John Tsai is a leader in drug discovery, known for his prolific career developing life-saving treatments. He’s currently CEO of Forcefield Therapeutics, revolutionizing treatment of heart attacks with cardioprotective biotherapies. Before Forcefield, he held leadership roles at Novartis, Amgen, and Bristol-Myers Squibb. John operates at a pace that is truly unmatched — as Chief Medical Officer at Novartis, he led 160 new projects and 500 clinical trials, leading to 15 new drug approvals, including gene and cell therapies. John is also an executive partner at the life science investment firm Syncona.
John joined me to reflect on his journey from big pharma to biotech, and his vision for the future of cardiovascular health. — Sajith Wickramasekara
* Editor’s note: The conversation has been edited for length and clarity.
Letting serendipity take the lead
Sajith Wickramasekara: Looking at your CV, you're not the average biotech exec. You trained as an electrical engineer, and then became a doctor. Later, you joined big pharma and now you're at an early stage biotech. What inspired the shift from engineering to medicine?
John Tsai: When I was a freshman in college, I wanted to go into biomedical engineering, but that major was just starting. My brother said, “Don’t do that. The next big wave is going to be in electrical engineering.” That’s how I started.
Sajith: You didn’t think you’d become a doctor at this point?
John: I had no intentions. I didn’t really know what I was doing.
Sajith: That’s really interesting because I think sometimes people get the idea that they need to preplan every step of their career path versus sometimes letting a little bit of serendipity take the lead.
John: Totally. Other leaders may not say this, but I feel serendipity is the best approach.
During college, I actually went to the big hospital at Washington University, to learn what it was like to try to combine medicine and engineering. But they had nothing for me. They asked me to run wires through buildings, fix keyboards, and I thought, “This is not biomedical engineering.”
So after college, I joined GE Medical Systems, designing CT and MRI machines. It was pretty cool. I worked with a lot of physicians, and had lots of questions for them, like “Why do you want to use contrast here? Why is that gray? Why do you inject dye in these people?” They got really tired of me and said, “If you want to know, you should just go back to medical school.”
Sajith: How old were you at this point?
John: Probably 22 or 23 years old. I figured I was young enough to try changing my career. So I took night classes and got into medical school.
This is around the time my grandmother suffered a stroke. And you could really see the power of these medical machines. And I think that’s where it came to me — the ability of science to improve people’s lives. It was such a powerful calling, that I knew exactly what I wanted to do at that point.
Pursuing transformative medicines
Sajith: So you were in San Francisco, practicing internal medicine for a few years. How did you get into the pharma industry?
John: It was a job at Pfizer. My fiancée at the time (now wife) decided to move to the East Coast, and I thought, let me see if I can find a job. That’s when a recruiter called and said, “There's a large pharmaceutical company in the Northeast that's building a pipeline in cardiovascular medicine — are you interested?”
Next thing you know, I’m in NYC. I told my wife, “One year and let's go back.” Well, that one year turned into 18 years. I started off as a director, designing clinical trials for the cardiovascular medicine group.
I got a chance to work on Lipitor, and ended up putting 100,000 patients in different trials over that time. It really gave me a taste of what it was like, working on a drug that became a true blockbuster. You really understood the power of designing clinical trials correctly, and the power of the benefit for the patient.
Sajith: At the time, did you know how special of a medicine it would be?
John: Probably not, but I remember having discussions with the CEO, Hank McKinnell at the time. Here I am, 2-3 years in the industry, and I'm talking to the CEO of a large pharmaceutical company. People were like, “That never happens. You should take full advantage of it.” So I was pretty bold, and asked him for a tremendous amount of money for clinical trials.
He gave us the majority of it, and that's when I realized there was real growth potential — and the impact that it could have on patients.
"If you can see where the future is headed for a specific medicine, have a passion for it, and pursue it — that’s when growth happens."
Sajith: Let’s talk about another transformative medicine. You were part of the first FDA-approved CAR T therapy at Novartis. Can you share some of the big hurdles in getting it approved?
John: I was lucky to work on the CAR T, as well as Zolgensma, a gene therapy for spinal muscular atrophy. Over the last 4-5 years, we've seen such potential for these drugs to have significant impact on patients' lives — but at the same time, there's so much we don't know.
In cardiovascular medicine, phase I and II trials are usually in the hundreds of patients, where you get to see what really happens with the toxicity profile. But with gene and cell therapies, it’s often single digits. Will you be able to see the full adverse event profile? No. How do you determine the dose? In some ways, we’re doing the best that we can.
Sajith: When you started on CAR T programs at Novartis, was there controversy? Were there points where you thought it might not work?
John: Yeah, you have to be passionate about certain programs, because it’s rarely ever full alignment. But that’s where you get the best output, actually.
“If you get challenged, take the challenge very seriously, but don’t take it personally.”
Having those discussions around CAR T programs was very controversial, because the early programs that break through are usually not profitable. CAR Ts are a losing proposition for most companies, and it costs in the magnitude of billions.
If you think about how long it takes, you have to set up an entire infrastructure; you have to be able to produce and administer the drug within a certain time window; you have to figure out the reimbursement. Manufacturing is a different challenge altogether. For quite a long time, we couldn't get the quality above the purity standards set by the FDA.
Sajith: The first version of any technology is usually the most expensive, but gets cheaper and more effective over time. Of course, cell and gene therapies have a lot to be worked on with supply, manufacturing, approvals, complexity of the treatments, costs — but it seems like investors have pivoted in a different direction over the last few years. What’s your take on why progress has stalled there?
John: I definitely think that cell and gene therapies are here to stay, and will become a common modality over the course of time. If we think about the early 2000s, it was the same for monoclonal antibodies.
Sajith: That's true. And they’re all the best selling drugs today.
John: Exactly, and it’s gotten a lot cheaper. So, what will it take? It’s going to take improvements in manufacturing, better vectors that can target different tissues, better quality, and lower costs. Currently many of the gene therapies are in rare diseases, but we’re also beginning to see it in more common diseases.
The next wave of innovation in biotech
Sajith: Cardiovascular disease is the leading cause of death worldwide, but breakthroughs in treatments have been limited. Why do you think progress has been slow?
John: Pharma is a fascinating industry, because it’s the only one I know of where you get patent exclusivity for 10-12 years. On one hand, it’s a great system because it forces the industry to innovate.
You get these cycles, like cardiovascular drugs in the 90s and early 00s; then monoclonal antibodies; then the oncology wave; the ADCs; and now, the obesity wave. We had a small wave for rare diseases, but that’s shifting back, as people realize you have to treat the most common diseases too.
Sajith: People got scared of going after big diseases and big scientific arrows for a while.
John: For sure. For a study in immunology and inflammation, two phase III studies typically means 600 patients, with maybe a year to get results. Because for something like atopic dermatitis, your endpoints are maybe 3-6 months. For cardiovascular disease, 8,888 patients was the ideal trial for us. And then you monitor them for 3.5-5 years.
But I think there will be a swing back to the diseases which have such an impact on human health, like cardiovascular — in part because it’s an adjacency to obesity.
Believe that the science will prove out
Sajith: Looking back, what advice would you give your younger self?
John: I think the advice I’d give is to be resilient. I’ve been lucky enough to work on a number of drug approvals. It feels great when you get a drug approved, because there are so many patients that will benefit.
But no drug approval that I've ever received has been a linear path. I can give you many stories where we thought there wasn’t a path forward — when in fact, the drug ends up being a potential blockbuster.
I'll tell you about Apixaban, a drug that I worked on at Bristol Myers Squibb. We were about a year and a half behind a competitor, and we had a really difficult decision to make. The commercial team didn’t think we could commercialize the drug — but it’s a $9 billion drug in the marketplace now.
We got the drug approved, but we had a lot of fights. There was no conviction behind the drug, and the drug launch was pretty flat.
We ended up doing some more cardiovascular trials. In the end, the data actually proved out. It was more efficacious, but it took time for it to play out.
Sajith: So you actually got money to run more trials, after the drug launched and was commercially unsuccessful.
John: That's right. But it took a lot of convincing. This is where resiliency comes in — you have to believe that the science proves out.