigrants, Sofia fell in love with science in a Catholic elementary school in working-class Baltimore, and that remains his focus today at age 57.
Sofia was the senior vice president for chemistry at Pharmasset Inc. from August 2005 to January 2012, when his team developed sofosbuvir, which borrows a few letters from Sofia's name.
Financial success came when Gilead announced in November 2011 that it was buying Pharmasset for $11.1 billion. At the time, some financial analysts wrote that Gilead might have overpaid, but sales have proved those predictions wrong.
After a transition period with Gilead, Sofia and three fellow Pharmasset alums - Patrick Higgins, Michael McElhaugh, and Bryce Roberts - cofounded a small biotech in Bucks County that is now part of Canada-based Tekmira Pharmaceuticals.
With Sofia as chief scientific officer, Tekmira is focused on finding a cure for hepatitis B, which afflicts more than 200 million people worldwide.
For decades, interferon injections and ribavirin were used to treat - but not cure - hepatitis C. Many patients quit or refused to start the long-term regimen because the side effects included vomiting, diarrhea, anemia, skin rashes, and sleep problems.
Depending on their type of hepatitis C, patients take one or both drugs with sofosbuvir, but the cocktail almost always clears the virus from the body, without side effects.
"Sofosbuvir helped usher in a new paradigm of care," said Raymond Chung, director of the liver transplant program at Massachusetts General Hospital in Boston, who was not involved with Pharmasset or Gilead. "In no uncertain terms, it was a real sea change in the approach to managing treatment of patients with hepatitis C."
On May 8, the World Health Organization declared sofosbuvir to be an "essential medicine," underscoring its effectiveness, though the agency also wants the medicine priced lower so it can help more of the nearly 150 million people worldwide with hepatitis C.
Gilead initially priced the pill at $1,000 a day in the United States - about $84,000 for a 12-week course of treatment. Some insurers restricted access to patients with advanced liver disease.
"I've been working in this business over 25 years, had many, many failures and a lot of hard work," Sofia said. "I'm in the science part of the business, not the business part. How a company decides to price the drugs is, frankly, something I don't get involved with. I try to solve a problem of high medical need and bring a solution to the table. In this case, this is a cure. How can you deny people access to a cure?"
Competition can lower drug prices and other drugmakers - including Gilead - have introduced hepatitis C drugs since the Food and Drug Administration approved sofosbuvir in 2013.
The drug's patents also became property of Gilead, which is heavily involved in a thicket of patent litigation over the drug. Emory University professor Ray Schinazi, a cofounder of Pharmasset, formed a different company, Idenix, which has sued Gilead over patent issues. Also involved is Merck & Co., which bought Idenix last year for $3.85 billion, trying to catch up in hepatitis C.
"I prefer not to be involved," Schinazi said by e-mail when asked about Sofia's work. "Mike is a great scientist."
Sofia declined to say how much he made with the sale of Pharmasset to Gilead, but noted the risk of casting his lot with a biotech company that had no products on the market.
"More often than not in the biotech world, the gamble leads to nothing and you are forced to look for a new opportunity," said Sofia, who graduated from Cornell University and got a doctorate in organic chemistry at the University of Illinois. "We at Pharmasset were able to do something important that will save millions of lives and already has saved hundreds of thousands of lives."
The process also underscores how team-oriented drug discovery has become, how the era of the lone inventor is long over. Sofia said he'd assembled "a lot of individuals with different talents - medicinal chemists, microbiologists, virologists, someone who can develop screens, computational chemists.
"They all come together in what we call project teams," he said. "You build the project team around a particular problem."
Asked about the "aha" moment with sofosbuvir, Sofia said he was doodling, as usual, in a hardbound notebook (now in possession of Gilead) as he and colleagues tossed out ideas about molecular structures.
The breakthrough boils down to making a molecule with a shield that survives passage through the bloodstream and into the liver, whereupon the shield falls away. The active ingredient attacks the virus and doesn't leave the liver.
The process allowed a higher concentration of active ingredient to more effectively kill the virus without causing undesirable side effects.
The masking trick - called "prodrug technology" - had been tried in drug development before, including with HIV medicines.
"In the case of hepatitis C, no one had ever developed or used the prodrug to do what we did," Sofia said. "The prodrug is the mask on the drug that ultimately falls off to reveal the active agent where you want it."
"It just kind of hit me," Sofia added. "It was one of those things you look at and say, 'This has real potential. There is a clear opportunity here.' But you don't know if an idea is going to be anything until you do the experiments and get the data that says the idea is valid."
The idea still had the twin problems of scale: testing and production.
Testing on chimpanzees would have been best, at least for the researchers. But cost and public pressure to end testing on chimpanzees was growing in 2007. Instead, Sofia's team developed a way to evaluate the drug's effect on rats and dogs.
His team also had to make a pure form of sofosbuvir, free of variations, then make a lot of it.
"We were treading on virgin ground here," Sofia said. "We were ultimately able to develop a novel chemical method that could be used on a large scale."
Sofia and his wife, Charleen, who also grew up in Baltimore, have two grown daughters. To unwind and exercise, Sofia rides his bike more than 100 miles a week over the roads near the family's home in Buckingham Township.
Besides reading, writing, and reviewing journal articles and books at home after dinner, Sofia said, he likes to think of himself as an amateur historian. He said he drew inspiration for sticking to his scientific beliefs through the ups and downs of drug discovery from the long haul traveled by Abraham Lincoln.
"Lincoln is someone I have tremendous admiration for, primarily because of his ability to weather very difficult times, get through and see through the muck," Sofia said. "In this business, you must have tenacity to keep going because so many things go wrong. So many people spend entire careers without discovering a drug like sofosbuvir, but they keep pushing the science, they keep pushing the knowledge, and that ultimately leads to something good."