PureTech Health plc (PRTC) Earnings Call Transcript & Summary

Good morning. I'm Allison Mead Talbot, Head of Communication at PureTech, and I'd like to thank you all for joining us for PureTech's inaugural R&D Day. This first one is virtual, but we look forward to hosting you all in person next time. During today's event, you will hear from leading experts as they share their clinical perspectives and insights into therapeutic opportunities and lymphatic disorders, fibrotic and inflammatory conditions and immuno-oncology. PureTech team members will also take a deep dive into our Wholly Owned Pipeline, in addition to discussing new and important drivers of our future growth. We will have a Q&A session following each key opinion leader presentation, and PureTech's management team will take questions at the end of the event. [Operator Instructions] As a reminder, during today's event, we will be making forward-looking statements. These statements reflect PureTech's current expectations regarding future events, including, but not limited to, statements regarding financial performance, clinical and regulatory activities, patent applications, timing of product launches and statements relating to market acceptance and commercial potential. Forward-looking statements involve risks and uncertainties, and actual events could differ materially from those projected herein. We encourage you to consider the important risk factors that could cause the actual results to differ materially from those in the forward-looking statements. These factors are described on Slide 2 of this presentation. Finally, an archive of today's call will be posted on PureTech's website in the Investor Relations section. It is now my pleasure to introduce our first 3 speakers: Chris Viehbacher, PureTech Board Chairman, former CEO and Board member at Sanofi as well as former President and Board member at GSK; Dr. Bob Horvitz, PureTech R&D Committee Chairman and Board Observer, Nobel Laureate and David H. Koch Professor of Biology at MIT; and Daphne Zohar, Founder and Chief Executive Officer of PureTech. I will now hand it over to Christy Viehbacher, our Chairman.

Hello, everyone, and I'd like to also welcome you to PureTech's Investor Meeting. If you don't know the company already, it's truly a remarkable company and it's been a privilege to serve on its Board for the last 5 years. When I joined the Board, I thought this really matched what I was conceiving of as a 21st century biopharmaceutical company. Over my years in the pharmaceutical industry, I've heard criticism that did we really pursue innovation? Did we really go after true unmet need? Were we thinking about everybody? And why is it so expensive to develop new drugs? And what I saw in PureTech was actually a company that was really addressing all of those and really doing things in a much different way. You start with innovation. They're not just looking at incremental innovation, but they were really going after what's really novel, what really could make a difference. And of course, they're not just doing science for science's sake. What could these innovations really do to help patients within their health and in their well-being? And having identified that, one of the most striking things that I have seen is how capital-efficient this company is at taking an idea and carefully putting the capital, including the human capital, behind that idea and derisking it and only investing further when they really truly derisk that. There's an awful lot of real scientific rigor here. But of course, as we all know, no business is a success without its people, and that is probably the most amazing thing about PureTech. It starts with, obviously, Daphne and her team. She's built a team of entrepreneurs, people with a lot of science expertise and a lot of technical expertise around here. And as these companies progress, she has always been able to find an awful lot of talent to bring to those companies. And at a certain point in time, she has validated the idea of these companies by bringing in outside investors. When I started 5 years ago, we were really just -- we had just a number of early-stage projects. And over those 5 years, we have now 2 drugs approved by the FDA, we've done several IPOs, there are 9 companies now, we've raised hundreds of millions of dollars and got lots of validation. And so it's a really amazing story, and I really can't think of another company that comes even close to this. Now along the way, she's not only built up all of this expertise inside the company but I think, and I'm excluding myself from this, but a truly remarkable Board. And this isn't a Board that just is there for governance. This is a real brain trust that Daphne has built. And if I look at our Board of Directors, I mean you're not only seeing what you see in a lot of biotech companies, which are obviously scientific luminaries, but these people have all patented medicines, developed medicines, developed companies. We start with Bob Langer probably one of the most prolific entrepreneurs of our century. We have Ben Shapiro, who was the Head of Research at Merck. We have John LaMattina, who is Head of all of Global R&D at Pfizer. And we have Raju Kucherlapati, who's the Harvard Professor of Genetics and the Founder of Millennium and other companies. And we have a few of us to help bring a business perspective, including myself and Marjorie Scardino, who was a former CEO of Pearson. And I think we've tried to help bridge the science with how do we develop that from a business point of view. And of course, she's got an amazing set of advisers in the Scientific and R&D Advisory Committee. Now more recently, there have been some other exciting developments. Now we are actually developing our own pipeline. We actually have our own research and development labs right in PureTech's head office. And also, that means that we need to evolve the Board. And most recently, we brought on Kiran Mazumdar-Shaw. Kiran is a phenomenal entrepreneur, built a company called Biocon in India from scratch, is one of the most influential executives in our biopharmaceutical sector. And she can be really helpful as we now move into this new phase and develop our own pipeline and bring that to market and benefit patients. And probably the most influential and my favorite Board member is Bob Horvitz, Nobel Prize winner in 2002, National Academy of Sciences, American Academy of Arts and Sciences, Howard Hughes investigator, Professor of MIT. Bob really symbolizes the scientific excellence that Daphne has brought to the team, to the Board and I think that's what's really behind the amazing ability to take ideas all the way through to companies, to getting them financed, to getting them approved and ultimately to helping patients. So with that, I'll turn it over to you, Bob.

Thanks, Chris. I'm Bob Horvitz, I chair the PureTech Research & Development, that's the R&D Committee, and I've long been an observer on the PureTech Board. I want to thank you for taking a few minutes of your time to allow me to describe my involvement with and my sense of PureTech. In short, I think PureTech is driven by a remarkable and exceptionally talented group. It's been continually innovative and pioneering in its approaches. And PureTech's been fearless yet always founded on the best of science. I became involved in PureTech some years ago through my friend and now PureTech Board member, Raju Kucherlapati. Raju told me about the PureTech vision. He told me about Daphne Zohar, and I met Daphne and I was sold. I became involved in PureTech first as a member of a small advisory group for a subset of PureTech projects and later became a Board Observer, Chair of the Scientific Advisory Board and then Chair of the R&D Committee of the Board. The PureTech Board, which you can see on this slide is truly spectacular. And its members have experiences and expertises that span the range of what you want when the mandate is to create and innovate and be always open to new ideas, ideas that oftentimes owners wouldn't have even thought to pursue. And then to critically assess whether those ideas are practical, not only scientifically and medically, but also commercially. And in short, will this work? Can it be developed reasonably? What would it take to answer such questions if the answers aren't known today? What other company than PureTech has successfully created an ADHD drug that is delivered via a video game interface or an obesity drug that is made from hydrogel particles that swell when you swallow them. Sitting in a PureTech Board or R&D Committee meeting is exhilarating. Some of the smartest people I know sit around those tables. And these are people who talk only when they have something to say and they engage and listened carefully when someone else speaks because we all know that someone is speaking that's going to matter. The internal PureTech team is similarly amazing. These are the people who truly made these things happen. And this is led by Daphne Zohar. Daphne is a true visionary who always starts with a problem, what is needed, and then figures out how to identify and assemble a diverse group of the world's foremost experts to think about that problem and then come together and meet in blue sky about novel ways that problem might be addressed. Daphne then recruits some of these same people to give them the opportunity to make real the dreams that they've helped generate. Daphne is an inspiration and a force. With its pipeline of wholly owned internal projects, PureTech now is poised to make even more innovative and significant advances. I don't think any of us can promise a 400x return, but I think what we can promise is that we'll do our best to find the most creative and successful ways to make a difference for patients and for investors alike. I hope to get to know you as you join us in the continuing adventure that is PureTech. And now I'd like to introduce the PureTech Founder, CEO and my friend, Daphne Zohar.

Thanks, Chris and Bob, for those kind remarks. We're really fortunate to have such a terrific and engaged Board and R&D Committee who gives so much of their time and truly care about our mission. I'm also really lucky to have an amazing and dedicated team around me on the senior level and also at every level of the organization. Throughout the day, I'm pleased to be joined by my colleagues, Bharatt Chowrira, President and Chief of Business Strategy. He was former COO at Auspex Pharmaceuticals. Eric Elenko, our Co-Founder and Chief Innovation Officer, who is the co-inventor of many PureTech programs, including Karuna's KarXT and Gelesis Plenity; Joe Bolen, our Chief Scientific Officer, who is the former CSO of Millennium and Moderna; Joep Muijrers, Chief of Portfolio Strategy at PureTech and former portfolio manager at a leading European biotech investor group; and then Steve Muniz, who's Co-Founder, PureTech, and Chief Operating Officer. He was a former partner of Locke Lord. With the leadership of our management team and the dedicated work of PureTech's team of scientists and entrepreneurs, we've developed a strong track record of advancing novel therapeutics. Across our Wholly Owned Pipeline and our Founded Entities, we now have 24 products and product candidates, including 12 that are in clinical stage and 2 that have been taken all the way from inception at PureTech through FDA and European authority clearance for marketing. An important and underappreciated point, all of the underlying programs and platforms were initially identified or invented and then advanced by members of our team. We're proud of our track record of clinical success, particularly in the stages where industry failures are typically high. We think that partly results from our unbiased disease-focused discovery process that starts with signals of human efficacy and involves doing those killer experiments early so we can move our resources to really -- the programs that have the most value. And we got to this point by thinking differently. Our R&D model starts with the disease or problem and we work in collaboration with a network of world-leading experts, some of whom join us today. We identify, invent and advance scientific breakthroughs usually before they're published in major scientific journals. And our focus area has generally been centered on the biology of the brain-immune gut axis, which we refer to as the BIG Axis. 70% of the entire immune cell population is in the gut in addition to 500 million neurons. And there's key components like the gut epithelial barrier, the microbiome and the lymphatic system, which play important roles. Today, we're going to be spending most of the time diving into our Wholly Owned Internal pipeline. And the science behind one of the most critical components of the BIG Axis, which is the lymphatic system. And before handing it over, I thought it would be helpful to put some context around the components that make up our value. And I think that today what we really wanted to do was to focus on this upper right-hand corner, which is our Wholly Owned Pipeline, an area that we've developed and which we believe people haven't really heard as much about. So we're really excited to dig deep into the Wholly Owned Pipeline. And we won't be spending a lot of time talking about our Founded Entities. So I thought I'd just briefly put that into context and talk a little bit about our history and where we're headed before I hand it off, and we do the deep dive into the Wholly Owned Pipeline. So we started PureTech with limited resources and partnered with venture capital investors to share the cost of early development by housing the new medicines that we were developing in what we call our Founded Entities. Among those, those programs include KarXT program at Karuna, which is now a clinical stage biopharma company and which is developing really one of the first novel therapeutic approaches in decades to treat psychosis in patients with schizophrenia. Gelesis , which received FDA clearance for its lead product, Plenity, for the broadest patient population of any weight management aid in addition to European marketing authorization and Gelesis has a pipeline of other really exciting programs. Akili, which you might have heard of, is a leading digital therapeutics company that received FDA clearance for the first and only prescription treatment delivered through a video game, which is called EndeavorRx, and they've also just recently received European marketing authorization. Vedanta has built an industry-leading microbiome platform and currently has orally administered clinical-stage product candidates in development for the potential treatment of serious infection, cancer, food allergy and IBD. We believe that the microbiome field is on the cusp of major validation with Vedanta leading the way. So those are just a few examples of our Founded Entities. We have 4 other Founded Entities, which we'll be hearing more about in the coming years. As I mentioned, all of these programs were initially identified or invented by the PureTech team through our differentiated approach starting from diseases and looking through the lens of the biology of the BIG Axis. And then the other key component is to always identify something or know something that we think the rest of the world doesn't. So bring in the key asset IP and work on that before it's published in a major journal. So as these programs succeeded and PureTech's resources grew, we developed our Wholly Owned Pipeline where we maintain 100% ownership, and that's a pretty recent development. Our Wholly Owned Pipeline was formed way: all the medicines we've been involved in discovering and advancing with the disease focus, data from our scientific experts prior to publication. The biggest difference in our strategy going forward -- there's basically 2 differences. The first is that we'll retain 100% ownership in the wholly owned programs. And second, we're doubling down on a theme where we've developed a substantial leadership position, and that is the biology of the lymphatic system and related immunology, which is a subset of our overarching focus on the BIG Axis. We still hold a sizable equity ownership in our Founded Entities and continue to benefit from their growth as they serve as a source of nondilutive funding through potential monetization events, which can include things like M&A transactions, IPOs and royalties from product sales. So even though we're not talking about them, we recognize the importance and we're very proud of what we've developed. Today, we're really going to be digging into the Wholly Owned Pipeline and the lymphatic system. So I'll just note that PureTech is well capitalized with cash resources into the first quarter of 2024, which is conservative because it assumes no additional Founded Entity monetization events. The Founded Entities are also well capitalized, having raised approximately $1 billion in the past few years. Given the importance of our Wholly Owned Pipeline as a driver of our growth, we'll be spending the rest of the time today digging into it.

Thank you, Daphne. Next, we will focus on the science behind the lymphatic system, which underpins our Wholly Owned Pipeline. We will first hear from Dr. Joe Bolen, Chief Scientific Officer at PureTech and former Chief Scientific Officer at Moderna and Millennium; and then Dr. Stanley Rockson who is the Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford University and Director of the Stanford Center for Lymphatic and Venous Disorders will provide a clinical perspective on lymphatics and the need for innovation in lymphatic disorders and beyond. I will now hand it over to Joe.

Thank you. I'm Joe Bolen. I'm Chief Scientific Officer at PureTech. Today, I want to tell you about what we're working on. It centers around unique access in the body that we call the BIG Axis, which stands for the brain, immune and gut. What's surprising is these 3 systems interact and affect our health in ways that most people don't realize. As it turns out, this brain-immune-gut axis really is the primary partnership through which we interact and react to changes in our environment -- acute changes in environment that aren't covered by evolution. As it turns out, we know now that the nervous system, the brain, can regulate systemic inflammatory reactions, so the brain can help control immune responses. Perhaps more surprisingly, as it turns out the immune system by trafficking immune cells through the body patrolling around the brain, communicating with the neurons in the brain can actually then modulate things like memory, behavior and cognition. And finally, in the gut itself, majority of our immune system, at least if you count cells, is in and around the GI tract. Now the GI tract is the site of the commensurate microbiome. This very large group of bacteria, there's actually more bacterial cells in our gut than we actually have in the rest of our body as just cells. So it's a very large population. But throughout evolution, this bacteria have been with us from the beginning and they played a number of really critical roles in terms of our health. They help digest food. And in that digestion, the metabolic products created help fuel the energy source for intestinal tract, basically shape our fundamental immune system in numerous ways and provide a mechanism to even directly send signals through those metabolites to the brain. If you think about it, the gut is outside the body. So in a way, that environment that is being monitored is the ingested environment. It's also important to note, too, by the way, that the GI tract is the largest endocrine organ in the body, okay? It makes more hormones than anything else put together. So it's quite an important piece of the puzzle. So perhaps it's not too surprising then that disruptions of the balance between the brain-immune system in the GI tract underline a number of pathologies associated with diseases such as autoimmunity, metabolic disease, neurodegenerative diseases as well as psychiatric diseases. Now in our efforts to think through how we might want to address actionable components of the system, we have a number of programs, a number of subsidiaries that you know about, we'll hear about. But in terms of what we are focusing on internally is the lymphatic system because, in fact, it is the lymphatic system that holds this whole network together. It's important to note that the lymphatic system does 3 primary things. First and foremost, in maintaining fluid balance. The blood system pumps a lot of fluid through the arteries' arterials. And while most of that gets returned through the venous system, as we know, as it turns out about 15%, which turns out to be an amazing 3 liters fluid, escapes out into the tissues where it combines with the secretory products of tissues, the garbage, if you will, and creates what we call lymph. That lymph then is returned to the circulatory system through the lymphatic system. So it takes that extra fluid and it filters it back through these lymphatic vessels into regional lymph nodes. And those regional lymph nodes, we have about 300 or 400 of them, they're each specialized for the tissue that they're associated with and drain. And this is where the immune system kicks in and basically samples, whether it's immune cells trafficking down that lymphatic vasculature or the fluid itself. It seeks out and detects self-antigens, which is really important for maintaining our peripheral tolerance and then importantly to find out if there are any non-self antigens there, perhaps then detecting a pathogen. If a pathogen is detected, it is those lymph nodes where the adaptive immune system is initiated. The cells are created there that go on to protect us from that potential threat and basically represent the foundation of our memory immune system, which we carry with us all of our life. It really defines who we are. And by the way, everyone's immune system is fundamentally different from every other individual. It's a different experience. So that's one thing. This is how -- this is all connected tissues and adaptive immunity. The second function is the fact that the lymphatic vessels are a specialized highway for which only certain types of immune cells can travel. Other cells can't get in, only immune cells. And this is so that our immune system can make cells that can recognize pathogens, it allows those cells to patrol all over the body. They then come back into the lymphatic system for reeducation or a rest, if you will. And the way they get back in and circulate around is through the lymphatic system going to the lymph nodes. So that's also quite important. The last thing that the lymphatic system does, it may be surprising, is with food ingestion. What does it have to do with it? Well, is it turns out the way that we all absorb long-chain fatty acids in our diet is due to the lymphatic system. And in this system, basically, the long-chain fatty acids, the lipids are broken down in the small intestine. They are taken up into the enterocytes in our small intestine. They are put back together these giant balls of protein fat called chylomicrons. They are then kind of spit out the basolateral side and then they're taken up by a special group of lymphatics called lacteals. And the function of these lymphatic vessels in the GI tract are they are to pick up and move those big chylomicrons into the lymphatic system through the mesenteric lymphatics up and around to the thoracic duct, allowing these chylomicrons in to be distributed in the blood. And in the blood, they are then metabolized, releasing cholesterol fatty acids and things like that, that help build the rest of the body and provide, importantly, an energy source for things like muscle and particularly, the heart. So those are the 3 functions that the lymphatic system play. So what's been created here is a chemical linker system that is modular, that allows us to take a drug and to link it to a triglyceride in a certain way such that the drug on the linker on the triglyceride is taken up into the enterocytes, just like the long-chain fatty acid, and then created -- taken up by the enterocyte and then put back together in those chylomicrons. Now it goes into the basolateral side, enter the lymphatics through the mesenteric lymph nodes, around and out. So you can do 2 things with this. First, it's important to note that part of this linker system allows us to release that API, that drug, anywhere we want to along the way. It's kind of like a fuse. If we make the fuse go off early, we can release drug in the mesenteric lymph nodes. I'll point out that the mesenteric lymph node system is the largest lymph node system in the body. This is where the adaptive immunity, tolerance and all that happens related to the microbiome. So we're back to that thing. So if we want to modulate the immune responses in the mesenteric lymph nodes, we can make a short fuse, if you will, allow immunomodulatory drugs to basically marinate the mesenteric lymph nodes. And if we do it at the right concentration by the time that immunomodulatory drug might be out into the circulation is below the effective level there, and importantly, below the toxic level. So we believe that this has a number of potential applications for modulating the immune system in the mesenteric lymph nodes. The second component of this is shown in this chart. And basically, what happens is these chylomicrons when they're released, again, into thoracic duct basically get a ride around the system before they get back to the liver. For drugs, who have high metabolism in the liver, and there are plenty of them, I usually call them liver candy. The reason that you can't give them orally is because they're taken up, put into the portal vein right to the liver first and then they're just destroyed. But using the Glyph technology platform, we can take these drugs, we can avoid the liver, release the drug in the rest of the system and therefore create an effective oral drug. And this is exactly what we've done with LYT-300, the Glyph version of allopregnanolone, the other technology platform that we've been working on for a couple of years. And we call it the Orasome technology platform. And this is based much like the understanding of lipid absorption, long-chain fatty acid absorption, taking advantage of a natural process and engineering it so that it might be useful in terms of generating new medicines. Here, what we're relying on are the extraordinary exosomes that are created as a part of lactation. The exosomes are part of milk. They're secreted in milk. And interestingly enough, what do they do? Why take the time to make these? Turns out, they're not important for nutrition. Let's hear what they are important for. These exosomes that get generated, they travel intact into the small intestine and it's in that small intestine where they land. That they are there to create tolerance for that infant as food is coming in, as the immune system is getting established and the enteric nervous system is getting established. So these are particles that are engineered by nature to be stable, to travel to the small intestine and in and on their surface to modulate the immunity in the infant, which is an amazing thing. Most exosomes that we find in the body are very fragile. These exosomes are stable. Now we've utilized this property to isolate vesicles from milk. We've been able to learn to purify these in great quantity. We've been further able to create technology where we can load cargoes into these exosomes. This allows us then to create an oral route where we can take something and have it travel through the stomach into the small intestine. Now there are lots of things that we could do with this platform. But the one that we're focusing on right now is the loading of expression systems in various types into these exosomes. And what we're really doing here is we're taking the expression system, loading it into these stable vesicles. And we've learned to do one other thing, and that is to program these to attach to different kinds of cells in the small intestine. For the purposes of what I'm going to tell you, we've programmed these to bind to enterocytes, the most abundant of the cells. And what these will do then is take that expression system orally. They will then get to the small intestine, adhere to the enterocytes and allow the expression system then to get into the enterocyte where proteins are made. And those proteins can be any protein. They can be small peptide hormones, they can be antibodies, they can be whatever you want. Those proteins that are made by the enterocytes then are secreted out until the lamina propria , it's an old story now, right, out to the lamina propria, into the lacteals, taken up in the mesenteric lymphatic system out to thoracic duct into circulation. So in other words, what we have here, we believe, is a way to make therapeutic proteins in the patient or in the person. So the idea is simple. You take a pill and basically through this Orasome platform, therapeutic proteins are made by the individual who takes these. So you make your own drug in your own enterocytes. And we believe that, that is a very interesting and likely a very disruptive way to think about delivering and making new biological medicines. Lastly, let me tell you about the CNS brain lymphatics or meningeal lymphatics program. The mystery of how the brain gets rid of its extra saccular fluids has been a raging debate for over a century. The brain was considered to be immune-privileged, and the mechanism by which it got rid of its waste like every other tissue was argued to be special and different. And if you're a biologist, the one thing that you can generally count on is there's not really anything that's particularly new, different special or unique. Biology uses a gadget that works and then uses it again and again and again. So the gadget the rest of the body uses is the lymphatic system to get rid of the waste, if you will. So why would the brain be different? So about 4, 5 years ago, it was discovered that certainly, while there's no lymphatic vessels in the parenchyma of the brain, the meninges of the brain is covered in a rich network of lymphatic vessels. And these lymphatic vessels are critical then for transporting things like cerebrospinal fluid, CSF, which basically bays the brain, keeps it buoyant allows it to absorb the interstitial fluid, the waste, if you will, from the brain. And these meningeal lymphatics are then connected to these regionally specialized lymph nodes in your neck called the deep cervical lymph nodes and that's where it's filtered and then out to the rest of the body. So as it turns out then, we have lots of lymphatics in the brain and they are critical for removing macromolecular particles and proteins and waste from the brain. As it turns out in animals, It has been documented that with age and with disease, but just with age, the set of lymphatics, which are most dense on the top of the brain in those meninges actually atrophy and stop functioning properly. And this has been associated with then, in animal models of disease, incredible buildups of proteolytic toxins in the brain like Abeta, alpha-synuclein, phosphate tau, things like that. And what's even more remarkable is our collaborators and others around the world have shown even in these elderly animals with the atrophied lymphatic system that if you can give back the right selection, growth factors, that aged and damaged diseased lymphatic system becomes functional once more, you get drainage of these toxic proteins. And where this has been measured, you regain cognitive function. So we believe that even though this is at a very early stage, when it comes to neuro degeneration, this may be one of the great keys to figuring out what we want to do with this in the future. So we're very, very excited about this, again, even though it's early. So again, I'm excited by what we've done in terms of putting together a number of potential therapeutics that address the lymphatic system, the BIG system, if you will. And by putting together and building our institutional knowledge and working with our collaborators, I'm very excited about the possibilities that we see going forward in the future. And you'll hear a number of stories today that I'm pretty sure will back me up. I would now like to introduce Dr. Stan Rockson, the Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford University Medical School, who will discuss his clinical perspectives on the lymphatics and the need for innovation in lymphatic disorders and beyond. Stan?

Thank you, Joe. And by way of personal introduction, let me say that I am Dr. Stan Rockson on the Allan and Tina Neill Professor of Lymphatic Research and Medicine at Stanford University. And in addition to serving as Chief of Consultative Cardiology, I'm the Director of the Stanford Center for Lymphatic and Venous Disorders. I have the pleasure today to speak to you a bit about lymphedema. And by way of introduction, let me start in a somewhat humorous vein, one that's not so humorous to patients, to acknowledge the fact that patients with lymphedema feel very underserved and underappreciated by the clinical community. They feel that they have very few answers for their problems, which they perceive to be extremely large in magnitude. So I think this talk is very apt and developments toward better treatments for lymphedema are very appropriate. A discussion of lymphedema has to start with the lymphatic circulation, which was first described by an Italian anatomist in the early part of the 17th century, Gaspare Aselli, recognized the lymphatic circulation in the mesentery of the intestine of a prosected dog. And over the next several hundred years, we've learned quite a lot about this circulation. We understand now that the lymphatics are an integral component of the cardiovascular system. With every passage of blood through the arterial to capillary to venous conduit, 1% of the circulating volume of fluid within the blood will be lost into the tissues and will require lymphatic participation in return to the central circulation. So it's clear that without lymphatics within 24 hours, the circulation would collapse entirely. This is the working in unit of the lymphatics. This is a lymphatic collecting vessel, a conduit that is divided into working segments called lymphangions that are delineated by the presence of valves on either end of the working unit. And through the auto-contractility of this vessel, this volume of fluid can be moved through the lymphatics back into the central circulation. Let's also acknowledge that in addition to the lymphatics forming an integral portion of the circulation, they also represent an integral portion of the immune system. So the ability of the body to undertake surveillance against pathogens and other toxins and noxious agents absolutely requires the participation of the lymphatics, which transports the message-containing cells to the lymph nodes where they can be interrogated and where, in turn, an immune response can be mounted. The lymphatic system is quite extensive. We can say that the lymphatics carry approximately 25 millimeters per second of fluid [indiscernible] a geography of 3,500 kilometers within the human body, and at any moment in time, the lymphatic circulation contains about 2 liters of body fluid. I also want to emphasize that the lymphatics participate in the natural history of a broad array and a growing list of human pathologies. I think it's fair to say that the lymphatics are integral to the maintenance of human health and that they participate very actively in the propagation and maintenance of human disease well beyond lymphedema. When we talk about lymphedema, we're basically talking about any part of the body that has a lymphatic circulation, which is literally now 100% of the body. But in general, in lymphedema, we are talking about the appendices of the body, the limbs, and by extension, the head and neck, and to a lesser degree, the trunk and genitalia. Lymphedema in broad terms can be defined into primary and secondary buckets. We think of secondary lymphedema conventionally as the manifestation of disease in a previously normal part of the lymphatic circulation that becomes damaged by the advent of cancer and cancer therapeutics and lesser -- to a lesser degree, at least in the developed countries in the world by trauma or by infection. Primary lymphedema is considered to be the subset of diseases in which there is a predetermined predisposition for the lymphatics to be either structurally or functionally abnormal. When we think about cancer, which is really the preponderance of the pathogenesis of secondary lymphedema in the United States and in the Western world, you can see listed the major cancers that are predisposing to the development of lymphedema through primarily the treatment of those cancers. I want to make the point that chronic lymphedema, while it starts as an edematous condition with the accumulation of interstitial fluid, we now understand very well that the presence of chronic edema leads to physical changes within the affected portions of the body. And you can see the list of those changes on the left-hand portion. We believe that it is the advent of all of these changes that, in turn, lead to the experience of lymphedema for the patient, which is quite profound. Although we can rely upon imaging modalities to confirm the diagnosis, the hallmark objective attribute of lymphedema is the presence of impaired lymphatic transit and the presence of dermal backflow or the back leakage of lymphatic fluids into the dermal spaces. We can document this in the gold standard imaging modality, which is radionuclide lymphoscintigraphy. It's important to say that radionuclide lymphoscintigraphy, which has been actively performed since the 1960s is a functional imaging technique. It does not show us the lymphatics well per se, but it shows us the attributes of their function. Increasingly, we can use magnetic resonance to actually see the lymphatic structures. And the latest addition to the imaging armamentarium, quite useful, particularly in surgical context is so-called near-infrared near-infrared fluorescent lymphangiography. This relies upon the subcutaneous injection of an auto-fluorescing compound that relies, in turn, on lymphatic transport. International Society of Lymphology has given us a staging format for analyzing patients and determining their particular disease stage. There are 4 stages defined from subclinical disease where there is imaging evidence of lymphatic dysfunction all the way to profound tissue change in Stage III. The progression through these stages has to do with the increasing presence of tissue damage based upon chronic edema presence within the tissues. So we start with this kind of presentation, which would be perhaps Stage I or early Stage II lymphedema where you see the profound ability to move the fluid within the tissue compartment through the application of external pressure. So we call this pitting edema and this would be the attribute of any form of chronic edema in the body, but also specifically can characterize the early stages of lymphedema. As lymphedema persists with time, we lose this pitting attribute here. The application of external pressure with an examining finger moves nothing. And this is because, with time, the tissue is thickened, there is cellular hypertrophy, there is accumulation of cross-linking proteoglycans within the interstitium that track the fluid in a gel-like phenomenon and eventually there is also the accumulation of fibrotic material within the dermis and the sub-dermis, all of which leads the pitting edema to no longer be present. The current clinical practice for lymphedema is largely based upon the use of physical measures to reduce what can be reduced in terms of the excess interstitial fluid volume and then to maintain that edema reduction to the best extent possible. The acute intervention is called complete decongestive physiotherapy. It involves a number of modalities designed to stimulate lymphatic contractility and to mobilize fluid. These include both specific lymphatic massage, the application of bandaging materials that stimulate the clearance of fluid from the tissues and exercise, which also indirectly stimulates lymphatic contractility. Ultimately, the goal is to attain a nadir of limb volume, which can then be maintained by the application of an elastic garment of some sort that will provide a semirigid structure to retard the redevelopment of interstitial edema. So here you see a typical arm sleeve. This can also be externally applied more rigid devices that attach with velcro attachments, but the purpose is to create a counter-pressure that will limit the accumulation of edema volume. At times, we cannot rely upon simple elevation in the bed to keep edema volume at bay and the patients actually have to wear nocturnal garments in addition to what they wear in the daytime. The concept is pretty straightforward. It is to detect as early as possible the presence of interstitial fluid edema based upon the lymphatic disruption, to use the aggressive approaches to arrest and reduce the accumulated volume and then to maintain the gains that are achieved in treatment and to treat complications as they arise. The concept is that the earlier one treats, the more one can arrest the progression toward the physical consequences of lymphedema. This is a theoretical construct that really has never been fully demonstrated to be true. But it is true that the earlier we intervene with these patients, the more we can stabilize edema volume and prevent complication such as infection, which commonly arises. We do feel that we can limit the clinical development of lymphedema. I want to say just a word about surgical options, which are increasingly being applied in lymphedema population. The most commonly applied is one for late-stage disease, which is to deal with that increase in adipose tissue thickness. The adipose material can be removed in an adaptive liposuction procedure done under general anesthesia. This is not a curative procedure, it does continue to require very aggressive use of compression. Increasingly, we also use microsurgical techniques to try to address the problem of lymphedema to try to restore some lymphatic function back toward normal or to remove the attributes of lymphatic dysfunction. I'd like to summarize by saying that the pathophysiology of lymphedema, as I've discussed it very briefly here, is very complicated. There are a number of factors involved and some of them are structural, some of them are functional. There are a lot of molecular aspects that we haven't touched on today. And there is work being done, I think, in all of these areas. But in summary, I would say that we still have historically lacked a very supremely efficacious intervention for a disease process that is very debilitating for those that suffer from it. The aspect of lymphedema of interest is determined by the scientists' or clinicians' point of view, of course. And just like the proverbial element -- sorry, proverbial elephant, what ones sees is dependent upon what one looks at or touches or investigates. In summary, no matter what part of lymphedema one engages with, it is a very important disease. It is a very common and debilitating and morbid condition. The natural history is one of continued progression, morbidity punctuating the natural history of the interaction with the patient, tremendous psychological losses, a loss of function, loss of presence in society and eventually tremendous use of hospital resources. So finding a good answer for lymphedema is going to be very high on my personal wish list as it should be yours as well. So thank you very much for your attention.

Thank you, Dr. Rockson. So we have a few questions now starting with, are you aware of other companies working on the lymphatic system?

I would say at the moment, there are some companies that are addressing aspects related to the surgical interventions to try to make those more efficacious. There is certainly a lot of interest in working on imaging to evaluate the lymphatic circulation, but I'm not aware of any companies that have a pipeline related to pharmacotherapy for lymphedema.

Great. And a follow-up to that. Are you aware of any other companies working on lymphatics outside of lymphedema, perhaps more broadly? Or perhaps academic research related to the lymphatic system in general?

I would say, academically, the lymphatics have become a source of tremendous interest across many disease disciplines. In fact, our major scientific conference, which will occur in the spring this year as a virtual conference, is very specifically devoted to looking at lymphatic manifestations in the natural history of disease by organ system. So of course, the skin is a very important source of concern. But increasingly, we have interest in the cardiovascular realm, autoimmune disease, inflammatory and immune manifestations in general, the central nervous system, the gastrointestinal tract, metabolic disorders, including obesity and diabetes. These are all areas in which I think there's active interest in utilizing the lymphatic arena in which to address disease either diagnostically or therapeutically.

Great. So our next question is, can you comment on some of the work that PureTech is doing in this space? What are your thoughts on deupirfenidone given its properties and its effect in the scale model?

Well, I think it's obviously a very, very interesting approach, not only because this is an anti-inflammatory molecule, and I believe I've shown that inflammation plays a very central role in the initiation and maintenance of lymphedema but also because fibrosis is increasingly an attribute of the latter stages of lymphedema. So the ability to interact with both of these very important structural attributes of the disease, if this proves to be an efficacious approach in the human clinical setting, is going to be a tremendous step forward because I think I've emphasized in this talk that it is really the structural progression within the disease tissues that represents the source of the morbidity for the patient. We can deal with interstitial fluid volume accumulation that's really dealing with what happens to that as lymphedema swim over time that becomes the central issue for the patient.

And our final question is, what do you hear from patients about the lack of treatment or even the lack of acknowledgment or awareness of lymphedema?

Well, it's very central to the patient community. I interact heavily with the patient community and have for the last 20 years. And honestly, they feel abandoned by their doctors. If they're lucky, they meet somebody who will even acknowledge the lymphedema as a clinical problem worthy of interaction. But most often, the clinician will say, I'm sorry, there's very little that we can do. There's very little we have to offer the patients really feel that this is a central issue in their lives and that the health care community is really not prepared to deal with it. Most of the patients that I deal with are cancer survivors. And I've heard innumerable times that the patient will say cancer is nothing compared to lymphedema. Lymphedema has taken over my life. So a successful treatment for lymphedema will be extraordinarily meaningful to this very, very large patient population.

Thank you, Dr. Rockson. Our next presenters will discuss the need for novel approaches to address fibrotic and inflammatory conditions, such as the therapeutic potential for LYT-100, our lead clinical stage fully owned product candidate. Our presenters include Dr. Michael Chen, Head of Innovation of PureTech and lead on the LYT-100 program and Dr. Toby Maher, Professor of Clinical Medicine and Director of Interstitial Lung Disease for the Keck School of Medicine of the University of Southern California. I will now hand it over to Michael, who will detail LYT-100 and its potential to treat a range of clinicians involving fibrosis, inflammation and impaired lymphatic flow.

Thank you, Allison. PureTech's discovery process for LYT-100 began with the foundational knowledge that the lymphatics are not a passive vessel for fluid, but a vibrant organ with an active and important role in regulating the immune system. With our interest in diseases of lymphatic flow, we worked with the leading experts in lymphedema, including Dr. [indiscernible] and Dr. Stanley Rockson, to leverage the knowledge that lymphedema is not just a disease of fluid accumulation, but also a disease of inflammation and fibrosis. We had access to unpublished data that show that an anti-inflammatory, anti-fibrotic approach may have the potential to treat lymphedema, which has no approved pharmacological therapies. We also have a unique connection and knowledge to clinical data that was generated in Auspex from Bharatt Chowrira and his team who helped build Auspex. This was to acquire and develop LYT-100, a deuterated form of pirfenidone from Teva. And we are developing LYT-100 for the potential treatment of inflammatory and fibrotic conditions. These include idiopathic pulmonary fibrosis, or IPF, where pirfenidone has sales of over $1 billion a year, but also has challenges, including a high rate of tolerability issues leading to dose reduction and discontinuation. We are planning to pursue registration-enabling studies of LYT-100 in IPF and have recently initiated proof-of-concept studies in lymphedema and Long COVID. Pirfenidone is an anti-inflammatory and anti-fibrotic agent that has been shown to slow the progression of interstitial lung diseases, including IPF. Multiple Phase III trials have demonstrated that pirfenidone compared to placebo reduces the decline in forced vital capacity, or FVC, in IPF. Pirfenidone also reduced FVC decline in unclassifiable progressive fibrosin interstitial lung diseases, or uILD, which has no approved therapies. Pirfenidone is approved for IPF and has breakthrough designation for uILDs, but has issues that impact disease management and efficacy. LYT-100 is designed to address these limitations at pirfenidone, including limited exposure and core tolerability leading to dose reductions and discontinuations that limit the efficacy of pirfenidone. Pirfenidone also has a high tolerability because of its limitations in pharmacokinetics, necessitating 3 large pills 3x a day. LYT-100, or deupirfenidone, benefits from the kinetic isotope effect of deuteration. This deuteration stabilizes the parent molecule and metabolism, but does not change dependent pharmacology and its multimodal mechanism of action. The result is enhanced exposure and the potential for greater activity, less treatment dosing and potentially improved tolerability. LYT-100 also has the potential to address the dose-limited efficacy of pirfenidone, and LYT-100 is a new chemical entity with composition of matter patents through 2033. Because deuteration does not change the underlying pharmacology, LYT-100 benefits from the proven efficacy of pirfenidone. LYT-100 is expected to have activity in indications where pirfenidone has been validated clinically, including IPF, uILD and multiple other inflammatory and fibrotic diseases with proof-of-concept studies conducted by investigators. The pharmacokinetic advantages of LYT-100 were first demonstrated in a Phase I single-dose crossover study conducted by Auspex. In this study, 24 healthy volunteers were given the approved single dose of pirfenidone, 801 milligrams or the same dose of LYT-100, 801 milligrams. At the same dose as pirfenidone, LYT-100 has an increase in Cmax of 25% and an increase in AUC or exposure of 35%. The data from this study show that LYT-100 had greater exposure at the same dose compared to pirfenidone and could have the potential for increased potency and activity. And interestingly, despite this increase in exposure, LYT-100 was well tolerated. We next studied LYT-100 in a multiple ascending dose and food effect study. LYT-100 is well tolerated at a dose up to 1,000 milligrams twice a day or BID. There were no serious or severe adverse events, all drug-related adverse events were mild to transient. And even at the highest dose at 1,000 milligrams BID, no maximal tolerated dose was reached. In fact, the only drug-related adverse events were 2 headaches. This study also had no titration, whereas pirfenidone is typically slowly titrated over 2 weeks. Based on this study and our model, we believe that LYT-100 can be administered twice a day and achieve a similar systemic exposure to that of pirfenidone. In the food effect study of LYT-100, we gave a single dose of 500 milligrams of LYT-100 fasted or fed. Pirfenidone has an increase in pharmacokinetic parameters like Cmax if taken faster or without food and a decrease is taken with food. This increase in Cmax, in particular, is thought to contribute to the gastrointestinal adverse events of pirfenidone and the recommended administration of pirfenidone is with food. LYT-100 show a reduction in Cmax with food versus the fast group of only 23%, whereas pirfenidone's reduction with food versus fasted is nearly 50%. LYT-100's change in exposure with food was similar in magnitude to dependent lungs change. The fact that LYT-100 has a less substantial increase in Cmax, if taken without food, combined with the tolerability profile observed in the math suggest that LYT-100 could potentially be taken without regard to food. To summarize, we have seen in Phase I studies, a drug that has the pharmacology and expected efficacy of pirfenidone, combined with a superior pharmacokinetic profile. LYT-100 has the potential to address a range of inflammatory and fibrotic conditions. These include IPF and uILD, where pirfenidone is efficacious, but limited by its pharmacokinetic shortcomings. Proof-of-concept of pirfenidone in interstitial lung diseases also suggests potency in other long fibrosis and inflammatory conditions such as Long COVID respiratory complications. We are developing LYT-100 for secondary lymphedema, a major unmet need with no approved drug therapies. Other lymphatic flow disorders include primary lymphedema, which can happen in childhood. Pirfenidone has already demonstrated proof-of-concept in investigator-sponsor studies beyond these areas, including diseases like FSGS or radiation-induced fibrosis. We are actively evaluating these conditions as additional areas where LYT-100's unique profile can address outstanding profile needs. Interstitial lung diseases are a growing unmet need. The IPF patient population continues to grow around the world from over 120,000 today. Pirfenidone and lymphagion slow lung function decline, but neither is well tolerated with gastrointestinal adverse events, and dose-limiting toxicities, dose reductions and discontinuations. Yet, these 2 drugs have been extremely successful in IPF alone and both have more than $1 billion in sales. We believe that there is a major opportunity to take a drug with a proven pharmacology of pirfenidone in LYT-100 and address the limitations of the current standard of care. Together, broad external input on this approach, we conducted a survey of 100 pulmonologists through an external market research firm. We were interested in understanding how physicians would perceive the value proposition of LYT-100 and that how they would anticipate prescribing it if you were on the market. The third-party market research firm tested 2 profiles. Profile X that describe the product with safety and tolerability benefits of the standard of care and profile Y that studied product with efficacy benefits in addition to improved safety and tolerability. From this market research, we learned that there is potential high interest in LYT-100 with physicians on average, indicating that they would prescribe LYT-100 in approximately 30% of new IPF patients, if it were more tolerable; and to 45% of new IPF patients if it were both more tolerable and efficacious. Late-stage IPF agents in development today are being studied in combination with standard of care. If LYT-100 has the potential to supply this standard of care, it also has the potential to be used alongside features combinations. We are planning to conduct additional market research to further probe the market potential of LYT-100 in IPF and beyond. Beyond that, yes, there are 200 or more interstitial lung diseases that impact 0.25 million patients in the U.S. alone. Within these interstitial lung diseases, patients can develop progressive fibrosing ILDs, in which there is a progressive deterioration of lung function and quality of life with an increase in early mortality. This can happen in IPF and autoimmune interstitial lung diseases or even in ILDs related to environmental exposure, like [indiscernible]. Up to 32% of non-IPF interstitial lung diseases may result in progressive pulmonary fibrosis. And there is a major unmet need for a therapy that can slow the progression and preserve lung function while having a superior tolerability profile compared to current antifibrotics. COVID-19 has infected tens of millions around the world, and like other viral pneumonias, causes respiratory complications. Even with a vaccine, there is an immense and urgent public help need to address Long COVID. And surprisingly, there are almost no treatment options being developed that focus on addressing these post-acute sequelae of COVID-19 including respiratory complications. The outcome of COVID-19 is not binary, and surviving COVID-19 is not the end of the story. There is increasing evidence of complications in survivors that persist after the acute infection has resolved. These post-acute sequelae are being collectively referred to as Long COVID or long-haul COVID. And there is a shadow pandemic of these Long COVID complications that may contribute to the enormous health, social and economic cost of the pandemic. We know that Long COVID is a complex pathophysiology that can involve tissue damage, residual inflammation and fibrosis in lung. These mechanisms can lead to lasting respiratory complications. Follow-up studies of patients from the first wave of COVID-19 have revealed a pattern of persistent respiratory symptoms in a study of 143 survivors from Italy, over 40% had dyspnea or shortness of breath months after their initial symptoms. Many reported chest pain or cough as well. Notably, this is a relatively non-severe patient population. Patients with more severe clinical cases and more respiratory interventions like ventilation are expected to have more post-acute respiratory complications. 1/3 of previous viral pandemic SARS and MERS patients have lung fibrosis, and these complications from SARS, in particular, lasted for years or even a decade or more. We believe LYT-100 is ideally suited to address this aspect of Long COVID based on its multimodal mechanism of action. It has a pharmacology that has been proven in interstitial lung diseases where pirfenidone can inhibit fibrosis. LYT-100 reduces profanatory cytokines, including IL-6 and TNF alpha that are part of the hyper inflammatory response to the virus. LYT-100 is also antifibrotic and suppresses TGF-beta downstream signaling and scar tissue components like collagen. We've initiated a global randomized, placebo-controlled trial this quarter in Long COVID respiratory complications and related sequelae. The trial is expected to have top line results available in the second half of next year. Beyond the current pandemic, the mechanisms of Long COVID are not unique to COVID. Inflammation and fibrosis are common in other viral pneumonias. And we have a unique situation to enroll a clinical trial to demonstrate the potential efficacy of LYT-100 in post viral pneumonia respiratory complications and related sequelae. These lymphatics had multiple important roles, as you heard from my colleague, Joe Bolen. One of the most important is draining and pumping lymph fluid from tissue. For example, on the left, you can see a tracer dye being pumped up to lymphatic channels in the arm. But when there is injury to the lymphatics, for example, from surgery or radiation, this can block the fluid flow and kick off a vicious feedback loop of inflammation and fibrosis that can lead to swelling or lymphedema. On the right, you can see the same type of dye injection is on the left, but in a lymphedematous arm. The lymphatics can no longer pump the fluid out, which simply spills out into the arm tissue, leading to more swelling and more inflammation and more fibrosis. Lymphedema is not just an injury to the lymphatics. It's not just a mechanical deficit in fluid pumping. It's an active process involving inflammation in fibrosis. Immune cells begin infiltrating into the tissue. They began releasing pro-inflammatory and pro-fibrotic cytokines like PDF data, and this can produce scarring or fibrosis of the arm tissue and of the lymphatics themselves. Beyond impairing lymphatic flow, this can also inhibit the natural regeneration of the lymphatics. So the treatment for lymphedema cannot just be mechanical, like the current treatments are today on compression pumps physical therapy. A treatment for lymphedema ideally would address inflammation and fibrosis to help the feedback loop and allow the lymphatics to regenerate. We believe LYT-100 is ideally suited to address lymphedema because it has both anti-inflammatory and anti-fibrotic properties. For example, on the left in an LPS model, LYT-100 can reduce proclamatory cytokines like TNF alpha, that are involved in this tissue immune response in lymphedema. On the right, we can see the anti-fibrotic effect of LYT-100 in the fibroblast model in reducing TDF dependence, increase in collagen, which, of course, is a component of the extracellular matrix or scar tissue. LYT-100 reduces the levels of collagen by 36% in TGF-beta-dependent increase also reduces the background level of soluble collagen by 23%. So in summary, LYT-100 is a totally anti-inflammatory and anti-fibrotic, and it targets the exact mechanisms of the feedback loop that contribute to lymphedema. We next test at LYT-100 in a preclinical model of lymphedema, the mouse tail model. This recapitulates all the features of lymphedema, but in a tail rather than in a rim. It has swelling, it has inflammation and it has fibrosis. We gave LYT-100 orally once-a-day, starting at 2 weeks when swelling begins to increase in the stomach. In the control group in gray, they get the surgery for lymphedema, but not drug, the tail increases in size and nearly doubles by week 4 and remains swollen in weeks later. In contrast in the LYT-100 group, the tail volume stops increasing by 2 weeks of treatment. And by 4 weeks of treatment, the tail volume is significantly reduced compared to control back to close to the baseline. We've now initiated a Phase IIa proof-of-concept study in breast cancer-related lymphedema to inform potential subsequent efficacy trials. The study is a randomized, double-blind, placebo-controlled study of LYT-100 in mild-to-moderate breast cancer-related lymphedema, with the dose informed by the human equivalent dose of the 1 week tested in the mouse tail model. The primary endpoint is safety and tolerability. And we will collect secondary endpoints to support selection of a primary endpoint and powering for any subsequent efficacy studies. These include limb volume, bioimpedance spectroscopy, trigonometry which measures fibrosis; tissue dielectric constant, which measures local edema, and we'll be also collecting patient-afforded outcomes, biomarkers and pharmacokinetics. To summarize, LYT-100 has completed multiple Phase I studies, including a single-dose crossover study, a multiple ascending dose and food effect study and nonclinical studies supporting the comparability to pirfenidone in pharmacology with the improved enhancements in pharmacokinetics and drug profile. We are advancing LYT-100 in IPF where the efficacy profile for pirfenidone has been demonstrated in multiple late-stage and real-world efficacy studies in IPF, including over a dozen single center studies. The next step for our IPF program is a registration-enabling study. We will guide on the time lines for IPF soon. We've also initiated a Phase II study for Long COVID respiratory complications and related sequelae as well as a Phase IIa proof-of-concept study in lymphedema, and we're also actively exploring a range of other conditions for the development. It's my pleasure to now introduce Dr. Toby Maher, Professor of Clinical Medicine, Director of Interstitial Lung Disease at Keck School of Medicine, at the University of Southern California, who will provide a pulmonology perspective on interstitial lung diseases, including IPF and Long COVID.

Thanks, Michael. So I'm Toby Maher. I'm Professor of Medicine and Director of Institutional Lung Disease at Keck School of Medicine, University of Southern California and Los Angeles. So it's a pleasure to be able to talk to you today about both idiopathic pulmonary fibrosis and fibrosis in the context of COVID-19 infection. I'll start by introducing idiopathic pulmonary fibrosis. So IPF is a condition characterized by progressive, irreversible scarring of the lungs. It tends to arise for reasons that are not entirely clear in older individuals who tend to be in their mid-60s onwards. It's a very rare disease to diagnose in anyone under 40. And these individuals often have a family history. So we know that there is genetic susceptibility. And in actual fact, we increasingly understand the genetics of the disease, which is to say that we recognize maybe 14 or 15 different gene polymorphisms that increase risk of developing disease. And interestingly, all of these polymorphisms are related to the lung response to injury and/or aging. So we see abnormalities in telomere complex genes that also predispose the development of fibrosis. In addition, from the epidemiology of the disease, we recognize that individuals who develop the condition are more likely to have suffered various forms of injury to the lung over their lifetime. And by injuries, I mean inhalation of dust or smoke, such as cigarette smoke. And even before COVID, we recognize the role for viruses in increasing susceptibility to the development of idiopathic pulmonary fibrosis. So IPF, when it develops, is characterized by progressive breathlessness. So patients early in the disease will only recognize breathlessness when they exert themselves heavily. But as the condition gets worse, patients will inevitably develop respiratory failure at rest. So usually, in the last year of life, they will become oxygen dependent. And the condition ultimately tends to kill the majority of sufferers through respiratory failure within 3 or 4 years from diagnosis. Importantly, over the last decade, we've seen improvements in how we diagnose the condition. There has been the publication of international guidelines, which have greatly improved the precision with which we diagnose idiopathic pulmonary fibrosis. We've also seen the advent of effective anti-fibrotic drugs. We've seen the development of both nintedanib and pirfenidone as anti-fibrotic drugs. And both of those were approved in the U.S. in late 2014. The clinical trials were done looking at disease progression as an endpoint measuring change in forced vital capacity over time. And both drugs were able to slow the rate at which the disease deteriorated compared with placebo. Importantly, as we're now seeing real-world data emerge, we are seeing that slowing disease decline does have an important effect on improving survival. So median survival has probably improved from 3 to 4 years, up to now 5 or 6 years. That said, we still recognize that IPF is shortening life expectancy for our patients with this disease. So there remains a huge unmet need for better treatments. And furthermore, both nintedanib and pirfenidone, as it stands, have significant issues with tolerability, which mean that about 1/3 of patients end up discontinuing therapy within a year of starting on it. So we definitely need improved therapies going forward. Now obviously, in the last 9 months, we have seen the onset of a worldwide pandemic of coronavirus which has made us reflect on and think about lung injury and fibrosis in different ways. And perhaps we should look back over the last 10 or 15 years and reflect perhaps on what we've learned from previous coronavirus pandemic. So COVID-19 is really the third coronavirus outbreak to have flicked us in the last 20 years. We saw the earlier outbreaks that first the SARS virus and then later the MERS virus. Although in contrast to COVID-19, these outbreaks were much more tightly controlled and did not develop into global pandemics. Nonetheless, enough patients were infected with these viruses for us to understand that there were important long-term sequela of infection. It seems that in susceptible individuals, severe coronavirus infection leads to acute lung injury. That's something that we see in many other settings. We can see it in the intensive care setting, patients often on mechanical ventilation, will develop acute lung injury. We can see it after massive trauma or surgery. And in actual fact, we see it in idiopathic pulmonary fibrosis in the context of acute exacerbations, where patients can develop widespread acute lung injury. This acute lung injury is characterized by damage and cell death of the alveola epithelium. So the cells lining the alveola spaces. It means that blood and tissue fluid can leak into the alveola space and it causes major impairment of gas exchange. And we recognize that there is a response following acute lung injury, whereby the lung heals itself, and goes through a normal wound healing process. And yet in susceptible individuals, that wound healing can lead to the development of fibrosis and scar issue development. And that's not just true of viral-induced acute lung injury, it is true of all forms. But what has been unique to the coronavirus outbreaks is that they cause a very high level of acute lung injury to sufferers. And so with MERS and SARS, we saw significant proportions of patients hospitalized with acute lung injury. Those patients spent time on the intensive care units, being ventilated. And post recovery, we recognize that a significant proportion of survivors were left with fibrosis. And as far as our understanding of this fibrosis goes, the mechanisms that drive it seem to be very similar to the mechanisms that drive the development of idiopathic pulmonary fibrosis, which is to say that we see aberrant activation of wound healing pathways, resulting in an imbalance of growth factors that favors the laying down of collagen and extracellular matrix that then leads to the scarring and destruction of the lung. And in MERS and SARS, upwards of 30% of patients were left with fibrotic lung injury. And although in many cases, this stabilized or even got slightly better, patients were left with significant long-term morbidity and mortality. Now clearly, we're only 9 months into the current COVID-19 pandemic. And so there is still a lot that we have to learn about the illness. Clearly, in the first wave of infections in the early part of this year, back in March and April, we saw a huge amount of acute lung injury, and we saw intensive care units around the world being overrun with patients with severe lung involvement. As some of those patients have survived to discharge and follow-up, we have increasingly recognized that a proportion of them are being left with residual fibrosis affecting the lung. And on this slide, you can just see an example of a patient in the top panel with normal structural lung appearances who has some subtle ground glass change that is signified by the arrow, and that's the early acute lung injury of COVID. And then if you go down to the bottom panel on the slide, you can see that post discharge from hospital, that patient has been left with fibrotic destruction of the lung. And you can see the way that the lung architecture has been changed by that fibrosis. And importantly, we're recognizing that within the lungs of patients with COVID and acute lung injury, we're seeing this activation of growth factors and cytokines that favor the development of fibrosis. For instance, interleukin 6 and TNF alpha, all of which are potent pro-fibrotic cytokines that favor the development of fibrosis. There's also a suggestion certainly from the preclinical literature that in the absence of acute lung injury in susceptible individuals, the activation of these cytokines and growth factors may in themselves be enough to trigger the development of progressive fibrosis. And it may be that acute infection with coronavirus such as COVID-19 may be enough for susceptible older individuals to now develop fibrosis itself. So it may be that we are ultimately seeing 2 mechanisms: one, being post-acute lung injury fibrosis, the second being the development de novo of a progressive fibrotic disorder indistinguishable from idiopathic pulmonary fibrosis. And as we understand more about COVID-19, we're beginning to try and tease out both the mechanisms by which this may occur, but also importantly, the epidemiology of this so that we can better look to understand and protect our patients going forward. So I think just to try and sort of summarize what I've said and then bring it back to what we might want to do for these patients. We increasingly understood the development of pulmonary fibrosis in the context of IPF as a sort of model disorder for fibrosis. We recognize the factors that make individuals susceptible, older age, past exposure to things that cause lung injury. And importantly, genetics and the presence of susceptible polymorphisms. And perhaps what I didn't say earlier is that up to 1/3 of the population will carry at least one of these susceptibility polymorphisms. We then recognizing COVID that with viral infection, we are seeing a number of these triggers occurring in a population of patients who share risk factors that overlap for the development of progressive fibrosis. And importantly, as we are seeing survivors of COVID come through into our clinics, we are genuinely seeing patients being left with fibrosis, that was not present prior to the development of their COVID infection. And so increasingly, we're having to look to ways to prevent this long-term morbidity associated with the disorder. And in the U.K., certainly, that this phenomenon has been given the nomenclature of Long COVID, which is to say the long-term sequela of the acute infection of COVID-19. And clearly thinking about how we might prevent such lung injury, of course, preventing viral infection and viral injury to the lung will be key. But once we're confronted with a patient who has been hospitalized with acute lung injury due to COVID, at the moment, we have no way of preventing those long-term sequelae. At the moment, we're very much focused on improving survival to discharge. But I think increasingly, as we see the long-term consequences of COVID, we're increasingly being made to think when we're dealing with acute cases, how it is that we can prevent long-term respiratory disability in this same patient group. And so having treatments that might prevent fibrotic lung sequela of COVID-19 are going to be incredibly important. And so the research program that you're hearing about today is going to be vital to help us in this battle to prevent a huge pandemic of pulmonary fibrosis following on from the already severe pandemic at COVID-19 itself. So thank you very much, and I think we get to open it up to questions.

Thank you, Dr. Maher. We have a few questions here, starting with, can you give us a sense of the data that support the severity and prevalence of Long COVID? And what are you hearing from patients directly?

So of course, the challenge is that we're in a rapidly evolving situation. We've gone from knowing nothing about the sequela of coronavirus infection 9 months ago to now desperately kind of learn as the situation evolves. There are a number of longitudinal studies in the United Kingdom. There has been a government-funded study to try and collect several thousand patients post-COVID discharge to understand the long-term sequela. There's also been research done with apps to try and record symptoms of patients who survived COVID infection. And certainly, what the early data tells us is that there is a large burden of symptoms in those patients who had COVID infection and those symptoms include breathlessness, cough, fatigue and exercise limitation. We're still at a point where we don't know the epidemiology of post-COVID fibrosis. But certainly, myself and all the pulmonologists I work with are beginning to see patients coming through into our clinic who do have evidence of lung damage and fibrosis as a consequence of COVID. But at the moment, it's very difficult to put precise numbers on that.

Great. Our next question is who else is working on treatments for Long COVID? What other therapeutics are being developed to address this public health crisis that is emerging?

So truth be told, I'm not aware of anyone else that's trying to develop therapies at this stage for Long COVID. I think a lot of the focus has been on the acute management of patients presenting with respiratory failure. So either the use of antiviral drugs at the point where the patient has active viral infection or, for instance, the use of drugs such as tocilizumab or dexamethasone to try and alleviate the inflammatory component of the acute lung injury. But I'm unaware of anyone else who has been looking at the sort of post-discharge or post-acute phase patients and focusing on trying to reduce long-term sequela of that COVID infection and reduce the impact of Long COVID.

Great. Our next question is shifting more towards LYT-100. Having seen the multiple ascending dose study data for PureTech's LYT-100, how would you imagine that could affect the potential use of deupirfenidone in IPFs?

So I think having seen the data, it's very encouraging. And the drug has a very good PK profile. It potentially allows a much more simplified dosing regimen than pirfenidone as currently used, which is administered 3x a day. And one would hope that the favorable PK profile and the sort of the outcome of the Phase I study, which seemed to show a markedly lower burden of gastrointestinal side effects will translate into better tolerability in patients with idiopathic pulmonary fibrosis. And so I think that combination of simplified dosing regimen and better tolerance would make a huge difference for patients. With idiopathic pulmonary fibrosis, we're essentially looking at lifelong treatment following diagnosis. And therefore, even mild side effects associated with the drug, low-grade nausea or sense of bloating after every meal can be difficult to tolerate when patients know that this is their long-term future. And so having a drug with a much cleaner profile would make treatment of patients much easier, would make adherence much better. And I think would make a real difference for both clinicians and patients managing this disorder.

Great. And our final question is, can you speak to the importance of initiating an anti-inflammatory anti-fibrotic treatment before fibrosis settles in?

Yes. So I think what is different about COVID-19 and idiopathic pulmonary fibrosis is that with COVID, we have a clear initiating event that's causing fibrosis. And in actual fact, that's much more similar to what we look at in preclinical drug development with animal models. So the bleomycin model, for instance, involves a widespread inflammatory injury to the lung that leads on to fibrosis. And in many ways, that's akin to what we see in COVID in patients with acute lung injury. And so intuitively, and we know this from animal models that if you can block the inflammatory phase and the fibrotic phase, then you're going to have a much greater impact on the subsequent development of fibrosis. And so it may well be that pirfenidone in the setting of a disorder such as COVID, where you have a clear initiating event that drives sort of inflammatory injury that then, in turn, becomes fibrosis, may well be beneficial but treating both components of the disorder, the inflammatory insults and the fibrotic response would be better than treating either one component alone. So at least from a sort of preclinical perspective, the mechanism of action is very favorable.

Wonderful. Thank you so much for your time, Dr. Maher. We will now focus on the immuno-oncology landscape and hear perspective from Dr. Sid Mukherjee, Clinician and Researcher at Columbia University and Pulitzer Prize-winning author of The Emperor of all Maladies and The Gene and Dr. Zev Wainberg, Co-Director of the UCLA GI Oncology Program. Additionally, Dr. Aleksandra Filipovic, Head of Oncology at PureTech and Practicing Clinician at Imperial College NHS Trust, will share details around LYT-200, a clinical-stage product candidate from a favorably announced pipeline. But first, I'd like to hand it over to Dr. Eric Elenko, Chief Innovation Officer of PureTech; and Co-Inventor of a number of PureTech programs, including Karuna KarXT and Gelesis Plenity. Eric will discuss the scientific connection between our fully owned product candidates, LYT-100 and LYT-200.

Thank you, Allison. As mentioned, my name is Eric Elenko, and I'm the Chief Innovation Officer at PureTech. Our presenters today discuss the critical roles that the lymphatic system plays, including maintaining fluid balance and highlighting some of the approaches we are advancing for administer therapeutics through the lymphatic system and to improve lymphatic flow related to the meningeal lymphatics. We also discussed how LYT-100 has the potential to treat lymphedema which is a major disease associated with lymphatic fluid imbalance. The disease is caused by inflammation and fibrosis, which also manifests themselves in a number of other conditions, such as respiratory sequela of Long COVID and idiopathic pulmonary fibrosis, all conditions where we believe LYT-100 has important potential. The lymphatic system is also recognized as a super highway through which immune cells circulate between tissues and lymph nodes, with lymph nodes acting as sites for tissue selective programming of those immune cells. Our next set of speakers will be discussing immunomodulation in the context of oncology treatments, including our immuno-oncology-related candidate, LYT-200. LYT-200 is a monoclonal antibody, designed to block galectin-9, which simultaneously activates a number of immunosuppressive pathways within the same tumor microenvironment. I would like to now introduce Dr. Sid Mukherjee and Dr. Zev Wainberg, who will share their perspectives on the field of immuno-oncology [Audio Gap] Sid, checkpoint inhibitors isn't where the story started, obviously, but they seem to have taken over as the most dominant force in immuno-oncology, as you know. But certainly, you've studied this and recognized this for a while that the importance of the immune system is -- goes beyond just checkpoint inhibitors.

That's right. So we knew this -- I mean, I'm -- I do bone marrow transplants and have worked with the bone marrow system for a while. And we knew, from the '70 is actually we knew that the immune system could control cancer or kill cancer cells. [Audio Gap] People who had bone marrow transplants and, for instance, raised in the immune response against that cancer. This was called the graft versus tumor effect. What the last 3 decades have shown us is that there's, broadly speaking, 2 kinds of things that cancers do that allow them to escape the immune response. One kind of thing that cancers do is that they somehow shield themselves from being attacked by the immune response, particularly by T cells and by the innate immune system like macrophages and monocytes. So in other words, they create their own shields. The second thing that they do is it's something that the body does, which is that the T cells themselves become paralyzed or become unable to recognize the cancer cells. And these are interrelated. They're not separate, but there are 2 separate -- there are 2, I would say, wings, as it were, by which cancers can escape the immune response. One, the cancer center itself becoming invisible; and second, the cancer cell somehow rendering the T cell unable to do its normal job to eliminate a foreign substance in which -- in this case, the cancer cell. And one of the things that's been really exciting is to watch which cancers are responsive and which cancers are not responsive when you start removing these 2 shields as it were from cancers armamentarium. And what we now know is that some cancers of -- some lung cancers become now responsive to immunological therapy. Your body's own immune system begins to eliminate them. Melanoma is another one that's very [Audio Gap] immunological therapy. And there are several others. And I used to tell my students, I will never, in my lifetime, think that I would see a therapy that works for smoking-related lung cancer. But here you have a situation where during my own lifetime, I've seen patients reach long-term remissions, 5 years of survival, 7 years of survival because of the use of these new immuno-oncology agents.

Yes. And I think the recognition of which subtypes to treat has grown dramatically. So we know that lung cancers, not all lung cancers respond, to these checkpoint inhibitors. But now we understand a little bit more detailed nuance of which lung cancers do and which don't. And that trend seems to apply across all cancers. But certainly, this explosion of drugs over the last 10 years in checkpoint inhibitors has been tested beyond just the simple PD-1, PD-L1 and CTLA-4 inhibitors and have gone and tried to approach different targets. And that's where our field is exploding. We see that there's a increased biotechnology companies every year developing new and exciting targets with which to either harness the immune system more effectively. Or themselves represent new targets and whether it's bispecific antibodies or whether it's antibodies directly or other cellular therapies, it's really grown so dramatically. And it's been remarkable to watch over just a 3 to 4-year period. But one of the challenges it is that in some ways, there has been such an explosion of PD-L1 and PD-1 inhibitors and CTLA-4 inhibitors that the field is supersaturated with these drugs and that there almost isn't any cancer where these drugs have not been tested pretty robustly. I wonder if you could comment on just how supersaturated the field has become with these, let's call them, first generation immunotherapy drugs?

Well, I think the field has become not just 2% a little bit oversaturated with the first generation growth. The main problem with these drugs, as I see it, is that we still don't have a reliable way to tell which cancers are responsive or which cancers are not responsive. And I don't mean which cancers as in lung cancer versus prostate cancer versus breast cancer. I mean which individual lung cancer is responsive to the first generation immunotherapy is your lung cancer, if you're a patient of mine, is your lung cancer likely to respond or not likely to respond? Is your colon cancer likely to respond and not likely respond? I think the most -- the toughest job here now is, I think they're 2 really hard jobs, or actually I should say 3 pretty hard jobs. Number one is to -- is exactly what I just said, is to define the individual cancers that are likely to respond to immunological therapy -- immune therapies of any kind. And we've made some progress in that. We now know that the formation. I think the most powerful set of evidence would suggest that if the immune system is able to create so-called secondary lymphoid organs. So secondary sites of inflammation within the tumor [Audio Gap] we don't know upfront whether how to find those tumors. So that's one challenge. How do you find upfront which tumors are likely to respond and which tumors are not likely to respond. The second challenge is it is clear that the 2 shields that I talked about, the shield of the cancer cell and the shield that blocks the immune response has multiple components. It's not just PD-1, PD-L1 or CTLA-4. There are multiple layers and layers, which cancer cells use and to, as I said, hide themselves as well as an activate immune system. So one of the most exciting things, I think, in immuno-oncology is figuring out what these other layers are, these secondary layers, these third layers, these fourth layers and fifth players and so forth. And finally, the third aspect of this is to figure out what is the immune system actually attacking? What is it about the cancer cell that the immune system is recognizing as foreign and not recognizing as foreign within your normal milieu? Because that will allow us to drive the stake into the heart of the cancer cell more acutely. We know some of them. We know there's some antigens that are particularly good at exciting an immune response or inciting an immune response, but we really don't know exactly what those antigens are and how many they are and how they are in one cancer cell versus another cell. So going down to the so-called single cell level and finding out how you can -- taking a single cancer cell analyzing it and finding out how you can answer these 3 questions. Again, which cancers are responsive and why? Number two, what are the other layers of shields that cancer is applied to the immune system? And number three, what is it that [Audio Gap] in the cancer cell? I think those are really the central questions that are driving the field right now.

Yes. I completely agree. I mean the really amazing thing for me to watch as a medical oncologist who treats primarily gastrointestinal cancers is the fact that we have, at least in my field, many GI cancer is the large majority of these immunotherapy approaches, at least in the classical sense, of which we've been speaking, don't seem to work very effectively. We're -- I deal with cancers like colorectal cancer, pancreas cancer and outside of very rare subsets, as you know, the microsatellite and stable subset, for example, there is really no great efficacy with these drugs. And they've been tested in thousands of patients. And sometimes, you don't see that in the publications, but you know it's true. For those of us who have been at these meetings, these drugs just don't work in this group. And that's been fascinating to watch because what is it about the GI system, for example, that prevents adequate penetration of effective T cell response into these tumors? And how to nuance that, I think, is a big deal and certainly in a large majority of cancers? I think in GI cancers, for example, we now are recognizing that it's novel targets. And maybe the novel targets can be targeted directly with antibodies. And maybe these novel targets that are expressed in GI cancer cells can be partnered with existing immunotherapy approaches to better reduce cancer growth in those cancers. So it's a lot of work to figure out, as you know. Because in some ways, there's a lot of patients, and we only have a limited amount of bandwidth to sort through all the great drugs and targets that are out there.

And we've been lucky, I mean, this slide just shows that there are multiple pathways and then moving -- and one of the things that we're doing is moving on to that sort of the so-called next generation, moving on from the old guard to the next generation. Our lab has been lucky to partner with PureTech in developing a really completely novel targets, in particular around leukemias and lymphomas and also myeloma, blood cancers that are very deadly. And moving on to that, even breast cancers. So we've been lucky in being able to collaborate with, I would say, an ecosystem that PureTech has set up with multiple partners who worked for decades on the immune system as immunologists. And coming to this field as a cancer biologist and being able to collaborate or to understand how immunologists think and how immunologists work, how lymphoid biologists work? How does a lymphatic system look like? What is the anatomy of it? What cells comprise it? All of this was very poorly understood about a decade ago. But I think we've been very, very lucky just to collaborate with PureTech. We've started a couple of companies with PureTech's Health. And what that's done is really create a kind of, what I would call, really an ecosystem of people who sort of think because each of us brings our own unique insights into this, me as a leukemia biologist or a cancer biologist, but someone else as a lymphoid biologist or an immunologist and putting 2 plus 2 in this case equals more than 4, and that's been one of the very fortunate things about our collaboration with PureTech.

Yes. And I'm excited to work on developing these new targeted immunotherapy combinations with PureTech because one of the things, and at least as I mentioned in my space is the GI space is a very immunosuppressive environment usually. So the classical approach is just aren't going to work here, and we've already tested them at nauseam. But some of these targets on this list have even been tested already fairly extensively and in GI track malignancies, whether it's OX40 or GITR or other checkpoints, and some are waiting to be tested. But I think the impetus in the -- has to be a novel target development on some level, not just approaching the ones that have been tested already. And I think in that regard, PureTech has an interesting and compelling scientific rationale to test some of their novel target drugs in these GI tract cancers, in particular. And we're excited to help in that development process. So now, we'll take this opportunity to hear from someone at PureTech directly about their novel approaches and novel targets. And Alex Filipovic will present to us a lot of information about their new approach to targeting [ galectin-9. ]

As mentioned, my name is Alex Filipovic. I'm Head of Oncology at PureTech, and I will be describing novel therapeutic target galectin-9, which we believe holds great promise in the space of immuno-oncology. And at PureTech, we have developed a monoclonal antibody targeting galectin-9, which we are now advancing into clinic. The reason why we're excited about galectin-9 in cancer is because galectin-9 plays a fundamental role as an immunosuppressor, which orchestrates and sustains immunosuppression in cancer to various different pathways. Galectin-9 is expressed on tumor cells. It is also secreted by tumor cells into the blood of cancer patients. And it interacts on the cell surface of tumor cell and immune cells with various different binding partners. And in doing so, it protects cancer from being killed by immune cells, and it also propagates and expand immunosuppressive immune cells and switches those that are not immunosuppressive to become immunosuppressive. For that reason, using LYT-200 as a selective and specific inhibitor of galectin-9 actually stand the chance to be a very potent therapeutic in the space of immuno-oncology. And we have developed LYT-200 as a fully human IgG4 monoclonal antibody which we believe holds potential to have both single-agent efficacy and to combine very well with other anticancer therapies such as checkpoint inhibitors and chemotherapy. Galectin-9, as a target in cancer, has now been studied across independent laboratories and multiple data have been published in the recent years confirming that galectin-9 is very important across various different cancer types. Here, we see a dozen cancer indications where high fresh galectin-9 is linked to worst patient outcome towards survival as well as to immunosuppressive features of the tumors themselves. And we know that checkpoint inhibitors have now been approved across these various different indications. However, as we've heard from Dr. Weinberg earlier, checkpoint inhibitors work better in some indications than others. And therefore, LYT-200 would be a very important addition to the armamentarium of immuno-oncology drugs, both in indications where checkpoint inhibitors do not work, do not work so well or to complement checkpoint inhibitors where there is significant room for improvement in terms of response rates. We have studied galectin-9 extensively, both as the therapeutic target as well as the biomarker. And we have done so by assessing its expression in cancer patient tissue and blood. The reason why we're looking at galectin-9 as a biomarker is because we believe that it may serve as a stratification marker for patients as well as a pharmacodynamic marker that could potentially predict efficacy of LYT-200. I would like to take us through our data around galectin-9 expression in correlation with important clinical and outcome measures in various different cancer types. This data shows that high galectin-9 expression in a cohort of over 1,000 breast cancer patients correlates robustly with shorter time to progress with the disease in terms of metastasizing and also when we look at galectin-9 in combination multivariate analysis with some of the parameters that have been very well established adverse prognostic indicators in this disease, like stage, size and grade. Galectin-9 emanate as an independent prognostic indicator of worst disease survival. Galectin-9 high expression can be captured on tumor cells, on immune cells, and it also correlates with what we now call an immune-excluded phenotype in breast cancer. As I've mentioned, we can see galectin-9 expression on tumor cells and on immune cells in the cancer types we have investigated, pancreatic ductal adenocarcinoma, cholangiocarcinoma and breast cancer shown as examples on this slide. And in pancreatic cancer and cholangiocarcinoma, high galectin-9 expression and particularly its expression on tumor cell surface where we are going to be targeting at using LYT-200. High galectin-9 expression again correlates with worse survival. So both shorter time stand between these 2 disease progression and also shorter overall survival. And we're also very excited about the data that we see in cancer patient blood. So we've looked at several independent cancer types, colorectal cancer, breast cancer, pancreatic, cholangiocarcinoma and non-small cell lung cancer. And each time, we consistently unequivocally and reproducibly demonstrate that gelatin-9 levels in blood of cancer patients are significantly higher compared to healthy individuals. And when we further assume into pancreatic cancer, we actually see that those levels are particularly high in patient with distant metastatic disease compared to those that have only locally advanced disease. And this data has interestingly been also independently validated and recently published in Oncogene. I would now like to talk to you about LYT-200, our first-in-class fully human monoclonal antibody selectively and specifically targeting galectin-9. We have rapidly advanced LYT-200 for preclinical development and have established its potency, stake and tolerability as well as mode of action across a range of preclinical models, including animal models, patient-derived organoid models and many others that I will talk to you about. And we firmly believe that our preclinical body of data supports the clinical utility of galectin-9 targeting by LYT-200. And we are very excited to announce initiation of the Phase I clinical study using LYT-200 in solid tumors, and believe we are the first in clinic with an anti-galectin-9 therapeutic antibody. Of course, for any therapeutic antibody binding affinity is crucial. We show that LYT-200 has picomolar and low nanomolar range affinity and importantly binds galectin-9, which is endogenously expressed by human cancer cells. And using an array of over 5,000 proteins, we demonstrate that LYT-200 specifically and selectively binds galectin-9 and does not have any off-target binding effects. And in terms of its mode of action, of course, it was very important to validate that LYT-200 can block immunosuppression mediated by galectin-9. And we have done so in multiple models. We've demonstrated that LYT-200 prevents galectin-9-induced effector T-cell death. And here, we show its effect on macrophages. So LYT-200 very potently and profoundly inhibits secretion of 2 of the most important immunosuppressive mediators by M2 macrophages, which are TGF-beta and IL-10. And it also blocks interaction of galectin-9 with its binding partner in macrophages, the protein called CD206. When it comes to the safety and tolerability of LYT-200, we have conducted GLP toxicity studies in both nonhuman primates and in rats. And we have dosed LYT-200 repeatedly at dose levels that are over 50x higher than some of the doses that we will be using in our clinical study, and we observed no adverse toxicity signals. Our next set of data really focused on single-agent efficacy and combinatorial potential of LYT-200 in animal models. We ran melanoma B16F10 model because it is the gold standard model that has a very well established profile of single-agent efficacy for anti-PD-1. And we also conducted studies of LYT-200 in the KPC orthotopic pancreatic adenocarcinoma model. As you can see, these studies have been conducted at independent CROs as well as in an academic NYU lab. In the melanoma model, we show a very expected around 20% tumor growth inhibition with a single agent anti-PD-1. But importantly and interestingly, LYT-200 has a superior single-agent efficacy in this model, inducing a tumor growth reduction over 50%. When we combine LYT-200 and anti-PD-1, what we show intratumorally is that the combination has mechanistic synergy and induces doubling of the intratumor presence of CD8 positive T-cells. And this supports the combination of LYT-200 with an anti-PD-1 agent in clinic. In the KPC pancreatic model, which is a very well-established model, that genetically and molecularly resembles human pancreatic ductal adenocarcinoma, and also in the past has demonstrated potential for clinical translation in terms of the relevance of the data served in this model preclinically. We see here very reproducibly and consistently robust single-agent efficacy of LYT-200 which induces tumor growth inhibition of over 40%. Again, this is a model with checkpoint inhibitor as a single agent do not show any efficacy. And in the survival model of orthotopic KPC mice, where we combine LYT-200 with gemcitabine/ABRAXANE, which is the gold standard therapy for patients with pancreatic cancer, only LYT-200 containing regimens show survival benefit in this model while chemotherapy does not. And also in the combination setting, we observed a complete response using LYT-200 with gemcitabine/ABRAXANE. So taken together, our animal models really firmly support the utility and the activity of LYT-200 and support that it may have single-agent efficacy and very good combinatorial potential for clinical development. And finally, in our preclinical development, we conducted the patient-derived organoid model where checkpoint inhibitors have been tested and their mode of action has been demonstrated. In essence, this model takes freshly excised patient cancer tissue from primary tumors or metastatic deposits. And the organoids are formed to contain the endogenous intratumoral immune microenvironment. We treat the organoids with LYT-200 and [ enhance ] the activity of intratumoral cytotoxic T-cells by measuring some of the very well-known activity markers of T-cells such as interferon gamma, CD44 and TNF alpha. And what we show here and having tested LYT-200 in this experimental model in over 20 tumors is a very robust and reproducible reactivation of intratumoral T-cells using LYT-200. And this is precisely the net effect that mechanistically, we hope to achieve with LYT-200 in clinic in our patients. So taken together, we believe that our preclinical data support preclinical translation and development of LYT-200. We will begin testing LYT-200 in solid tumors in the dose escalation, dose finding part of the study. But in this part of the study, we will also be looking for preliminary efficacy. And also we'll be very keenly looking at pharmacodynamic markers and exploratory endpoints by testing patient tumor tissue and blood, and we will be assessing the utility of galectin-9 as the biomarker by looking at its expression in both patient tumors and patient blood. This part of the study will be followed by expansion cohorts in cancer types where the relevance of galectin-9 as the target has been very firmly established as we have seen from our preclinical development data. And on this study, we are very proud to be collaborating with and working with some of the main clinical trial investigators and trial sites across the U.S., including Dr. Weinberg. I know that this is an oncology presentation, but I would just like to note, given the interest at PureTech for inflammation and fibrosis that galectin-9 as a target has also been implicated in disease states where inflammation and fibrosis actually underpin disease pathology and progression. And data that have been published support that high levels of galectin-9 are important in, for example, systemic sclerosis, both cutaneous and diffuse and other fibrotic lung cancer diseases such as idiopathic pulmonary fibrosis, IPF. In these diseases, high galectin-9 expression correlates with worse lung function and in animal models of pulmonary fibrosis, inhibiting galectin-9 very potently prevents the position of collagen in lung tissue, which effectively means that it can stop fibrosis in its tracks. So we will be announcing potential further clinical applications of LYT-200 soon. And we believe that galectin-9 as a therapeutic target should be explored in other disease indications beyond oncology. So in summary, we are very excited that LYT-200 represents a very exciting start in our immuno-oncology clinical programs. And we are proud to be leading galectin-9 development as a major emerging therapeutic target, both in oncology and in other diseases. And with that, I would like to thank you and also say that I have been very interested in the discussion that doctors Mukherjee and Weinberg have had around immuno-oncology. And I would like to hand it back over to them now. And I'm interested to hear what both of you think about where this space is headed. So Sid and Zev, over to you, and I thank you again for your attention.

Okay. So I think as we talked about, there's a lot of targets out there, and that you have to be selective. And we already have some good ideas about which ones look a little more exciting than others. In my space, in GI oncology, there's a few that really have peaked my interest, including CD47 because it's a not just relying on T-cells, but also involves macrophages and macrophage delivery. And I think -- and certainly, in a lot of the GI cancers, I think there's already recognition that it's not just going to be the T-cells alone, we're going to have to engage more than the T-cells to get a full immune response. We also have started to see interesting early work from potent immune stimulatory molecules, whether it's CD40 or others or the ability to more potently stimulate both the innate immune system, maybe perhaps along with a checkpoint inhibitor and chemotherapy can lead to a more profound immune effect, which might be necessary in treating some of these immuno-resistant diseases. The list goes on. I think that in a lot of these impressive already. I happen to be a fan of a few of these. I have a few interests in my program that really interest me, particularly the adenosine pathway inhibitors and trying to understand the interplay between the excess adenosine that is developed as a consequence and trying to block that pathway, perhaps combining it with existing immune approaches will be the way of the future. And then on the flip side, I've already been involved with a number of these drugs that have seemingly not been sufficient to control aggressive GI cancer, such as CSF1R inhibitors, which unfortunately figured out a little bit early, along with other immuno-stimulatory molecules like OX40. So the list goes on here. I think we're going to be testing more and more of these as time goes on. And one of the keys will be clever clinical trial design and eligibility to allow, hopefully, some of the drugs where we know these targets are novel and exciting to shine.

I think the interesting thing here is to think about not just the cancer cells but the milieu in which the [ cancer ] lives. It's really what cells [indiscernible] cells surround it. We now know that the [Technical Difficulty] citizen. It takes some citizenship in an organ like the duct or like the brain. But that citizenship is licensed only by essentially making its grounding milieu resistance to the immune response to drugs and to over the time with therapies. And these resistance mechanisms are not just located in the cancer cell itself, but are also located in the milieu or the cells that it surround itself with and other factors that sort of pulls out of these cells. So I'm very interested in this milieu -- this cancer milieu. I'm almost very interested in the role of the innate immune response, which has been underexplored. You talked a little bit about it, not just T-cells, but macrophages and monocytes and potentially natural killer cells, all of which are slowly becoming targets of drugs so that they can be activated against the cancer.

So we have a few questions here. The first is we've talked a little bit about gal-9 and how it's a foundational immunosuppressive mechanism. Are there other drugs that you're aware of the development that aim to block multiple areas of the immune system?

I can answer a little bit. I mean, yes, there are many other drugs that are attempting to block multiple aspects of the immune system. I think there are drugs that we now understand much more. I'll just give you one example. We understand much more about what natural killer cells are actually recognizing as [Technical Difficulty]. We've done an experiment in which we've taken leukemia cells and expose them to natural killer cells. And the natural killer cells works better than any drug I have seen, and this is all in [ futureness, ] they will recognize really 100% of these leukemia cells and kill them. Where if you expose those same natural killer cells to normal blood cells, not a blood-forming cells, stem cells, et cetera, the natural killer cells don't touch them at all. So we've, in collaboration with multiple other labs, identified factors that the natural killer cell uses to recognize or discriminate the cancer cell from a normal cell. And amazingly, some of those factors have to do with things that Zev was talking about, sort of metabolic pathways, things that cancers use to propel their furious cell division, things that cancer draw from the milieu to propel them to become invisible to such killer cells. So that's one area in which -- I'm just giving you one example, but that's one area in which we've discovered that the complexity of cancers is enormous. And this is again something that we're developing with PureTech to figure out how can we preserve the normal milieu, whereas -- and at the same time, kill the cancer cell, and there are multiple strategies by which that can be done.

Zev, could you speak to the potential of anti-galectin-9 in GI cancers.

Yes. Sure. So I mean I think that in GI cancers, as we've indicated earlier, they're particularly immunosuppressive. And what that means is that there's both, as Sid was alluding to, a tumor-associated immune system component, which almost expels any interest of the T-cells and even other immune system cells to gain access to the tumor milieu. And in GI cancers, in particular, this milieu is a very potent immunosuppressive environment. And even in studies that have been done, which carefully looked at how much T-cells are getting into a disease like pancreatic cancer, you see that the problem isn't that the drugs aren't getting in, is that the immune system not being sufficiently engaged in a way that allows it to penetrate into that stroma or into that cancer cell directly. So gal-9 is a really interesting example of something that is trying to get around that and trying to block some of the immunosuppressive component aspect of the tumor. And perhaps even in combination with other drugs may afford us an opportunity to get in there and that be more effective. And I'll point out that it may not be single-agent drugs alone that give us the best opportunity, it may be sensible combinations of targets like gal-9 with perhaps low doses of chemotherapy or other immuno-stimulatory or checkpoint inhibitor strategies. That's what we're trying to do here is to not necessarily rely on a single target or drug itself, but we're in the best way to combine things and that's going to be part and parcel of the next few years and so forth.

Our final question is, what have been the impacts of COVID on the oncology deal?

So I do a lot of clinical trials. And in the early days, there was a huge impact, of course, as a drug developer on how we're going to do this safely and in a timely fashion and not just care for the patients who themselves, we know are higher risk of getting COVID but also not slow down what is very important critical work to do, which is drug development and trying to find new targets so that when COVID beyond us one day, we don't lose too much ground, and that's been a critical thing that we've tried to balance carefully and safely. I think by and large, the care of cancer patients with COVID or in the COVID era, I should say, has been quite good in the way we -- and by we, I mean, the oncology community has handled this. We recognized there are certain malignancies and treatments that put patients at higher risk of getting COVID, but doesn't necessarily mean that we shouldn't treat them for their cancers. And that balance and interplay over the last 6 months is evolving, and we're learning more and more. There's not a week that goes by now in the journals where we don't read an article about how to address these topics in the COVID era. So we have to balance 2 things: one is how to treat the patients; and the other side, on the drug development side, how not to get too caught up to the point where we're not able to advance science anticipating that one day will be beyond this and we don't want to lose time in that regard.

Sid, do you want to answer that question as well?

I just want to -- just agree with Zev on every level. I think for a while we struggled to keep our -- I mean cancer -- the care of cancer patients, I think, was to the largest extent not compromised. We put into place at Columbia, I'm sure UCLA at various other places, we put into place strong protocols so that cancer patients who are protected from the effects of COVID, we tested frequently. We asked them to monitor symptoms frequently. And in fact, so far, we've not really had a sort of explosion as it were of COVID within the cancer patient community. What was slowed down for a while was clinical trials. So it was harder and harder. Clinical trials take time. They take time to -- because they have to go through regulatory approval. They have to go through many, many layers before the clinical trial is finally approved. And ultimately, of course, they have to recruit patients. And that was slowed down in the first few months. We, as a community, I think, and this is not only true for one university, but true for all of the entire community of academic oncologists, made a very strong effort to keep those regulatory protocols alive and without compromising quality. And I'm very happy to say that we're recruiting again. We started up again. Our clinical trials are active again. We are recruiting again. Obviously, mindful of COVID, obviously mindful of the fact that we have to make sure that the patients are safe. But all of this said, I was -- I'm really delighted to say that [Technical Difficulty] as it is in most major clinical trial centers. So this, I think, COVID will end. We can see the end in sight. It may be 6 months, it may be 8 months, but it will end. We will vaccinate. We will test. We will get out of this, and then we will resume the important work that we started with cancer and the important thing is not to lose traction or speed during this crucial period of time.

Well, thank you both so much for your time today and for the work that you're doing on behalf of cancer patients. And with that, I will turn it back over to our Founder and CEO, Daphne, for some closing remarks.

Thank you, Allison. Throughout the day, we've had the opportunity to hear from experts as they share their clinical perspectives and unique insights in lymphatics and related immunology, in addition to sharing an overview of our wholly owned pipeline. Across our wholly owned pipeline and founded entities, we achieved a number of exciting catalysts this year, which are captured on this slide. Building on our track record of advancing novel therapeutics, we expect multiple value drivers in 2021, including at least 6 clinical study initiations and 8 readouts as well as potential financings and strategic transactions across the founded entities and the commercial launch of 2 products in our founded entities. In particular, we look forward to multiple readouts for our lead wholly owned product candidate, LYT-100, and other progress that we will be sharing around our wholly owned pipeline. Looking beyond 2021, we anticipate the future of PureTech to be defined by strong clinical, commercial and financial momentum across our wholly owned pipeline and founded entities. As we embark on our exciting new phase of development, we remain focused on maximizing the value of our groundbreaking programs. We'll continue to leverage our experience in network with the goal of identifying, inventing, developing and commercializing innovative new therapeutics, focusing on the science of the big access to address significant medical needs. This proven strategy will enable us to increase value via 4 paths: driving product candidates forward through clinical development and potential commercialization, pipeline growth and expansion. We're not going to be able to develop everything ourselves. We have so many opportunities coming out of our platform and product candidates that we do expect that we will have to partner or spin out some of the noncore applications of our wholly owned pipeline while developing the core applications and product candidates ourselves. Additionally, we are looking forward to deriving value from the growth of our founded entities, including potential monetization events and royalties. So you could think about the founded entities really like partnered programs. We're excited to be listed now on the NASDAQ global market, as we're poised to really accelerate the advancement of our wholly owned pipeline. Most importantly, we're delighted to have advanced new therapies that could prove transformational for millions of people who have long struggled to find effective treatments. And we look forward to deepening our work together and sharing our progress with you. Thank you very much for your time today.

And now I'd like to bring back our full management team for our final Q&A of the day. In addition to Daphne, Joe and Eric, we are now joined by Bharatt Chowrira, our President and Chief of Business and Strategy; Steve Muniz, PureTech Co-Founder and Chief Operating Officer; and Joep Muijrers, our Chief of Portfolio Strategy.

Our first question is what are your plans for moving forward in idiopathic pulmonary fibrosis? When do you plan to provide more information around the registration-enabling studies?

Thanks, Allison. So we were really pleased to have the results of the multiple ascending dose study, which we announced recently, and that gives us a lot of confidence to move forward in IPF. Following those results, we believe that we have a product that could be a potential game changer in addressing IPF. And we think that given that it has the potential to displace the standard of care, if all were to go well. And it's important to note, and I think Michael noted it as well that the new agents are being developed in combination with the standard of care. So we think that this could be potentially used together with new agents as well. Given all of that and the importance of this program, we are planning registration-enabling studies. And before we guide on specific time lines, we really want to make sure that we get feedback from regulatory authorities and are able to guide something that will really bring us to a registration in IPF.

Our next question is, will LYT-100 trials look to recruit patients with early ISL staging, what is an appropriate endpoint or progression of ISL staging? And how long might that take?

Eric can take that one.

Yes, absolutely. So we're going to be looking at patients with mild-to-moderate lymphedema, which corresponds to stage 1 and 2. And that really goes back to some of the comments that Dr. Rockson was making in terms of likely having the greatest chance of efficacy for an intervention earlier on in the process. In terms of endpoints, the primary endpoint of our next study will be safety and tolerability. We will be looking at a number of secondary endpoints, which will be efficacy end points. And those will include both quantitative measures of disease such as bioimpedance spectroscopy as well as some more qualitative measures such as patient-reported outcome.

Great. Our next question is...

Sorry, that was our combined study of 6 months. Sorry, Allison.

No worries. Our next question is if pirfenidone is generally used early to prevent fibrosis worsening, will it need to be given preventatively against long COVID? And how confident can you be that this will be effective post infection?

Eric can -- I think Eric can take all the LYT-100 questions.

Sure. Absolutely. So really probably what's critical here is to intervene in a window where there's continued and residual inflammation and fibrosis. We think that process is still going to be going on immediately post acute infection. Now probably if one waited too long, at that point, the fibrosis and lung damage would likely, in fact, be persistent. But we think that post-acute window is a good one. And one doesn't necessarily have to get that prevented in play. And I think this is really something that Dr. Maher was talking about in response to a related question, which is if you look at IPF versus post-acute COVID-19 at the point an IPF patient has seen they've progressed much further, whereas post COVID-19, it's much earlier in the process. And that actually resembles the preclinical animal model such as bleomycin more in terms of the COVID situation versus the IPF situation.

Great. Our next question is also LYT-100 related. And the question is, what do you expect in terms of the duration of treatment that will be required with LYT-100 in the various indications you are pursuing?

Yes. So it will really depend on the indication and probably one should distinguish between what will be done in the clinical trial versus what we've done in clinical practice. The trial for us always been a proxy for what's done in practice. So in the case of post-acute COVID-19, we'll be treating patients for 3 months. In the case of lymphedema, as I indicated, we'll be treating patients for 6 months. But we should recognize that these are chronic conditions in some cases, right? So for instance, lymphedema, as Dr. Rockson was describing as lifelong chronic condition, IPF is a chronic condition. And so the treatment duration both in the context of a clinical trial and then potentially in the clinic might vary in general, the way you would look at treatment region reflects the chronic nature of these conditions.

Our next question is with the IPF program is the intention to match ESBRIET on efficacy, but show better safety? Or is the ambition to be ESBRIET on safety and efficacy, presumably head-to-head trials will be part of the program? So I think we're having an audio issue for Eric right now. So maybe I will ask Bharatt to answer that question.

Yes. So as Daphne was mentioning earlier, we just got the multiple ascending dose study and the food effect study. And we are very excited about the data from that study in terms of its tolerability and potentially not having to administer the drug regardless of the food. So that will kind of dictate in terms of the trial design. And as Daphne was mentioning, we do plan to speak with the regulatory agencies to design those -- the registration studies. And so we are initiating registration-enabling activities to support a potential study. And the study design, we'll be able to speak more in the coming weeks and months once we have had a chance to discuss it with the regulatory agency as well as with some of the key opinion leaders.

Our next question is related to LYT-200. Can you give an indication of the proportion of cancers that would qualify as gal-9 high? Is there an overlap with PD-L1 expression signature?

Joe, do you want to take that one?

[indiscernible]

There is an audio issue.

Yes.

Joe, there's an audio issue.

Okay. Eric, can you take it?

Okay. And if you're having any issue, please questions on me now. So we are looking into overlap with PD-1 expression. But what we see is gal-9 has expressed where you don't see PD-1 express in both in low and negative tumors. We've seen galectin-9 expressed across a number of different tumor types, and that's not just us. It's work coming from other groups. And with regards to any specific tumor type, what we've seen is anywhere from 10% to 15% of cases having that type of high galectin-9 expression.

Great. And a follow-up question on gal-9. Could soluble gal-9 swamp LYT-200 such that not enough unbound LYT-200 combined cancer cells?

Sure. So we think we're going to be able to give sufficient quantities of LYT-200 to be able to soak up the galectin-9. And in our first study that we're going to be doing, which my colleague, Alex described, started get into. One of the key things here is going to be looking at -- first at PK and a key parameter is what dose level of LYT-200 that we need to give, not only from a tolerability point of view, but also one where there's going to be sufficient PK to overcome any type of sync that might occur, but we feel like we have a good chance of getting there.

Wonderful. So our next question is, can you discuss the stability of exosomes? Are there potential issues for shelf life or storage? And I'll ask Bharatt to comment on that one.

Yes. So as I think Joe was mentioning in his earlier comments, a lot of these vesicles or exosomes that people are working with are derived from mammalian cells. And they are naturally developed to be highly unstable and very fragile. So it will be very difficult to come up with a formulation for those types of exosomes for oral administration compared to, for example, the vesicles or the exosomes that we have isolated from milk, for example, and bovine milk is loaded with these exosomes. And they have naturally evolved to be highly stable and be able to withstand the stomach environment and then get into the small intestine. And as Joe was mentioning, the stability will also allow us to potentially engineer these to try and target them to different types of tissues and cells that would otherwise would not be possible with the other exosomes.

Great. And Joep, do you want to add to that?

Yes, just to mention that I've heard Joe say literally try to torture these things and done everything you can do to kind of make them less stable and they've survived through all of that. So remarkably stable would be my short answer. And we don't expect anything in terms of shelf life issue because of that. So actually one of the key features of our approach.

And I think one of the other things we have done with the milk exosomes is that we can actually lyophilize these. And we've done a whole bunch of other testing to show that these are actually can be very hardy and stable. And from a long-term shelf life perspective, that bodes really well compared to the other sources of exosomes, so just wanted to add that.

Perfect. So our next question is, what do you see as the best combination therapies for LYT-200?

Yes. So we'll -- of course, checkpoint inhibitors, typically for the anti-PD-1 is of high interest, but also in the case of pancreatic cancer chemotherapies so the gemcitabine/ABRAXANE combination is of interest. And my colleague, Alex, had presented some data in the KPC model, which is a good model for pancreatic cancer in terms of the reflection of underlying pathophysiology. And the fact that things like checkpoint inhibitors don't work in that model like human counterparts. And in that model, there appeared to be a very nice result in terms of that combination with chemotherapy and gem/ABRAXANE. So I think that chemotherapy combination is of interest as well as the checkpoint inhibitor combination in other cancers.

Yes. And maybe I'll just add that we are also very pleased by the potential for single-agent efficacy with this product.

The next question is, I'm curious to understand how your oral allopregnanolone product candidate relates to the Biogen stage deal to develop zuranolone. Dr. Bolen mentioned that LYT-300 was created using your Glyph technology. Can you elaborate further?

Joe, do you want to take that one?

[indiscernible] if I'm connected.

No. Bharatt, do you want to take that one?

Yes. I can jump in. Sorry, Joe. So the Glyph technology, as Joe was mentioning, it's really powerful in trafficking a small molecule, for example, to bypass the first pass metabolism and go through the lymphatic system and into circulation. And so what that allows us to do, in addition to targeting certain aspects, certain regions of the lymphatic system, it allows you to create these prodrugs using this triglyceride moiety to potentially make a small molecule that is otherwise not orally bioavailable to become orally bioavailable as well as have a PK profile that is differentiated from otherwise stand in a small molecule. So we've been able to demonstrate with allopregnanolone quite nicely that you can actually use the Glyph technology to achieve 30% to 40% oral bioavailability in a range of preclinical models we have tested so far in rodents and dogs and as well as nonhuman primates. So what this allows us to do is, if you think about ZULRESSO, which is the product that got approved for treating postpartum depression that Sage is developing. It's a 60-hour IV infusion, right? So -- and that's a natural allopregnanolone. It's -- it cannot be orally administered. So a 60-hour IV infusion really is limiting its usage beyond -- even within postpartum depression, it's not being widely used. So by making something like allopregnanolone, which is a natural neurosteroid orally bioavailable, then that opens up a range of neurological indications that one can go after. And so we are excited about advancing this molecule, which we term as LYT-300 into development. So we expect to have a potential IND next year in 2021 as a Phase I. And then that opens up the possibility to advance LYT-300 for a range of indications, including neuropsychiatry indications as well as epilepsies and seizures and such.

Our next question is what are the efficacy endpoints of the long COVID study?

Eric, do you want to take that?

Sure. So there, we're going to be looking at 6-minute walk test, which is a measure of function in particular lung function. And then we have a number of other secondary endpoints that we'll be looking at, which reflect various patient-reported outcomes, for instance. So patient-reported outcomes for things like shortness of breath, but then we're also going to be employing a scale called the SF-36, which is a fairly standard scale for overall function and well-being. And we think that will allow us to capture a number of other domains of the disease. So we have a number of different secondary endpoints we'll be looking at in addition to our primary.

Great. Our next question is, can you please explain again the mechanism of action of your molecule related to upper extremity lymphedema, secondary to surgery or radiation as this is mechanical disruption of the lymph channels.

Sure. I think Dr. Rockson, in his presentation, was talking about in the case of secondary lymphedema where you have injury due to things like surgery, radiation, that sets off a process of inflammation, like lead to fibrosis that leads to impaired pumping of the [indiscernible] lymphatic vessels. And the reason this becomes a chronic disease is the inflammation leads to fibrosis, leads to impaired pumping, which leads to increased fluid buildup. So the problem only gets worse and remains chronic. Now LYT-100 has anti-inflammatory and anti-fibrotic properties. And so the goal is to disrupt the inflammation and fibrosis, which is occurring during lymphedema and by doing so, has a therapeutic benefit.

Our next question is, are you doing any work on milk exosomes and siRNA to deliver drugs to the body that bypass the liver?

Joe...

Joe, do you want to take?

Can you hear me?

No, yes? I'll just mention that we are working on siRNA and importantly, messenger RNA, which is an area where Joe obviously had a lot of experience at his previous role at Moderna. And we're really pleased about the potential for oral administration of messenger RNA, along with other approaches that we're pursuing with the milk exosome technology.

Great. So our next question is, as lymphedema as a result of other disease like chronic kidney disease, isn't it likely to improve as those diseases are addressed?

So with things like chronic kidney disease, you do see edema. In the case of secondary lymphedema, the main cause really is complications related to treatment of cancer. And so the real drive for lymphatic -- immunology of lymphedema going forward really would be based on cancer treatment. Of course, you have a lot of people who currently have lymphedema who are seeking a solution. And as we heard, the current treatments are mechanical in nature. There isn't a pharmacological solution or approved pharmacological agent.

Great. And a follow-up question to that is, aren't some fibrotic tissues capable of regenerating like in the liver, could that be an effective way to mitigate long-term sequelae?

Yes. In the case of lymphedema, we've seen typically are that these patients are chronic. They have the condition really continuously and you don't have some sort of spontaneous remission of the disease. Now there is a thought that lymphatic vessels can hone, and they have kind of almost this built-in prepared mechanism, where they could start to hone and form connections in a way that might be healing. But even if that was the case, one of the central issues is the presence of fibrosis and inflammation, which would prevent that. So at the end of the day, if there isn't a way to address some of the underlying pathophysiology, particularly the fibrotic inflammatory component, it will be tough in terms of seeing any type of spontaneous remission of disease.

Okay. And our last question is, has COVID affected our ability to function or caused any major delays?

Yes. So I'd love for Steve to take that. I'll just take an opportunity to note that Steve is our amazing behind the scenes, makes everything run so smoothly. So Steve, do you want to take that one?

Thanks, Daphne. Yes, we haven't had any delays. We closed our lab for the first 2 weeks back in March. But since then, we opened back up the lab. We're testing the team 2 times a week. And our trials have really continued to run as well. No real impact on the business.

Great. Well, that concludes our virtual R&D Day. We thank you all for joining us, and we wish everyone a happy and safe end to the year. Thank you, everyone.

Thank you, everyone, for joining us.

Thanks.

Thanks.