As well. Try and keep it going. Good afternoon. What time are we at now? We're getting there. We're right there. Good afternoon, everybody. John Walden with Citizens. Welcome to day two of our Life Science Conference. We're pleased to have Rein Therapeutics and CEO Brian Windsor to come give us a presentation on the story. If we have time at the end, we'll have some Q&A. Brian, I'll pass the floor to you, and please take it away. Great. Yeah, thanks, John. Really appreciate John and the Citizens JMP folks for having me here today to take the opportunity to tell you about what we're doing to rein in disease and really put an end to fibrosis. Following a reverse merger in October 2023 with Aileron Therapeutics and subsequent rebranding to Rein, we have been intensively focused on pioneering first-in-class treatments for orphan pulmonary conditions, fibrosis indications. We've got two clinical stage assets, both at phase two, orphan pulmonary kinds of assets, that I'll tell you a little bit about today. These really include our lead asset, LTIO3, which I think is a potentially groundbreaking asset in idiopathic pulmonary fibrosis. This is something that we are moving into a phase two trial presently. We hope to launch a phase two trial any day now. We've seen great results in a phase one healthy normal volunteer study and also a phase one B study in IPF patients in which we looked at not only safety and tolerability, but a large number of biomarkers. We believe this is the only drug in development that not only has a powerful antifibrotic effect, but more importantly, has a regenerative function. We have paired this drug with LTI-O1, another phase two level drug. This would be the first drug approved anywhere in the world for a loculated pleural effusion. This is a hospital condition, consequence of pneumonia, affects about 60,000 people in the US each year. No drugs for this condition. Right now, doctors use an off-label approach. They really would like a pharmacologic, FDA-approved solution for this. We've put this drug into a small phase two trial, ready for a larger phase two study. Beyond this, there's a lot that we can do in fibrosis. LTI-O3, I mentioned we've completed phase one A and phase one B studies recently. We're preparing for phase two, and we will be looking at the kinds of lung function measurements that have really given other companies tremendous value in the space with positive lung function readouts. We hope to be able to do a release on the launch of that trial very, very soon. LTI-O1, we did do a small phase two study, unfortunately, at the beginning of COVID. Need to do a larger phase two B study. Again, a lot that we can do in fibrosis. Joined by a great team, a very supportive board of directors. I just want to point out Corey Hogeboom, below me right there. He's also a professor of medicine at Cedars-Sinai Medical Center. Corey is a well-recognized thought leader in the field of IPF. He has studied this disease for more than 25 years, looked at 40 drugs plus in his lab. The compelling nature of our drug spurred Corey to call me and ask if he could join our company at one point. He said, "I've been offered this position at other companies. I can never get behind their drugs. I think I could put my career behind LTI-O3." Huge vote of confidence from a really well-recognized thought leader in the field. LTI-O3 is for a really terrible condition, idiopathic pulmonary fibrosis or IPF. This is an age-related, fatal disease that's characterized by scarring inside the lungs. It's a scarring, as the name implies. Not sure where this comes from. It's part of a broader disease class called interstitial lung diseases. About 100,000 people in the U.S. are living with IPF. About 40,000-45,000 new cases are diagnosed each year, and no one survives from this disease. Median survival is between three and five years. It is a truly devastating, deadly condition. There are two drugs that are approved for this: pirfenidone and nintedanib. They only slow disease progression for about a year. Very poorly tolerated, lots of GI side effects, but a very large market, estimated to be almost $12 billion by 2031. The global leader, OFEV, which is nintedanib, did about $3.6 billion in 2023, about the same amount last year. We believe that those drugs are just incrementally trying to address something that we could have a much bigger effect in. Not only in the lung. We have seen our mechanism work in models of the heart, the liver, the kidney. A lot that we could do with this mechanism in fibrosis. And our drug is related to the caveolin-1 protein. And caveolin-1, in addition to the structural role that it plays in cells, also has a regulatory function. Regulates a lot of different proteins, many involved in multiple fibrosis pathways. And Corey and I really pound the table on this point, because the two drugs that work at all also work across multiple fibrosis pathways. I think what we have seen in the past couple of years, in terms of failures, is that, you know, targeting any single protein, no matter how important, ultimately, leads to toxicity or is just not effective enough. Caveolin-1 affects a lot of proteins involved in many fibrosis pathways. And it does this, through a 20-amino acid region called the caveolin scaffolding domain, or CSD. The job of this domain is to bind proteins with a caveolin binding domain, of which there are many. It affects their phosphorylation and thus affects trafficking of a lot of different kinds of proteins. In the lung, it is also important in the heart, in the liver, in the kidney, in the skin, in the eye. Pretty ubiquitous kind of mechanism. Unfortunately, caveolin-1 is lost in a fibrotic state, dramatically downregulated both at the transcript level and the protein level. This kind of begs the question, you know, if your target is missing, then, what do you target? The answer is that our drug is a seven-amino acid peptide. It is the peptide sequence on the bottom there. That is a portion of that critical CSD region. We've done substitution-deletion analysis to determine it's the smallest fragment that retains full functionality. And non-intuitively, you put this peptide into a living system and it's like CAV1 has been restored. We don't cause expression of caveolin-1, but it basically mimics that regulatory function of CAV1, binds proteins with the caveolin binding domain, affects their phosphorylation, and thus affects trafficking of a large number of proteins. We dose this drug direct to the lung by dry powder inhalation for really good local, local lung delivery. And what we see, like I mentioned, is really a twofold effect. On the one hand, this is a pretty potent antifibrotic, but on the other, more importantly, has a regenerative aspect that I'll tell you a little bit more about here in just a second. On the antifibrotic aspect of the drug, we work in a system called the precision cut lung slice, or PCLS. This is a tissue culture system in which we take an actual sample from an IPF lung. It is a lung that has been removed due to transplantation. We are able to get a sample of that lung. We can culture that. Importantly, all the cell types that are present in the fibrosed lung are present in this model. Then we can look for inhibition, in this case, of a large panel of bad actor pro-fibrotic proteins, which are the ones that are down the left-hand side, and see, can we cause inhibition of these bad actor proteins. In this case, we compared to nintedanib, both at concentrations that are similar to what would be given in the clinic. In this patient sample, you can see LTI-O3 inhibition of these bad actors was virtually identical to nintedanib, which is the market leader. The one thing about nintedanib, however, is that it will also light up markers of apoptosis, cellular necrosis. It's quite toxic. Up to half the patients who go onto that drug have to come off, many within the first month, due to the terrible GI side effects. We just haven't seen any of those side effects so far with LTI-O3. It's a pretty potent antifibrotic, but more importantly, it preserves critical cells in the lung that are progenitor cells. They're called type II epithelial cells. These cells are responsible for making new lung tissue, for remodeling the lung, potentially restoring lung function. How we learned about this was, it was serendipitous. The lab that runs these PCLS studies for us, Andreas Günther's lab in Gießen, Germany, they will add a dye called LysoTracker to every culture that they run. In panel A, the LysoTracker dye is the bright green dots against the dull green background in these panels. That dye is specific for these type II epithelial cells, these progenitor cells. The lab just wants to see, do we have any viable type II cells? Is this a viable culture? Those cells will die off after a couple of days in culture, just like they're going to die in an IPF patient. The technician that ran our studies had a medical emergency. She couldn't come back to the lab for 48 hours. When she did, she called us and she said, "These are crazy compounds you all have. They're keeping type II cells alive. What we could see qualitatively was an increase in this LysoTracker staining with increasing concentration of LTI-O3, indicating, I felt, like an increase in the viability of these critical type II cells. At the time, we were just consulting with Corey Hogeboom, like many other IPF companies. I was very excited about the data, sent this all over to him, and he promptly threw cold water all over my excitement. He said, "No, I don't believe it. I think it's an artifact. I've never seen a result like this in my career. I just don't believe that, that you're really protecting these type II cells." He said, "If you are, I've got a lot of confirmatory experiments to give you." He gave me a big laundry list of confirmatory experiments, the major one of which was, he said, "If you're really protecting type II cells, they should be making surfactant protein C, which is one of their jobs." We went back and sure enough, with LTI-O3 administration, we could cause production of surfactant protein C in panel B. It's this red image. We could also light up its transporter, and the Western blots on the right just confirmed that in an IPF lung, you get diminished levels of surfactant protein C, which we can raise with administration of LTI-O3. Packaged it all up, sent it back to Corey. He said, "Wow, I've just never seen anything like this in my career." Six months later is when he called and asked if he could join our company as our Chief Scientific Officer. Armed with all of this data, we have done now two clinical studies. We started with a healthy normal volunteer study, typical SAD/MAD design. Again, it's dry powder inhaled drug. We did very high doses in the single ascending dose, up to 80 mgs. In the multiple ascending dose, we did hit a dose-limiting toxicity in the MAD at 40 mgs. Happy to discuss with anyone what that was. Fortunately for us, that was about 10x higher than what all of our model systems would say is a human effective dose. 5mgs, 10 mgs, 20 mgs, perfectly safe and well tolerated. We took two of those doses forward into a phase one B study, in IPF patients. This is a trial that we announced data on at the end of last year. We completed this study. This was a pretty unique phase one B trial because not only did we look at safety and tolerability in an IPF patient population, we also measured a lot of biomarker proteins. We did this by interrogating the lung directly. We took bronchoscopy samples before dosing and then after 14 days of dosing, looking at lung-specific proteins that would indicate, are we getting the drug to the fibrosed lung? Is it getting into different cell types in the lung? Is it doing what we think it's supposed to be doing? The answer was really a resounding yes. We had four biomarker proteins, these four on the right, interleukin 11, CXCL7, TSLP, and GAL7, which were reduced significantly over just the two-week period in our study. These are all important proteins. They come from different cell types in the lung. The galectin-7 is only made by an aberrant cell type called a basaloid cell in the deeply fibrosed portion of the lung. One question I get all the time is, you know, with a peptide, with inhaled, how do you know that it's going to get to the right place in the lung, get to the fibrosed lung? These proteins are only made in that fibrosed portion, and we're causing significant inhibition. Good evidence to us that we are getting the drug where it needs to be, and it's doing what we think it's supposed to be doing. All of these biomarkers, I realize this slide is a bit busy, but we had literature evidence that they were important proteins in IPF, and then we tested them preclinically. Panels A, B, and C highlight this galectin-7. There was a paper that came out that said this is an important protein. It's expressed highly in IPF. It's not found in a normal lung. We then did preclinical studies, cell studies, animal studies, and showed that our drug could cause significant inhibition of this protein. Sure enough, this was replicated in humans in our phase 1b study. Literature would say it's important. Our preclinical model said that we can affect it. Sure enough, in patients, that's exactly what we did. Another protein that we looked at was surfactant protein D. This is an important biomarker because this is one that we interrogated through plasma samples. This was not direct to the lung. This is a protein that other drugs, including nintedanib, have seen inhibition over a clinical trial. There was a trial, this MARC trial, which is where this graph is from, showed a 5% reduction with Ofev over 12 weeks. We saw a 5% reduction in just the two weeks in our study. They set the clinical bar for inhibition of this protein, which we matched with LTI-O3. We are really set up well, we believe, for our next trial. This is a schematic of the study that we hope to be starting any day now, a phase two trial up to 24 weeks of dosing in IPF patients. These will be IPF patients with a diagnosis within five years. We are allowing background standard of care therapy. So, some of these patients will certainly be on nintedanib or pirfenidone. We'll have three arms to the study. A low dose will be 2.5 mgs capsule BID for a total daily dose of 5 mgs. And the high dose will be 2mgs, 2.5 mgs capsules, BID for a total dose of 10 mgs, up to 40 subjects in each group. It is placebo-controlled. Again, dry powder inhaled drug, treatment for up to 24 weeks. We're hoping to be able to get a look at data within about 12 weeks. That would be something, later this year or early next year, that we could potentially be able to see. And we will be measuring lung function. So, FVC, FEV1, we'll be taking high-resolution CT scans. The reason why this is important is because other companies in this space, and John, you know this very well, that have looked at lung function measurements, when this is positive, they just get tremendous value in the market. Other companies that have shown increase in lung function values with administration of their drug, $500 million in market cap, a billion dollars in market cap. Of course, I'm not representing that that will happen with us, but this is the kind of value that the market ascribes to this type of lung function measurement. We are very excited to be kicking off a phase two trial. We hope to be announcing very soon that we're in this study and we'll get the chance to see how does this drug perform in terms of lung function. We think that, because of the regenerative aspect of the drug, the powerful antifibrotic aspect, we could really bring significant benefit, hopefully to patients, with IPF. I do not really have time, I think, to talk about the other drug. Loculated pleural effusion is a consequence of pneumonia, where you get fluid buildup. Basically, our drug allows for fluid drainage, without surgery. This is important for this patient class. There is no drug approved anywhere in the world. If we just price this at the point of the off-label drugs, it is a $400 million market between the U.S. and Europe. Market access studies that we have done suggest pricing could be much higher. We do have a partnership with Taiho Pharmaceutical in Japan for Japan rights to commercialize LTI-O1 in that region. We hope to be moving this drug back into a larger phase two B study as well. but then again, very soon, hopefully we'll be able to give you more information on the phase two trial for LTI-O3, and see the benefit to these IPF patients. I think with that, we can— I'll let you catch your breath for a second. Wrap it up. Yeah, that's right. want to see, we have a few minutes. Want to see if there's any questions in the room. I have a general question about CAV1 and just like, do you, is there any reason why it's lost? Is there kind of like a mechanistic rationale for why, like IPF in particular, it's lost in fibrotic disease? And then also, is there any downregulation of any of the kind of the effect, like the things that it acts on in the IPF state? Yeah. We're not sure why it gets downregulated, but it is downregulated both at the transcript level and the protein level. Both are degraded in a fibrotic state. We're not sure what causes CAV1 to be lost, but it is lost across the board in all kinds of fibrosis. We've seen the loss in heart, in the liver, in the kidney, everywhere that we've looked for CAV1, it's lost. In every single IPF patient, as far as the literature would suggest. Not sure what's causing the loss of CAV1. Essentially, it should be kind of a protein replacement therapy essentially for CAV1. You're essentially assuming that everything else downstream is working for downstream therapy. Yeah. We think this is similar to Akero's approach with their FGF21 mimic for looking at liver fibrosis in a similar way. This, CAV1, sort of mimic, peptide, we think would be doing, the kind of job. Interestingly, their drug, the FGF21 mimic, acts on the cloth receptor, pathway, which needs functional CAV1, for its effect. So, CAV1 does have a pretty broad, ubiquitous role in the cell. Sure. How should we think about expectations for your phase two trial? And do other mid-stage trials allow background meds, or does that make interpretation more difficult? These days, you have to do a study with background therapy. All this, all the studies, allow or almost all the studies, any, anybody who's enrolling, allows background. So, stratify and then just, you know. Correct. try and match . Yeah. Yeah. Correct. Do you think the regenerative potential translates to a greater FVC, FVC benefit, or how should we think about how that manifests? Yeah. We're hoping that it will translate to a better FVC, FEV1 sort of benefit. The reason is because the cell type that we're causing protection of or even generation of, these type II cells, those are the cells that are under attack in fibrosis, in IPF specifically. Those cells get under attack. They become distressed. Many will sort of evolve into this basaloid, aberrant cell type or just cause fibroblast to myofibroblast activation. That's the cell type that's really kind of doing a lot of the damage. We're hoping by preserving, even generating those cells, that we'll see an even greater lung function measure. Is 12 weeks enough time to see that, do you think? Like, what are you, what about cell turnover in the lung, especially in a fibrotic state? Yeah. You know, we have seen with the biomarker studies and the PCLS work that we've done that even within a few days, we can start to see some changes. Now, whether 12 weeks, 24 weeks is long enough to see it, in the lung, I think other drugs have certainly seen benefits, within 12 weeks. We believe 12 weeks should be plenty of time. Is the goal to see stabilization and placebo worsening or a benefit? How do you think about that dynamic and, you know, what would get people excited? Yeah. I, I, well, I think, you know, if we can show a difference between placebo and our drug, even, you know, even a lessening of decline is what others have been able to show, that would be important. I mean, just the, the drugs that are approved are really terrible, side effects. Just having something that is safe and well tolerated, that would slow decline would be very important. I'm hoping, of course, you know, for the moon, I hope that we can cause an even a better increase in the FVC compared to placebo. Last question for me is how do the doses you choose, the five and 10 or 10 and 20? I can't. Five and 10. How does that correlate to the preclinical data you showed? 5mgs would be 5x higher than most of what we saw in the preclinical studies. Wow. Yeah. We're already starting at a 5x increase over what most of the models, where most of the models showed a benefit. Okay. I lied. One last one. How, you know, how should we think about timing of enrollment for IPF studies these days? You know, what's typical? When, you know, if you start soon, when could we see 12 week data? We're hoping that we get better enrollment than kind of what the historical norms are. Of course, we've seen a couple of things drop out in the IPF space, so that opens up enrollment, I think, for some studies. This will be a global study, U.S., Europe, U.K., possibly Australia. We're trying to hit, you know, every place that's going to have IPF patients. I think we could have 12 week data, certainly first half of next year, maybe early next year, Next year. Yeah. Brian, thanks for giving us the rundown. It's exciting times at Rein and we appreciate your time and being here with us today. Yeah. Thank you all.