IRulya Therapeutics (IRLA) Fireside Chat (FKA Orphai) - IRULYA THERAPEUTICS INC

All right. Hello, everyone. I'm Albert Lo, Senior Biotech Analyst, and thank you for joining our Craig Hallam Biotec Catalyst Conference. And I want to welcome our live viewers to submit their questions here on the webcast, and I'll be happy to ask them here to the team from Irulia Therapeutics. Irulio is developing an inhaled version of rapamycin for rare lung diseases. And the important catalyst that will be part of the discussion today is the data readout from the Phase II BOS study expected in the first quarter of 2027. So we're joined today by Bridget Roberts, the CEO, Keith Vandrick, the COO, Patrick Sarmier, the SVP of Clinical Research, and John Mitello, the CFO. So maybe to kick things off, I really just relaunched with this new name, Bridgette. Can you tell us about the meaning of this new name and the vision of the company? Yeah, so the new name is Irolia. Capital I, capital R is for inhaled rapamycin. And then for each of the remaining letters, U-L-Y-A, it stands for Unlocking Life-Extending Years of Airflow. And what we've created internally here is this proprietary inhaled formulation of rapamycin, which is an mTOR inhibitor, and directly targeting this pathway that is found to be highly upregulated in a number of important pulmonary diseases where treatment options are just limited today. So we're excited about the potential of this drug to help a number of these patients. All right, great. And maybe before we jump into the clinical studies, can you share what makes rapamycin particularly well-suited for lung delivery as a dry powder inhaler? And maybe what gives you confidence that you're getting the right exposures here? Yeah. So maybe if we back up a moment just to talk about the problems with oral rapamycin. So So oral rapamycin, unfortunately, comes with a number of systemic toxicities that have really been prohibitive for its adoption across these diseases, where we do know the mTOR pathway is implicated. And those toxicities, in many cases, can also limit the amount of drug that can be delivered to these patients, and thus limiting the amount OF pulmonary exposure. And then, And secondarily, it's really a poor oral drug. It has low invariable bioavailability due to first-pass metabolism in the liver, as well as being a substrate for these efflux proteins in the gut. And so by delivering this directly to the pulmonary tissues, we're bypassing those latter problems, right? We're bypassING the first-past metabolism inthe liver. We're bypassING those effluxe proteins. So that's ideal. but also, and less intuitive, this drug really has ideal properties for pulmonary delivery. And because of this, we're able to deliver a very tiny fraction of the oral dose. We're delivering 100 micrograms in our last study. That is 1 20th of the standard oral dose, and because that amount is so low, the fill that's required, you know, in these capsules to deliver it is also low. And so we're seeing really a minimal amount of cough in our studies thus far, and it's been very well tolerated. All right, great. Well, yeah, I guess good to know that this is an important part of the story is that we're getting kind of on target, or sorry, on tissue to the lungs. Maybe you could just briefly touch of the mechanism of the target in these lung diseases. Yeah, Pat, you want to touch on that? Yeah, absolutely. So we know in PHILD and PH patients that the mTOR pathway is highly upregulated in the pulmonary vasculature. And so that's, you know, based on immunohistochemical analysis of actual lung tissue from patients. So upregulation of the mTOR and its downstream signaling targets. We also know that if you take primary cells from the smooth muscle from the vasculature and induce proliferative changes by hypoxia or PDGF, that rapamycin is extremely effective at preventing proliferation in those cells. And furthermore, when you extend this into in vivo models, such as the SUGEN model and MCT models, rapamycin is very effective at not only reversing the hyperproliferation of the smooth muscles tissue, but also attenuates the vascular remodeling. And then that has positive consequence on cardiopulmonary dysfunction in those animals. So improvements there. Secondary to that, we also know that mTOR is very effective as an anti-fibrotic. And so obviously in ILDs, the fibrosis is a key metric that we want to address there. And mTOR can promote fibroblast activation, differentiation, extracellular matrix deposition. And again, it's been shown both in vitro and vivo to prevent those endpoints. And then finally, we also know that rapamycin is a very good anti-inflammatory agent, and it blocks cell recruitment and downregulates cytokine signaling in the lung in those disease models. All right, great. And I know you have shown some nice clinical proof of concept from this phase two study in PH ILD patients. Maybe you can just briefly highlight some of these findings, maybe particularly some of the takeaways on the pre-K profile as well. Yeah. So, well, okay. So in terms of the findings, right, the clinical findings. So I think it's important when you think about a disease like PH I LD, it's really a dual compartment disease. There's disease in the vasculature and then there's disease in the surrounding, you know, parenchyma, the fibrotic parenchymal. So what's really beautiful about this drug, which Pat has just alluded to, is that our drug is targeting, you know, these both, we believe both of these components. I mean, the focus of the study obviously was the pulmonary hypertension, but we've learned more from the study. So in terms of its impact on the vascular compartment of the disease, we did see improvements in metrics like PVR, which directly correlates with obviously the drug's effect on that compartment. In terms of its effect on the parenchyma, we actually saw improvements in FVC and in many patients as well, DLCO. And then overall, we saw a really nice functional benefit in patients with improvements in six-minute walk distance and notable changes in functional class as well. So these patients, numerically, we saw functional class improving across all patients who completed the study, and their lives actually, in many cases, were truly changed. They were, you know, performing, biking again, hiking again, etc. So all strongly supporting the drug's mechanism and disease-modifying potential. And then in terms of the PK profile of the drug, what we're seeing is a PK profile that's very consistent with what we saw in the LAM study, as well as all the initial modeling that was done prior to embarking on this entire process. Great. So yeah, very encouraging signal of efficacy that was found in this early study. and you recently initiated a phase 2B PHILD study. Can you tell us about the design and maybe also share what you're expecting to see in the placebo arm and some of the powering assumptions? Yeah. So the design is pretty consistent with the prior study. We are focusing on PHILDR. Our initial study was a basket study with group one and group three patients. The primary endpoint is going to be the PVR over the 24-week duration of the study. I would say and we're again maintaining that the pulmonary vascular resistance, it needs to be greater than four for inclusion in the studies. There are just two noticeable changes. One is that we have layered in a 200-microgram dose, so 100-200, and then we'll have a placebo arm. And that's really to check off the standard regulatory request for dose analysis work. And the second thing is that we will allow some functional class 2 patients in the study as well as functional class 3. But again, we're maintaining that that PVR needs to be greater than 4. And patients, if they're on background therapy, must remain symptomatic despite that stable background therapy. So that's the study design in a nutshell. In terms of what we're expecting in our powering and what we'RE expecting in a placebo arm, so we'RE enrolling 75 patients. It's powered at 80% to detect a PVR difference between the two arms of 20%, percent, assuming a standard deviation of 25 percent, 0.25. So what we know now is from three prior studies about what to expect in a placebo arm. From the recently announced Pulmaban study, their placebo arm showed a PVR increase of 6.6 percent. There was a study published by Corte back in 2014, looking at Bocentin. In that particular study, the placebo had a PVR increase of 7%. And then finally, the Nathan study published in 2019 for Riosiquat, that placebo arm had a PBR of a high double digit, 18.2%, so increase. So all of those were increases in PVR. If you go and take a look at what we saw in our phase 2A study in that PHILD arm, the PVR actually declined by 34%. So we think we're in good shape from a powering standpoint. All right. And I guess you mentioned a Roivant's drug. They just started this phase 3 study. I guess maybe looking further down the road. Potentially, how would you think that drug would affect the treatment landscape for PHI-LD? Yeah. So, I mean, I think what I can talk about is really from our perspective. Our drug has an entirely different mechanism from any drug out there. And if you notice, take a look at our phase 2A study. It was studied on top of a plethora of background medications. Most patients were on triple background therapy, and every patient had at least two background meds. So we believe our drug will be able to be used in conjunction with any other agent out there, including the Pulmovant drug. So from our perspective, we think it's great for patients that they have additional, will likely have additional treatment options, but we don't see it having an impact on the future of our compound. We think we'd be able To be used In conjunction with it. All right. That number probably definitely stands out. So let's shift gears a bit to BOS. Can you just give us a quick overview of this disease and maybe share the prevalence and incidence rates in the U.S.? Yeah, so BOS is a lesser-known condition from PHILD. What it is is a progressive decline in FEV1 in patients post-lung transplant, And it's irreversible. And unfortunately, it is the leading cause of death post-transplant. So patients don't die from something like an infection or cancer. They're susceptible to a number of these other sequelae, unfortunately. They will succumb to this condition. And the median survival post the development of BOSS is about two and a half years. Unfortunately, there's absolutely nothing approved for these patients today. And so pretty dire consequences with limited treatment options. So the prevalence of this particular disease state directly follows the number of lung transplants performed every year, since nearly every patient will develop this condition who has received a lung transplant. And so there are now, the number of lung transplant is growing considerably. So when I first joined this company six years ago, it was about 2,500 in the United States. We're approaching high 3,000, nearly 4,000 this year. So it's just continually grown. So assuming that sustained trajectory with a certain attrition rate as these patients pass away, unfortunately, we would expect that by the early 2030s, there will be about a little like high 20,000 number of patients, close to 30,000 between the U.S. and Europe. Okay. Thank you. So yeah, no treatments out there. What kind of proof of concept data supports the use of rapamycin for this disease? And yeah, maybe I'll let you take it from there. Yeah. So similar, well, Pat alluded to this earlier. This pathway we know, and it's becoming, I think, more and more well accepted, is an important pathway that's sub-regulated in this fibroblitter process that occurs in BOSS. And what we have at our fingertips is some retrospective data in patients who have been treated with oral mTOR inhibitors over the years, because originally these oral mTOR inhibitors were actually approved for kidney transplants. And so there's a small 11-patient study that was published back in 2005 that followed patients pre-rapamycin dosing. And what you see is really this just characteristic FEV1 decline over the course of a year. And then post-rapamicin dosing, where you see a stabilization of that lung function. And there's an additional study actually was published back in 2024 by a Spanish group. Again, retrospective study looking at patients who had received oral everolimus, 57 patients. And it similarly showed a decline in lung function over the course of a six-month duration, and then a similar slowing in the rate of decline and over windows of time, actually even a slight improvement over the remaining six to 12 months. So there is some supportive proof-of-concept data, but unfortunately, while some sites will occasionally use, you know, some form of an oral mTOR inhibitor, it's used very sparingly because of the side effects, which of course become even more important in the context of an immunosuppressive transplant regimen. Okay. Yeah. So this ongoing BOS study, it'll be a placebo-controlled study. Can you tell us what will be included in this upcoming data readout in the first quarter? Yeah.So this is an investigator-sponsored study. It's been led at UCSF by Dr. Stephen Hayes. So, what we will be able to announce will just be, you know, top-line data that allows Steve to present this data at an upcoming medical conference in the spring. Okay. Yeah. All right. And, you spoke about how meaningful this kind of FEV1 decline is. What kind of delta would be meaningful to support advancing to a pivotal study? Yeah, so this FEV1 endpoint really is meaningful, to your point, in this population, because for every 1% decline in FEV2, it's been shown to be correlated statistically significantly, actually, with an increase in mortality. So the most conservative metrics we found in the literature to date associated with a 3.4% increase in morality for every one percent decline. So highly relevant. Now, in terms of what would be meaningful, we have to put this in the context of the data we have, which is limited today. But at the UCSF site, what we know is that over the course of one year, which was the duration of our study, they would expect at least 50% of their patients to have a 10% or greater decline in FEV1 over that duration. And so when you put, when you simply just do the math, that obviously will lead to somewhere, you know, likely in the high single digit percent decline, but we'll see, you know, what emerges from this particular study. And so what we've guided to, and actually this comes with, you know, tremendous amount of PI and KOL input, is that anywhere between a 5 to 10% delta between the two arms would be clinically meaningful. It's a 19-patient study, so we're not guiding for anyone to expect statistical significance, but we're really looking for that delta. And again, 5% to 10% would be very meaningful for this population, given the correlation with survival. If we saw 10% or greater, that would just be a great outcome. And then if we actually saw the drug arm itself, even individual patients within the drug arm improving FEV1, that wouldn't be a home run because this is an irreversible fibroproliferative disease process. And so there's nothing known out there today that can actually help to reverse that disease process. So that would be a homerun if we saw that. But we're glad to get back to that 5% to 10% delta. That's what we would like to see. All right, great. And the FEV1 is certain this will certainly impact, or it sounds like there's a really direct translation to survival here. Yeah. So great. So we'll look forward to that data readout next quarter. We have a question coming in here from the audience. So maybe we'll circle back to, I guess, this patient population. And the question is, what do you attribute the increase in lung transplants to, whether it's perfusion devices or centers using more marginal organs or a combination of these effects? Yeah, I mean, I think we think I think it's a combination Of all of these. It's a combination of all of the above. So Just to give a direct answer. Okay. All right. Yeah. Great. Thanks. Maybe we have a few more minutes here. It'd be great to touch on the next study in the pipeline here, which is the phase 2 sarcoidosis-associated pH study. Maybe you can just share what makes this a logical next indication for LAMA01. Yeah, so this is a neat indication. We actually did allow one patient in our phase 2A study who had SAPH. That patient had a really nice response to our compound. SAPH, it's neat for the following reasons. So we believe that we're targeting the pulmonary hypertension component of the disease. Now, SAPH occurs in the setting of underlying pulmonary sarcoidosis. And that's a disease that affects close to about 200,000 patients in the United States. It's characterized by the formulation of these masses of cells called granulomas. It can be a systemic disorder, but in many patients, it's the pulmonary tissues alone that are primarily affected. Now, SAPH, so pulmonary hypertension, occurs in about 15% of those patients, but the mortality is increased eight to tenfold versus patients having pulmonary sarcoidosis alone. And so we believe that our drug should be able to have a benefit on the pulmonary hypertension component of the disease. We know the drug's an anti-proliferative agent, as Pat was talking about. We've seen this across multiple animal models and even in one patient thus far. But what will be nice and interesting to look at is the potential impact of the drug itself on the granulomas that underlie this disease process. And that's what ultimately become so interesting down the road, these granulomas have been found to be mTOR driven. And when you dose animals with them, you'll see a reversal of, you know, these masses. But there have also been case studies, when you give patients with the systemic form of the disease or the cutaneous form of a disease an oral mTOR inhibitor, you see clear clearance of these granulomas. It's really some beautiful case studies. And in the case of some of these cutaneous lesions, you see clearance of the lesions on people's faces, hands, et cetera. So we think it's a very neat indication, really like BOSS underserved. There's absolutely nothing for these patients today. And so we're looking forward to starting a study in the very near future. But again, the readout will be down the road. It hasn't been much of a focus yet. Okay. I guess maybe to highlight this kind of through line that you're describing these indications that these are settings where oral mTOR inhibitors have shown some promise, but again, it's this kind OF systemic effects that really eliminates you. So this is what you're aiming to address with your drug. So in this indication is pulmonary hypertension, a progression event in pulmonary sarcoidosis, or is it more like a subset of patients that develop it? It's a subset. It's only about 15% of patients who develop it. But again, the mortality has just increased dramatically. And so we think it's a really important subset for us to try to help. Okay. And you mentioned there's 200,000 of these patients. Can you just tell us how this compares to the PHILD and BOS patient populations. Yeah, well, so there's 200,000 patients with pulmonary sarcoidosis approximately, but this just affects about 15% of those. So it's a smaller percent, but you have the numbers now, it's about 30,000 we estimate in the United States and relatively comparable in Europe. um uh the boss indication as we heard is much smaller but they're both you know orphan diseases the bosses we said we think will be uh not quite 30 000 in the early 2030s but but close to that um and then obviously we know the phild market is quite a bit larger and we have a number of players that are participating that space um the troprosinols and obviously there are a number of clinical studies being performed there now. All right. Maybe the last question here, a question for John. What's the current cash runway and what does it enable? We disclosed in our Q2 earnings press release that our cash and cash equivalents are expected to fund operations to the end of 2028. We expect our cash-in-cash equivalents to support the advancement of LAM-001 through multiple clinical milestones, including data from the Phase II clinical trial and BOSS anticipating the first quarter of 2027, data from the Phase IIb study in PHLA-D anticipating the 1st quarter of 2020 and data from Phase II study in SAPH anticipated in the 4th quarter of 2018. All right, great. So yeah, a lot of studies ongoing and certainly looking forward to first step to BOS data next quarter. And maybe with that, I'll say thank you to the whole uh the whole uh i rule i rule yeah right i rule ea team um for jo and thank you to our audience for joining us here for this great opportunity to get to know the story