Unlocking Potential Cures For Rare Diseases With Gene Therapy - Dr. Gaurav Shah, CEO of Rocket Pharma


Eighty percent of rare diseases are caused by genetic mutations, which is why many of our recent guests have highlighted the importance of pursuing gene therapies as potential treatments and cures. That’s why we’re particularly pleased to have Dr. Gaurav Shah on Raise the Line today. He’s the CEO of Rocket Pharma, a company that’s in hot pursuit of developing curative gene therapies for patients with inherited genetic diseases, and showing remarkable results in some cases. For instance, a gene therapy for a rare and fatal heart condition called Danon disease is moving every parameter in the right direction, a result Dr. Shah is understandably proud of. “When gene therapy works, it really works. We were able to demonstrate the power of gene therapy for heart disease for the first time in our species,” he tells host Michael Carrese. Don’t miss this fascinating look at the art, science and practicalities of developing gene therapies and where Rocket Pharma is seeing progress. You’ll also learn about the many career options in drug development and hear how Dr. Shah’s background as a Grammy-winning artist informs his approach to leadership. Mentioned in this episode: https://rocketpharma.com/




Michael Carrese: Hi everybody, I'm Michael Carrese. It's estimated that 80% of rare diseases are caused by genetic mutations, which is why so many of our recent guests have told us about pursuing gene therapies to treat and hopefully cure the conditions with which they or their loved ones are afflicted. With that in mind, I'm happy to welcome Rocket Pharma CEO Dr. Gaurav Shah to Raise the Line because that company's mission is very simply to seek gene therapy cures. Rocket Pharma focuses on potentially curative first-in-class gene therapies for devastating pediatric diseases that have high unmet need. Prior to this role, Dr. Shah was a global program head in the cell and gene therapies unit at Novartis, where he had strategic oversight of twelve functions and helped spearhead pivotal trials with CART19 for patients with leukemia and lymphoma. He's a medical oncologist and neuro-oncologist by training and in a first for Raise the Line, he’s also a Grammy-winning musician of Indian classical music. Dr. Shah, it’s great to have you with us today.


Dr. Gaurav Shah: Thanks for having me. Great to be here.


Michael Carrese: We like to start by learning more about our guests...get some highlights personally and professionally. What got you interested in medicine in the first place, and then oncology?


Dr. Gaurav Shah: I grew up in Fort Worth, Texas, surrounded by a lot of science-loving peers and other children. My father loved science as well and gifted me several science kits when I was small and took me to Cape Canaveral. So, I guess my first interest in science started with astronomy. I used to gaze up at the night sky -- my backyard had a small telescope -- and saw the moons of Jupiter or the rings of Saturn and that was probably in middle school or even before that.


Medicine started being of interest to me some time in high school. I was actually watching a PBS show where neurosurgeons were manipulating electrodes in a patient's brain in order to understand what parts of the brain were still important in function from patients with epilepsy, and I remember stimulating a certain part would make patients feel an emotion, and another part would make them move their thumb. Another stimulation of another area might make them feel a sensation in their left leg. 


I was just intrigued by the connection between the physical, the emotional, the mental, and ultimately the spiritual aspect of our brains. But in parallel, I'd grown up fascinated with philosophy and sort of natural philosophy and thinking about who we are, where we come from, meaning. I pursued a lot of spiritual pursuits in my high school days. Neuroscience brought it all together. It brought science together with spiritual pursuits and I wanted to understand where the seat of consciousness resides in the brain. Now, there are a lot of books written about this, many of them are popular literature. I thought medicine would be the best place to bring all this together, and so I became a doctor ultimately, and went into neuro-oncology and cancer research.


Michael Carrese: And has that proven to be true? Has medicine been the place that brought it together?


Dr. Gaurav Shah: Interestingly, I think the questions have changed, right? I think that all the fascination with meaning and purpose now find different manifestations. Now I find that I can find meaning and purpose through rare disease drug development in a much bigger way than seeking the source of consciousness in the brain. So, it did ultimately lead me to the right place, but not where I thought it would be.


Michael Carrese: When did rare diseases come on your radar?


Dr. Gaurav Shah: First of all, "rare disease" is a little bit of a misnomer because each rare disease is rare, but rare disease is not rare. Many types of cancer are actually rare diseases. During my fellowship, I discovered a deep fascination with brain tumors. That's why I eventually went into neuro-oncology. Most brain tumors are actually rare diseases, and if you look at all the rare diseases and you add them together, there are probably almost half a billion people around the world who have some form of a rare disease and there are at least ten thousand different types of them.


So, in my journey here, at some point, various mentors and advisors had suggested that I may be able to help and potentially help cure more patients through the research of either cancer or rare disease than through actually being a practicing physician, which is what I would have done otherwise. Somehow, maybe in 2007 or 2008, it all came together where I made a move out of medicine -- still being a doctor -- but into drug development and into cancer research at the time.


Michael Carrese: And as we’ve pointed out on this program before, research into therapies and cures for rare diseases have ended up positively impacting the health of hundreds of millions of people. The top example usually is that statins to control cholesterol came out of rare disease research. So, this is all much more interconnected than perhaps people realize.


Dr. Gaurav Shah: Yeah, and I can also add to that with an angle from gene therapy. Right now, the way that we apply gene therapy most effectively is by addressing monogenic rare diseases. The commonly known ones are Duchenne muscular dystrophy, hemophilia and cystic fibrosis. But Rocket pursues different types of rare diseases -- Fanconi anemia, Danon disease -- which is a heart condition. These are monogenic, which means that there's a mutation or mutations on a single gene that defines the disorder, and typically, monogenic conditions tend to be rare because they can't become that prevalent in the population because the population is usually severely affected and the diseases can be fatal. 


However, once we figure out how to crack the monogenic code, we can then crack the biogenic code, two genes, transgenic three genes, ultimately the multigenic code, and when you're multigenic...multigenic gene therapy could potentially ultimately be applied to much more common diseases such as heart disease, stroke and Alzheimers. That might be actually something that people might pursue as the early gene therapy for multigenic diseases. So, while we're starting in rare disease, it's a window to addressing a much broader and more common set of indications through gene therapy.


Michael Carrese: Let's get into Rocket Pharma a little bit. Can you give us an overview of the company and currently what you're focusing on?


Dr. Gaurav Shah: So, we are a gene therapy company. Our mission is to seek gene therapy cures for patients with rare and devastating diseases. While many gene therapy companies have been founded around certain scientific platforms -- whether it's AAV, lentiviral, gene editing, etc. -- the philosophy by which we started was we focused on indications, on diseases first, where there's a high unmet need, where we can really potentially create a large difference in patients’ lives for diseases that are devastating and often fatal, and often manifest in childhood. 


Because we start with the clinic in mind and the disease in mind, most of those who started the company were healthcare providers and/or physicians.  Because we start that way, we're able to think about clinical development much earlier than most companies would. Even before we choose the disease, we think about what the clinical development pathway will look like to get us from here to approval, and even beyond approval, to hopefully thousands of patients. And if that doesn't look right, then we don't go down that path. 


We try to be first, best and only-in-class in rare devastating diseases where there's a clear mechanism of action which is on target. We’re targeting the gene in the cell that causes the disease, and as we grow as a business, we want to keep targeting larger and larger diseases so that we can potentially treat thousands of patients down the road. 


So, with that philosophy, we've actually siphoned in two different platforms. One is the ex-vivo lentiviral platform for bone marrow, hematologic conditions. The other is the in-vivo AAV platform for all other organs. Right now we have bone marrow, and cardiac; ex-vivo lenti for bone marrow, and in-vivo AAV for cardiac conditions. We may expand to a third therapeutic area in the future. We've been around now for seven years. Five of those years have been as a public company. I've been here since the beginning and we keep growing our pipeline and people. We also now have in-house manufacturing to produce the cardiac therapies, all the way through commercialization.


Michael Carrese: What has been your most promising work, do you think?


Dr. Gaurav Shah: It's interesting. It's hard for me to choose which program has worked the best. The reality is that when gene therapy works, it really works. This is the only way that we can truly potentially cure a disease because we're replacing faulty DNA with corrected DNA and if it's the faulty DNA that causes the whole condition, then, by definition, replacing it with corrected DNA should correct the condition and it almost always does. 


Michael Carrese: In other words, a one-time treatment is possible?


Dr. Gaurav Shah: A one-time treatment is possible. I hesitate to say cure until we see these patients a decade or two down the road, but this is as close to cure as I think we can get as a human species. You know, we are fundamentally made of DNA and we're templates of DNA that copy themselves, and sometimes they make an error. If you correct that error, then patients and people should have normal healthy lives. 


Out of the programs that we've worked on so far, I would say that maybe the most visible and differentiating is the Danon disease cardiac program. It's an X-linked cardiomyopathy, meaning a type of heart failure that affects boys more than girls but affects both boys and girls. In boys, without any treatment, they typically passed away in their late teenage years and even with a heart transplant -- and they don't always survive a heart transplant -- they usually get to the age of twenty, on average. Only 50% of patients survive a heart transplant over the course of ten years. So this really is a fatal, devastating disease and hits people at the prime of their life right as they're entering their working and college years. 


What we've developed is an in-vivo AAV approach, which means that you inject the therapy directly into the patient, in this case IV. And the AAV vector, which is loaded with the corrected trans gene goes to the heart, because the type of capsid that we've chosen loves the heart, AAV9. Once it's in the heart, it makes copies of this protein. It basically inserts the DNA into the heart and eventually we get protein expression over the course of several weeks and that protein corrects the missing protein in those boys who had Danon disease. That missing protein is called LAMP2b. It's like the on switch of the vacuum cleaner of these patients' heart cells. Without it, you get a lot of debris and vacuoles and other literally garbage building up that needs to be thrown out. But the on switch is missing for that vacuum cleaner, so we supply the on switch, and the heart cells clean themselves up. 


We just released data at the end of last year -- and we updated this a couple of weeks ago -- on the fact that every single parameter measured in six appropriately treated patients has improved. That ranges from seeing protein expression inside the cell now, which we see across the board; number two, you see a reduction in those vacuoles. You can see that on histology slides just like a medical student would. You can see the vacuoles actually being thrown out; number three, lab values like troponin and BNP -- which are markers of cardiac injury like heart attack or heart failure -- decrease. 


Remarkably, we've seen on echo in every single situation, a decrease in left ventricular mass, which means the hearts are shrinking. What used to be very large hearts full of vacuoles are shrinking now, and we see improvements in how a patient functions and feels based on NYHA class as well as quality of life measures. So, every single parameter is moving the right way. Again, I think you only see something like that with gene therapy when you're replacing the missing DNA with the right DNA. Now we're in discussions with the FDA about how to potentially bring this to a much larger pool of patients with this devastating disease and I think we're especially proud of this is because we were able to demonstrate the power of gene therapy for heart disease for the first time in our species.


Michael Carrese: So, I’m just curious about your personal reaction the first time you got an indication that this therapy was working? If you think about the seven or eight-year-old boy that was interested in science, the idea that you can manipulate the DNA of a human being and cure disease is just unbelievable, right?


Dr. Gaurav Shah: Yeah. So by the way, the most recent Jurassic World is about this and they talk about how no one has cracked the code into getting enough DNA into enough cells to cure disease. Whoever wrote that movie should have called the right advisors because it's here. It's been here for ten years, so someone missed the cue there. So, I'm gonna make that point.


Michael Carrese: [Laughs] Noted.


Dr. Gaurav Shah: But how I feel about this every time is surprised. Every single time I hear an outcome I'm like, "There's no way that could be, really?" This is true for Danon disease, certainly, but also for some of the other diseases as well like LAD1. These children who usually die of fatal recurrent infections at two or three or four years old, are now living antibiotic and infection free, going back to school and living normal lives. This doesn't come from me, our beloved KOL (Key Opinion Leader), Dr. Don Kohn from UCLA, said that as far as he's concerned, these patients are cured. This is not coming from me, it’s coming from him. 


But you might consider it a cure in the sense that this patient who would have lived to two, three or four may live to ninety-two, ninety-three, or ninety-four, now, right? And every time we see some positive outcome like that, I don't believe it at first. The scientist in me wants to look at the data again, make sure that the data sources are validated and accurate. But then eventually, it speaks for itself, you know? And we've been audited. Once you see it all come through, it just surprises me that something this complex -- although it is elegant and simple in many ways -- can have such a profound effect on people's lives.


Michael Carrese: Let's bore in on the complexity of it a little bit, because I want to ask you about the process of drug development. We've got a lot of medical students and early career professionals in the audience, and it'd be great for them to get some sense of that process and where they might see themselves plugging into it or, you know, just at least create the proper expectations for how difficult it is.


Dr. Gaurav Shah: Yes, so typically, to develop an idea from its nascent stage to the ultimate approval takes fifteen years or so, whether it's a small molecule or a gene therapy. This spans everything from discovery to candidate selection, to preclinical studies, to clinical studies, to confirmatory clinical studies, to regulatory discussions. Then even post-approvals, you still have to manage very carefully the sentiment amongst those who might be early adopters, and really think of it as a business. So, drug development spans everything from science to true commercial business. There are a lot of opportunities here for growth, and you can plug yourself into any area. 


MDs, and PhDs and Pharm Ds often find themselves drawn to the earlier stages of drug development. Some of the folks who are more in the business end of things like to plug themselves into the latter ends of it and regulatory, I think, spans all of it. There are so many points. When I was staring up at the night sky in Fort Worth Texas, or even when I was in medical school trying to figure out what path I wanted to choose, I never knew that I would end up doing a job that is, in some ways, not a job at all, but in some ways it's all jobs, right? It's thinking about all of these different drug development issues and integrating them and being able to deliver the message in a meaningful way to our partners and outside supporters.


So, there are so many ways to plug yourselves in. It used to be that medicine and industry were siloed, but I don't know anyone who thinks like that anymore. I think everyone recognizes industry and academic medicine and clinical medicine to be an integrated whole that learn from one another and generously give to one another as well.


Michael Carrese: We had a guest on recently who is a physician in drug development who said that one thing I never thought about was logistics because they’ve got to get test samples back and forth across the country. There's this whole other piece of the business. So, once you started looking into it, there's just a lot of different angles to it.


Dr. Gaurav Shah: Both the CMC and clinical supply chain were stretched and challenged during COVID, and I think a lot of leaders have emerged in that field. That's a very important point. I agree.


Michael Carrese: So, Osmosis is a teaching company. We love to have our guests give us some direction to fill a knowledge gap or bust a myth or something along those lines. What is something that you're particularly interested in -- and it could be related to what we've been talking about, or not -- where you would say "Osmosis, you should make a video about that." What would that be?


Dr. Gaurav Shah: I would go back to the types of rare cardiac monogenic diseases that are out there. Danon is one of them. There's another program that we have in PKP2 which we call Pegasus named after the Greek mythological winged horse, with the idea of bringing magic into the real world. So, there's Danon, there's PKP2 and there's another program we have called BAG3. There are many others. There are probably thirty or forty that are valid targets in cardiac gene therapy and I think it's an elegant and easy way to demonstrate how a potentially curative treatment could work. Something where we're discussing tropism, which means what kind of vectors love which types of cells? In this case, AAV9 is a good one. There are also others. 


So how do you develop a gene therapy designed for a particular heart condition like Danon disease, walking folks through that. As I think about it, when we recognize that there's a disease out there called Danon with fifteen to thirty thousand patients that we could have a real impact in a very big way, we went back to figure out what's the right vector. AAV9 is probably the right vector, it's turning out so far. We then optimize the transgene cassette. What do you attach to the vector to go to the heart? Then you think about what the right delivery is and we figured out by testing -- both local delivery near the heart and IV -- that IV was just as good if not better, so why try to do a procedure for the heart when you don't have to? So vector design, the type of total vector cassette and transgene, the delivery methodology, the dose we have to figure out, and you can figure that out through preclinical studies in mice.


We also went to non-human primates to figure that out. There's a process for that, which is enlightening and teaches us a lot about what to expect when we start clinical trials so that by the time we're in the clinic, we've de-risked the program from a safety viewpoint as much as possible. Then, we're doing trials in real people, but then the stakes are much, much higher. The gene therapy world has, in the early days, seen some deaths and they have stalled the field. So, there's well deserved, but extreme FDA scrutiny. So, once you're in the clinic, we have to figure out how to keep that regulatory dialogue, educational, two way iterative, and respectful so that first we're doing no harm, and then we're trying to provide some efficacy.


Then ultimately, I would say you need to cover looking at the data set, and there's a whole learning on how to translate this to partners and stakeholders who could be supporters both from an academic view as well as economics view. So, that's the video that tells a whole story. If you're interested in making it, I’m happy to help.


Michael Carrese: Well, that would be a fairly long video, but action packed because there's so much in there for everybody to learn about. 


I can't let you go without asking about your music. Can you describe for us what that's all about and also talk about how your creative life and work supports, informs and influences your medical and scientific work, and vice versa?


Dr. Gaurav Shah: So, I grew up in Texas somehow fascinated with Indian classical music, and I spent a lot of time in India and with teachers here in the U.S. Eventually, I took up singing and took a year off after college before medical school to dive every day for twelve to fourteen hours a day. That was my obsession, even when I applied to medical school. The interviewer asked me what I think about all day, and I said, "Honestly I think about Indian musical notes most of the day. That's what anchors me, and that's what drives me in a meaningful way." 


I've been in a band since I was in eighth grade. I will say that despite my love for Indian classical music, I started a Guns and Roses cover band in eighth grade. So, I’m influenced by all sorts of different bands and singers. But being in a band, and now having performed between a thousand and fifteen hundred concerts at least over the course of three plus decades, I think I've realized that I've learned more about this job as CEO by being in a band than any book I've ever read, or any training I've ever done because the lessons are similar. 


You have to hire people you admire, and you have to be able to step back and listen to them. You have to be the person who's not always talking and is always not sort of directing, but more enabling and coaching. If someone's not working, and someone else is working you give them the stage, right? There are also lessons in the audience and reading the audience. There's an EQ component to being a performer. You're here for the audience and you serve the audience, the same way that a CEO serves the constituents of the company -- the employees here, but also investors and other stakeholders. 


It's the same performance in some ways but every audience member can tell when a singer is being authentic or not. The soul comes through. The same thing is true here. You have to be authentic about it. So, yeah, the creativity from a technical view is certainly there, but it's more about the business relationship and communications creativity that's helped me a lot as a musician here.


Michael Carrese: I can totally see what you're talking about. That's fascinating. So, we like to give our guests an opportunity at the end to give some of their best parting advice to learners and early career professionals who are looking ahead to their career. What's your go-to advice?


Dr. Gaurav Shah: I would say the same thing that I would say to probably the 250 employees here now, which is that career growth and personal growth really go hand in hand. You can't separate them and there's no such thing as a career move. Every career move is also an opportunity for personal fulfillment and personal growth and to discover things about yourself you didn't know, discover strengths and gaps and help other people grow as well. So, there's no isolated career versus personal. I think these days it's increasingly accepted that it's one integrated whole.


Michael Carrese: That's great advice. Great wisdom dropped here today from Dr. Gaurav Shah. We really appreciate you spending the time with us.


Dr. Gaurav Shah: Thanks, Michael, so much for having me on the show. It's been a pleasure.


Michael Carrese: I'm Michael Carrese. Thanks for checking out today's show, and remember to do your part to raise the line and strengthen the healthcare system. We're all in this together.