Welcome to the second day of the Bank of America Healthcare Conference. I'm Geoff Meacham, I'm the Senior Biopharma Analyst here, and we're thrilled to have Gossamer Bio. On stage with me is Faheem Hasnain, who's Chairman and CEO, and Richard Aranda, who's Chief Medical Officer. Although I think. Development. I think he would like that title. Yeah. It's an upgrade. Right. Exactly. Exactly. Well, let's kick it off, Faheem, with sort of a bigger picture. When you guys founded Gossamer, the idea was to have, you know, different therapeutic areas and differentiated drugs and drawing from your many years of experience, you know, knowing what you know what constitutes that. You've had some de-risking data sets, and you've had some that, you know, that are sort of mixed. Yeah. Give yourself kind of a where are we today with respect to the whole portfolio? Right. Geoff, as you said, we started off the company with a number of different assets. We've had, I'll call it a clearing event of a couple of those assets. Yep. Where we've deprioritized any further work. The most notable one was GB004 for IBD. We didn't hit on the primary endpoint, so we made a pretty quick, rapid decision to terminate that program. What that's actually done now is it's given us the chance to elongate the runway, which will allow us now to see a stronger data set for our brain penetrant BTK in CNS lymphoma. Yep. As a lineup, we've got seralutinib, which of course we're very excited about. We'll see that data at the end of the year. We completed enrollment. It's a novel mechanism that I think investigators and patients deeply need new mechanistic approaches in that disease. We'll see that data at the end of the year. That's the TORREY study. We will see some level of data around ASH time for our CNS lymphoma program. Yep. That's a dose escalating trial. I think probably the clearer inflection point will become a couple quarters later where we'll have a more robust data set at more relevant doses. That elongation of the runway really allows us to get to that second inflection point beyond seralutinib. Perfect. Let's talk about the PH space in general. We've seen a lot of BD activity, I think, in the PH field. You know, there haven't been a lot of novel mechanisms, and it's been a lot of the same drugs and various, you know, combinations, but there still is a significant unmet need. Walk us through the backdrop of, you know, how you view a PDGFR as an add-on and what impact it could have, and we get into some of the data. Great. Well, as you rightly said, this space is in need of new mechanistic approaches. Right now it's really characterized by prostacyclins, vasodilators and a new mechanistic approach is, you know, really much needed. At this point now, there's 2 approaches that appear to be really promising. Sotatercept, which is Acceleron's program that sold, and then seralutinib. Our program, really the genesis of that was the imatinib data that was generated by Novartis in the IMPRES study, where we saw really impressive results in their phase 3. Consistent results through to phase 2 and phase 3. The problem was that program was plagued with toxicities, safety problems. Really we came along a molecule that had been developed with the concept of targeting specifically the targets of interest, so in this case PDGFR, c-KIT, CSF1R, and specifically designing this molecule to be inhaled. That's really a critical component, because that's the added safety wrapper to the program. We're getting the drug to the site where it needs to be in the lung, designed it specifically to be an inhaled approach to the molecule, is tailored for that, and then hitting the mechanism, the targets of interest. Gotcha. What we would expect is that, you know, what we saw early in the preclinical studies was some really interesting remodeling disease modifying effects where we saw complete clearing of the lumen. Of course, you know, that'll be a little bit more hard to define in the human context, but there is a notion out in the community already that these two programs, sotatercept and seralutinib, appear to be where they're being viewed as disease modifying or reverse remodeling agents. Yep. that means that not only will they be used in combination, but potentially earlier in the course of therapy. Right. Presumably with a longer duration of therapy too. Right. Let's talk a little bit about, you know, kinda the evolution of PAH in terms of the endpoint. Used to be six-minute walk, you know, and that sort of became the leading indicator for things like, you know, outcomes, you know, transplantation, you know, death, hospitalizations, et cetera. Going before that, though, things like looking at things like PVR, right? Vascular resistance is really key. Walk us through kinda what, you know, how predictive do you think, you know, some of the biomarkers you're looking at are going to ultimately be, looking at a walk test or a real outcomes kind of trial? The phase 2 TORREY study, our primary endpoint is PVR, which arguably is a more objective measurement. We're not powered for six-minute walk. Right. Let me turn it over to Richard to kinda fill in the rest. I think there still remains challenges in the field on what the endpoints and how they act as surrogates for predictive value in the future. You know, as we all know, PVR is an important phase 2 endpoint. It's important to show hemodynamics. Yep. The literature is rather mixed, and it's not very strong that it is predictive of six-minute walk effects. Nonetheless, if you have a positive hemodynamics, you should improve your functionality, you know, at a patient level. The issue is, are you able to demonstrate it at a population level as part of a clinical trial? I think right now, for a phase three program, I think six-minute walks remains an option. Although folks are trying to think of ways to add something onto the six-minute walk to first of all improve its sensitivity for detection, because now as patients are getting better treated, the ceiling effect is really becoming more prominent now. Right. Is there a way that we could use heart rate monitoring or other biomarkers that really yet needs to be defined, but NT-proBNP could be one that you make some kinda composite? Right. You know, it seems to me looking at some of the six-minute walk tests over the, you know, a lot of the pivotal studies over the past, say, decade or so, a lot of the success or failure depends on how the standard deviation and the baseline. There's a lot of subjectivity, there's a lot of variability, but PVR is a more natural. You're not really affected by baseline, right? I mean, it's a more natural, you know, predictor of sort of a. More of an objective measure. Yeah, objective. Yeah, that's exactly right. But the other ones that you mentioned, though, you know, NT-proBNP, like what's sort of the field saying in terms of the validation of a lot of these other biomarkers, and the totality of how that may ultimately, you know, get a patient on the study or convince physicians the value of the drug? Yeah. I think it's another concept is around risk stratification. Yep. Right? Low to high risk, where NT-proBNP and six-minute walk and to some extent PVR are components of that. One could envision that composite, you could enroll a patient perhaps that are at high risk, and you try to move them down to intermediate or low risk, they're intermediate risk and you try to change them to low risk. You just need a move in one of those three parameters, if not more. Right. Beyond PH though, if you see an effect on resistance, you know, how are you thinking about other indications within cardio? There's actually a lot, you know, with respect to, you know, COPD, ILD, et cetera. What's the kind of capital consideration and investment consideration beyond PH? Well, I could go through the indication part. Yeah, go ahead. I think the natural extension at this point would be some other groups of PH, like for example, as group three, PH. Yeah. that associates with ILD. That's probably the more natural extension from a group one. Gotcha. Right. Okay. When you think about you know the study readout coming out, is there sort of a you know a clinically meaningful. What would be sort of a, I wouldn't say a bogey, but what would be in your minds you know ultimately predictive potentially of six-minute walk and put you on the same track as, for example, like you know Acceleron was with their initial you know phase 1, 2 data? Well, as it relates to the TORREY, I mean, obviously we're mostly focused on the, on PVR. Yeah. Being able to see kind of results that were in the range that we saw with sotatercept. Yeah. That kind of 18%-30% kind of delta is what we would hope to be able to see. Gotcha. Okay. Well, let's switch gears to the rest of the portfolio, Leon. The BTK. You know, it's interesting. There's been a lot of pretty significant investments in the BTK field of late. For many years, you know, it was pretty much just ibrutinib, right? Now we know there are lots of, you know, CLL, you know, a number of different liquid tumors, right? That we need, you know, patients are refractory. There are some that are not as responsive or suboptimally. The brain-penetrant component here. Help us with kind of the, you know, how you first thought about this and looking forward to, you know, the differentiation. How do you see that shaking out? As you said, GB5121 is a very interesting compound in that it has a really potent brain penetration abilities. When we compare it against all the other BTKs, I think we believe we've probably got a best in class in that context. Yeah. As it relates to CNS lymphoma, it's just high unmet need, Geoff. It's, you know, these patients, they're treated with high-dose methotrexate. It doesn't work particularly well. What's really interesting is that we have some good level of validation with ibrutinib that is used in these patients, but actually at double the dose that you normally would dose ibrutinib. Of course, that comes along with some challenges and toxicities, but we do see good results. Ibrutinib is not approved for CNS lymphoma. We have the potential to be a first in class in the context of approval for this at a with an agent that's more tailored to be able to cross the blood-brain barrier and make an impact for these patients. That's the point of differentiation, and, you know, these patients really don't have a lot of options, and, survival is not great. Hopefully, we can make a difference in that context. Gotcha. How do you see, you know, when you look at some of the competitive landscape here, you have sort of covalent versus non-covalent, you know, Faheem, you've seen a lot of different, you know, nuances in terms of the product profile, and that does matter ultimately to patients and in the marketplace. You know, how do you see some of the other BTK potential products playing out as a potential competitor? Well, right now, tolebrutinib, which the Sanofi program is vectored towards MS. They don't appear to be going into these types of indications. We've got ibrutinib as well. I mean, both are covalent brain penetrant, but when we do our kinda side-by-side comparisons pre-clinically, again, I think we feel that we've got superior brain penetration capabilities. We seem to be moving forward to CNS lymphoma where others aren't. Ono has a program that is approved in Japan for CNS lymphoma. Whether they can do some work here in the States, I think still remains to be seen. Gotcha. Okay. Just given the mechanism, I know, you know, CNS lymphoma is the primary indication, but how would you see the brain penetrant attributes, like, playing out with respect to other indications? Yeah. We think there are a number of adjacencies that would also be appropriate to explore. Richard, do you wanna comment on? Obviously, secondary CNS lymphoma that goes from peripheral lymphomas that go to the brain. There's vitreoretinal lymphomas that are part of the constellation of CNS lymphomas that BTKs are mechanistically have shown some promise. In addition, there's even non-Hodgkin lymphomas where you could get recurrence in the brain. If we even go to the solid tumor, there's some preclinical data coming out or has been out that glioblastomas seem to have some BTK component to them. I think beyond just the primary CNS lymphoma, there's, as Faheem was mentioning, there are some other tumor type adjacencies. Yeah. I mean, you can definitely cross the blood-brain barrier with a mechanism as broad as that. Mm-hmm. Yeah. Switching gears to, you know, to MS. You guys have had, you know, you have earlier stage asset on that. Just talk a little bit about, you know, where are we with that development? We can talk about, you know, differentiation. Yeah. That's also a brain-penetrant BTK, a separate molecule. It's called 7208. We actually have hit the pause button until we see the TORREY study. Largely, that's back to the notion of expanding the runway to make sure we've got a robust data set around 5121. When we turn over that, those data cards, we'll still have a year of cash in the bank. Having said that, moving forward with 7208 would likely be in the MS space, but unlikely to be a straight run-of-the-mill run into relapsing MS. We are really exploring differentiated paths into MS. Think of secondary progressive MS, PPMS, subsets of MS. The main reason for that is that, you know, we've got other BTKs, as you've already mentioned, Geoff. Yep. that are ahead of us. Yep. We're gonna look to try to leapfrog through some other points of clinical differentiation. Gotcha. Yeah, I mean, when you look at MS, and you consider it to be a potential inflammatory disease, right? I mean, you can hit a lot of, you know, forms of MS, but also, you know, other CNS-related indications. How fast do you think you could restart, you know, or sort of allocate capital, you know, to this program when you get the de-risking of it? Yeah, pretty quickly. Okay. I mean, the program was slated to do healthy volunteer study, back half of this year, so we're poised, ready to go. For us, it was just a decision of prioritization around, you know, best use of our capital and making sure we get to inflection points that the street kinda cares about. Right. I mean, MS is a pretty large, you know, investment in terms of the market opportunity, it's there obviously, but it's a, you know, phase one, phase two studies are fairly capital, you know, intensive. What about could you evolve the model a little bit to go after more rare, you know, kind of orphan, you know, diseases that have maybe a BTK in neuro itself, that BTK kind of implication? Yeah, it's interesting. We're exploring. Do you wanna comment on? You know, I guess the way we conceptualize it is there are other indications where B-cell-targeted therapies, not necessarily BTK per se, but B-cell-targeted therapies like NMO, neuromyelitis optica, or MOGAD, another one of those antibody-driven diseases that primarily affect the brain. Then there's even you know, there's emerging data that microglia signal through BTK, and that seems to drive a lot of the neural degeneration that's actually seen in MS as well as other diseases such as Parkinson's. That's the other angle our scientists have been looking at researching on, is can we leverage that to do something other than MS. I know that the TORREY study is sort of the gating factor here. You know, Faheem, what about bringing in other assets from a capital perspective? You know, what sources of non-dilutive capital could you leverage? And is there an appetite to kind of expand it and along the same line of thinking with respect to CNS or and BTK as a mechanism? Well, at the moment, as we sit here today, all of our capital is really laser-focused on getting these next two programs over the finish line, as you can imagine. In the event that we see positive TORREY data, you know, we'll be able to reevaluate. We're gonna be getting ready to move that right into phase 3, so the capital allocation will be pushing that forward as fast as we can. Of course, expanding the opportunities with GB5121 into the adjacent indications. Whether we get back to the business in-licensing a play, you know, I'm not sure. We do have a research pipeline where we've got some really interesting programs that we'd be filing for IND next year. you know, at this point in time, I think the programs that we've got in place are the ones we're most excited about. Gotcha. Okay. With respect to the TORREY study, maybe give us a sense for, you know, size and scope of, you know, of a PH, you know, phase 3. What are the lessons learned from some more recent ones that maybe you could have an expedited sort of trial? Richard? Yeah. I think Acceleron has a pretty broad program. You know, they have one in what I call early PH, one in their standard PAH population of their phase 2, and then they have one in really later stage PH, where they're trying to rescue patients. To be competitive, we probably need to have a broad vision and broad scope as well, and even consider that assuming sotatercept makes it on the market ahead of seralutinib, that it could be used in combination in some way, or at least the field may be interested in that. I think that's the breadth. Obviously, we do wanna focus on what I would call the registrational trial itself, which, you know, as we sort of discussed earlier, likely six-minute walk or six-minute walk plus will be the endpoint, and we would try to execute upon that as quick as possible to get the drug to patients. Right. If you look at some of the more recent, you know, for example, United had the success of Tyvaso in interstitial lung disease, PH associated with ILD. Is there sort of an adjacent, you know, if you were to go into a pivotal, are there indications that you think you wouldn't have to quite go back and do a phase one, but you could do maybe a registration phase two? Is that reasonable, or is you know PH just you know gonna be the sole focus of the investment? No, I think there is an opportunity like that to supercharge a phase 2 in another group. You know, for example, group 3 as we discussed. You know, we'll have to have discussions with the regulators and then look at the strength of our data. Right. Hopefully by then, we'll. I mean, we haven't seen much of a COVID impact on so far. I think things in development in the cardio field, but have you guys seen anything over, you know, of the development of the program that, you know, that sort of would be a delay or would be impactful? Well, I mean, this program, the TORREY study, I mean, we absolutely dealt with delays as it related to COVID. You know, the team persisted, and we're incredibly resilient, and we're able to get the trial enrolled as we've now announced that we're fully enrolled. There's no question that COVID was a bit of a challenge because a lot of the treaters were the ones that were being required to go into the ICUs and treat COVID patients during kind of the height of Delta. You know, that's always gonna be a concern as we go forward now in terms of whether or not it creates a delay. The Omicron variant, it wasn't as much of a delay and because we're not seeing as much hospitalization. Hopefully we're through the really difficult spots now. Yep. Perfect. Okay. Well, with that, guys, thank you very much. Yeah. Thanks. Appreciate it. Okay.