Summary

On the latest episode of the Bioverge Podcast, Shankar Ramaswamy, M.D., Co-Founder, Chairman and Chief Executive Officer, Kriya Therapeutics, sits down with Neil Littman to discuss how Kriya is changing the way gene therapies are designed, developed, and manufactured in an effort to cut costs, and accelerate the time to market.

Shankar discusses how Kriya is expanding the reach of gene therapy to a broad universe of diseases of high unmet need, with a focus on metabolic disorders, neurology and ophthalmology.

Kriya recently closed a $270M Series C led by Patient Square Capital, with participation from Bluebird Ventures, CAM Capital, Dexcel Pharma, Foresite Capital, JDRF International T1D Fund and others.

Transcript

00:29
Danny Levine (producer)
Yeah, we've got Shankar Ramaswamy show today. For listeners not familiar with Shankar, who is he?

00:37
Neil Littman (host)
I am really excited to welcome Shankar to the show today. Shankar is the co founder, chairman, and CEO of Kria Therapeutics. He was part of the early foundational team at Roy Vint Sciences, where he was responsible for helping to identify and evaluate assets across therapeutic areas and launch Roy Vint's first public subsidiary. He went on to become chief business officer at Axovant Gene Therapies, which was part of the Vant ecosystem. He holds a medical degree from Brown and an undergraduate degree in economics from Harvard. I'm really excited to talk with Shankar about his experiences at the Vant companies and how that has informed what he's doing today at Korea, because Kria has this really big and bold mission of moving gene therapies from orphan rare monogenic diseases to much larger patient populations. I'm really excited to dive into how they're doing that, what the platform is that they're building, and talk about some of therapeutic areas and indications that they're going after.

01:49
Danny Levine (producer)
You talked about his experience at advance, his last name may be very familiar to people who follow the biotech industry. How do you think having that kind of up close and frontline view of the creation and growth of these companies might inform what he's doing at Korea?

02:10
Neil Littman (host)
Yeah, sure. And so you mentioned it. I mean, Vivek is his brother, who's one of the founder of the Vance, but I think his experience there is going to bring a lot of information and learnings from some of the successes and some of the failures probably in the Vance ecosystem. They were doing a lot of innovative things in terms of the business model and really trying to push the field of gene therapy forward with all the public subsidiaries that they had. He saw that first hand, particularly as the CBO of accident and leading some of the development and some of the strategic fireflies there. I have to imagine that there's probably some scar tissue and a lot of learnings as well as what successes they had that he can port over to Korea. It's interesting as I look at the Korea team, they've pulled in people with expertise across the field of gene therapy at various companies, which to me is really cool because you couldn't have done that probably even five years ago.

03:16
Neil Littman (host)
There just weren't that many companies out there. There weren't that many approved products, there weren't that many therapies in the clinic. Now Korea has the ability to draw on all this expertise and build a team that does have deep expertise. I'm excited to hear how that all informs the efforts to build what they call this fully integrated gene therapy engine at Korea.

03:37
Danny Levine (producer)
Korea is focused on gene therapies, but thinking about them as having a potential that reaches well beyond rare monogenic diseases. What's, the vision?

03:49
Neil Littman (host)
Yeah. Well, that's what I want to talk to Shankar about. What is the vision? To my understanding, the vision is moving gene therapies from the monogenic rare orphan diseases into much larger patient populations, much more common diseases that affect large patient populations. There's a lot of issues with doing that. There are some technical challenges that I want to get Shankar's input and thoughts on, but then there's a lot of issues around needing to bend the cost curve. Right. The approved gene therapies, I believe the most recent one that was approved for beta thalassemia had a $2.8 million price tag. You can't really have a $2.8 million product that has hundreds of thousands of patients or more that are going to be prescribed that therapy. It'll break the healthcare system. How do you think about trying to bend the cough curve? What are they doing in terms of manufacturing and everything that goes into developing these novel gene therapies?

04:47
Neil Littman (host)
They have a couple platform technologies, one around their computational biology engine, another around manufacturing. I really want to dig into some of the details there.

04:57
Danny Levine (producer)
Well, if you're all set, let's do it.

04:59
Neil Littman (host)
Danny Juncker, thanks for joining us. I am incredibly excited to welcome you to the show today.

05:08
Shankar Ramaswamy (guest)
Yeah, thanks for having me. It's great to be here.

05:10
Neil Littman (host)
We are going to talk about gene therapy and specifically moving genetic medicines beyond rare diseases to address more common conditions. At Korea, you are working on improving how novel gene therapies are designed, developed, and manufactured, all with the goal of improving the speed to market while also reducing costs, which is a critical factor. We'll get into more here shortly. You started your career at Royvant as one of the earliest team members. Later, you became chief business officer at Axovant Gene Therapies. Both were part of the Vance, founded by your brother Vivek. I want to get into what you learned from those experiences momentarily, but before we do, you have an MD from Brown, and I want to ask what made you decide to go into the biotechnology industry rather than practice medicine?

05:59
Shankar Ramaswamy (guest)
Yes. Just a little bit about my background. I studied economics at Harvard and went to medical school at Brown and really went into medicine with a passion for drug development. I think that it's just exciting to have the opportunity to bring new medicines, new tools into the toolkit of physicians, and that's what we can do as an industry. If it's done well, that's what we're supposed to be doing. And that always appealed to me. My experience in medical school and being a part of the medical community has been very grounding as far as giving perspective on what matters to patients, what matters to physicians. Ultimately, it was my kind of career goal and personal mission in life to be in a position to be able to bring new medicines to patients, and Korea is certainly an extension of that. So, looking forward to advancing that mission here at Korea.

06:51
Neil Littman (host)
Yeah, let's talk about that here in a minute. I do want to circle back to your earlier experiences and talk about what you may have learned from your entrepreneurial trials and tribulations at Royvant and Axe event about developing novel gene therapies.

07:05
Shankar Ramaswamy (guest)
Sure, I mean, it was a phenomenal experience just in being a part of building what was a very successful company agnostic to industry at all. I think the Roy Vent story was just such a huge success and it was exciting to be a part of that and many learnings as far as how to build a company. Well, at Royvint, the model was different than what we're doing at Kria in a lot of ways. Where Royvint had really a thesis around how to accelerate drug development full stop and to reduce the time, the cost, the risk associated with development in close partnership with different companies and different organizations to do that in different therapeutic area, verticals. The model there was to set up different subsidiaries that could be focused on each of those different initiatives. Now, that was a very novel concept in biotech and to be a part of that foundational team in being in a position to help bring on the first assets into the portfolio, help to set up what became the Vance structure across multiple different vans.

08:10
Shankar Ramaswamy (guest)
That was a lot of learning through that experience. Rovent has really perfected that over time. What I took away from that was really in the accident journey where I was the chief business officer, were focused on neuroscience in particular, initially as a small molecule company. We had a phase three program for Alzheimer's disease that unfortunately didn't work in a phase three study. That forced us to really think about pivoting the organization to a focus on something else in neuroscience. That was really my first foray into gene therapy, just studying the magnitude of effect that we saw from products like Zolgenzma and Luxturna, these one and done, life changing, curative types of therapies that was really appealing to me as a physician, as a drug developer, as someone who really cared about helping patients. We took accident in that direction of building a neurology focused gene therapy company.

09:05
Shankar Ramaswamy (guest)
I was the chief business officer in assembling that pipeline together with the rest of the leadership team. I think the learnings through that experience were that while there's a huge opportunity to actually deliver really novel gene therapies, that can have a big effect. It's very complex to do that, and it requires significant infrastructure and scale and depth of experience in team and capital to do that successfully and repeatedly. That's really what led me to start Korea as a company that from its foundation could pull together the right pieces to do this process of actually delivering gene therapies at scale to do that systematically and with the right pieces in place to be effective at delivering products for a variety of diseases. Great learnings, great experiences at Roycent and Accident, and incredibly proud of what that company has done. It has really shaped my thinking on how we've gone about things at Korea.

10:03
Neil Littman (host)
Yeah, I followed the whole Vance story very closely over the years and it was just, I think, really innovative at the time and a lot of success with those companies and a novel way of developing therapeutic. Let's move on to Korea and what you're doing. Before we get into some of the complexities that you referenced before, let's start with the 30,000 foot vantage point of gene therapy and then we'll whittle our way down to your pipeline and what you're doing specifically. I think today, and probably rightly so, people still largely think of gene therapies as a treatment for rare or monogenic diseases. But you're looking beyond that. Where do you see the greatest opportunities in the space today?

10:43
Shankar Ramaswamy (guest)
Well, I think we're at an interesting inflection point in the field of gene therapy. Just to take a step back and look at what makes gene therapy so exciting, so appealing for patients, for physicians, for investors, it really offers the promise of delivering a one time treatment that could durably, potentially permanently improve the life of that patient, potentially even cure them of their disease. There are very few types of medicines in the history of medicine that can even claim to do anything close to that. So that's a tantalizing possibility. We've seen that play out now a couple of times in a few different rare diseases where patients who previously had no treatment options are now living much better, if not close to normal lives. That's been true in spinal muscular atrophy with Solgenzema, with RP 65 related blindness, with Luxura, soon to be with patients with hemophilia b with hemogenics, which was recently approved.

11:40
Shankar Ramaswamy (guest)
That's the possibility that makes gene therapy so exciting. It's what drew me to this space. Now, if you look at what that technology could apply to in principle, there's no reason to think about gene therapy as only relegated to ultra rare diseases, where you can charge a multimillion dollar price if you have the right ingredients to drive down costs, to be able to run large development packages as you would with other therapeutic modalities like small molecules or antibodies. If you could do all those things and actually manufacture these products at scale, in principle, that technology should work for a much broader universe of diseases. At the end of the day, with the gene therapy, what you're doing is providing the actual genetic material to drive protein expression within the body itself. You're converting the cells in the body to be their own therapeutic biofactory to produce these proteins that treat disease.

12:40
Shankar Ramaswamy (guest)
So that's the fundamental concept. If you apply that more broadly, it does extend beyond rare diseases, beyond monogenic diseases, to polygenic and non genetic diseases. So that's the ultimate opportunity. That's why we started Korea, to really make gene therapy a part of mainstream medicine, to make gene therapy for the masses. What we took note of is what you actually needed to build as a machine to be able to deliver these types of products for that ultimate promise of actually delivering gene, therapies driving, continuous protein expression for these very large market opportunities.

13:18
Neil Littman (host)
I want to jump into some of that machinery here in a second. But I couldn't agree more. When I was at the California Institute for Regenerative Medicine, were funding a gene therapy program targeting children born with severe combined immunodeficiency for skid. I had the opportunity to meet a little girl who was enrolled in the clinical trial, and she was cured of Skid. She lived a normal life and went to school and had a normal life expectancy in it. It really is along the lines of what you're saying. I mean, it was really treating a previously incurable disease, and it was just really incredible to see her first hand and see how much that changed her life and the life of her family.

13:57
Shankar Ramaswamy (guest)
It really is. Just add on that. I think this is why I went into medicine, to be able to help patients. There's really no larger magnitude of help that you can deliver a patient if you can cure them of their disease. I think that is to even be able to speak about cures or these types of transformative effects. I mean, we're living in just such a golden era of medicine, and we should be thankful for that. We also need to think about what can be done to industrialize that, to take it out of the academic realm and a one patient at a time realm, to an industrial realm at hundreds or thousands, millions of patients at a time realm. I think that's what we're going to see over the next two decades. I started the company with one of my co founders, is Dr. Fraser Wright, who is a professor at Stanford.

14:41
Shankar Ramaswamy (guest)
He was a co founder of Spark Therapeutics. He was their CTO. He's been a pioneer in this space, and he often talks about that experience of seeing those first few patients cured with luxury, which he was heavily involved in developing. It is such a memorable experience for anyone who's been involved with any part of the development process. It's also a bit sobering that as a field, we're still sitting at only three approved Aev products in the US after this many years, and only for very rare patients. So something needs to be done. That's really why we started Korea, to help unlock that potential, to take gene therapy to a totally different dimension.

15:17
Neil Littman (host)
Let's talk about that for a minute. What do you see as some of the limitations of gene therapy today? How is Korea going about trying to address and overcome some of those limitations?

15:28
Shankar Ramaswamy (guest)
Yeah, so there's a few limitations. I think first and foremost is manufacturing. This is the most expensive medicine in the history of medicine. You have $3 million plus products, which is unheard of historically medicine. Part of the reason you have that is because this is probably the most complex or one of the most complex modalities to manufacture in the history of medicine. There are so many different pieces of the manufacturing process that need to be put together. It's really daunting. That's a big challenge where the cost per dose of even producing the material is just so astronomically high. So that's one major limitation. I think the second, from a corporate standpoint, is access to capital. This is a really intensive, capital intensive area of drug development. It does require significant investment infrastructure and talent, running very large scale experiments. I view gene therapy development is the inverse of small molecule development.

16:27
Shankar Ramaswamy (guest)
What I mean by that is kind of 80 20 rule to get into the clinic is 20% of the effort with a small molecule. You go through phase one trials and healthy volunteers, and you have a very challenging road ahead in clinical development because the effect sizes are smaller. The opposite is true in gene therapy, where it's an 80 20 rule. 80% of the challenge is actually getting the product into the clinic itself, because you got to do the vector design, you have to do the analytical method, development, the manufacturing. There's just so much to do. Once you get into the clinic, you start right away in patients rather than healthy volunteers, and you have very high degrees of confidence in the translation of that work into clinical success. That's the inversion of 80 20. That's why it takes so much capital to actually upfront be able to advance these products into the clinic as opposed to more conventional drug development, where you can unlock that capital over time as programs mature.

17:25
Shankar Ramaswamy (guest)
Funding is definitely a major constraint in this space. The third major constraint I'd point to is just expertise, which has contributed to candidly subpart execution relative to original expectations. This is still a young field, all things considered. We're still in the early innings of what gene therapy can do. There aren't infinite pools of talent and probably not enough talent to sustain the number of companies that exist today. That is a critical reagent to success, is having the right expertise in place and access to talent that knows what it's doing, that it's been through ups and downs in gene therapy. We're at an inflection point in that regard because we've had some successes and a number of failures that we can learn from. I think you put all of that together. What implications does it have for someone like me who's starting a gene therapy company, who's built one to address those challenges and take gene therapy somewhere no one has gone before?

18:21
Shankar Ramaswamy (guest)
I think the way that we thought about it was set up the engine solving for those critical issues from the very beginning and start with that before even thinking about a pipeline. From the very beginning, we started with our own in house manufacturing facility that we secured right around the time of our Series A. This was super early on, and this was a large scale facility that we renovated to be GMP ready for gene therapy production. It was in use for a different modality. We had set this up in Research Triangle Park in North Carolina with a lot of industry veterans running that facility. So that was point number one. Point number two was we secured a large amount of capital. We knew that this is going to take a lot of money to do this the right way. We've raised about $460,000,000 over the last three years to be able to actually invest in what needs to be done and withstand some of the body blows that you're inevitably going to experience in advancing a gene therapy product.

19:20
Shankar Ramaswamy (guest)
The third was consolidating some of the top talent in the field. We recruited heavily based on personal relationships from companies like Spark, Vexis, Bluebird, Biogen, Pfizer, people who have been in gene therapy for years, who see the promise of gene therapy to go more broad and really have affinity for Korea's mission. That was the first part of actually assembling the engine to cure some of the core operational technical challenges of this field. We layered into that engine a pipeline that we felt we could actually mature using that engine to deliver products for patients.

19:57
Neil Littman (host)
Shankar there's a lot to dive into. There just one comment, maybe something that I noticed that really jumped out at me. You mentioned the team, and it's really amazing to me that you really have assembled a team that has a diverse set of experiences at several different gene therapy companies, which to me is really amazing that is now possible. That probably wasn't possible five plus years ago to draw on those various experts because there weren't that many companies that had approved products or therapies in the clinic. It's really nice to see that you could draw in that pool of expertise.

20:32
Shankar Ramaswamy (guest)
Totally. I would say that it would have been challenging to start a company like Kris five to seven years ago because you had to have those battle scars worn by people who have been through it. They've been through registrational processes, they've been through failures of preclinical clinical failures. There's a learning that comes from that and battle scars that are worn that we can now actually build upon a critical, massive experience in a way that some of the early pioneering companies couldn't. They're shooting completely in the dark, flying blind. Huge credit to those pioneers for being able to deliver successful products like luxury and solgensma, because it was incredibly challenging to do that. Now the bar is much higher. That okay, now we know what we're doing more or less in this space, what can we actually do with the technology? When we recruited Creo, we use very few recruiters as part of our recruiting process.

21:28
Shankar Ramaswamy (guest)
These are industry veterans that we know personally or people that we know can get the job done based on their set of experiences. We systematically recruited those individuals to really the mission that we have, which resonated with them, which is let's build on all of these years of experience, all of these successes and failures, and perfect the engine that could deliver products for a much broader set of diseases.

21:56
Neil Littman (host)
Yeah, maybe we could just follow that line of thinking one step further and talk about the platform. Now, because you've developed what you call an integrated model. Can you explain what you mean by this integrated model and how that works in practice?

22:11
Shankar Ramaswamy (guest)
Yeah, absolutely. I would say our machine, if you will, at Cree is composed of three foundational pillars. So one of those is manufacturing. We control our own manufacturing that is not just the GMP supply, but also all of the things earlier in development that tie into construct design and candidate selection. Manufacturability assessments, packaging efficiency, purity of product, the analytical methods, the release methods for those products. All of that is deeply embedded in the manufacturing category and pillar of the company. So that's one. The second is a research biology pillar. This again is based in North Carolina in Research Triangle Park, right side by side with our manufacturing facility. There we have our own in house capabilities for vector design, immunology, bioanalytical development, genomics, next gen sequencing. All of that is integrated and tightly coordinated with our manufacturing. The third core pillar is computational biology. We have a team focused on genomics, large data set generation and analysis, machine learning, programming, algorithmic engineered, algorithmically enhanced vector engineering.

23:24
Shankar Ramaswamy (guest)
Basically, thinking about algorithms that can identify particular problematic elements of different products that contribute to poor expression, poor manufacturability, high immunogenicity, and help engineer these products to avoid those challenges using a computational approach. Having those three pillars in one company allows us to make iterative improvements of each of our products and embed learnings from product A to product B through Z and in completely orthogonal therapeutic areas. That's where the scale of our company just allows us to utilize that engine more effectively and effectively spread that across different products. That's just a different approach than, frankly not as well capitalized or more academic type of company or effort where you might have one of those pieces, but you're reliant on an external party for manufacturing. You're relying on an external party for bioanalytical development. The consequence of that is that you don't have the flywheel effect of learnings in real time that contribute to iterative improvements in the product.

24:32
Shankar Ramaswamy (guest)
If you are sending a vector out to be manufactured by a CDMO, they'll make it exactly the way you want it for one particular version of that construct. Let's say it doesn't package very well or it's not a very pure product. You're going to be left scratching your head as to why that was the case. Was it a process issue, was it analytical issue, was it a molecular issue with the construct? Whereas in our case we can actually look at that flywheel in real time and say, hey, we're seeing a pattern of this particular sequence, let's say contributing to this poor tighter. Let's correct that issue at the molecular fundamental issue fundamental level. I think those are the types of learnings that we can benefit from by having this fully integrated machine and think about where the solution may lie, whether it's a manufacturing, a computational or research solution.

25:25
Neil Littman (host)
Yeah, that's really fascinating because I know early on in many companies life cycles, they have to make the decision whether they want to build out manufacturing capabilities in house or outsource. It always is a big question early on. It sounds like that was never really a big question that you wrestled with. It sounds like it was always something that you knew needed to be built in house so you could have full control over all of these different processes and as you mentioned, could learn. Iterate from which I think is really powerful.

25:52
Shankar Ramaswamy (guest)
Yeah, I think it was never a question for us because we've lived this space, a lot of us, in different ways. I come from where the business and medical background. Fraser, my co founder, was the CTO of Spark, britt Petty, who's leader manufacturing. He was the chief Technical officer at VEXAS. We've seen this and lived it, so we know what's needed to do this right. I don't think most gene therapy companies would dispute that. The challenge is really the capital and the team that's required to do that. So it's easier said than done. I've lived this last few years building the company. It is challenging to raise that amount of capital to really recruit that type of team. If you do that, I firmly believe, and I don't think anyone would contest this, that's the right way to do it and it just unlocks opportunities.

26:36
Shankar Ramaswamy (guest)
Just to step back on your question, manufacturing, I think that we have to be more specific about thinking about what manufacturing is. I split it in two categories. So there's a sharp dichotomy between these. One of these is commercial late phase manufacturing so if you think about phase three commercial manufacturing, that requires large capacity. It requires large scale, good quality. It's more industrial at that phase. If you think about early phase manufacturing, phase one two, preclinical manufacturing assessments early on, that's really where the scientific innovation happens, because there's a direct feedback loop to the molecular design of the products which have an impact on the process performance and process that you will actually use for that particular product. Those are two very different types of manufacturing activities. We've made this decision for sure to build out the earlier phase to support products through that phase one two manufacturing.

27:38
Shankar Ramaswamy (guest)
We have the opportunity to build the phase three commercial, and we'll evaluate whether that makes sense at the relevant time. You can also outsource some of that. It's not as, let's say, sophisticated from a technical standpoint. The way I think about it is think about the recipe. You have your world expert chef who's coming up with a very precise way to make that particular dish. That's one of a kind. There's only a handful of those types of chefs in the world. We're fortunate to have some of them at our company. You have your commercial kitchen that can just crank it out. We may build our own commercial kitchen. We may expand our facility to be a commercial kitchen, or we may find another commercial kitchen, but that's a different part of the process that's frankly easier solved.

28:23
Neil Littman (host)
Yeah, and I like thinking about it. Broke it down into those two discrete parts. As is often said in the cell and gene therapy world, the process is the product. It's really important to call that early.

28:34
Shankar Ramaswamy (guest)
It really is. I mean, I would venture to guess a lot of the failures that we've seen in the clinic or safety and toxicity issues. There is some element of manufacturing performance that is a contributor to some of those effects. I'm sure this data will come out over years when we have large data sets and we look at this. That is a hypothesis that we have that the purity of the product, the way these are manufactured, the heterogeneity of that product, even those things contributing to the quote unquote dose of the product, those are impacting the immunological profile of these products, the durability, and ultimately the efficacy. There is a direct tie in across manufacturing that doesn't allow you to segregate that from the rest of development.

29:20
Neil Littman (host)
Yeah, I couldn't agree more. We could probably spend the rest of the episode talking about manufacturing. But I do want to move on. I want to talk about your pipeline, which you don't advertise on your website, but you have been building a gene therapy pipeline, at least in part through acquisitions. Can you talk a little about the strategic rationale behind these acquisitions and what made these particular acquisitions and. Indications, ones that you wanted to go after?

29:49
Shankar Ramaswamy (guest)
Yeah, absolutely. You're right, we haven't disclosed a lot on the company website and that will change over time. We're a private company and one of the benefits of being a private company is you can focus on the work at hand and not have to give updates every time that people expect them. We look forward to sharing more in the pipeline, I think. To tell you about our pipeline, we focused on really three core therapeutic areas metabolic diseases, neurology and ophthalmology. I'll talk about some of the specific diseases we're going after, but the common thread across these different areas and diseases we're focused on obviously one and done approaches. With gene therapy, one of the benefits is that you have the opportunity for a one time delivery that can drive a lifetime or several years of benefit. We are looking to target diseases where that benefit would be of significant impact to patients.

30:48
Shankar Ramaswamy (guest)
So that's one key parameter. The second is where the biology is well understood. As a company, we're focused on really taking technology risk. Can we engineer the gene therapy to do what we wanted to do in terms of driving durable protein expression as opposed to taking on biological risk, where we're trying to validate a new target that may not have prior validation. We're focused on validated biology and driving better engineering of therapeutic. All of our approaches are focally delivered. This is targeting specific tissues where we want the actual gene therapy to be transducing cells and expressing proteins. We deliver directly to those tissues, whether it's direct injection into the eye, into the muscle, into the trigeminal ganglin as you'll hear about, with the goal of making sure that our product gets where it's supposed to get and minimizing the toxicities from off target types of effects.

31:49
Shankar Ramaswamy (guest)
That also has the benefit of reducing the total dose that the patient is exposed to. So that's a core parameter. Lastly, we're looking at diseases where there's opportunity for significant clinical benefit to the patient, so transformative types of effects, not incremental, and where there's large commercial opportunities where there's a validated market for these types of products. So, as I mentioned, that led us to really focus on three core therapeutic areas. The pipeline being built through a combination of internal R and D, company acquisitions, licensing partnerships with academic groups, all of those leveraging the same engine that I described before in metabolic disease. The lead program is for diabetes, both type one and insulin dependent type two diabetes. This is a program that originated from one of the leading academic groups in Spain. Fatima Bosch is the lab. She's one of the pioneers in gene therapy.

32:41
Shankar Ramaswamy (guest)
She and her group had done a phenomenal job of building a program that had shown really robust efficacy across multiple different animal models, including in diabetic dogs for eight years. They actually generated data showing eight years of complete disease correction and insulin independence and diabetic dogs. That is now a program that we're advancing with some of the things that needed to be done to turn that from an academic package into an actual industry package and scale up manufacturing, optimize the vector and actually take that into the clinic. So that's the work that's ongoing there. In Neurology, this pipeline came through the acquisition of a company called Redpin Therapeutics, which is one of the pioneering chemogenetics companies using a small molecule, in their case Chantics, which is for smoking cessation. A super safe product that's been in millions of healthy adults to basically regulate the activity of an expressed engineered ion channel that can reduce hyperexcitation in overactive neurons, in focal epilepsy and trigeminal neurotra.

33:51
Shankar Ramaswamy (guest)
That's the program there that has application even far beyond those two diseases. Lastly, in Ophthalmology, we have a pipeline focused on really immune modulators for highly prevalent ophthalmic diseases. The lead program there being for geographic atrophy, which is a space where hopefully we'll see some small molecules actually get approved in the next coming months. We have the opportunity with a one and done gene therapy to really deliver a much larger effect, we think, in that particular disease. That's a program that came through a collaboration with the University of South Carolina and a couple of other academic groups. All in all, it's a vast pipeline. We have over a dozen programs in the portfolio and we're continuing to advance these through the various stages of preclinical development with an eye to bringing these all into the clinic and ultimately to commercialization. That's something that we intend to do ourselves.

34:46
Neil Littman (host)
Shankar all of the programs that you just referenced, as far as I'm aware, are built around Ad, no associated viral vectors or AAVS.

34:55
Shankar Ramaswamy (guest)
That's right.

34:56
Neil Littman (host)
Why the focus on AAV specifically?

34:58
Shankar Ramaswamy (guest)
Well, AAV is a very validated delivery vehicle, so there's many different ways to deliver gene therapy and there are unique challenges to each of them. I think one of the things that we view AV as being validated based on the number of patients who have been treated with it, the durability that's been established, the manufacturability that has been established. Our platform is really built to deliver these AV therapies very quickly and consistently. We recognize some of the limitations of AV ultra high dose, systemic AAV desposing challenges from an immunological perspective and it can be difficult to manufacture. That's why we invest in what we have. So there are some limited challenges. There are certain tissues where it can be very difficult to actually transduce and you need novel capsids and novel work to do that. We've picked a set of targets where we can actually give the AV at a low to modest dose focally administered, so there's minimal contribution of systemic toxicity and that we are confident can be manufactured at scale based on the doses that we're advancing.

36:12
Shankar Ramaswamy (guest)
That means that we can focus on some of the challenges on the actual protein itself. We can actually put most of our innovative effort on expressing these complex proteins that go after these multifactorial diseases on validated pathways. Over time we will continue to evaluate where AAV could be the right delivery vehicle or in the future, if we want to go after a disease where a different delivery vehicle would better, we'll certainly consider that as well. We think AV has wide application and with the right engine behind it, can actually do a lot.

36:49
Neil Littman (host)
Yeah, I think that makes total sense. Shankar I want to circle back to actually a comment that you made earlier and talk about funding. You mentioned before you raised about 400 million in total. Your last round was a $270,000,000 Series C led by patient Square Capital. First I want to just talk about and ask you about your ability to absorb and put all that capital to work and what that enables. Does that enable you to do more in parallel with the same programs, fund more programs, make more acquisitions, or how do you generally think about deploying that amount of capital?

37:28
Shankar Ramaswamy (guest)
Yeah, so we've raised a little north of 460,000,000 in the last three years. We raised about 87 in the Series A, 100 in the Series B, and just north of 270 in the Series C. That is a lot of capital for any company to take on, especially one as young as ours. We felt it was really essential to a moving fast. We wanted to build this company in lightning speed, which we have done. The second was make the right investments infrastructure with confidence at the beginning. The third is we are building ultimately a company that we think can be a pharma like company. I think you look at companies like Moderna who have done this in mRNA, we think there is room and need for that in gene therapy and we hope to be that type of company. The ultimate ambition here is to really deliver an entire portfolio all the way through commercialization for these big market indications.

38:26 SEO
Shankar Ramaswamy (guest)
If we're going to do that, it's going to require a lot of capital which we're prepared to raise and access. With Patient Square leading the Series C and the Series B, they have been pretty much an ideal partner to us because their mission is also to build industry defining dominant companies. They've shown that confidence in us and we have a great partnership in actually what it will take to build that type of generational company as well as with the rest of our syndicate who have that as the ultimate vision to build a company that isn't here just to do a quick flip for a modest step up or whatever it might be. This is a company that is built to be a generational company. If that's the ultimate end goal, you need to raise a lot of capital to do that, which I think it's been a nice marriage of both the investors and the company to do that.

39:17
Neil Littman (host)
Yeah, and I want to dive into that last point for a minute, because your Patient Square just announced that they closed a $3.9 billion fund, which, to my knowledge, is the largest healthcare specific PE or VC fund ever. So, just at a very high level, Shankar, how do you think that impacts companies in our ecosystem? Do you think there's going to be more funding that are going to be dedicated to building generation defining companies, as opposed to companies that are built for M and A, for example? How do you think about that at a a high level?

39:49
Shankar Ramaswamy (guest)
I do think so. I think it's good for the space, first of all, to have investors like Patient Square who are patient is in their name. They are focused on being there to support companies all the way to the very end. That very end may be no end. Right. I think that is just great to have that type of dominant investor. What they're building is really going to transform the healthcare and biotech universe. They're a great set of people and a great team that believe in what they're doing. I think for a long time, biotech had been in this kind of flip mode of just putting in just enough to flip it to the next person to hold the bag. That really doesn't track with scientific progress and medical innovation. You need to have patients, you're going to have obstacles and challenges. You're going to burn a lot of money because you need to figure those things out.

40:49
Shankar Ramaswamy (guest)
The other side of that is you have the opportunity to help a lot of people with products that can work and make a lot of money if you deliver products that work. I think it requires a different phenotype of investor, which we're starting to see from groups like Patients Square who are transforming that landscape. I think that's a net positive for patients at the end of the day. Now, what that means as far as the biotech model of the last decade, which is really around, I think, a lot of incremental, therapies, a lot of kind of quick exits. I think we'll have to see how that ripples through. The current market environment is certainly forcing that to some degree. I think from a strategic perspective, investors like Patients Square are kind of here to define health care over the next few decades. Yeah.

41:39
Neil Littman (host)
I think it's a huge innovation in our ecosystem to have that amount of capital being put to work within our industry in general. Shocker, I have one burning question that I do want to ask before we wrap up, I want to go back. You mentioned you have a program targeting diabetes. I want to tie that back to this idea of bending the cost curve. You had mentioned multi million dollar gene therapies that have been approved. Those are for monogenic diseases. How much do you think we need to bend the cost curve to be able to afford a gene therapy for a disease like diabetes, for example, so that it doesn't break the bank of the healthcare system?

42:19
Shankar Ramaswamy (guest)
Yeah, I mean, it's top of mind for me, and it's personal for me, actually. I mean, one thing I'll share is my grandfather had type one diabetes his whole adult life, and he grew up very poor india. It was a challenge and a struggle for them in that environment. My mom is actually she's a physician. One of the things that she did when she first came to the US as a practicing physician, as a resident, was to buy clean needles for her parents to send back home. That was one of the most meaningful gifts they could give. It is the thing that so many people struggle from around the world of all socioeconomic statuses that we need to do something to address big problems in medicine like that. That is, I think, something all of us who have some means to address problems of that scale have an obligation to try their best to do that.

43:25
Shankar Ramaswamy (guest)
With a gene therapy, you have the opportunity to deliver a type of clinical benefit that we haven't seen historically in that space or in any of these other spaces we're going after. That's the potential benefit and impact to patients around the world that could, from a pure clinical perspective, take cost out of the equation would really live much better lives with therapies like these. The question is, what do you need to do to bring down the cost to make those types of therapies affordable and accessible? There's different factors that we've talked about over this conversation, whether it's manufacturing, development costs, you have it. If we can solve that issue, just the magnitude of impact that we can have across society at this type of scale is just really exciting to think about. I think we have that obligation starting from the patient first. That patient being, in many cases for these diseases, it hits close to home for a lot of us.

44:28
Shankar Ramaswamy (guest)
We suffer from these diseases. Loved ones suffer from these diseases. That's the ultimate goal of helping those patients. Stepping back from that, what a gene therapy could do, it would completely change the life of that patient for the better. Stepping back from that, how do we actually make that gene therapy accessible and affordable to each and every one of those patients? You need to drive down cost in every dimension. That's where I start, just working back to why Kria exists, to be able to deliver those types of cured effects to all patients at lower cost and more consistently. It's kind of a rambling answer to your question, but I do think cost is at the center of a lot of the equation, and I think there's something we can do about it.

45:13
Neil Littman (host)
Chakra, I love your perspective on this, and it's really we need to work backwards with the patient in mind and use the patient as the North Star, the guiding light for all of these developments, whether they're manufacturing or whatever they may be. We could probably talk for another two or three days about these topics. I'd love to invite you back on the show once you have some more progress with your pipeline and talk about more about what you're doing, but we better leave it there. So, Chakra, I just like to say a huge thank you for joining me today, and thanks for a really great and wide ranging discussion.

45:46
Shankar Ramaswamy (guest)
Yeah, absolutely. A lot of fun and happy to come back anytime.

45:53
Danny Levine (producer)
Olivia, what did you think?

45:55
Neil Littman (host)
I thought that was a fantastic conversation with Shankar. I mean, I love all the topics that we hit on. I mean, we could have spent a couple of episodes just on the manufacturing component of what they're doing. What really struck a chord with me is you heard Shankar say they've raised, I believe, just north of $460,000,000. The company is only about three years old. This idea of having very deep pocketed VCs behind them like patient Square gives them a huge competitive advantage in building out this fully integrated machine that you heard Shankar describe to really control manufacturing preclinical development all. Those things through the entire process, which gives them the ability to iterate and learn as opposed to outsourcing stuff to a CDMO with the goal of building a generational type company. And to me, that's just so powerful. You heard Schenker talk a lot about the patient and working backwards, with the patient in mind, and how their approach will really ultimately benefit the patient by having control over the entire process from start to finish.

47:11
Danny Levine (producer)
These have been expensive therapies, in part because they're one and done for small patient populations. What does Crea have to do to reimagine gene therapies?

47:23
Neil Littman (host)
Well, you heard Schenker talk a lot about the manufacturing, and I think he made this great analogy with the 80 20 rule in the gene and cell therapy world. 80% of the work is done upfront before you even get into the clinic, unlike small molecules, which is essentially the reverse of that. You heard us talk about this idea of the process is the product. For them, they need to really lock in the process and spend a lot of time, a lot of capital to ensure that they have a robust and scalable process with proper QC to be able to characterize the product that they're putting into the clinic at the end of the day. There's a lot of complexities around that. We barely scratch the surface of some of those. They have obviously built and are continuing to build some of that infrastructure to enable them to do that.

48:14
Neil Littman (host)
Obviously the goal of doing all that is, at the end of the day, to be able to move the cost of these therapies from multimillion dollar therapies for the monogenic diseases to something hopefully much more affordable that a much larger patient population can access.

48:31
Danny Levine (producer)
There are some other companies out there looking to develop gene therapies that would treat large market conditions by getting the body to produce a therapeutic protein company doing this with eye disease and other with joint disease for arthritis. Their focus has been on individual therapies, though, rather than the manufacturing process, and building with cost and scale in mind, as Korea is doing. How do you think that might play to Korea's advantage?

49:04
Neil Littman (host)
I think it plays to their advantage in a massive way. Right. They really are building out this entire platform. As you heard Janker talk about, their focus is on AAV. Might not always be that way in the future, but there are certainly some, I would imagine, large economies of scale that they get from their investments in all this infrastructure that will be harvested across their programs. I think about it in terms of what were doing at the California Institute for Regenerative Medicine when I left. We were funding over 50 different clinical trials, but we also funded a tremendous amount of infrastructure to support those clinical trials, whether that was in our Alpha Stem Cell Clinics network, which were specific clinical trial sites for the delivery of cell and gene therapies to preclinical manufacturing initiatives or whatever it may be. There's a whole host of infrastructure that needs to support the clinical development.

50:07
Neil Littman (host)
A lot of times companies outsource some of that stuff, but I think by doing it in house, there's a tremendous amount of learnings that were accrued to Korea that can be spread across the platform. The capital that they have raised to build that type of infrastructure, I think gives them a pretty big competitive advantage.

50:28
Danny Levine (producer)
You did talk about the team, which is made up of people who have been at companies that have brought gene therapies through the pipeline and to the market. What do you think that suggests about where we are with gene therapies today?

50:41
Neil Littman (host)
Well, to me that's really exciting because Korea has been able to draw upon all of this diverse set of experiences at multiple companies that have developed gene therapies, whether they're approved products or they're in clinical trials. That type of talent pool probably didn't exist even five years ago. And so to me, that's really exciting. That the field has moved so far, so fast that Korea is able to draw upon this diverse talent pool and bring all this talent in house with all these different sets of experiences. It's becoming I don't want to say it's mainstream, but it's becoming much more easy to access the talent. Although it's still a challenge, right? This is still a new field. There's still a lot of challenges with developing and manufacturing these. There's not that many approved products yet, right. To me, it is a sign of excitement for the industry.

51:36
Danny Levine (producer)
Well, until next time.

51:38
Neil Littman (host)
Okay, Danny. Thank you.

51:42
Danny Levine (producer)
Thanks for listening.

51:43
Speaker 1
The Bio Verge podcast is a product of Bio Verge, Inc. An investment platform that funds visionary entrepreneurs with the aim of transforming healthcare. Bio Verge provides access and enables everyone to invest in highly vetted healthcare startups on the cutting edge of innovation, from family offices and registered investment advisors to accredited and nonaccredited individuals. To learn more, go to bioverge.com. This podcast is produced for bioberge by the Levine Media Group. Music for this podcast is provided courtesy.

52:20
Shankar Ramaswamy (guest)
Of Jonah Levine Collect.

52:22
Speaker 1
All opinions expressed in this podcast by participants are solely their opinions do not reflect the opinion of Bioberge, Inc. Or its affiliates. The participants opinions are based upon information they consider reliable. Neil Bioverge.com, its affiliates, warrant its completeness or accuracy and it should not be relied on itself. Nothing contained in accompanying this podcast shall be construed as an offer to sell, a solicitation of an offer to buy, or a recommendation to purchase. Any security by Bio Verge, its portfolio companies, or any 3rd party past performance is not indicative of future results.