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The Bioverge Podcast: Addressing the Challenges of Chronic Liver Disease

Jack O’Meara, co-founder and CEO of Ochre Bio, sits down with Neil to discuss the large unmet health need created by chronic liver disease and the company’s efforts to develop RNA therapies address it.

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Jack O’Meara, co-founder and CEO of Ochre Bio, sits down with Neil to discuss the large unmet health need created by chronic liver disease and the company’s efforts to develop RNA therapies address it.

Available on SoundCloud, here.

Available on iTunes, here.

Full Transcript


Danny Levine (Producer)
You're listening to the bio verge podcast with. Neil. We've got Jack O’Meara on the show today, who is Jack?


Neil Littman (Host)
I first met Jack during the company's last financing where for full disclosure, by words participated in. I'm thrilled to have Jack on the podcast today. Jack is a biomedical engineer by training. He has a background in bringing new novel therapies to market. He helped get one of the first blockbuster gene therapies through approval at the FDA. EMA was a drug being developed by AveXis against ma for spinal muscular atrophy, which is a rare genetic disease for listeners who are deep in this space. AveXis was bought by Novartis for about $8.7 billion at the time. Jack has a lot of experience in the space developing novel therapies. He is the CEO of okra bio, which what we'll talk about in a minute, but they're developing novel RNA medicines for chronic liver diseases.


Danny Levine (Producer)
Well, what makes Ochre bio so compelling to you?


Neil Littman (Host)
Yeah, so they're doing a number of things I think really differently, which is super compelling. Number one, they are using a live human livers as a way to test their drugs. These are livers that are not suitable for transplantation, that they keep alive, obviously outside the human body, and then they're able to test their therapies on these live human liver. The idea is that by using a live human liver, as opposed to animal models, they have a better sense of, recapitulating human disease clearly. The idea is that should better translate into human clinical trials. So to me, that's really exciting. Of course they have this whole platform technology, they call it complexity at scale that involves your computation automation, something that they call deep phenotyping, which we'll get into. They're using all of that in the context of testing therapies in live human livers to me is a huge differentiator.


Neil Littman (Host)
I think it gives them an edge as they move into human clinical trials.


Danny Levine (Producer)
There's a chart on the Ochre bio homepage that is rather striking. It shows chronic liver disease. The only of the top 10 killers that has been rising since 1970. You think of the liver is being one of the most accessible targets for drugs. Why is this such a growing problem?


Neil Littman (Host)
That's a really good question, Danny. To be perfectly honest, I don't have the answer. I'm excited to ask Jack about that, but you're right. I mean, it is a top 10 global killer. It feels like we have not made really any significant advances, right? Liver transplant is still the gold standard. We know that there's a shortage of available livers in this country. We know that even a lot of levers that are available for transplant, aren't suitable for transplant for a variety of different reasons. So it's a major problem. I don't know why we haven't made more progress, but I'm sure Jack has a good opinion about that.


Danny Levine (Producer)
Well, what are you hoping to hear from Jack today?


Neil Littman (Host)
I'm hoping to hear from Jack A. Little more about, what, what I classify as their edge, right? Why do they think their model of keeping, human livers live outside the body and testing, their drugs in those livers will help them translate their therapeutics into human clinical trials in a more successful fashion than what is ordinarily done. I'm really curious about their technology platform as well, right? What are the inputs they're looking for? What is this , human liver Atlas with they're creating it. Deep phenotyping is a term that I had never come across before we started doing diligence on the company. I'm excited for Jack to explain, what deep phenotyping is and why that helps give them an edge as well. So, this is, I think a really interesting approach between their computational aspect and their novel approach to testing therapies and in livers.


Danny Levine (Producer)
Well, if you're all set,


Neil Littman (Host)
Let's do it. Then today we are here with co-founder and CEO of Ochre, bio Jack. O'Mara Jack, welcome to the show today.


Jack O’Meara (Guest)
Hey, thanks for having me glad to be here.


Neil Littman (Host)
I am really thrilled to talk to you today about what you are building at okra. Today, we're gonna talk about your efforts to develop RNA therapeutics, to treat complex and chronic liver diseases. Why don't we start with the problem, how big a problem is chronic liver disease?


Jack O’Meara (Guest)
This is the thing I think people don't fully appreciate is that chronic liver disease is the only is the third largest leading cause of premature death. For much of the Western world. It's almost on par with cancer. It is one of the it's the only chronic disease that continues unabated. There is that most other indications we've made significant headway with, but chronic liver disease is the only top 10 killer that continues to get worse. There is remains a serious dearth of innovation for patients. It affects a huge number of people and we're really optimistic and excited to hope one day make a difference for those patients.


Neil Littman (Host)
Jack, why do you feel like there's been such a dearth of innovation in this area?


Jack O’Meara (Guest)
Yeah, I mean, this is a really good question on par, a big part of the founding thesis behind OCA bias, try and solve some of the challenges that plague chronic liver disease, drug development. The first thing is for like a lot of chronic diseases of aging, we still don't fully understand the biology. Like Alzheimer's and others, a lot of the biological hypothesis have been disproven and still don't really get efficacy in the clinic. Secondly, the preclinical models we use to study therapeutics just don't recapitulate the disease in patients. Mice models are very poorly predictive of how its clinical trials will go. Mice actually have 12 liver lobes where humans have to it's quite a different physiological state. Lastly, clinical trials for chronic diseases of aging, like like caught a lot of chronic liver diseases is, are really difficult because it's a silent disease for so long.


Jack O’Meara (Guest)
We don't have very good biomarkers to actually test and determine the efficacy of new therapeutics. As a result, you end up having to run these very long, very expensive clinical trials. That just serves as a major disincentive for pharmaceutical developers to actually enter the space and particularly challenging for small biotechs. We've basically built a company at okra around trying to solve each of those individual problems. I can tell you a bit about that, but I'll pause there before I go any further.


Neil Littman (Host)
Yeah, no, that's great. There, there's a number of points that I want to dive into there, particularly around the preclinical models, but what I want to just circle back to the underlying pathology of liver diseases. Obviously the biology, as you said, is, is still being elucidated. We don't necessarily understand all the pathologies, but is, is there a a single pathology that typically leads to chronic liver disease? Or is, are there multiple underlying pathologies? Is that understood at this point?


Jack O’Meara (Guest)
There is there, it's definitely not one disease. It's definitely a, a variety of, it's a multifactorial problem. There's a variety of underlying areas that they kind of all converge in the same thing, like a lot of different ways to get to the same place that ultimately ends up in needing a liver transplant. I cirrhotic failing liver, but there are definitely a multi-factorial problem. That's one of the things you've got to think very carefully about as drug developers is how do you, yeah. How do you make sure you're giving yourself the best chance of success bearing in mind that there are multiple cell types and multiple different things going wrong for these patients?


Neil Littman (Host)
Let's talk about that one point for a minute in terms of the gold standard for treating liver diseases today is transplantation. I think as probably everyone knows, right? There's a significant shortage of livers that are available for transplant and even the ones that are available for transplant, there can often be an issue in terms of the quality of the organs that are deemed appropriate for transplant. Could you talk about those two issues?


Jack O’Meara (Guest)
Yeah, so this is it. Transplant is such a blunt tool at such and such a, as he said, it is there's very few organs available for patients, but over the past 20 years, transplant surgeons have been plagued by this challenge in that donor organ quality continues on the decline. It's largely as a result of also, this is society, number one, living longer, which is a good thing, but it means our organs are in worse shape. By the time we w we pass. Secondly, the lifestyle we now live in much of the Western world is a lot more calorie dense, and a lot more sedentary. That ultimately means that organ quality tends to be a lot fattier, a lot less healthy by the time it's actually being given to a patient who needs that. As a result on the front side of the funnel, the organ quality is actually going down in the availability of donor organs is getting less despite the need, particularly for fatty liver disease and other indications that are driving the number of transplants needed.


Jack O’Meara (Guest)
Despite the need getting larger, the actual solution is getting smaller. That at Oak Hubei was of the initial light bulb moment for us was that we could develop therapies using preclinical models that are these discarded fatty donor livers is a great way to test out whether our therapeutic interventions will actually work and ultimately go to clinic initially to try and improve the use of these, trying to expand the pool of available donor organs by pre-treating and essentially rejuvenating fatty donor livers, so that they can be used and have better outcomes for patients who received them, but in doing so, stepping stone, our way into larger and larger indications, like fatty liver disease and ultimately one day like liver cirrhosis and other later stages of the disease.


Neil Littman (Host)
Jack, I want to pick up on that thread, right? One of the things that really attracted me from an investment standpoint to Ochre and in full disclosure, by verge, isn't an investor in Ochre is that you're using actual human livers that are kept alive outside of the body to test drugs. Right. First, first of all, I mean, it's really kind of amazing. We can do that at all, but, but I'm curious how this approach compares to using some of the standard animal models that you referenced earlier.


Jack O’Meara (Guest)
Yeah, so we are really pioneering a new approach to do in discovery for not only liver disease, but this is a real step change. We, we like, we think for a lot of drugs for a lot of big indications like this. There really isn't anything that recapitulates human disease better than a diseased human organ. It, there are obviously some, it's not a perfectly clean model and there are obviously challenges with just logistics of getting access to human livers and being able to get them onto the devices in the requisite time period and sustaining them there are definitely scientific challenges that we've been throwing a lot of effort into solving, but in terms of the quality of the data that we're going to get out of them, we really don't think it's, we think it's night and day by comparison to an animal who oftentimes just doesn't get chronic disease in the same way humans do, or even a lot of the IPSE models that are now quite invoked for liver disease.


Jack O’Meara (Guest)
They're oftentimes more Airlie by their nature are kind of young cells. Whereas this disease is really a disease of old livers. We think by actually taking them and keeping them alive, we've got the best possible chance of de-risking our therapies and being sure that what we actually put into the clinic and into a human being is really going to improve that human beings health, which is ultimately the goal here.


Neil Littman (Host)
Yeah. I mean, I, I think as many of our listeners know, I mean, one of the major obstacles is being able to recapitulate human disease in animal models. And, we've cured countless mice of cancer for example, but of course those therapies fail to translate when you move into human clinical trials. I really love the approach that you're taking here. I'm sorry. I do want to spend another minute on it. What is the goal then to compliment what you, what others are or what you would be doing in animal models, or to completely replace the need to use animal models?


Jack O’Meara (Guest)
So,


Jack O’Meara (Guest)
First off we will be doing humanized mice work primarily for regulatory submissions and primarily for long-term safety data, which you don't get in a human organ on a device to be sure that what we put into that Sonic is safe and effective. For us to get conviction on the biology that we think is going to be most impactful for patients, we are solely basing those decisions around which target, which therapy off of the data we develop from the whole human organ model. There are other workups animal models and other models have a strong view, bring a lot of value for particular elements of drug development, but for pure conviction of what biology is really gonna make an impact for patients that for us is the actual whole human liver model. That is still to this day across any indication. The primary reason drugs fail is that the biological hypothesis was wrong.


Jack O’Meara (Guest)
Not that the chemistry or the ligand was slightly better than the other. It tends to be that we actually don't rush. You're not picking the right target. That's a lot of what OCHA bio is kind of founded on, is really studying, using advanced genomic, using big computation, big data and human relevant models to study, get conviction on the right areas of biology. Be sure that what we go while we go into the clinical work and then thinking about clinical development and a creative and strategic way as a company.


Neil Littman (Host)
Yeah. That's, that's so cool. I, I wanna, I do want to dive into the data that you're collecting and your actual drug development process in a minute, but just, one comment from an investor standpoint, one of the things that we look for biomarkers is like, we are super interested in companies that we feel like have some edge in some form or fashion to better predict how a drug is going to perform in human clinical trials. Right? If, if, as an industry, we can solve that singular issue. We're going to unlock a ton of value both financially, but even more importantly for patients. To me, what you guys are doing and this approach of using live human livers is a huge point of differentiation. I know you recently launched a, I guess what you call your liver ICU in New York. Could you talk about that?


Jack O’Meara (Guest)
Yeah. This is one of those I was there when we did our first liver profusion in New York, and it is a really profound moment to be in the room for, but this is a, yeah, it was a real seminal moment for the company where essentially what we've done is we've set up a facility that operates. It's almost like a hospital ICU in that we have transplant surgeons there, twenty four, seven we're on call or onsite to take organs that have gone on offer for transplant on every patient, weren't a fit, or they were too disease to be taken. They arrive middle of the night anytime of day. We take them, put them on these devices, these human liver perfusion devices. Essentially what that does is it recapitulates human physiology. It has an oxygenator and it has a sped, a lungs, a kidney, a heart beating, and it pumps the they liver with blood to essentially sustain it as if it were thinking it's in a human.


Jack O’Meara (Guest)
We use that as a model to test out our therapeutic interventions. Ultimately, as you say, really get confidence in a way that's quite unique around the types of drugs that we think will be most impactful for patients. It's a really big, and I should also give a shout out to just the team. Who've been able to pull this off. This really isn't my achievement. We have a wonderful team internally to coordinate all of that work and make sure we've got processes in place to fly in livers from at the right time and have very sophisticated systems now for handoff, between teams. We also have partners with Yale university life share of Oklahoma, which is an organ procurement organization in Oklahoma who have just been incredible partners and incredibly strong belief in this vision for liver disease. So, yeah, it's been a team effort is what I would say.


Neil Littman (Host)
Jack w one additional question comes to mind, right? You're using livers that are not appropriate for transplantation, obviously, otherwise they can't be transplanted. Do you need to do anything to those livers that get them healthy enough to use for your purposes? Like how predictive are these damaged livers for your needs?


Jack O’Meara (Guest)
Well, that's exactly the kind of beauty of this is they are the organs. We hope to improve such that when we go into a clinical trial, that's the type, the same type of biology. We hope to remedy for patients who ultimately will lead will end up receiving fatty donor liver. The typical inclusion criteria for the organs we receive is severe steatosis. In clinical, right into local context, right now, transplant surgeons are having to transplant 30 to 60%, the atonic donor livers. Anyway, just because of how severe the shortage is. We're taking those that are on that kind of brink are worse, putting them on our device and ultimately aiming to improve the physiology of those organs, such that we can do prove that out in a pre-clinical context, so that when we go into the clinic, we can be really confident that when I'm able to have the same impact on that same category of liver, potentially even slightly less fatty.


Jack O’Meara (Guest)
We have, we're even in a slightly better position, we're going into the clinic to make sure we have an impact for patients, but in summary, it is the organ we hope to be able to. We're glad to take that, those, that those slightly less lower quality organs.


Neil Littman (Host)
I think this is actually a great segue into what I want to talk about next, which is your actual drug discovery platform. You're doing , drug discovery that allows you to do what, I guess, what you guys call complexity at scale, which combines computation automation, deep phenotyping, which I want to get into momentarily, but let's start with the range of data that you are able to capture. Like what types of things are you looking for? What are the inputs you're trying to capture and how do you envision that helping to inform your drug discovery efforts?


Jack O’Meara (Guest)
Yeah, so the, from a readout perspective of, on the liver ICU piece, the primary and the biomarkers, the end points, we look to, we divide into primary, secondary, and tertiary end points that we're ultimately measuring in these levers to get conviction that therapies we're taking forward are going to be successful. Primary end points are what the regulator wants to see. That's histopathology. Do we fundamentally change the histopathology of those organs while on the device? Secondary is also with a view to the clinic that's around some of the liver enzymes, as you would get out of a blood readout from a patient on a clinical context, do we see changes in alt AST bilirubin, some of these kind of quintessential clinical readouts that ultimately doctors use in for patients. Third, the tertiary readouts are all around the genomics. Do we see changes from transcriptomic level that ink that encourage us, or discourage us around the irrelevance of the biology that we're moving forward for?


Jack O’Meara (Guest)
Ultimately taking this, this therapy into a clinical context, that's our primary endpoints from a preclinical perspective for, from an inputs into our platform to give us to actually study disease, biology and give us confidence around certain targets that we want to test out. We, we built up a robust, probably more genomic data. We can quietly confidently say one of the most rich data sets of genomic data on the human liver out there. One of our kind of premier flagship projects when we first started the company was to take a thousand donor livers from a biobank in Oxford and did a full spatial sequencing workup match to 150 of clinical variables on these patients and all the outcomes data from a transplant context to really build a very robust disease progression model. Cause it was such a wide spectrum of disease stages to really understand what are the drivers of the disease and what are the targets to play a role at different stages of the disease to give us the best chance of success when we take those forward into pretend a component of the testing.


Jack O’Meara (Guest)
Anyway, I'll pause there. I think there's a lot of information in that. I want to give you a chance to,


Neil Littman (Host)
Yeah, no, that that's great. I want to, I want to tie that back to this concept of deep phenotyping and that how that fits into this Atlas, that your liver Atlas, that you're building. We were doing diligence at Bioworks, this wasn't a term I was familiar with before. Can, can you describe what you mean by deep phenotyping?


Jack O’Meara (Guest)
Deep phenotyping is the convergence of phenotypic data. In our case, imaging and AI algorithms to study the actual disease histopathology and live human liver or human tissue sample, I matched with genomic data. Transcriptomic data, so that we can see how that changes across different sections of tissue in partnership with genetic data, as we have some of the underlying kind of basis of the tissue types and an element of machine learning or computational statistical tools to model all that, to give us clues as to water actually driving the pathology and how can we best intervene in that pathology.


Neil Littman (Host)
Okay. So that all makes sense. I, the goal of doing all of this is to then develop therapeutics, right? And, and in your case, you're focused on developing RNA based therapies with the hopes of modulating activity within the liver. Let's, let's just start with why RNA therapy specifically and why not other modalities.


Jack O’Meara (Guest)
We love RNA for a whole host of reasons. The first one is speed. Like we can go very quickly from seeing a target shine, the thing signal and our data to believing in a target to testing out an RNA therapy in a whole human liver. I mean, in a matter of weeks, whereas if were doing small molecule discovery or take years to get confidence in that biology, it's also an incredible of modality in terms of longevity of effect. We can deliver a therapy to an organ ex-vivo and then see that therapeutic window play out for six plus months in the patient thereafter, which is particularly exciting for us given our first clinical study would likely be it an ex vivo therapeutic for transplant patients. Lastly, I mean, it's, it's been clinically de-risk now regulators are more comfortable with it. We know it has a very high safety profile.


Jack O’Meara (Guest)
For our chronic divert chronic disease, like Nash or chronic liver disease, you can confidently say you'll be able to re dose without worries about off target effects as much as other modalities. And, and yeah, it's definitely feels like the era of, or an a it's gotten it's even now a household name. People are even more uncomfortable talking about it outside of the drug development space, or we're pretty excited about that RNA.


Neil Littman (Host)
No, that's so true. And, and actually, I, that brings up a good point is the, everyone's now familiar with MRMA, right? Are the types of therapies you're developing? Are they specifically RNA or are they another flavor of Barnett.


Jack O’Meara (Guest)
Now? W were the, if I'm RNA is the, what tells the turns of the gene on where we're turning it off. We're an sir. Primarily we are beginning to branch out as well, but primarily to date our interest is in all of those.


Neil Littman (Host)
And, and as you said, I mean, everyone knows what RNA is in today's world. Regulators are much more comfortable with, RNA based therapeutics, at least in the context of vaccines, obviously, but there are still some challenges and you alluded to some of them, but, some of them include the ability to control duration of therapeutic effect, the specificity, and targeting that these drugs, making sure they are going to the right tissue, the right cells, how significant do you feel like these challenges are? And, and where are you in terms of trying to address some of these?


Jack O’Meara (Guest)
Yeah, great question. This is actually a a nuance point, and maybe it gets lost in when we've brought it to categorize all these different approaches as RNA medicine, which they are, but for M RNA, that the real challenge has been specificity. That's why they've been so successful with, with vaccines, but I've been less so with other diseases, but for ISI or RNA, which is the opposite effect on RNA. The specificity is less of a challenge. There's been this incredible breakthrough in recent years called whole gala, which is essentially a sugar. You, you conjugate onto your SIU RNA that makes these therapies extremely liver or extremely hepatocytes specific. They've got this beautiful pharmaco kinetics where they can stay in the out of sigh for quite some time, maintain a very long duration of effect with a very clean and very safe profile for patients. For sir RNA, that specificity is, is less, it's actually much less of a challenge as well as what if you're that being said, if you're targeting a podocyte targets, primarily I'm, the director of fact is also was quite nice what we've been doing as we now begin to expand our portfolio beyond our initial program in transplants and Nash.


Jack O’Meara (Guest)
Look now at later stages of the disease like inflammation, and even with a view into her cirrhosis and regeneration, we're particularly focused on finding similar delivery technologies, like, like what Galileo has done for our POTUS sites, but for other cell types of the liver. So, so for folks, not that familiar with it as the disease progresses, it just becomes more and more cell types contributing to that pathology. We, in order to reverse that or be able to treat that we already think it's important to both continue to have an effect on metabolism and others in, from a hepatocytes cell type, but also change some of the immuno or some of the actual satellite cell composition so that we can really have the best possible effect for those later stages of the disease. We are investing quite heavily internally, and haven't made any big announcements yet, but will be soon around some of the delivery technologies we think will have an effect or a particularly be quite exciting for liver diseases more generally.


Neil Littman (Host)
Well, I look forward to those announcements, Jack, you mentioned your pipeline. I want to break that into two components. Number one, how successful has your approach been in uncovering new targets? Let's do that one first. I want to talk about, where you are in terms of finding a lead candidate through four, but let's start with identifying new targets to begin with.


Jack O’Meara (Guest)
Yeah, so were really excited. I, some of the outputs from our first major Atlas thing effort, which was this thousand livers we took from a partner here at Oxford university here to rebuild this large spatial sequencing study. We came out of that with about 200, 250 targets. We were really excited about it. It was relatively evenly split between targets that were very novel and targets that we wouldn't surprise folks very close to the literature that we're also seeing that, but that's great validation, right? Your platform is onto something. If it's telling you all of the, what everyone else knows, but it's just telling you more giving you larger clues until they're potential avenues that could be impactful for patients. We've taken those 200, 250, went through a very robust screening exercise and the models that we developed here in Oxford, a variety of different liver disease models to give us conviction that these targets will actually sit consistently and coherently improve the biology.


Jack O’Meara (Guest)
We're now down to about nine, we think are really interesting and moving those towards, into our leaf lead development stage and ultimately help to get start getting those into profused livers later this year, such that by some time next year, we'll, it will nominate our first lead for ind enabling studies and really move those into the clinic in the next 24 months is our as our target.


Neil Littman (Host)
That's that's very cool. Very cool. I want to talk about your process for identifying a lead candidate. I know, that's an ongoing effort right now, as you just mentioned, but what are some of the attributes you're looking for in an, into like in an ideal lead candidate to move forward?


Jack O’Meara (Guest)
For us, the way we're thinking about clinical development, the first program where we've thought about it in our heads is that we want to improve outcomes in a transplant context. The two big areas of biology that we're interested in are cell death and stress and metabolism, the reason being to improve outcomes for transplant patients at the primary end point there we're trying to hit is essentially reducing early allograft dysfunction, like, well that means essentially reducing cell death and reducing it re ischemia in organs that have been transplanted such that they sustain the first few choppy months of post-transplant and ultimately perform well for patients long term. The key secondary end point we're interested in that transplant study is around recurrence rates of steatosis or recurrence rates of fatty liver disease, which is oftentimes the actual cause of the transplant in the first place. If we can see that we improve both south of the cell resilience or the ability to resist cell stress so that those organs do continue to perform well, but also that we've improved the metabolism, such that we see a recurrence of fat buildup.


Jack O’Meara (Guest)
That's all we know we've got a really interesting therapy that we can take both beyond the transplant setting, where it's, where we hope it will be having a big impact into larger indications, like Nash and beyond. That we can really go in and build a multi, expand the label essentially, and build a multi product portfolio off of that initial indication. That's our, those are two areas of biology or particular interested for our lead program. We are now as we get more bigger and bolder and begin to expand and diversify beyond that, we're looking at later stages like fibrosis regeneration, we're even starting to look at cancer and cancer prevention through hepatoprotective agents that we've been studying in our labs.


Neil Littman (Host)
Jackie, you just sparked another question. And, as far as I know, the liver is the only organ that is able to regenerate. To what extent are you able to rejuvenate a regenerate livers today to make them more suitable for transplantation, right? That your goal or are you really focused on delivering InVivo therapy to restore the function of someone's liver? So they don't need a transplant?


Jack O’Meara (Guest)
Of both and yeah, you're you hit the nail on the head. The liver is the only organ, and we've never really been able to figure out how it does this, but it can fully regrow. If you could have two-thirds of someone's liver, the whole organ can regrow to the original size and state really quickly, which is this just bizarrely, a bizarre function, kind of abnormality of biology that if we can try and uncover and study could really lead to amazing biological breakthroughs for human health more generally. So, and we're thinking quite deeply about that as we set up this new liver ICU in New York, I can study whole organs and as closed circuit system to really try and tease, maybe tease apart some of that biology, which will be amazing breakthrough for human health more generally. Anyway, that, that aside your question was I'm actually, your question was around whether, sorry, I completely forgotten your question.


Jack O’Meara (Guest)
Yeah,


Neil Littman (Host)
No, no. My question was around. If, if you're really focused on regenerating livers to make them more suitable for transplantation, or if you're in vivo therapy, so people don't need a liver transplant.


Jack O’Meara (Guest)
It's been a, it's been a long day for anyone missing laid here in the UK. The time zones are always a challenge. Our initial indication in the transplant space is essentially you could consider it a regenerative tool, but essentially to regenerate organs such that they would be more useful for patients who received them. The long-term goal for the company is not to be a transplant therapeutics company per se, but to be more generally a liver regeneration company thereafter, but we think if we can prove it out in this first use case in transplant, we can then take those learnings and really expand our ambitions into InVivo therapeutics and thereby reduced the need for liver transplants, that horrible and really awful experience for a patient to go through. If we can resist our delay or actually re ultimately reverse some of the damage has been done in vivo patients, hopefully when they won't have to actually go through that.


Neil Littman (Host)
Yeah, that, that, I mean, that would be incredible if you can certainly achieve those outcomes check. I, I, before we wrap up, cause I know it is getting late in the UK. I do want to switch gears for a minute and talk about financing. Obviously your UK based company love to understand your investor base. If there are many or any European VCs that have supported you, or is it mainly U S venture firms?


Jack O’Meara (Guest)
And it's such an interesting question. I was talking about this at length reef that this past weekend, actually we, one of the team from ex-ante, I said they hadn't a UK investor until the IPO, which is crazy to make w w we unfortunately aren't that bad. One of our, one of our early seed investors was a UK based fund. We're big fans of shout out tobacco VC, but to be quite honest with you, the large majority of our cap table is both us and on Asian funds. And Europe really does. I I'm banging the drama. I don't know if you follow me on Twitter, but I say this all I'm always critical of European financing landscape. It's it tends to be very conservative. It doesn't want to take bets on high risk, high ambition projects, like the one where we're developing. Yeah, it is a shame that there is less capital on this side of the pond.


Jack O’Meara (Guest)
There is, but I mean, living in a global world, I think COVID maybe accelerated this it's wonderful that capital can flow democratically to all over the world, wherever the best sciences and capital will ultimately chase the best science with the best possible chance of them improving lives and delivering returns. Were happy to take money from wherever the best people are and what we found a lot of those to be actually in the U S.


Neil Littman (Host)
I couldn't agree more. I mean, I, if people have been following me or by virtue for a while, I mean, we certainly beat the dumb drum of democratizing access to companies like yours. I mean, to me, that's so powerful and exciting. I do need to ask before I let you go about, obviously the current financing environment is challenging to say the least, as you think about, going out for your next round, as you think about the near term milestones and inflection points, how do you think the current financing environment, if at all, has impacted your plans moving forward?


Jack O’Meara (Guest)
Well, it w we've, it's definitely impacted how we're, how we're thinking about setting up our programs. Some of the things we've done in response to just how quickly and dramatically things have shifted in the market is we've now put a, that's actually why I was late to this podcast. We've started engaging in business development conversations a lot more seriously. We initially, I mean, if we only want access to capital, you could take all these programs forward yourself and retain is all of that value, but just being mindful of that may not be the case in the next couple of years. We've, we've decided to see if there are opportunities within the context of a multi-product portfolio, like the one we're building to part around bringing some expertise in larger pharmaceuticals or otherwise, and ultimately bringing some funding that way as well. We've also, it also is just forced to the organization to just be more, it's put a bit more of a challenge on how, how you think about growth.


Jack O’Meara (Guest)
I mean, just even in small ways, and as we think about longer term development plans and so on, I think it will be a good thing for companies to be quite honest, if it puts you in a position where you need to just really justify every dollar in a way that, that wasn't the sentiment of the market over the last couple of years, when, and I think that will force ultimately better science to get through. I'm more focused and concentrated portfolios would ultimately, I hope think will be a good thing for everyone, but let's hope it doesn't stay as, as bleak as things. Look now, we are really in a, quite a bleak period of finding thing for important companies like biotech, there's so much money in tech and I really, every frustrates me that I'm more, doesn't damn as luck to those medicines that will save, ultimately improve human health, human existence for everyone out there.


Jack O’Meara (Guest)
Hopefully we'll see COVID, although we've things have reversed almost worse than they were before. COVID I hopefully we'll start to see a bit of Goodwill back in the biotech markets.


Neil Littman (Host)
Jack, I'm going to have to invite you back for another podcast and we could talk for an entire, another show about some of the discrepancies between the amount of capital flowing into tech versus biotech and early stage, healthcare related assets. I mean, that is something I'm super passionate about.


Jack O’Meara (Guest)
I do know. Well, yeah, we've tried, I couldn't agree more with you. I do think like some of the younger generation and some people are starting to really, as they ask themselves, what do I want to do at my life? Do I want to work on like back office automation software, or do I want to work on something that could fundamentally change human health? I think people are coming to the sector in ways that they never were before in their droves with this idea of impact and improving the world we live in. I hopefully hope that will increase the output of the sector and ultimately then increase more funding inflows into the sector, but it's not going to be going to happen overnight, but I, I am bullish that this is going to be the decade or our century of biology. So, so let's see if that prediction plays,


Neil Littman (Host)
Oh, I couldn't agree more. I mean, I really do think we're in the age of biology and in particular, this, this, right where you guys sit, right? It's this intersection of technology being combined with biology, right? I mean, you mentioned all of the , genomics and deep phenotyping and all of the, like the liver eyelids, all those things are based on a core technology platform. You're wrapping that around digital, trying to solve fundamental problems in biology to me, like that's so exciting. Like, that is the next wave of, I think, where a ton of innovation is going to happen within healthcare. That's going to directly impact patients. And, by the way, we're all patients at some point in our lives, whether we like it or not. And, I, I just got to say Jack, before I let you go, I, I think, investing in these types of companies, right?


Neil Littman (Host)
Like, like okra and, early stage innovative companies that are trying to make a real impact in healthcare on patient's lives are not mutually exclusive with generating outsize financial returns. Right. If you guys are successful, there's huge upside here for investors that are supporting your company. No, it goes back to like one of my underlying thesis just as like a human being is like, we can all do well by doing good,


Jack O’Meara (Guest)
Totally agree, but not agree more, could not agree more.


Neil Littman (Host)
With that, I'm going to, I'll get off my high horse and I will Jack, I know it's getting late there. We could talk for another, probably four days about this stuff, but I will let you go. I, I did want to say a huge, thank you for joining me on the show today in a really wonderful discussion.


Jack O’Meara (Guest)
I'm so glad. Thank you for having me. I'm looking forward to catching up in 3d soon.


Danny Levine (Producer)
Well, now, what did you think?


Neil Littman (Host)
Oh, that was a really fun and fascinating conversation. I, you heard me say during the podcast, one of the things that we're super interested in at Bioverativ is companies that we feel like have some advantage in better predicting how drugs are going to perform in clinical trials. Right. We all know that animal models don't necessarily recapitulate human disease. So, what Jack and okra is doing is they're using human livers, right. It makes a ton of sense. It's like, well, that's sounds obvious. Why haven't we done that before? It was really interesting to hear about that approach, to hear about this , liver ICU that they originally launched in New York. Like, that's really cool. I haven't heard of anything like that before. Of course, how all that is going to help them translate medicines that will ultimately help patients with chronic liver diseases.


Danny Levine (Producer)
They're able to capture tremendous amounts of data in real time on these livers that are kept alive and functional outside the body. What's the potential to develop new understandings of the liver and discover novel targets.


Neil Littman (Host)
Yeah. You heard Jack mentioned, talk about that. When I asked him a question about developing novel targets and, it sounds like this is twofold. It sounds like what they're doing now has validated a bunch of existing targets, which to me is really exciting because it helps validate their platform. Then, you heard him talk about that. They've identified a bunch of new targets as well. I think, this is part of the overall thesis for investing in these types of companies that are marrying computational biology and some like advanced, whether it's machine learning, artificial intelligence or whatever it may be to come up with novel targets and usher drug discovery into the 21st century. You wrap that around what they're doing with live human livers. I think that one, two punch is a really powerful combination. I think it's really cool that they already have some validation.


Neil Littman (Host)
They've already found some new targets. They have a bunch of lead candidates that they're , processing through to try to, settle on, one or a handful to move into the clinic. Sounds like they're playing to be, hopefully, moving forward in 2023 with a lead candidate and probably moving into ind enabling studies, I would assume shortly thereafter.


Danny Levine (Producer)
With the ability to capture so much data, how challenging do you think it will be to separate signal from noise and determine what data are meaningful?


Neil Littman (Host)
Yeah. I mean, that's a hugely important question, Danny. I mean, that's, separating signal from noise is the holy grail of, making sure that you have usable data. It sounds like they have systems in place to set that up. It sounds like they've invested heavily in, again, what they call developing complexity at scale, right? They have the computational throughput, they have a lot of the automation in place. They have this deep phenotyping know platform sounds like they're able to, you ingest all this data and analyze it in a way that gives them information, that then informs their discovery efforts. So, I'm sure there's still a ton of work to be done. And, of course the proof will we'll see the proof when therapies move into the clinic, but sounds like they're on the right track.


Danny Levine (Producer)
It's an interesting approach to rescue and rejuvenate livers for transplant. Are there regulatory challenges to this approach?


Neil Littman (Host)
I'm sure there are regulatory challenges to this approach. I mean, I, I think obviously you don't need to prove that, therapy is safe and effective. There aren't all target effects. You have to prove the, obviously the efficacy and the duration of those therapies. So yeah. You heard Jack talk about some of the challenges of the MRNs therapies, for example, on there they're using therapy. It's a little different flavor of RNA therapies. There's a different risk profile associated with these, but absolutely. I mean, there are going to be very high regulatory barriers to make sure that their therapies are, are doing what they're supposed to do. Even if they're not being used in vivo, they're being used in livers, outside the body. If those livers are gonna be transplanted, then they're gonna incur all the same regulatory burdens,


Danny Levine (Producer)
Obviously the potential to take this approach and do it in vivo would have tremendous payoff. What do you think the potential for that will be?


Neil Littman (Host)
Oh, it's huge. I mean, there's no question. It's huge. It, it sounds like what Jack was referring to was doing this in a stepfather stepwise fashion, right? You start with livers to make them more suitable for transplantation. That would be like, step one. Let's see how that goes. Let's prove that works. Step two would be more of the, like in-vivo model where you're treating patients to try to regenerate their own liver instead of needing a transplant. To me, that sounds like step two. It maybe they can do some of this in parallel. I don't, I don't really know. You don't have to see how they'll have to see how things play out in terms of, clinical data and things like that. The way I think about it, the sequentially, but no question, they would both be hugely impactful. I mean, even if you could, start with making a larger percentage of organ suitable for transplantation like that in an of itself as a game changer.


Danny Levine (Producer)
Well until next time.


Neil Littman (Host)
Thanks, Danny.