All right. Good morning, everyone. Thanks for joining us here at day three of the Leerink Partners Global Biopharma Conference. My name is Tom Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to introduce our next company, PureTech Health, and they're represented today by President Bharatt Chowrira and Chief Innovation and Strategy Officer Eric Elenko. Gentlemen, thanks for joining us.
Thank you.
Thank you.
Awesome.
Yeah.
Bharatt, maybe you can just start by giving us a brief overview of the company for those in the audience who may be a little less familiar.
Great. Thanks, Tom, and I wanted to thank Leerink for inviting us to present today. Also, welcome to people here in the room, as well as those who are following on the webcast. So, you know, today, we'll talk to you about the exciting PureTech story, our innovative R&D model, and all the progress we are making across our pipeline, both through the founded entities as well as internal wholly-owned pipeline. So before we start, I wanted to kinda remind everyone that during this discussion today, we'll be making some forward-looking statements, and so please follow our filings, regulatory filings, including SEC filings, for up-to-date information, so.
So with that, the mission for at PureTech is to, you know, what we call, you know, breathe or give life to new medicines that have the potential to change people's lives with devastating diseases. And we are, you know, addressing that and delivering on the promise of that mission through the, you know, the pipeline that so far looks very promising. And this pipeline was developed using our, you know, very differentiated R&D model, which we call the hub-and-spoke model, and which we pioneered. And these programs are poised to really, you know, deliver, you know, major benefits to the patients, you know, dealing with the devastating diseases. And so we will talk more about that as we, you know, go through today.
So we have been very successful with our R&D model, where we've been responsible for developing, you know, 28 new therapeutic candidates and products to date, either through our founded entities or through our wholly-owned pipeline. Two of these programs have gone from inception at PureTech all the way to FDA, EU regulatory clearances. Another one, KarXT with Karuna, is being reviewed by the FDA, and hopefully, you know, we'll get some positive news from that later this year. One of the other, you know, unique aspects of our R&D model is that we've had really good, you know, a track record of success.
You know, more than 80% of our clinical trials, either through founded entities or internal, have been successful, which is about six times , you know, better probability, compared to the industry average. So we have, we have a pretty good track record of delivering on these, you know, new medicines, and I think the key to this R&D engine is that it is repeatable, it's scalable, and we have demonstrated this multiple times, as built around the three pillars. You know, we start with the validated efficacy, so we start with a program or a molecule that has demonstrated some kind of a human data, and for one reason or the other, has been held back because of either, you know, oral bioavailability issues, tolerability issues, and so on.
So we then deploy a proprietary, either technology or approach, to address those shortcomings and then open up the, you know, broad potential of those molecules and unlock that for the patients. And then, you know, these have to be meaningful benefits to the patients, and, so we have. Very early on, we do these so-called killer experiments to actually, you know, validate or test the hypothesis. And then, because, you know, we have multiple programs, you know, we are very disciplined about, you know, shutting down programs that do not, you know, have a strong data set for the hypothesis, and then deploy those capital to those programs that are showing more promise. So we have, through this, we have had a very strong track record of success.
As I mentioned earlier, about 80% of our clinical trials, you know, have been successful. So this unique R&D model, which we call the hub-and-spoke model, we pioneered a number of years ago, and so we have a number of companies. So the central part, the hub, is the PureTech, where we have, you know, an experienced R&D team, and capabilities, and extensive network that allows us to start these programs de novo. At PureTech, we incubate them, and then as they show some promise, we then, you know, house them in wholly-owned subsidiaries, which we call founded entities. Those are the spokes in the hub.
So we've had, you know, a number of these, you know, founded entities over the years, and, by far, our one of the most successful of these founded entities has been Karuna, and its KarXT program, which is currently in front of the FDA for approval. We also announced a couple of new founded entities in December. Seaport Therapeutics, which has a group of really exciting, we believe, you know, CNS programs, you know, along the lines of, what we were able to do with Karuna. And so, you know, these programs, you know, could have significant potential, which we call Karuna on steroids, you know, potential. So, and then we have this oncology program, LYT-200, which is targeting galectin-9, which we are also looking to spin that out.
We have a very strong cash position. We have GBP 320 million last reported cash, estimated cash, cash equivalents, and short-term investments. And this does not include, you know, the proceeds that we expect once the Karuna transaction with BMS closes, about additional GBP 294 million coming into PureTech. With the current cash, without including the Karuna proceeds, we have cash through operational runway through 2027, into 2027. And our, you know, so-called evergreen model is where we, you know, monetize our stakes in our founded entities and bring back the cash into PureTech to deploy, to create new programs.
It's almost like an evergreen type of a model and has, you know, enabled us to fund all of these programs, and we haven't had the need to go out and raise money in the public markets for the last six years. So we are in one of those unique situations. Our Founded Entities are not dependent on us for capital either. You know, each one of our, you know, combined, our Founded Entities have raised over the last few years, about $3.8 billion, and 96% of that have come from external investors. So it's a fairly, you know, robust model and well-validated and scalable.
So, you know, with the Karuna, it's a great case study where, you know, we invested about $18.5 million before we spun it out and took it public, and it has already delivered about $815 million in value back to PureTech. And that's not including the additional $294 million we expect to receive after the Karuna transaction closes with BMS. And we, in addition, we have royalties on the KarXT program, which we were able to monetize, you know, through a transaction with Royalty Pharma, where we got $100 million upfront, and we are eligible for additional $400 million in milestones, both regulatory as well as commercial milestones.
So it's been a very good, successful story for us for this and validation of this hub-and-spoke model in which we are, you know, repeating and scaling. So, our wholly-owned pipeline, which we've been building over the last several years, have really been quite exciting. And, out of this, we have now decided to, you know, house a group of CNS programs at Seaport Therapeutics. Our oncology program is gonna be housed as a new founded entity, Gallop Oncology, and our lead program at PureTech is LYT-100. That's currently in phase II-B study. That's, we expect top-line results, in the fourth quarter of this year, for treating idiopathic pulmonary fibrosis, and we'll talk more about that as we go forward. So with that, I'll, invite, you know, Eric to join me on the fireside chat and Tom, take it away.
Sounds, sounds good. And, yeah, let's start with the wholly-owned pipeline and the lead program, LYT-100. And this is a deuterated pirfenidone. Maybe you just level set and walk us through high level, some of the expected benefits of the deuteration here, and then talk about the phase II-B trial design, and then we'll, we'll kinda go from there.
Yeah. So I, I'll start, and then Eric, feel free to join, right? So LYT-100 is a program that we initiated a number of years ago. It's a deuterated form of pirfenidone, which is an approved one of the two approved standard of care treatments for IPF. And so the current standard of care has significant limitations in terms of the you know severe adverse events and tolerability issues, which limits its broad usage, even though the you know pirfenidone is a very effective drug, its usage is significantly hampered by you know significant dropout of once people start on pirfenidone, you know, about half the patients drop out or dose reduce because of tolerability issues.
So deuterated form of pirfenidone aims to improve the safety tolerability of the treatment, and we'll talk more about that. So that's a program that's currently in phase II-B. You know, the beauty of deuterium modification is that you're not changing the pharmacology, you're maintaining pharmacology, but vastly improving the differentiating PK profile. That then translates into, you know, potential benefits from tolerability. So maybe Eric can talk more about the clinical data so far and the trial that's ongoing. So...
Yes, so we've run a few phase I studies, but probably the one that is most relevant to this discussion of comparison of adverse events to pirfenidone was a head-to-head study in healthy older adults. The reason for older adults is that IPF is a disease of older adults, comparing the equivalent dose of LYT-100 to the highest dose use of pirfenidone, so on an exposure basis. What we saw was very clear, significant reduction in adverse events, GI adverse events being the most prominent, about half of the incidence of GI adverse events being observed. And so that was something that we were very happy with. One of the things, you know, Bharatt was outlining was this idea of trying to define success in advance.
You know, one of the things we heard is, "Hey, even have a 25% reduction, 30% reduction, that would be great." And we saw something that was actually even better than that. And then in a separate study, we were able to go and, you know, titrate up and actually have a dose of the LYT-100 that was about 50% higher dose of the commercially equivalent used dose of pirfenidone. And so what we've done is, we're now running a phase II-B study. It's a 4-arm study, 240 patients, same number of patients per arm. Placebo pirfenidone, the dose of LYT-100, equivalent to the commercially used dose of pirfenidone, and then also this higher dose of LYT-100. And that will be reading out in fourth quarter.
Great. Maybe we could just follow on to that and walk us through your expectations for that readout, and then just high level, is the goal here to be more efficacious than pirfenidone, better tolerated than pirfenidone, more convenient, or a combination of all three? Like, what's the base, what's the base case?
Yeah. So, we see this program in two different ways to win, you know, with LYT-100, you know, for the patients. One is with a matched exposure, which is our 550 mg dose, 2x a day. You know, if we are able to demonstrate better tolerability, we'll be able to allow these patients to stay on the treatment longer. That could translate into a better disease outcome for the patients.
So that's one, you know, clear way to win, and that's what we hear from a lot of the pulmonologists that we have surveyed, where they said, "If only you could keep the patients long enough on either pirfenidone or nintedanib, that they would get, you know, a significantly better disease management." So we think with the LYT-100, we have the opportunity, with that matched dose, to become the backbone therapy with, you know, better tolerability, better you know, adherence and compliance, and so on. So the bonus, of course, is that, you know, if we could increase the dose of deupirfenidone to the higher exposure, then that would, you know, potentially have an added advantage in, you know, having better disease, management as well. So there are two different ways we see as, you know, potentially be attractive for the patients.
I don't know if, Eric... Yeah.
Got it. Okay, and let's, I guess based on the, the Q4 2024 guidance for data, it seems like you'd have to complete enrollment in the study somewhere between May and June. I guess, do you feel like you're on track to do that? And when we think about enrollment, I mean, there have been a number of IPF programs that have concluded recently. Have you seen anything, I guess, concurrent with those programs wrapping up that has maybe boosted enrollment or changed the, the rate of enrollment into the phase II-B?
Yeah. So we've been enrolling. The study is a global study, of course, includes U.S. sites. Yeah, we feel good about the guidance that we've given in terms of being able to have the readout in fourth quarter. So based on what we're seeing and what we've seen, that guidance remains on track.
Yeah, and we're. And this is, as you know, Tom, and this is one of the only study that we are aware of where we are actually running against placebo, right? So, and that, you know, initially had some challenges for us, but we've been able to overcome that, and we are on track right now, so.
Okay, that makes sense. And just, when we think about the commercial opportunity for this, where do you see this fitting into the IPF treatment paradigm in a world of generic pirfenidone and generic Ofev?
Yeah. So I'll start, and feel free to chime in-
Yeah, please.
Eric. So we've done a bunch of market research on this, right? And also published data from other people have shown that the combined usage and adoption of the current two standard of care drugs, right, nintedanib and pirfenidone, the combined usage is about 25%. So the vast majority, 75%, of the, you know, patients with IPF are currently not on either of these two drugs. And so that's primarily because of the poor tolerability of the two drugs. And so with the advent of generic pirfenidone, you know, we did not expect a significant increase in prescriptions, and that has actually played out. You know, if you look at the last year, the number of prescriptions, or at least the usage of pirfenidone, hasn't jumped up very dramatically.
So we see that, you know, generic pirfenidone or generic nintedanib, when that comes to the market as well, that it's not gonna change the prescription behavior because you still have to deal with the same level of, you know, safety tolerability. So we feel like with the LYT-100 profile, with, you know, at a minimum, comparable efficacy, with better safety tolerability, that we have the opportunity to become the backbone therapy for IPF, where we could not only take market share from existing standard of care drugs, but also expand into that 75% or so of patients who are currently not on the drug. So we see this as a pretty, you know, significant commercial opportunity.
And beyond IPF, we see PF-ILD as a broader opportunity as well because, you know, pirfenidone is never really studied actively and approved for PF-ILD. So we have the opportunity to go expand into that broader group of ILDs. So-
I mean, the only other thing I'll add as we think about the market landscape, there are a number of new drugs in development. Of course, we'll see, ultimately, what goes forward or doesn't go forward is an empirical question. One of the challenges for any new mechanism is the I part of IPF, right? No one really understands the fundamental pathophysiology. But, you know, if one of those drugs does manage to go through regulatory approval, if you look at how those are being trialed and how they're gonna be used, they're, you know, really gonna be used on top of standard of care.
If you think about adding adverse events to adverse events, it really is going to make having a standard of care drug that's more tolerable, even more important, not only for all the reasons that Bharatt was saying about people not starting drug for a deadly disease, but half the people dose, dosing down or discontinuing, but also to allow newer agents to actually be used. And so we really kind of look at ourselves as trying to become that standard of care.
That makes sense. And how do you think about sort of next steps post phase II-B data? Is this we move sorta directly into a phase III IPF study, we do that ourselves, we're looking for partnerships, or are we also contemplating, as you alluded to, the PF-ILD opportunity? Like, just help us think through sort of the next steps post data.
Maybe you can start with the regulatory path.
Yeah. So, first, the exact design of any study and exactly what happens next is gonna depend somewhat on the data, right? So, you know, for instance, we're going with two different doses. The ultimate dose you would use as part of the pivotal study, for instance, would depend on what we see in this study. In terms of regulatory paths, you know, 505(b)(2), we do anticipate doing, you know, one more pivotal study as part of approval. And again, that'll probably depend a little. The exact design will depend on what we're seeing as part of this IIb. And then we can, as you said, you know, think about PF-ILD as a really nice opportunity.
Also, I think, you know, we've had some inbound interest from, you know, companies who are currently in phase III, you know, who could be interested in combining, you know, with LYT-100, and we could, you know, look at running some of those studies as well in parallel. But again, you know, in terms of are we gonna develop it ourselves, I mean, currently, the plan is to, you know, evaluate all options, and again, data-driven.
Once we have the data, towards the end of this year, we'll then evaluate, you know, in terms of, how to really advance this for IPF, but also, you know, broadly across other PF-ILD indications, and how best to do that while still maintaining a significant upside, with this program and opportunities, and get some non-dilutive funding to the extent we can. And so there are a lot of optionalities in front of us that we can tap into, you know, if the data are good.
Got it. That makes sense. I'm gonna switch gears and talk about the two recently created founded entities, Gallop Oncology and the CNS-focused Seaport Therapeutics, which you alluded to as Karuna on steroids - and, it's not lost on me. Can you just talk about, I guess, the decision to create these entities rather than keep them as part of the PureTech wholly owned pipeline, and I, I guess that - how that opens up optionality for you with across both?
Yeah. So, you know, for the Seaport Therapeutics, I'll start there first. You know, it is-- the underlying technology there is what we call the Glyph platform, which is a fairly robust, you know, approach to actually creating these prodrugs or small molecules that bypasses the first-pass metabolism and goes through the lymphatic system. And that, you know, offers a number of advantages, and we've been able to utilize that technology to create this really a series of programs that initially are all focused around, you know, CNS indications. And we felt that, you know, with the data that we generated with LYT-300, which is the Glyph allopregnanolone program, oral, in phase I, as well as, you know, in phase I-B/II-A studies, that it validated that platform.
And now we had behind it a number of really exciting additional programs, where we felt a dedicated effort around the CNS programs could benefit, you know, accelerated, you know, advancement of those programs, as well as bringing in some external validation and investment so that we can then, you know, deploy some of our capital to creating some new programs. So that was kind of the, you know, thinking behind creating Seaport. Similarly, for oncology, we felt, you know, we had some initial encouraging data where, you know, again, requires a dedicated effort in oncology versus being part of one of, you know, many programs within our wholly owned pipeline in different therapeutic areas. So that was sort of the thinking behind it.
Yeah, that makes sense. Okay, and maybe just with respect to the Glyph platform, can you just talk about the aim, I guess, of the platform and trying to create drugs that aren't just sort of like me-too drugs, but, you know, you're trying to leverage, I think, really pretty well-established clinical evidence and find a way to more conveniently and maybe in a better-tolerated way, deliver, you know, deliver drugs that hit those clinically validated targets. You wanna take that? Yeah.
Yeah. So by bypassing first-pass metabolism, what that allows is for drugs that aren't orally bioavailable to become orally bioavailable, and also to circumvent hepatotoxicity when the cause of those issues is high first-pass metabolism. And that can be applied to a range of different drugs, but our focus has been on CNS. And the goal really has been this idea of taking agents which have shown potential, but which have been held back either by lack of oral bioavailability or by, you know, for instance, elevated liver enzymes presenting a problem. And the nice thing there is, it's especially for CNS, the philosophy has been rely on validated pharmacology, and that's really what one wants to bet on. And the other nice thing about Glyph is it also puts a lot of emphasis on phase I.
you know, because we then show that if we can go and give a drug and reach a therapeutic level of drug, then that really starts to de-risk the programs, because we know fundamentally a drug has efficacy.
From additional advantage of Glyph, it allows for composition of matter patents on some of these things. So from a lifecycle management, it, you know, provides very attractive optionality, as well as, you know, 505(b)(2) pathway, you know, for advancing some of these programs forward. So all of those are, you know, some additional aspects of Glyph technology that makes it very attractive for advancing this.
Yeah, that makes sense. So LYT-300 is your program currently in the clinic. You've generated some data there. You've shown an ability to reduce acute stress response in healthy volunteers. Can you just give us the high-level takeaways from that data set, and then how you see that extrapolated into other CNS disorders?
Yeah. So this was using a paradigm called the Trier Social Stress Test or TSST. It's a validated clinical model of anxiety, utilizing healthy volunteers, where individuals are asked to engage in a public speaking task and also to do math while doing this in front of a panel of two stern-looking judges and a video camera. What we measure there is an objective biomarker of stress, which is salivary cortisol. You know, this is double-blind, placebo-controlled, and what we saw was a highly statistically significant difference in that primary endpoint compared to placebo, as well as a very meaningful effect size as measured by a Cohen's d.
And so really what that did is validate not only does the drug have pharmacological activity, which we weren't surprised at, given that it's endogenous allopregnanolone, and also because of our biomarker data in phase I, but it also really showed the path forward in terms of an anti-anxiolytic component to the drug. We have said, you know, we're interested in developing this for depression with anxiety, which is an area of huge unmet need. Patients who have depression with anxiety are often more treatment resistant. There isn't an agent specifically approved for that indication. And given the data with allopregnanolone itself, as well as what we observed in this TSST paradigm, we think it'll be particularly suited for that indication.
Got it. Okay, and just in the last minute or so that we have, I wanna make sure that we touch on Gallop and the oncology program. So this is a galectin-9 targeted-
Right
- antibody. Can you just talk about the current study and I guess, expectations, both in terms of amount of data and timing for next readout?
Yeah, absolutely. So we're excited about this really, because of the mechanism of action, the preclinical data, and now in the clinic, developing this for both hematological malignancies, initially, AML, high-risk MDS. We're also looking at solid tumors, starting with head and neck. You know, mechanism here in the case of hematological malignancies, blocking galectin-9 has been shown to result in cell death, so, apoptosis, DNA damage. And, in the case of solid tumors, galectin-9 is known to be immunosuppressive in the context of the tumor microenvironment. So in the context of AML and MDS, we're doing single agent and then combination with standard of care, venetoclax, and, hypomethylating agent. In the case of solid tumors, combination with tislelizumab.
Okay, great, and
Those are ongoing-
Yeah.
Studies.
When can we expect to see a cut, I guess, of the either-
Yeah
of those studies?
So we did an initial cut, and I imagine, you know, since these are open label studies, what we've guided is that we'll be, you know, releasing additional data this year for at least the solid tumor. And, you know, because it's the nice thing about open label is you kinda see the data, and then we would, of course, look to present any data at a relevant scientific forum.
Yeah. Got it. Okay. Well, unfortunately, we're up against time, but I wanna thank the PureTech team for joining us and for sharing the insights, and we'll stay tuned.
Great.
Thank you.
Thanks, Tom.