BioBoss host John Simboli speaks with Reenie McCarthy, CEO of Stealth BioTherapeutics, headquartered in Needham, MA.. Hear Reenie's thoughts about leadership in biopharma and how Stealth Biotherapeutics is working on developing therapies to treat the mitochondrial dysfunction associated with genetic mitochondrial diseases and many common age-related diseases.
John Simboli 0:00
Today I'm in Needham, Massachusetts with Reenie McCarthy, CEO of Stealth BioTherapeutics, headquartered in Needham. Welcome to BioBoss, Reenie.
Reenie McCarthy 0:09
Thank you so much, John. It's great to see you, in person, and to be here with you today.
John Simboli 0:14
Reenie, what led you to your role as CEO of Stealth Therapeutics?
Reenie McCarthy 0:18
I worked for about 20 years at Morningside Ventures, which is a private venture, early-stage venture investment group, investing in transformational biotech opportunities, but also tech and others. And I was based in Boston in that role and Stealth was one of our portfolio investments, which I had, you know, worked on when it was formed and sat on the board of. When we decided to move from what's known as virtual mode, to actually hiring employees and building out a team and getting into the clinic, there was a bit of a leadership vacuum at the company. So I jumped in on an interim basis, to fill that vacuum for a short period of time. And it was a huge learning curve so it felt like drinking from a firehose. But the team actually asked me to stay, which was very flattering. And I think that we just clicked and connected well, and it worked.
John Simboli 1:10
Is that's something you anticipated as you were going through your career? Did you think at any point prior to that, you know, I think I'll be a biopharma CEO at some point?
Reenie McCarthy 1:18
No, never. I mean, I'm a lawyer by training. I did join Morningside in 1993. So there, I was leading the biotech investment team. So I certainly learned a lot about working with early-stage biotech companies. When you invest early, you tend to have a closer look under the hood, as it were, and you're more involved as a board member. But I never saw myself in a leadership role.
John Simboli 1:40
Once you made that transition. Did you have the sense, or maybe it took a little while to figure out, but it did feel like, Oh, this is something I probably it was meant to do? This feels right. I'm cast well, here.
Reenie McCarthy 1:52
I don't know if I felt I was meant to do it. But I will say it's incredibly fulfilling, You feel like you're a part of something bigger. So I'll back up a little. As a lawyer, it's unclear what team you're on. You work for different clients and different projects, often short-term and so you don't have that sense of ownership. As an early-stage biotech investor, you certainly have a closer sense of ownership because you're nurturing young companies. But you're still a step away. When you're in an operating company, particularly one like Stealth, where we're tackling diseases that there's no approved therapies for. You're kind of blazing trails, right and left. It just gives you this sense of fulfillment and purpose that is different, I think, from any of my prior professional experiences.
John Simboli 2:39
People probably wonder what does a biopharma CEO do. People can picture what a scientist does; people can picture a lawyer does. What does a biopharma CEO do?
Reenie McCarthy 2:49
You do what you need to do. You pitch in where you need to pitch in. I think I brought to the table a different perspective than somebody coming out of a pharma background. As an investor, you're taught to ask questions, and challenge the norms and think outside the box. And so some of that was maybe refreshing. And that's certainly part of the role, because you're on an executive team, and you develop strategy together. And a lot of that is asking questions, and trying to challenge perceptions. But you also have to bring the Stealth story to the outside world, and you have to bring the outside world perspective into the company. And so a lot of it is really communicating and bridging that communication gap, making sure that the teams work together in an integrated fashion, which doesn't always happen. Pharma companies can be somewhat siloed, we hire many people from those backgrounds. So trying to break that down and establish more dynamic communications cross functionally. But I'll write regulatory documents when I need to, too. So you do what you need to do.
John Simboli 3:54
You had an insight into the company from the investment world, when you came in. When you made that decision to become the leader, what were you hoping to achieve at Stealth that you might not have been able to do someplace else?
Reenie McCarthy 4:06
I think that really, we were trying to define a path to bring first-in-class medicine and first-in-class approach to the treatment of human disease forward for patients. And to do it in a way that made sense both commercially and from a clinical development perspective and financially for us as a company. That was the objective. And many of these are rare diseases. The others are diseases of aging. Again, there's no therapies. So really trying to understand the patient perspective, use that in designing our trials and bring forward therapies for patients. I mean, that's the mission and that certainly was mine.
John Simboli 4:44
What have you learned over the years of being the leader at Stealth BioTherapeutics about what management style works for you, is you, describes you?
Reenie McCarthy 4:51
I work better through teams. I do think you should be able to have a conversation with anyone in the organization. We bring in people who are smart and who are creative and who can contribute and so I think everyone's voice should be heard. I don't think that it should be sort of siloed or really super hierarchical. And you know, that's worked well for us at Stealth. I also try to get feedback. I mean, I've encouraged broad 360 feedback on my performance, for my team, which I will say I cringe every time I get it, and my stomach is all knotted. But I think it's super important to get that. It keeps you real.
John Simboli 5:26
Can you remember when you were eight or nine, what image you had of what you might want to be when you grew up, realizing that for most of us, it was trying to figure out what our parents thought we should be when we got to be adults?
Reenie McCarthy 5:37
I don't know that I had a clear view. But I will say that I was the kid who always had my nose in a book in the back of the car. Usually, it was a science fiction book. There's an interesting thing, when I first came into Stealth, and I kept going back to it. I'm not a scientist. So I was reading and learning about mitochondria because you have to speak to the science as a CEO. And I knew generally, but I remember, one of the series I loved was Madeleine L'Engle's, Wind in the Door. And there's an episode where Charles Wallace goes in and communicates with his mitochondria because he's sick. And so that came very much to mind. So I think for me, I was definitely a reader and a writer, as a kid. This is different. But in some ways, it's all about communication. It's about telling a story. It's about crafting a story, and keeping it held together, both internally for my team and externally for the world. So maybe some synergies.
John Simboli 6:35
What do you say when people ask you, Who is Stealth BioTherapeutics?
Reenie McCarthy 6:38
We're working on mitochondrial-targeted therapeutics. When you think about our mitochondria, they are essential for us to live, they produce most of our energy, and they are broadly implicated across human pathologies. So that's what we do as a company. Rare diseases for sure, as well as diseases associated with aging.
John Simboli 6:57
If there are other companies in the space, how do you differentiate yourself from them?
Reenie McCarthy 7:02
We were one of the earliest in the space. So mitochondria are essential for human life, they're really hard to get to. So targeting mitochondria is challenging. There are, as of recent years, other companies starting to come into the space or other companies with drugs that might work downstream of mitochondria, but they're implicating some of the same pathways. I think that what distinguishes us is, mechanistically, we really are targeting directly the mitochondria. And one of the key aspects of mitochondrial dysfunction that leads to pathology, broadly across disease. So we're not looking at a specific mitochondrial gene, we're targeting, really, a structural issue of structural damage that happens to mitochondria when there is a genetic defect, or when there is some type of pathology, like a stroke that's going to damage mitochondria. So it's a fairly ubiquitous mechanism.
John Simboli 7:59
In my experience, when a CEO makes a presentation, let's say to an investor conference, it's often the case that what you're looking for is to divide and figure out quickly, who might be a good person have another conversation, a follow-up conversation with; who might just not fit. There's an interesting third group that appears to be a good fit but after you speak with them, you realize they heard something different than what you intended. And that's often interesting. How do you bring that back into focus? How do you say, you know, this is actually not this, it's this? Does that happen? And if so, how do you get back on track?
Reenie McCarthy 8:36
Mitochondrial dysfunction is closely associated with aging and the aging process. And so you will sometimes have conversations with people who talk about well, can you treat aging or prolong healthspan? Or this, that, or the other thing? And the answer there is, yes, maybe, probably. But there's no approved regulatory pathway for aging. We are not in longevity therapeutics, although we will target diseases associated with aging. We're pretty clearly trying to develop drugs to treat human disease, not develop nutraceuticals, essentially, because that's really the only thing on that side of the equation. I think you sometimes have other conversations where people don't really understand the technology because they're used to therapeutics working a different way. We're retargeting an organelle, which came from bacteria, for goodness sakes, in the first place. So it's really not like mammalian biology, even though it's well integrated with people. And so I do think there's a lot of education with people who are used to blocking receptors or doing things that are much more closely suited to human biology, who wonder why we're targeting a lipid in the inner mitochondrial membrane. So there is a lot of education that has to happen there.
John Simboli 9:52
What's a good partner fit for Stealth BioTherapeutics?
Reenie McCarthy 9:56
We have over 100 peer-reviewed publications discussing elamipretide across disease models. Many of those came out of academia. So in terms of academic partners, I would say it's a group that you can work closely with that will keep you apprised of when they're going to be publishing what experiments they're doing, who you can have a dialogue back and forth with. We know a lot about how our drug works. And what doesn't work, particularly. Mitochondria are a little bit finicky. So certain assays might have to be done a certain way. And so having a partner who you can build that dialogue and communication with, and it's a respectful situation, is important in terms of academic collaborations. Industry collaborations, I think we look for common missions. We look for partners, certainly who know that therapeutic area, but who also are dedicated to incorporating the patient voice, particularly in rare disease settings, because that's so important. It's crucial for clinical success. It's crucial for commercial success. It's crucial for regulatory success. So certainly in rare disease education, that's really, really important.
John Simboli 11:07
What kinds of people thrive as employees at Stealth BioTherapeutics?
Reenie McCarthy 11:11
What defines our team is people who are passionate about the science, passionate about developing therapies for patients, and really want to learn. There's just a lot of opportunity at a small company that has a fairly flat managerial structure, and just a dedication not to be siloed, to have good cross-functional communication. That brings a lot of learning opportunities for people to kind of stretch their wings and move into other areas or fully utilize their capabilities and their creativity across the organization. And so those are the people who do well here, people who are a little bit brave in that way, and who are willing to learn and push themselves.
John Simboli 11:55
Reenie, what's new at Stealth BioTherapeutics?
Reenie McCarthy 11:57
We do have a major data readout coming up next quarter in dry age-related macular degeneration. But I think that on the new and exciting front, we have very recent data in Duchenne muscular dystrophy, which really defines a potential path in that disease. We're seeing more than doubling of dystrophin levels in the old standard animal model when we treat on top of the standard of care. And we're also seeing some very promising preclinical and rationale for moving forward to target cardiomyopathy, which is the leading cause of death and Duchenne. So two different development paths there; I think there's a lot of enthusiasm about, certainly in the DMD community and with us internally. We are also, with new compounds that we're just bringing into Phase one right now, seeing really strong signals across a number of neurological diseases. So ALS, and frontotemporal dementia, and Huntington's and Parkinson's. SBT-272, this new compound, can improve neuronal function, in some cases, reduce protein aggregates, like tau tangles, improve motor function across these different disease models. So that's super exciting because it just opens up a whole new therapeutic area for us.
John Simboli 13:17
How do you figure out when to pivot or change from one direction to another, and have it all still stick together?
Reenie McCarthy 13:25
I think when you're first-in-class, which this is, from a mitochondrial-targeted therapeutic perspective. There's a lot that you don't know from animal models. And it's not just in rare diseases, it's in common diseases, too. So we see with elamipretide and SB 272, an almost immediate improvement in bioenergetics of mitochondria. But that doesn't mean you're going to improve end-organ function. What we've learned in our studies, where we originally were doing pretty short clinical trials, a day or a week or a month, is that really, to see changes in organ function, it is taking many months. In Barth Syndrome, we saw signs of cardiac reverse remodeling after about nine months. That isn't necessarily what we would have expected. But it is incredibly informative for new approaches. And so, with the learnings from Barth, that's what brought us over to Duchenne. To look at the cardiomyopathy in Duchenne, we had always seen that elamipretide can improve cardiac function. But until we really saw, well, it's this duration, it's this specific function, and how could that apply to other diseases? That's where you bring those learnings. It's interesting because one of our key investors has said, the investment thesis is stronger now than it has ever been at any point during the company's history because you've learned so much.
John Simboli 14:46
How does the Stealth BioTherapeutics pipeline express your vision for the company?
Reenie McCarthy 14:50
We're looking at disease areas where there's the highest demand for mitochondrial energy. So that's kind of roughly how we've chunked up our approach. You will go into meetings with investors or others who say, Oh, you need to be focused in your approach. And we come out with like six new ideas of new indications we should look at. So we've tried to really focus on particular disease areas where there's a huge demand for mitochondrial bioenergetics. And then within that, we focus primarily on rare diseases. And the reason for that is that we can do smaller clinical trials, there is a huge unmet need. And we can commercialize those indications ourselves as a small company. I will say that doesn't mean that we aren't still in the back of our mind thinking about aging because it is an obvious fit for mitochondrial-targeted therapeutics. And so clearly, we're in phase two in dry age related macular degeneration, we would probably look to partner that program to commercialize because, and to do Phase I, because it's a big chunk for us to bite off. But I do think that, optimistically, looking to the future, if we establish a rare disease franchise, we can grow with that and then move into larger disease areas where there's a huge rationale for mitochondrial targeted drugs.
John Simboli 16:09
What good can you do in the world if Stealth BioTherapeutics succeeds, as you hope it will?
Reenie McCarthy 16:13
I do think that this is a very differentiated and sensible approach to the treatment of human disease. Restoring normal bioenergetics has so many downstream consequences, that it could make a big difference in the day-to-day lives of patients. So we are in some rare diseases and, I think, in rare diseases you can kind of go into anecdotes. We've collected data from patients in a fairly structured way, in a pre-specified way. But it's patients talking about the impact of therapy on their activities of daily living. And so for example, in Barth syndrome, which is an ultra rare disease, we have four of seven patients who were on long-term therapy, working jobs, going to school, which really isn't something that you expect to see for patients affected by that disease. It's very challenging for many of these patients to even go to school for a full day, nevermind taking on a part time job afterwards. Patients who talk about being able to be social or go to the gym for the first time ever. Or patients with another rare disease, Leber's hereditary optic neuropathy, who tell us, we can see colors now, and red is a really important color, it tells you when to stop. The effects you can have in the rare disease setting are meaningful. The effects you can have if this approach works in dry AMD, for patients affected by that disease, the isolation and depression that comes with losing vision as an elderly individual, it's similar to end-stage renal failure, as patients describe it. So if you can slow down the progression, potentially even restore visual function to patients, it makes a huge difference to their quality of life, to how they feel and function. So it's that concept of healthspan, I think, both for patients affected by rare disease and for older patients, bioenergetics goes to healthspan, it goes to how you feel and how you function.
John Simboli 18:11
In the rare disease world, you get a pretty close-up view of how your work potentially can affect the lives of individual human beings. You're also in knee deep, neck deep in the world of data and scientific platforms. How do you keep those two in balance?
Reenie McCarthy 18:28
When we first started looking at data in Barth Syndrome, where we could only enroll 12 patients—the disease affects less than 150 in the U.S.—You don't see a clear statistical signal or a good P value. And you say, That's done. But when you then start to look and say this was a really consistent signal for every patient across just about every endpoint that we studied, you start to reset your mind and your expectations. So you have to straddle that; you have to be grounded in the science and in the data. But also recognize it's an ultra rare disease. And I think you have to be informed on the clinical meaningfulness of the data by what patients tell you. I mean, I think you have to be scientifically robust and rigorous, but recognize that you're dealing with small patient samples and recognize that your early trials may have to inform later trials because nobody's done trials in these diseases before. It's not like developing a drug for a disease that there have been multiple previous trials done for. I would tell you, the Duchenne opportunity we're looking at on top of exon skipping drugs, that's been done before. You know how to design that trial. You know how long you have to run that trial, and you know what data you need to see to succeed. If you're in a disease where there's really no approved therapies, you're blazing that path. And so I think it does take some creativity and some patience, but also some scientific rigor to get you there.
John Simboli 19:56
Which of your therapeutic candidate would you want to try to describe?
Reenie McCarthy 20:01
Both elamipretide, our lead compound, and SBT-272, which is our next clinical stage compound, have a similar mechanism of action. 272 gets into the brain better. That's kind of a way to think about the differences, very simplistically. They both target the mitochondria. So mitochondria are organelles, they function really very synergistically with one another within our body. So think of it like an energy grid. They're in almost all of our cells, they produce 90% of our energy. And as a byproduct of energy production, they produce oxidative stress. So that's why we drink red wine and eat blueberries and things is to get rid of the oxidative stress in our lives. Our approach is to try to turn it off at the source or reduce it to normal levels at the source. So what happens when mitochondria produce oxidative stress is that it starts to cannibalize the mitochondria themselves. So it starts to target a lipid, which for a double membrane-bound organelle, lipids are super important. It starts to target a lipid called cardiolipin and it damages it. Barth syndrome is a disease of cardiolipin deficiency. And with that, it's often lethal in infancy. So cardiolipin is essential for human life. What our compound is doing is it's going in and it's essentially protecting cardiolipin, re-aggregating it. So we can see normal mitochondrial structure, which turns into normal mitochondrial function. That's what the drug does. It protects this key lipid, which is central to mitochondrial biology. When mitochondria get dysfunctional, they produce more oxidative stress, which cannibalizes cardiolipin. And so it's not necessarily the cause of the disease, but it's one of the first downstream events, which then amplifies the cycles of inflammation and fibrosis that we see across diseases. So mitochondria are also really adaptable. They'll compensate for other insults our bodies have. I'll give you the example of Duchenne. That's caused by a dystrophin deficiency, which causes calcium overload/ Mitochondria buffer that calcium overload. So in that disease, you see the mitochondrial dysfunction happen first, before there's any clinical symptoms. Once the mitochondria are overwhelmed, that's when you start to see the muscle issues and the cardiac issues in that disease. So if you can shore up the mitochondria, which are helping our bodies compensate for bioenergetic deficits in multiple situations, it can be a mechanism that has broad applicability.
John Simboli 22:29
As you look forward to the way you see the regulatory environment developing, what are the different arguments you foresee? And how do you think will play out?
Reenie McCarthy 22:38
The current regulatory environment doesn't have a clear path to approve drugs for ultra-rare diseases on the basis of a risk versus benefit type analysis. That pathway exists in Europe. And so one approach would be to expand the accelerated approval pathway to explicitly permit the FDA to conduct an analysis of that nature in ultra-rare diseases where it is really, really hard to establish clinical benefit by conventional statistical means. But on the flip side, what I've also heard from FDA, and I'm absolutely sympathetic to, is that one of the challenges of the accelerated approval pathway is that it is conditioned on doing postmarketing studies, which could take years to conduct because that's part of the challenge. They may take too long, and patients shouldn't have to wait. But sponsors don't always start those, even, on time. And so I think that FDA would like a way to better enforce that postmarketing commitment to make sure that sponsors are actively enrolling patients, for example, at the time of approval, that the Phase IV commitment is clearly articulated at the time of approval. We could design that next trial. We could have sites open; we could be recruiting for it, certainly, within the nine months that it takes to get an NDA submitted, reviewed and approved.
John Simboli 24:01
Thanks for speaking with me today, Reenie.
Reenie McCarthy 24:03
This has been great, John. Thanks for inviting me. It's been a fun conversation.