So Brian, for people that may be unfamiliar with the story, why don't you give us a large overview, an overview of the company, how you got here today?
Yeah. We started as a private company called Lung Therapeutics, and did a reverse merger to get public in October of 2023 with Aileron Therapeutics. They had been cancer-focused. Obviously didn't work out for them, but they really like our program in idiopathic pulmonary fibrosis. We did the merger with them, a small pipe at the time that we did the merger, and then we rebranded to Rein Therapeutics early last year to kind of highlight our focus on fibrosis. As we like to say all the time, we want to rein in fibrosis. We have a small team, but kind of spread out across the country in a phase II trial presently, in IPF. We kicked off the study earlier this year. We announced that enrollment is going great, so very excited to be at this stage finally.
Amazing. You've had a lot of progress in the last year and a half. Let's dive into the molecule, the mechanism of action, and why it's so attractive for a condition like IPF.
Yeah, it's a great question. LTI-03 is our drug for IPF, and the mechanism is pretty unique. This is a drug that mimics the protein caveolin-1. We're focused on caveolin-1 or CAV1, and CAV1 is a regulator of other proteins in the cell. We think of it as kind of an effector of homeostasis. It just promotes balance in the cell. It keeps pro-fibrotic proteins in check. It promotes things like ECM turnover, this sort of thing. But caveolin is lost in a fibrotic state, so all of this regulation that you get is also lost. Our drug is a small portion of the region of caveolin that binds other proteins, affects their phosphorylation, affects their trafficking.
We're kind of adding back a small part of that protein. I will say non-intuitively, when we put this peptide into a living system, it sort of mimics the activity of CAV1. We get the same sort of regulation. We get inhibition of pro-fibrotic proteins. We get protection of epithelial cells. It's really amazing. CAV1 is something that's needed not just in the lung. It's in the heart, the kidney, the liver, skin, eyes. Basically everywhere that you can have fibrosis, CAV1 is normally present in the body and missing in a fibrotic state. It's a pretty unique mechanism. We give the drug, LTI-03, by dry powder, simple dry powder inhaler, and we're dosing BID right now in our phase II study. It's a mechanism.
We kind of describe it as a dual mechanism in that we are anti-fibrotic, like most of the drugs in the space. We're inhibiting the scarring process, and I'm happy to kind of talk about IPF and what the problem is. But more importantly to us, we're preserving cells, causing preservation of cells in the lung epithelium that are the progenitor cell. They're called type 2 alveolar epithelial cells. These are progenitor cells. They can make new lung tissue. They make surfactant. They can restore lung function. We think this is something absolutely not seen in drugs in this space today.
It's very interesting. In your mind, you think preserving these cells and that create surfactant is what's kind of doing the legwork for LTI-03 plus the anti-fibrotic effects.
Yeah, it's really both. You really need both. You've got to stop the scarring process or slow down the scarring process. But I think what's been missing from the disease so far in terms of developments of new agents has just been this protection of the lung epithelium. If you only address the fibroblast cell or the cells that are making the scar tissue, you really are not addressing the part of the lung that can restore new tissue, that can resolve fibrosis, this sort of thing. You've really got to have both, in my opinion.
Got you. Thank you. And then, you guys recently had data in Nature, and you guys were at ERS. Can you walk us through that data and what the receptivity of the physician community was?
Sure. We just had our phase I-B trial published in Nature Communications. We were thrilled that such a top journal would publish this article, and it highlighted the work that we did in a phase I-B study in IPF patients over a couple of years. This was a trial, of course, looking at safety and tolerability. It is a phase I, but we did a lot of biomarker work, and to do that, we took lung samples before and after 14 days of dosing. Actually, the patients were willing to undergo bronchoscopy, and we used a technique called deep bronchial brushings, which was pioneered by Rob Kaner at Weill Cornell, and it is exactly what it sounds like. You put a brush into the lung. We are able to get protein samples.
The reason we did this is because we had seen the ability of our drug to inhibit a lot of pro-fibrotic proteins in preclinical studies. Does that translate to the lungs of IPF patients? That is what we really wanted to see. We were able to do eight different biomarkers from lung samples, and seven of the eight trended in the direction we were hoping they would go, four with statistical significance, IL-11, CXCL7, TSLP, and galectin-7. We picked these proteins because, again, we had seen preclinically that we could inhibit the proteins. We wanted to match that up. Now we also saw in the lungs of IPF patients, we are seeing the very same thing. This was important to us for a few reasons. One is that our drug is a peptide drug. It is a dry powder drug.
I would always get questions about, "Well, how do you know your drug is even getting to the lung, getting to the fibrosed part of the lung?" We took proteins like galectin-7 is only made in an aberrant basal-like cell that is found in the deeply fibrotic part of the lung. We looked at proteins that were deep in the lung. The other thing is that some of these proteins are indicators of lung function, FVC. Just for example, interleukin 11 or IL-11, the inhibition of this protein has been linked in the literature to positive changes in forced vital capacity or FVC. That is the lung function measurement that we will be measured on in this phase II trial in terms of efficacy and going forward. It is the lung function measurement that drugs get approved on.
We wanted to look at markers that were maybe indicators of how are we going to do in a phase II trial, how are we going to do going forward. We were thrilled with the results. In fact, you talked about physician receptivity, clinical receptivity. The KOLs that we work with, we got on a call with them. We showed them this data initially. I would say they were giddy. They were so thrilled. One of them said, "You couldn't have imagined that you'd seen anything better than this, could you?" It was extremely positive. We were fortunate to work with Phil Molyneaux, Nik Hirani, Andreas Günther, Teja Kulkarni, some great investigators, all of them on this publication. We just, as you mentioned, we highlighted this data at European Respiratory Society Meeting in Barcelona this past weekend. We had a poster there.
Phil Molyneaux was sharing with the audience about the phase I-B study. Lots of great questions, lots of interest. There's a huge need in this disease, so I think the receptivity was really, really good.
Definitely IPF has placed a lot of unmet need, and it's a big market, so I can get why people get excited about it. On that phase I-B, on the safety side since you have an inhaled powder, is there any cough AEs that you're seeing or any other type of AEs that you did see during the phase I-B?
There are. We had seen mostly mild cough in the phase I-B study. Occasionally, some moderate cough. If you've ever had a dry powder drug, the first time the powder hits the back of your throat, you kind of you want to clear your throat. Well, that's counted as cough in the study. Physicians would say that was a lot of what was seen. We're not causing a lot of severe, serious kind of cough. We didn't have SAEs in the trial, so mostly mild and moderate cough was the primary AE.
Amazing. So it sounds like it all went well. You saw the biomarkers trending in the right direction, no safety signals, and now you guys are on a phase II. Can you talk about how that's going, enrollment, and just give us an overview of that program?
Sure. We actually kicked off the phase II trial last year and then got put on clinical hold by the FDA. I want to walk through what happened because this is obviously something that people are highly interested in. To do chronic dosing for inhaled drugs, you have to do a six-month inhalation tox study in rats and a nine-month inhalation tox study in dogs. In the rat study, there was a finding that was called minimal mucus cell hyperplasia, which means the lungs are making a few more mucus cells. The study reports listed this as adaptive to dry powder, non-adverse, not a safety concern. The FDA sent us a letter and then later had a phone call with them. They said, "We think it's a safety concern.
We want you to stop the study and to get the clinical hold lifted, you need to do another rat study at a dose low enough to where we don't see any of this." Of course, we want to fully meet up with what the FDA wants. But our toxicologist had the thought. They just said, "I just don't think this is really a problem." That rat study takes a long time to run. It's very expensive. So we hired an independent veterinary pathologist who re-reviewed our study. Independently looked at all the slides in the study, basically came to the very same conclusions as the original study director said. There's no architecture changes. It's only in the large part of the airway, no inflammation. I just don't believe this is a problem.
So we put all of this into a briefing package and requested a Type A meeting with the agency, which they granted. This was for September 18 of last year. Two days ahead of that meeting, they responded to our briefing package, and in the response letter, they said, "Based on what you have sent us, we now agree that your study is not dose limiting for IPF patients." They asked us to adjust the protocol, put in a couple of safety points in terms of looking at some lung function measurements. We were happy to do that. But they indicated we didn't need to do another rat study, and then subsequently lifted the clinical hold. So that was really great to be in sync with the FDA and to get off the clinical hold.
But as you know, it can be quite devastating for a company to get a hold like that. We were able to keep going. We re-kicked off the phase II trial early this year. We have announced enrollment is going great, that we were 25% enrolled. We have got five countries currently open, the U.S., U.K., Germany, Poland, Australia. We are considering opening some other sites. We are trying to get up to 49 sites, and happy to finally be at this stage. We have announced that we will have full data later in 2027, but we will likely do an interim look at the data, blinded look. We are not going to unblind the study, but just kind of a look at interim later on this year.
Appreciate the transparency on the clinical hold. I think like you mentioned, this could spook people away from investors from the name and like-
Yeah.
-think the drug had some toxicity problem, but sounds like the FDA agreed with you guys. This was something that was found in rat models, no problems in humans, and you were able to continue away. Talking about that interim that is coming up, what triggers that analysis? Is it time-based? You mentioned you were at 25% enrollment. Is it an enrollment-based interim?
It is really not. We want to just get a snapshot of how things are looking, even in a blinded way. We are hoping to get as many patients up to 12 weeks of dosing as we can, 30 - 40 patients, but we have not given any sort of guidance on that. It is just going to be, I think, once we get enough patients enrolled to that point, then we are just going to take a snapshot and probably release that at that time.
Got you. So it's going to be a blinded look at efficacy. Any other data points that you'll be sharing at that time?
We're not sure. We would like to share something on safety, as well as a blinded look at efficacy, but we're still working on that right now.
Okay. Got you. On a blinded basis, is there anything that you would hope to see or something that you could say is an encouraging signal about what you're seeing of the drug's effect?
Well, again, they're blinded data points, so we don't know who's on what, who's on placebo, who's on active drug. I just hope that we don't see all the data points in one place. We just don't want to see them all clumped together. I think seeing a nice spread is more of an indicator of potential therapeutic effect. So we'd like to see a nice spread in the data points.
Got you. In a condition like IPF, there's enough data out there where you know what natural history looks like. After the interim, you're hoping to have the phase II and the data fully enrolled by 2027.
Correct. We would be fully enrolled sometime hopefully earlier on in 2027 and then 24 weeks of dosing, so data later in the year.
Okay. Probably towards the back half.
Probably so.
Got you. And then, if we could rewind it back a bit, where do you guys find this molecule? It sounds like it's doing an effect. It's not toxic. It's working on a very hard indication in a large market. Where do you guys find this molecule?
We licensed this out of the lab of our physician founder at the University of Texas. We actually, as a private company, we had started with a different drug program, but I licensed in this LTI-03 asset. And then, interestingly, when I was doing some patent searches, I found another group at Medical University of South Carolina also working on the caveolin-1 scaffolding domain, the same sort of region as our drug. They had done a lot of studies of fibrotic models and had come to all the same results. Interestingly, neither lab knew the other was working on this. It was an independent confirmation. I went to MUSC and licensed that technology into the company as well. Really out of two different institutions, but the primary one is University of Texas.
Got you. I think that's a pretty positive signal that you have two independent scientific data sources pointing towards that like, hey, this mechanism of action is doing the same effects on both sides.
Yeah.
Replicating results is sometimes hard in the scientific world, so that's very incredible.
Yeah, absolutely.
How do you see LTI-03 fitting in the IPF markets? Currently a lot changing right in front of our face, a lot of development in the space.
Yeah.
Where do you guys ultimately see LTI-03 fitting in?
No, that's a great question because there was a third drug approved last year, as you probably know, JASCAYD was approved. This is on top of OFEV and Esbriet, the two drugs that have been around since 2014. So now there are three. pirfenidone or Esbriet is now generic. OFEV or nintedanib will soon be generic. So Boehringer Ingelheim got JASCAYD approved last year. There's also TYVASO, United Therapeutics drug, that they had two nice phase III studies, TETON 1 and TETON 2 , and that drug will also be in use for IPF. I think where the current drugs really are focused is they are strictly anti-fibrotic. So, they're focused on stop the scarring process in the lung. That's absolutely important. That's something that LTI-03 does as well, but what's lacking is this protection of the lung epithelium.
You can inhibit the scarring process all day, like I said, but if you don't have a healthy epithelium, there's no chance to get restoration of the lung, no chance for new cells, no chance for increase in function. I think that's really where LTI-03 shines because no drugs in development, we believe, really are doing this, protecting the epithelium. Don't get me wrong, our drug is a powerful anti-fibrotic. All the testing that we've done points to that, so I think it would be a great monotherapy, but this is an age where I think doctors are thinking about combination therapy. We're allowing any standard of care drug in our current trial. We believe that LTI-03 would be beneficial on top of other drugs as well.
Gotcha. You mentioned something quite interesting right now. You're allowing background therapy in the trial. This trial started pre-JASCAYD approval. Are those patients dropping in? For the phase II, it's only OFEV and pirfenidone and nintedanib?
Yeah. We're allowing JASCAYD in the study. We allow any approved drug that the doctor feels is a fit for his or her patients. We only ask that they be stable. So it's stable for 12 weeks on whatever background therapy they're on. So they could be on JASCAYD, they could be on nintedanib or pirfenidone, any of the approved drugs.
Got you. As you think about it, let's assume you have a successful phase II, and as you're thinking about designing a phase III trial, hopefully there's TYVASO approved by April next year. In that phase III, will you allow TYVASO, given they're both inhaled therapies? How do you think about just having orals and then you're inhaled therapy or allowing TYVASO? How are you thinking about a phase III program in general? I know it's-
Yeah
-a couple of months out or maybe a year out.
It's a great question. I don't know the answer on TYVASO, whether that would be something that we would allow in a phase III or not. We are absolutely focused on phase III right now, in addition to getting through the phase II, but we've started preparing for phase III. These are the kind of questions that we're thinking about. I wish I had a better answer for you in terms of TYVASO, but we're just right now considering what to allow and what not to allow.
I know you guys are early on in the process-
Yeah.
-of designing a phase III trial but just wanted to pick your brain on it.
Sure.
Then you guys had a financing recently. How do you think about moving the company forward, and what's your financial position?
Yeah. So in April, we raised $57.5 million, which was great. We had some really nice, good healthcare-focused funds and general funds that came into the deal. We were able to do that deal with no warrants, so we're very happy about that. That gives us cash. We've told the street that gives us cash into Q1 2028, so well past the end of the study. We've got the phase II completely funded, really no finance overhang. I told some investors the past few days, I was like, "I think this is the first time I've ever not asked people for money.
Yeah.
It's quite different, but it's great being funded through the phase II results.
Amazing. Then something that caught my attention, you're fully funded on a global phase II, five countries. What's the split of patients that we could expect from ex-U.S., U.S., if you have an idea, or are you guys blinded to that?
Well, we're completely focused on idiopathic pulmonary fibrosis or IPF, where there's no patients who have progressive pulmonary fibrosis or any kind of other interstitial lung disease. We actually reconfirm their diagnosis when they come into the trial. As you probably know, misdiagnosis of someone who is not progressing has been a problem in previous trials. That can really kill your placebo group. If people are not progressing, it looks like they're on active drugs. We reconfirm the diagnosis of IPF. We work with an imaging partner, Qure.ai, in the U.K. They have a central reader that does all of our scans. Simon Walsh, the chief scientific officer, probably the best radiologist in the business for this. These patients will all have a diagnosis of IPF. It's a pretty heterogeneous disease.
Typically, I think kind of was your point, you've got lots of different kinds of fibrosis and different interstitial lung diseases. IPF is progressive, and that's really what the focus is. Beyond that, I think we have a diagnosis of less than five years, so there's certain lung parameters where they can't be too far advanced in the disease. Apart from that, it's all comers.
Got you. You mentioned you don't want patients to be too far off advanced in the disease. Is that particular to your drug? You think that since you guys are kind of protecting, like you said, the epithelial cells and kind of helping the lung create more surfactant and have healthy tissue, how do you find the patients that are earlier on in the season? You have a cutoff of, like, "Oh, you need to be diagnosed in the last two years, a year.
Yeah. Our cutoff is five years. Any diagnosis within five years is eligible for the trial. We don't look for or ask for patients who are early on in the disease. That being said, what I've heard as far as patient interest in clinical trials is that a lot of them, kind of on first diagnosis or early on in the disease, will seek out a clinical trial. So we will probably have patients who are more early on in the disease. I think to your point, we do want to help the epithelium. But we want to address the later stage disease also, middle of the disease. We just don't want someone who's so far advanced the lung function, we really can't see any kind of benefit in the lung function.
Basically, you want to avoid patients that are almost at the point that they need a lung transplant.
I think so. Yeah. Correct.
Got you. And then, what do you think the street is missing from the story? I think from my point of view right here, it's pretty clean story. The drug's not toxic. It's the biomarkers that you saw trending in the right direction. You're rolling on phase II. What's the disconnect here?
I think that we just have not really been on the radar for a while. Before the financing last year we were on the clinical hold. We also needed to get the financing done. It was a time when we were just internally heads down. We weren't really facing the street, weren't really talking about the drug, for obvious reasons. We just were focused on, "Let's get this hold removed and let's raise some money." Which eventually we did. But after we did the fundraise, I told my team, I said, "Look, guys, we haven't been part of the conversation in IPF. I think we deserve a spot at the table when people talk about IPF drugs." This is a drug that's absolutely needed. Something is needed to help the lung epithelium as well as kind of inhibit the pro-fibrotic proteins.
So, this, again, we deserve a spot at the table. We have been out talking to folks like you, talking to investors, trying to get the word out a little bit more. When you are on hold, obviously people want to see, what does the FDA think about this? To get this resolved, not everyone gets the hold resolved. We were really grateful to the agency to work with them and be able to get off of that clinical hold and move forward with what we believe is a safe and well-tolerated drug. The other thing is just that our I-B study, we recently, as we have talked about, got this published in Nature Communications, a really great prestigious journal. I think that has elevated the thinking about the trial. We have got great investigators.
They have known about our drug for a long time, but now we are getting the word out to many others. It is just kind of getting the word out, getting the name out.
Yeah. You guys are on the later stage of development, right? You are enrolling on phase II, potentially reading that out next year, starting on phase III by 2028. Like you said, you do not have any tox issues. The FDA cleared that out without any new studies. I think their initial suggestion of having a rat study that would have taken 14 months would have been a big setback. I think you guys managed that well. Avoid a setback, continue hammering forward. Is there anything else that you might want to share with the people?
Yeah. Well, just concerning the FDA, again we, like every company, want to make sure and work closely with them, to have a safe drug moving forward. But we were able to get orphan drug designation, not only in the U.S. but in Europe, which gives you some exclusivity as I think you know. Independent of patent protection, seven years in the U.S., 10 years in Europe, so great to get the orphan designations there. Really for those designations you also have to show a benefit above and beyond what is in the field today. We were glad that the FDA and the EMA agreed with us that there is a significant benefit. Then more recently we got fast track designation from the FDA. I think a further nod in the direction that, "Hey, this is a drug. This is something that is needed.
This is something that we want to make sure that we're kind of pushing forward from a regulatory standpoint.
For the orphan drug dimension that the agencies kind of look at, is this drug benefiting patients? Do they base that off the biomarker data? Maybe, "Oh, you guys are having two effects versus everyone else is just an anti-fibrotic." Or what was that decision based off, if you could share that?
Yeah. No. I think they look at the biomarker data. That's something that we highlighted to both agencies when we did our application, as well as the preclinical studies that we've done kind of on the protective effects of the type 2 epithelial cells. So really, I think it's the totality of the data package that we had.
Got you. That's an incredible achievement. It was great to have you here.
Hey, thanks.
Nice. Yeah.
Yeah. No, I appreciate the time. Thank you all.