Great. Thank you, Peyton, and thank you to the Cowen team for inviting us to present. Welcome to everybody in the room and to everybody that's joining us via webcast. So I'm really excited to tell you about PureTech, and in particular, to share with you our R&D model and how that success that we've had, for example, in developing KarXT and Karuna Therapeutics, is actually something that we're scaling and repeating it at PureTech. We'll be making some forward-looking statements today, and we ask that you go to our SEC filings at sec.gov for a full list of risks and uncertainties. We do not undertake to update this information. It's accurate only as of today.
So at PureTech, our mission is to give life to new classes of medicine in order to change the lives of patients with devastating diseases, and I'm really proud of how we're delivering on that mission. If you look across the top of this slide, our R&D engine has now generated 28 new therapeutics and therapeutic candidates, of which two were taken from inception at PureTech through FDA and EU regulatory clearances, and a third, KarXT, has now filed for FDA approval as well. I'm particularly proud of what you see across the bottom of this slide, and that is that 80% of the studies that have been run by PureTech and our founded entities have been successful. Our probability of success in the clinic is about six times better than the industry average based on our historical track record.
We think that that's due in large part to our strategy, our R&D model, which starts with, for example, a drug that has validated efficacy. We think that that positions us in for success in a different way, because we're starting with drugs that we know work, but had some issue initially that held back development. And then we're able to apply our proprietary technologies to address the key limitation that held back that drug in the past. And then the third piece, or the third pillar of our R&D strategy, is to then take the program that we're developing and our hypothesis and do a killer experiment, which is basically something that, if it works, will really de-risk and prove out the hypothesis, and if it doesn't work, then we know to move our resources to other programs.
And I think that's really a unique advantage of the hub-and-spoke model that we pioneered at PureTech. The idea that our team is fully aligned with our shareholders to move you know, move resources from one, project to the next based on what, where we think there's the greatest likelihood of success. Another advantage of the hub-and-spoke model is that it's capital efficient. So what you have is a hub or a core group of people that are working across multiple programs. Some of them are wholly owned, and some of them are housed in founded entities. And then the third advantage of this hub-and-spoke model is it's actually generated a tremendous amount of non-dilutive capital for us, so much so that we haven't had to raise capital from the equity markets in about seven years.
So it's enabled us to fund the next generation of pipeline programs that we have at PureTech. Quick snapshot on the right. We have last reported cash of $320 million at the end of the year, and that does not account for the cash that we will receive when the Karuna BMS transaction closes, which would be close to another $300 million. We've guided that we have operational runway into 2027, and, you know, we haven't had to raise money actually, it's almost seven years now, as I mentioned. The founded entities are fully independent. They've been, basically, funding themselves, so they raised $3.8 billion, and most of that, 96% of that, came from third party, so we haven't had to support them. In fact, some of them are supporting us.
So, this is a brief snapshot of our wholly owned pipeline, and we'll be spending time talking about how this wholly owned pipeline builds on that same R&D strategy that I mentioned in the beginning. And, in addition to our wholly-owned IPF program, we've announced recently that we're gonna be taking our CNS programs and advancing them through a founded entity called Seaport Therapeutics, and our oncology program will be advancing also through a founded entity, called Gallop Oncology. So if we want to take a step back and think about why this, you know, how this R&D model has translated to success for patients and for shareholders, the KarXT example is a really good one to start with. So we knew that there was a huge unmet need for new treatments in schizophrenia. There hadn't been new mechanisms developed in over 50 years.
And we also knew that xanomeline, which had originally been developed by Eli Lilly, was sitting on a shelf because it had some GI tolerability issues, even though it had really remarkable efficacy in studies that were conducted by Eli Lilly. Members of our team, including Eric Elenko, who's here and will join us for Q&A later, came up with the idea of KarXT, which is the idea of, of combining xanomeline with a muscarinic receptor antagonist, trospium chloride, in order to overcome the GI-related AEs. We then ran a killer experiment, and we showed that we were able to reduce these GI tolerability issues by about 50%. At that point, Karuna did an IPO, and they then ran three successful registration-enabling studies, which is really unusual in CNS.
And again, I think that's partly due to the strategy of starting with an active program. As mentioned, Karuna Therapeutics is expected to be acquired by Bristol Myers Squibb for $14 billion. And in addition to generating value for patients, which we think is, you know, if this is approved, this could be the first new mechanism for treating schizophrenia in 50 years. In addition to that, we believe that this has created a lot of value for our shareholders. We initially allocated about $18.5 million to this program. And actually, that's, that's what we put in, all in. We've now taken $815 million in cash off the table, and we have another close to $300 million that's, that's gonna be coming from this BMS Karuna transaction.
In addition to that, the value of the remaining Royalty Pharma deal that we struck is about $400 million in milestone payments. And if the KarXT program sells above $2 billion annually, anything above that $2 billion, we get a 2% royalty. So, a lot of success in terms of the cash generated, and we've been able to take that and reinvest it in developing an exciting new pipeline of programs, which I'm gonna tell you about right now. LYT-100, which is deuterated pirfenidone, is a perfect example of our R&D strategy at work. So as you probably know, idiopathic pulmonary fibrosis, or IPF, is a rare, fatal, and progressive condition, which causes scar tissues in the lung, in the lungs, leading to shortness of breath and loss of lung function.
The median survival here is about two to five years, and there's a huge unmet need. We know that there's two standard of care treatments that work and actually are proven to slow the disease, but they have significant side effects, including GI, mostly GI-related side effects. And only about 25% of patients with IPF are on either of the standard of care treatments. Pirfenidone, which is one of those standard of care treatments, has been clinically validated to work in IPF. In fact, it's been shown to extend life in patients with IPF by an average of two and half years. And that's really meaningful for patients that have a median survival of between two to five years.
There's been over 12 late-stage real-world efficacy studies and late-stage studies which have demonstrated efficacy, but there's GI-related tolerability issues that significantly limit its usage. So patients can't stay on the drug, and they can't stay on the drug at the right dose. So that is a reason that they're unable to benefit from pirfenidone. Despite these drawbacks, in 2022, the sales of the two standard of care treatments together reached about $4 billion in annual sales. So we believe that LYT-100 is a potential game changer for patients with IPF. What we've done is we've made a key substitution, which substantially improves the adverse event profile, and we're able to maintain the pharmacology or activity. And I'm gonna tell you more about this and how we've proven it out. So we actually ran.
This was our killer experiment in this case. We ran a head-to-head study of LYT-100 versus pirfenidone, and we showed a 50% reduction in the GI-related AEs. Before we did this study, before we embarked on it, we went and we talked to leading experts in the field, and we asked them what would be clinically meaningful. The response that we got was anything above 25% would be clinically meaningful. So we were obviously really delighted with the outcome of this head-to-head killer experiment, and we're moving this forward. In addition, we've recently announced and presented at CHEST that we were able to test a higher dose. It's about 50% higher dose, which translates to about 43% higher exposure than the approved dose of pirfenidone. We believe that the higher dose has the potential to show improved efficacy.
In fact, we know that pirfenidone has a dose response. Nobody's ever been able to dose higher, but we did see a dose response that, where a lower dose showed less efficacy. We're gonna be testing both the 550 mg dose, which is equivalent to the exposure level of the approved dose of pirfenidone, and also this higher dose in the phase II-B study that's ongoing right now, and it's gonna be reading out in Q4. We have two ways to win here. The first is that we have the 550 mg dose shows similar efficacy, but a greatly improved tolerability profile, similar to what we saw in our studies so far, in terms of the tolerability profile. That would mean that patients could stay on the drug longer and achieve more durable efficacy.
The other way that we could potentially win for patients is if the 825 mg dose, which is that higher dose, shows improved efficacy, which would enable potentially patients to retain more lung function. We're testing this, as I mentioned, in our ongoing phase II-B registration-enabling study. This is the first of two registration-enabling studies that we're running for IPF, and the primary endpoint here is the slope of decline in FVC for LYT-100 compared to placebo over six months. We also have pirfenidone in there as a comparator, and we have the two doses, which will be pooled together. Six-month treatment duration, phase II-B top-line data expected in Q4 of 2024. I'll now transition to telling you about Seaport Therapeutics, which again builds on this unique R&D model that I talked about before.
In this case, Seaport Therapeutics is focused on CNS disorders, and we like to think of it as almost like Karuna on steroids because we have the CNS focus, it's clinical stage. We're doing the same thing where we're taking active drugs that had an issue and applying our unique technology. In this case, we have the Glyph technology platform, which was invented by PureTech and Monash University, which creates new composition of matter IP, and we have a pipeline. So it's extremely exciting, and I think that we're all really keen to make a difference in neuropsychiatric disorders. There's obviously a lot of excitement around the space on the back of the Karuna and Cerevel transactions. If you think about the patients, depression and anxiety are among the most disabling neuropsychiatric conditions, and they're growing.
We see suicide rates on the rise, and for me, what's been really alarming is the rise in pediatric suicidality. There's kids that board in the ERs for weeks at a time, and a lot of this is driven by the pandemic, social media. If you zoom out, there's 120 million people who have both depression and anxiety, and the existing healthcare system is not well equipped to really answer that. We need better medicines. Neuropsychiatric drugs have been among the most commercially successful in history. So you have multiple drugs that have reached, you know, blockbuster sales despite their limitations. So many of them have modest efficacy. About a third of patients don't respond. These agents take weeks to work, and they have unfavorable side effects, including weight gain and sexual dysfunction.
Also, it's important to note that neuropsychiatric drug development has had challenges in the past, and we believe that Seaport Therapeutics is uniquely positioned to address those challenges. The first is that these unvalidated mechanisms have had a very poor clinical trial success rate, and we're starting with drugs that we know are active, so we have a very big advantage in this arena. Also, we mentioned the poor oral bioavailability and side effects profiles that have held back these drugs. We're able to overcome some of these issues with our Glyph platform and create new composition of matter IP. And then the third issue is that clinical studies in this space have been challenging. We have high placebo responders, professional patients, subjective endpoints, and we think that we're really well positioned to address this as well.
Number 1, because we know a lot about the drug and how it worked before in humans, but also because there's better technologies today, including EEG biomarkers that can help us separate out placebo responders and other technologies. So all of the, the programs in the Seaport Therapeutics pipeline are based on PureTech's Glyph platform. Again, that was invented, co-invented by PureTech, building on the work at Monash University of Chris Porter. And what it does is it takes advantage of how the lymphatic system absorbs fats, in order to enhance oral bioavailability, reduce the dose, reduce first-pass hepatotoxicity, and provide novel composition of matter IP, and we've proven this in the clinic. So, the Seaport Therapeutics pipeline, we have multiple programs all building on the same strategy.
The most advanced is post phase II-A, LYT-300, which we're advancing for patients with depression, with comorbid anxiety. Those patients with MDD and anxiety are less likely to achieve remission, slower to respond to treatment, and have a poor quality of life. So we really believe that these patients need a new medicine for their, to make a difference for them. And LYT-300 is a Glyph version of allopregnanolone. It's an oral version. As you may know, allopregnanolone is an endogenous neurosteroid. It has clinical validation in postpartum depression, which is really the quintessential anxious depression, as well as in anxiety, including in our hands, and we'll talk a little bit about that. But in the past, the other forms of allopregnanolone have had issues. There's an IV version which requires a 60-hour infusion.
There are oral chemical analogs that may not retain the full therapeutic potential of endogenous allopregnanolone. So 300 retains activity and potency of endogenous allopregnanolone in an oral form, and we've now shown in a phase I study that we can achieve bioavailability 9x greater than published data with oral allopregnanolone. We've also shown that we can get target engagement and therapeutically relevant blood levels. The AE profile was generally well tolerated, so it all looks really good. We then followed that with a phase II-A study in acute anxiety, and this is with healthy volunteers. Those of you who aren't familiar with it, the Trier Social Stress Test is a validated clinical model of anxiety, and what it does is it puts the subjects in a stressful situation and measures salivary cortisol.
What we were able to see in this study that LYT-300 blunted the salivary cortisol response, and the effect size was on par with the best that was seen in this model. The p-value is 0.0001, and we think this provides further support for the anxiety portion of the anxious depression that we're gonna be pursuing here, and also further validates the Glyph platform. As mentioned, all of the programs in Seaport Therapeutics, and actually many of the programs in PureTech, build on this concept of validated efficacy. In the case of LYT-320, Glyph agomelatine, very similar story. Agomelatine has been clinically validated, it's approved in Europe and Australia, and it has a differentiated mechanism of action, which is really important because we haven't had new anxiety agents since the early 2000s.
So one of the things that we're really excited about is the consistent and statistically significant efficacy against placebo in four out of four generalized anxiety studies that were run with agomelatine. And it has superior efficacy and tolerability to benzodiazepines and SSRIs, but it has low oral bioavailability, and as a result of that, it requires liver function monitoring because it has sometimes elevated liver enzymes. So LYT-320 has now shown, first of all, that we have 10x greater bioavailability than agomelatine in non-human primates, and we've also shown in the FDA DILIsym model that we believe that there's much less likely to have these liver enzyme elevations. So, and of course, novel composition of matter IP.
So, this is just a snapshot of all of the things we're doing at PureTech, but one of the things that we're really excited about is this R&D model and how it's proven itself and how it's repeatable and scalable. We have a number of milestones coming up, both in our wholly owned pipeline and our founded entities. Importantly, the results from the phase II-B study of LYT-100 in the fourth quarter. And as I mentioned at the beginning, PureTech is dedicated to our mission of changing the lives of patients with devastating diseases, and that would not be possible without an amazing team of people that are really committed to this mission. And so I'm really pleased to be joined by Eric Elenko, who's one of those amazing team members, and to join Peyton for Q&A. So thank you very much. So yeah. Okay.
I guess, does the audience have any questions to start off with? All right, then I'll read some of the ones that I have. The main question I've got for you guys is: how do you, how do you, with your R&D platform, how do you make sure that no one else can copy your secret sauce? Like, what gives you that, like, ability to do it better than other hub-and-spoke model companies that are out there?
Yeah, I think we were the OG hub-and-spoke model. So, I think that there's room for multiple models, just like there's room for multiple biotechs, and the approach is one part of it. The other part of it is the ideas and the, you know, the team and the research. So I don't know if you have anything to add to that.
No, I think there can definitely be more than one hub-and-spoke model and have more than one company be successful. It really just comes down to the details of what a company is doing.
Yeah, and so I guess moving on to kind of the next questions, just because you have pointed out that neuropsych development is so difficult, and you guys have already had one major win for $14 billion, as you guys have noted, are you sure that you can reproduce that, or is this a once a blue moon recurrence? Because it seems like you guys are going for it again.
Yeah, for sure. I mean, I think that that's really what we're doing with this model is we're taking, you know, these three elements of starting with validated efficacy, addressing a key limitation, and then running a killer experiment to really prove out our hypothesis. And that's exactly what we did there, and we're doing it, and, and actually part way of doing it across multiple programs in our pipeline.
So I guess kind of, following up on that, why did you choose to go after, neurosteroids, especially given, you know, some of the recent developments in the space, and especially in MDD, where it's been a little difficult? What makes, your particular program better, than, you know, say, some of the other competitors out there?
Mm-hmm. Do you want to answer that?
Yeah, you know, in our case, we are taking endogenous allopregnanolone versus synthetic analog. Of course, allopregnanolone worked in postpartum depression, as Daphne was outlining, which really is as you were describing, Daphne, a quintessential anxious type of depression, and then we're taking that and making an oral form of the drug. And because of the nature of allopregnanolone, if you look more generally around the evidence for the class and also for allopregnanolone in terms of its experience in PPD and preclinical evidence, we think depression with anxiety will be particularly well suited for that indication and program. And again, key here is being able to have an oral version of the drug.
I guess kind of as a follow-up question on that, are you making any modifications, or is it just endogenous allopregnanolone? Because it's synthesized pretty quickly.
Yeah, so, what we do in the case of Glyph for each of our various drugs, these are prodrugs that we make. And so we take the drug, and we attach a proprietary linker and then a lipid tail. And that's what allows these prodrugs to be absorbed like dietary lipids that go through the gut-draining lymphatics, ultimately through the thoracic duct, to end up in circulation, the enzymes cleave off the linker. And so the active component here is the endogenous neurosteroid itself. But we are making these prodrugs, and the benefit of that is we end up with novel composition of matter intellectual property.
Great, and I guess moving kind of to more of the near term, the near term program and your LYT-100. I mean, it's kind of a similar thing with the neuropsych space, right? IPF has been proven to be really challenging, and multiple companies have discontinued their IPF programs. What are some of the differentiating factors and reasons to believe in IPF for LYT-100? And I guess as a follow-up, what kind of indications would you also kind of consider for the program?
Yeah, if you think about some of these unvalidated mechanisms, they have run into issues as they've expanded the n. You know, they might show some really intriguing efficacy with small numbers, but then as they get more patients and longer follow-up, that benefit shrinks somewhat. In the case of pirfenidone, we know that, you know, it extends life in these patients, but patients can't stay on it. And so we think that, if we're able to repeat the efficacy, but with our improved tolerability profile or increased, increase the efficacy at the higher dose, then that could be really meaningful. I don't know if, Eric, you want to take the second part of that?
Yeah, absolutely. So the other area that we're, have thought of and considering is progressive fibrosing interstitial lung disease, PF-ILD, IPF, being an example of PF-ILD. There are a number of other PF-ILDs that exist. Really, the theory is that while there are a number of insults, those insults ultimately converge on a common pathway of fibrosis, and therefore, an antifibrotic drug in the context of pulmonary setting, could be therapeutic across the PF-ILD spectrum.
Great. And then one of the other questions that I have is with CNS drugs, prodrugs in particular, it's a lot difficult, more difficult to titrate them, especially in epilepsy indications. How are you guys thinking about ultimately developing the cannabidiol program for that? And when it comes to titration, can you get really good, like, step-up on it with the prodrug formulation, or is there some other modifications that you'll need to use?
Mm-hmm.
Yeah, it's interesting. So I think the challenge with CBD really is the low oral bioavailability, and, and you're right, it tends to be dosed by body weight. And the challenge then becomes that as one goes up on body weight, you need higher and higher volumes because CBD is given the sesame oil formulation. And that becomes problematic because that can cause adverse events, you know, GI tolerability being the most prominent. And so what we'd be looking at here is reducing the volume that's required and actually being able to use capsules instead of, these large volumes of sesame oil. And we think that would be particularly important for an adolescent or adult population. And presumably then, while there might be some body weight component, it would be much easier to have likely flat dosing.
But in general, I would say, you know, with our Glyph platform, what we're really trying to do is, we know what a therapeutic dose is based on exposure, and then in phase I, if we can match that exposure level and also have the tolerability profile we want to see, then that becomes a really key de-risking event. So it's kind of interesting for us, phase I is actually a major value inflection point for anything coming on the platform.
Yeah, and then, so I know that you guys have this large model where you can build a lot of different companies. How do you prioritize one company over another? Does it have to be preclinical data, or is it really, as you pointed out, like you have proven efficacy? Is it all about clinical data, or is there any way else that you can, like, differentiate these things? Do you also think about like IP or patent life or?
Yeah, so, I think one of the things that we really pride ourselves on is that we set the bar for what we think is gonna translate into success from our perspective before we do the experiment. And usually, it is a clinical experiment. Sometimes we can get the answer in an early clinical experiment. Sometimes there's a preclinical experiment that can really help de-risk the program. In terms of like what we prioritize, it's really areas where we can make a big difference for patients, where we have novel IP, of course, and I think where we believe that the chances for success are really greater than in other cases.
The team is motivated to shut down programs that don't meet that bar, which I think is one of the unique elements of this model, sort of the diversified approach, is that we can, we don't mind shutting something down. It's not like it's our only program, and we have to keep it going. And I think that's actually a really important incentive that's built into our model.
Great. I guess in the last 30 seconds here, what are you most looking forward to in 2024 from PureTech and, I guess, the entire biotech space?
Ooh, that's a hard one. The entire biotech space. I mean, I'm excited about what we're seeing in the markets in biotech, and, you know, I think that most people I talk to are really optimistic about that. From a PureTech perspective, I'm really excited about the things I talked about today, so the phase II-B study in IPF for LYT-100 in Q4, and, Seaport Therapeutics and also other founded entities and other programs that the team is, advancing. So, yeah, very excited.
Well, thank you very much.
Thank you. It's nice to meet you, Peyton. Yeah. Thank you.