By Rich Soll, SVP of Research Service Division at WuXi AppTec (@richsollwx)

“As you toil and try to solve some scientific problems along the way, you’re so focused on solving some of these problems that you really don’t necessarily appreciate the impact that your work has on patients. It wasn’t until I met, personally face-to-face, the first patient and had them tell me their story that I began to really appreciate the magnitude of what we have been able to do.”

During his recent acceptance speech for the 2016 Lasker-DeBakey Clinical Medical Research Award, Michael Sofia told the story of his dad, an immigrant with an 8th grade education, and mom, a payroll clerk, who instilled in him and his siblings the value of an education, the immigrant work ethic, and the desire to do something good in life. It seems as though Sofia, who won the award for his role in the discovery of the cure for chronic hepatitis C, is still living that legacy.

For Sofia,“Drug discovery broadens your horizons, challenges your thinking, and if you are persistent, occasionally rewards you with the most gratifying, real world medical breakthroughs.”

The celebrated chemist has driven innovation throughout his 27-year career that has led to multiple clinical development candidates, including the successful hepatitis C drug Sofosbuvir, which has been described as a miracle drug, and its contribution to the cure of HCV is regarded as one of the most significant public health accomplishments of our generation. The drug was developed by Pharmasset, which was sold to Gilead Sciences for $11.5 billion in 2012.

These days, Sofia is focusing his efforts at Arbutus Biopharma as Chief Scientific Officer to develop a cure for hepatitis B, an infectious liver disease that affects an estimated 2 billion people worldwide and is the most severe form of hepatitis. Although a vaccine was developed in 1982, the World Health Organization estimates that more than 360 million people have chronic liver infections from HBV, with approximately 780,000 people dying every year due to causes related to HBV infection.

I recently spoke with Sofia, who explained why he prefers the constant innovation in the small biotech field over large pharma, and opens up about the failures, disappointments, and doubters along the drug development journey.

Rich Soll: Congratulations on the Lasker Award. Was the award a surprise for you?

Michael Sofia: It was an absolute surprise. Someone from industry never really contemplates being recognized with an award of this magnitude. It was something that wasn’t even on my radar screen. If you look at the 71-year history of the Lasker Award, there have been over 200 award winners, and including myself, there are only 12 individuals who have come from industry. There has been only one other medicinal chemist who has won this award, and that was Miguel Ondetti in 1999. Miguel Ondetti’s claim to fame, as you may know, is the development of the angiotensin converting enzyme inhibitors, and he worked at Squibb. In fact, I knew Miguel when I started my career at Squibb.

Rich Soll: So many people have been cured of hepatitis C due to your drug Sofosbuvir. Was there any moment when you grasped Sofosbuvir’s impact?

Michael Sofia: It’s estimated that over 800,000 individuals have been cured. It’s a staggering number, but if you look at the 170 million patients worldwide, there is still a lot more work to be done. Yet, I did not appreciate the magnitude of this drug and what it meant for those who succumb to hepatitis C until I personally learned from the patients. I documented one experience in an article that I authored in the journal Cell. This patient, who ran out of treatment options after HCV recurred following liver transplantation, was told to get his life’s affairs in order for the inevitable “end.” Soon thereafter he learned of Sofosbuvir’s clinical trials, enrolled, and 36 weeks later was declared cured.  In fact, he stood in front of the FDA advisory panel and told his moving story of survival directly attributable to the drug.

Rich Soll: That’s so wonderful to be able to touch peoples’ lives like that. The patients must feel enormous gratitude.

Michael Sofia: The direct interaction with patients has profoundly impacted me – their gratitude is overwhelming. As a researcher, you toil and try to solve some scientific problems along the way, you’re so focused on solving some of these problems that you really don’t necessarily appreciate the impact that your work has on patients. It wasn’t until I met, personally face-to-face, the first patient and had them tell me their story that I began to really appreciate the magnitude of what we have been able to do.

Rich Soll: You led the discovery of Sofosbuvir at Pharmasett, a start-up devoted to anti-virals. What was the motivation for you to move from a large pharma company to a small biotech?

Michael Sofia: I realized the big company environment is really not for me; it’s not in my DNA. I like the dynamic, fast-paced, quick decision-making in a small company. The fact that in a small company you survive on innovation, to me that environment was more akin to my personality. I realized how exciting the HCV arena was becoming and I was particularly interested in trying to find an opportunity in that space. And so maybe to my luck, as I was contemplating a move, I got a call from a recruiter inquiring whether I’d be interested in looking at this small biotech company called Pharmasset, a company I had never heard of before, but he did say that they were in the anti-viral space and they had a program in HIV and hepatitis B, but also had an early program in hepatitis C. I took the opportunity to visit them and there was a gut feeling that there was something there, something exciting – the possibilities and opportunities to build and grow a research organization and to make a significant impact.

Rich Soll: When you look at your experience with big pharma what are the differences in the R&D paradigm versus your biotech experience? Did you take risks at Pharmasset that you wouldn’t take at a pharma, and how did you manage those risks?

Michael Sofia: When you look at the two research paradigms, in the small biotech world you have limited resources, limited capabilities, and limited dollars. In big pharma, obviously you have what appears to be unlimited resources, unlimited capabilities, and much larger dollars. In the small biotech world, you have to stay focused; you can’t do too many different things. You have to focus your efforts on certain key projects in order to be successful because you cannot dilute yourself with your limited resources. That’s not necessarily the case in a large company. It’s certainly my experience that in the small biotech world you will only succeed by innovation; you can live and die based on your ability to innovate because you have no products and a limited source of revenue, so you must keep innovating and convincing people that you are worthy of them putting their money into what you’re doing.  In large companies, the success or failure of a single discovery project won’t dramatically impact the company’s overall success. At Pharmasset, we made a decision to focus on a particular area – viral hepatitis. We stayed focused on a particular set of target areas, and built a capability that allowed us to stand out and be a leader in what we were doing. We had a small group of about 33 scientists who were able to out-innovate the big pharma competitors out there. That was really quite an accomplishment.

Rich Soll: Do you still hold the same views on small biotech versus large pharma today?

Michael Sofia: Absolutely, I think even more so. What you see is the retrenchment of large pharma in research, and they are more and more betting on buying their innovation. That innovation is going to come from small companies, from a small group of people/scientists focusing on particular areas trying to solve problems in an innovative way. I think that paradigm is continuing to expand and I don’t see it changing in any way, shape or form.

Rich Soll: During Pharmasset’s ability to innovate, were there limitations and challenges with the program?

Michael Sofia: In any drug discovery endeavor there are ups and downs along the way. There were problems – the early compounds had poor bioavailability; they had a major problem with an inactive metabolite that was being formed; you had to give high doses of the early drug candidates. We were able to demonstrate a proof of concept clinically that this early molecule could work, and could provide the ability to reduce viral load in in HCV patients. But it wasn’t a molecule that we believed was going to be able to go all the way. We then stepped back and completely redesigned this molecule, taking advantage of what we knew about the metabolism of that drug and leverage that information and applied this concept of a nucleotide prodrug to build in some characteristics that we wanted, which was to enable us to deliver a nucleoside phosphate and target the liver, which is something that nobody had ever done before.

Rich Soll: What kind of general insights did you gain from the development of the drug?

Michael Sofia: When we look at the clinical programs we had, we were executing small clinical studies to answer specific questions. The answers to those questions would help guide us to do the next clinical study. If you look at what we were doing in the clinic, we were trying to push the boundaries on clinical development. We were the first to actually do a combination study of two direct antivirals in HCV infected patients. It was a study called INFORM-1, where we took an early version of our nucleosides, plus a protease inhibitor and looked to see if we could achieve the same viral load decline that people were observing when combining protease inhibitor plus interferon. That was an important pivotal study that demonstrated to the entire field that two antivirals can be combined and that you can get a similar viral load decline as if interferon was in the combinations. INFORM-1 was also a study we did outside the U.S. because in the U.S. at the time the U.S. Food & Drug Administration would not allow anyone to do combination studies of two investigational agents. They would only allow you to do a study with an investigational agent with a currently marketed drug. So we did the study outside the U.S. in New Zealand, and that, in fact, propelled the FDA to ultimately reconsider the idea of doing combination studies of two investigational agents in the U.S..  The change came as a result of many advocacy groups saying, why aren’t we doing these types of studies in the US? Lastly, when we did our famous trial, called Electron, where we did a combination of Sofosbuvir, plus ribavirin, thus, eliminating interferon, and  then looked at a 12-week short duration therapy; we were able to cure 100% of the patients. That changed the thinking in HCV therapy.

Rich Soll: Now you’re at Arbutus with a big focus on Hepatitis B. How is the company doing and do you think you have the next big winner?

Michael Sofia: Once Pharmasset was acquired by Gilead, I clearly made the decision to stay in the small biotech world.  I decided to start my own company, which ultimately became OnCore Biopharma, with a focus on hepatitis B. I knew the space, and realized that there was another big problem: hepatitis B. Although there is a vaccine, there is no cure. That was an area I felt I could bring my expertise and experience to help address the problem. We started OnCore Biopharma and we believed that as in HCV and HIV, combination therapy was going to be the solution to a cure. Exactly what that combination of agents is going to be, I don’t think anyone today can even tell you what that is. But because we believe that a cure will come using a combination therapy approach, we felt we needed to approach the problem through multiple mechanisms and bring in programs that looked at both direct acting antivirals and immune stimulation, because the hepatitis B virus is really quite cunning in the way it controls the host immune response. One key difference between hepatitis B and hepatitis C is the fact that hepatitis B has a viral reservoir. Hepatitis C doesn’t have a reservoir. So for an ultimate cure, we hope to find a way to eradicate this viral reservoir.

Rich Soll: Any results you can share with us so far?

Michael Sofia: About a year-and-a-half in the OnCore space, we decided to merge with a company called Tekmira that had an RNAi technology that was looking at hepatitis B. So we put together what we called a total solutions company in the hepatitis B cure area. We have some of our RNAi assets in clinical development right now, and we have a number of other programs that hopefully we will bring to the clinic in the very near future.

Rich Soll: In 2013, in the New Yorker, you talked about having to be comfortable with failure, because 80% of what you’re going to do is probably going to fail. What is your advice to young scientists in the industry regarding that?

Michael Sofia: You have to be passionate about what you do. Through that passion you can do incredible things. If you’re passionate enough you can weather the ups and downs of drug discovery or any scientific discipline. Generally science is an experimental field where you’re going to have more disappointments than you will have successes. But the successes bring tremendous satisfaction. The ability to impact human disease from the work that you’ve done, there couldn’t be anything more gratifying than that. And if there’s a little bit of luck on your side, you can actually change the course of a disease forever.