Hi. Good afternoon, everyone. Welcome to day one of our Cantor healthcare conference. My name's Olivia Brayer. I'm one of the senior biotech analysts here at Cantor, and really excited about today's fireside chat. We have Brigette Roberts, who is CEO, and we have Keith Fandrick, who is Chief Operating Officer. Thank you both for being here.
Thanks.
You guys have had a busy year. Maybe just give us a sense of what has unfolded over the last six months, where the company is positioned today.
How excited you are heading into 2027.
Yeah. Our company was a small private company focused on this drug called LAM-001. It's a proprietary inhaled formulation of rapamycin, a DPI, one puff once a day. It was a long, arduous path, but we just reversed into Quince Therapeutics in May of this year, along with a $150 million PIPE. We're progressing the asset through multiple pulmonary indications where the mTOR pathway is clearly implicated. It's pretty exciting. We had a readout in pulmonary hypertension at ATS, May of this year, and our next readout will be coming in bronchiolitis obliterans syndrome post-transplant in first quarter of 2027.
Yeah.
It's exciting.
Coming up quickly. mTOR inhibition, can you just talk about why does that make sense in pulmonary diseases? Why did you decide to look at mTOR, and how does that potentially address something that existing therapies currently don't?
Yeah. I think overarchingly, we are targeting a pathway that's highly implicated across a number of these disease states. It's hyperactivated, that has heretofore not been targeted. It's a totally different pathway, and it's turned out to be quite important across a number of different disease states. What has plagued the drug and prevented its adoption in oral form, which we know is available, is the systemic toxicities that come with that oral form of delivery. What we've created in this inhaled form, is a manner of delivering this directly to the pulmonary tissues at a tiny fraction of the oral dose, 1/20th of it. We are seeing very low systemic levels, and thus far quite a nice safety profile, which is allowing us to treat these patients where it's really needed.
You're also doing it once daily DPI.
Yeah.
Can you talk about the work that you've done behind this molecule to get to this stage where you are able to deliver it once daily, and talk about the PK profile and what gives you conviction in a once daily delivery mechanism?
Yeah. I can give you big picture. Keith can talk about everything he did to develop this. We know, really across multiple studies at this point, that at that 100 microgram dose, we are seeing systemically less than one nanogram per ML blood levels. That compares to the targeted blood levels with the typical oral rapamycin dose of 2 milligrams. They are targeting 5- 15 nanograms systemically. We're seeing less than one-fifth to one-fifteenth those systemic levels seen with oral, and that's why it has been so well-tolerated. We also have nice evidence from animal models where the PK profile really mimics the profile we see in humans with our drug, that when delivered at, again, a fraction of the oral dose, we're seeing multifold exposure in the pulmonary tissue.
Maybe I'll turn it to Keith in terms of how difficult it was to make this.
No, thank you. Rapamycin is a large polyketide. It's actually a quite difficult molecule to formulate, and I think we've done a very good job in making a very stable commercial formulation that can treat these patients. More in particular, I think we've been very patient-focused as well. We've really designed this around a well-known, easy-to-use inhaler. There's low resistance. It doesn't take a lot of airflow to effectively extract, aerosolize the powder, and deposit to where it's needed, which is the deep lung.
Okay. You mentioned your data set that you presented at ATS earlier this year, and I'll get to that in a minute. But now that you do have some proof of concept data in humans, does that change the way you think about success in other indications, like BOS or SAPH, that you're-
moving into phase II on?
Yeah. The one question always is whether or not. We did a lot of work in impactor studies. We felt quite comfortable that our drug was going to reach all areas of the lungs that are aerated. We felt quite comfortable it would get there, but of course, the test is in humans. Post that PH data set, we now know that our drug appears to definitely be getting to these tissues based on the data that emerged from that study. So yeah, to that point, yes.
Why don't we talk about that data set a little bit?
Sure.
Maybe at a high level, what were some of the biggest learnings coming out of that data set? I am just curious, the receptivity that you got from doctors at ATS. I do not know if your team was at ERS more recently this weekend, but what is the buzz in the community just around the impactfulness of the data set that you have been able to produce so far?
Yeah, it was quite exciting, actually, coming out of our data presentation earlier this year, because, again, we were a small company. That trial was focused at four sites in the U.S. There was a significant amount of inbound interest from top KOLs post the announcement of that data. I think the overarching big picture learning was that the mTOR pathway is important in this disease, and that we found a way to deliver it in a very well-tolerated manner. Numerically, it was exciting data. Small data set, we obviously need to run more studies, but we had very nice improvements in six-minute walk distance, in PVR, NT-proBNP, oxygen utilization, even improvements in forced vital capacity. Obviously needs to be studied further, but really nice data.
Yeah, you mentioned some of the KOLs that are interested, and you do have some big-name KOLs that are involved. How did you get some of those KOLs on board to begin with, right? How did an Aaron Waxman come to be part of such a small private company?
Yeah.
Or not part of, right? But be part of-
Yeah
your program.
No, you are right. They were very critical to us getting to where we are today, because we were so small, and we needed help from everybody we could get. I was introduced to him through another KOL in the industry whom I had known for about two decades. As soon as he heard about it, he said, "Wow, I have been looking for a way to get an mTOR inhibitor to these patients for over a decade now." He was just excited from the get-go, fortunately, and he took this under his wing with us, and we are now where we are today.
Keith, maybe I will ask you, a big question that comes up a lot in my investor conversations, and I am sure your conversations, is just around making sure that you are getting enough drug to the right part of the lung. The importance of that in an indication like PH-ILD. Can you just talk about the confidence and again, maybe some of the PK/PD work that you have done that gives you conviction that you are hitting the right part of the lung, but also with the right amount of exposure?
Any type of inhalation development requires multiple lines of evidence. The first of which is usually your impactor studies, as Brigette has mentioned, which is well known. The FDA requires this, it is from USP <601>. That, I think, is the really key test because it is not just testing your formulation, but tests the actual configuration the patient will use. It is the capsule in the inhaler pierced. It simulates a breath, and when it deposits through this impactor, kind of like simulates a lung. You kind of have a section that has a high airflow, think the back of the throat, down into the upper airways, and the airflow decreases, and that is where the drug would deposit. What we can see clearly through this experiment, the drug deposit is effective where everything is aerated.
That usually is due to basically getting this right particle size, as Brigette has mentioned, which is between 1 and 5 micron, and we have discussed this before. Our product is really tight. It is around about 2.7 or 3.1 micron. So it is really effective at delivering it to where you need it, which is pretty much in the deep lung to where the patients need it. As for the PK studies, I do not know if you want to take that question.
Well, I think I mentioned this earlier. We have seen highly consistent PK across our studies. Normal healthy volunteer, an original LAM study that was done, our PH study, where we are seeing a little less than 1 nanogram per ML systemically at the 100 microgram dose level, and that is very consistent with all the modeling and predictive work we did prior to entering all these studies. I mentioned earlier that there is an animal model, that in animals we are seeing a very really similar PK profile to what we are seeing in humans. In those animals, after just a single dose equivalent to the 100 microgram dose, we see greater than 90% inhibition of the mTOR target all the way out to 24 hours. If you take a dose even lower than that and you treat in vitro human pulmonary arterial smooth muscle cells, you see reversal of that hyperproliferation.
Again, this is all just corroborative to what we are seeing in humans.
Yeah. Okay.
Yeah.
Very interesting. We will come back to the once daily profile and the fact that you guys are looking at this on top of other
Yeah
assets in PH-ILD. I do want to start with BOS.
Okay.
Because BOS, I do think, gets a lot of investor interest from a timing perspective.
Yeah.
It is coming first quarter of 2027. Is that still on track?
Yeah.
Can you just talk about what makes BOS such an attractive initial proof of concept indication? I know you have data in PH-ILD, but this will be your first phase II readout that you will have as a company.
Yeah. Big picture, it is just such a major unmet medical need. BOS is a disease, it is effectively like a chronic rejection of a lung transplant. What it is this chronic hyperproliferative process that is occurring within the airways. It has been found, it has been elucidated that the mTOR pathway is very much upregulated in this process. From just a mechanistic standpoint, it will be yet more proof that our drug is indeed getting where it needs to go in the lungs and treating these patients. Big picture, we have the ability to help a population, an orphan population, where there is absolutely nothing available to them today. They will all die within about 2.5 years. Nearly every lung transplant patient will develop this, and they will unfortunately succumb to it.
And it is a single center study.
Yeah.
Can you maybe talk about how this study got off the ground and why a single center?
Yeah. We were a very small private company when we embarked on this. We ended up, again, similar to Aaron Waxman, Steven Hays at UCSF became very interested in studying this in BOS. It is one of the largest transplant centers in our country today, UCSF, and he took it under his wing as an investigator-sponsored study. It is very well designed, placebo controlled, and it is actually beautifully designed. A small study, a single center because we were small.
But we do think we will be able to generate. Well, he will be able to generate pretty relevant data. We will learn a lot from it.
What do you think success in this type of study looks like?
Yeah. It is a small study. It is 19 patients, right? That needs to be taken within context. But what we are really looking to see is a separation of the curves. What we are measuring in this study is the percent change in FEV1 over the 48-week duration of the study, or until termination of treatment. FEV1 is a very important metric in this disease state because for every 1% decline in FEV1, it is directly associated with an increase in mortality, statistically significantly across multiple papers. A very highly relevant metric. What we would like to see in this study is a differential between the curves, right? We want to see at least 5%-10%, because given that correlation with mortality, that would be a meaningful outcome that we could then use to power a pivotal study.
If we see 10% or greater, that would be a great outcome, and if the drug arm itself actually improves, or even patients within that arm improve, that would really be a home run because it's never been seen before.
Improves from baseline.
Yeah.
Yeah.
Yeah.
Well, this is a patient population, to your point, right? There's nothing else out there. From an FEV1 trajectory perspective, it can be quite heterogeneous.
When you think about designing the study, when you think about enrolling patients in this study, are there ways or are there things that you're doing to help mitigate against that?
Yeah
so that you don't see a noisy signal?
Yeah, absolutely. What was done in this study, and again, this is Steve Hays' study, but he enrolled patients all within the first year of diagnosis of BOS, and nearly all of his patients were within the first six months of diagnosis. BOS is diagnosed when FEV1 has fallen to 80% or less of baseline levels, with those baseline levels being measured post-transplant. He enrolled patients anywhere within 85%- 51% of those baseline levels. They were all declining on their way in, but they were early on, so there was sufficient lung function for them to potentially benefit from an agent. It was very well controlled for any potential reversible causes of an FEV1 decline. BOS, by definition, is an irreversible decline in FEV1. Those reversible causes can be things like an infection, GERD, or even this disease called neutrophilic reversible allograft dysfunction.
That latter one was taken care of because he has all of his patients. They respond to azithromycin if they have NRAD, and he had all of his patients chronically on azithromycin. In terms of these other reversible causes, he measured FEV1 at 30 days apart for patients to even be eligible for screening. He measured it twice, and then it was measured a third time at screening. Anyone who had a reversible cause of FEV1 would've improved across these multiple FEV1 measurements. It was well designed.
Sounds like you're confident that you guys enrolled-
Yes
the right patients. Okay, great. How are those being handled in the study?
Yeah. All patients in this study were on the CCC regimen. They are all on the same regimen, so a calcineurin inhibitor, a cell cycle inhibitor, and a corticosteroid. So they were all on that chronically. If patient's FEV1 fell more than 10% over the course of the study, they were allowed to be rescued because of course that's the ethical thing to do. The two things that are used at this particular site are extracorporeal photopheresis, or ECP, and the second one, this is one of the few sites, not many do it, but they do use oral mTOR inhibitors at his site. Given that an oral mTOR inhibitor was a potential rescue therapy, it was importantly and intelligently designed such that the primary endpoint was either at the 48 weeks or until termination of therapy.
Because obviously if a patient, let's say, were on a placebo arm and declining and reached that endpoint and then received an oral mTOR inhibitor and perhaps did better, if the endpoint continued to 48 weeks for everyone, it would have masked-
what was happening in that placebo arm. I think pretty well designed.
But those patients that may have received an oral mTOR inhibitor, they will still be included in the data analysis, just up until a certain time point.
Yeah, up until termination of treatment. Because if patients went on an oral mTOR inhibitor, you have to take them off treatment because you can't dose them with two different.
Sure
mTOR inhibitors.
Okay.
Yeah.
Given that BOS is a small airway disease, can you just talk about the importance of particle size and then going back to the idea of making sure that you're targeting the right part of the lung?
Do you want?
Sure. To expand on what I mentioned previously, that 1-5 micron range is key for what is known as the MMAD, which is basically the mass median aerodynamic diameter of the particles as they actually fly through the air, which is measured through this impactor apparatus that I've talked about. What's key about this is that if it's below 1 micron, they usually don't deposit well and most of it just gets exhaled. They're too large. They tend to deposit in the upper airway, and they never actually reach the deep lung. That 1-5 is actually the key metric to use and be in the middle, which is batch to batch variability really tight between that 2.7 and 3.1 micron. We're pretty sure that it gets everywhere where the lung is aerated, our drug will effectively deposit.
In fact, we actually see this through this impactor study as well. That gives us great confidence is where it aerates the drug will actually reach that part of the lung.
Okay, interesting. Data in first quarter.
Yeah.
What for this program?
Yeah. Then we meet with regulatory authorities, then at least at present, we're planning on a pivotal study.
Okay, great. We're looking forward to that. Why don't we switch gears to PH-ILD?
Obviously, you've had some data. We talked through it already at American Thoracic Society. Can you talk about the decision and the strategy to look at LAM-001 on top of other background therapies in PH-ILD? When you think about the go-forward basis and the phase II that you are running, how many patients do you expect to be on background therapy, and how central is that to the thesis?
Yeah. Because LAM-001 is targeting such a different pathway from every other drug out there, we frankly didn't and don't see any other agent it can't be used in conjunction with. We know that the vast majority of these patients in our country are on a number of background therapies.
As long as they were on stable doses of those therapies and still symptomatic despite those therapies, that's a population that needs to be treated. Strategically in big picture, it sets us up so that our drug can be used in conjunction with anything out there, or even potentially as a single agent, at some point down the road.
Yeah. No, I think it's a very thoughtful approach. We were actually just in a fireside chat with United Therapeutics.
They were talking about how treatment markets like PH-ILD and IPF and PPF down the road will become more and more of a polypharmaceutical market.
Yeah.
So maybe I will ask you,
Yeah
When you think about PH-ILD down the road, how do you envision that market playing out in terms of layering multiple therapies on top of each other?
Yeah, I think it 100% will be a polypharmacy. I do not think anybody out there would state that there is any one drug that will cure these patients today. I think there are multiple pathways that will need to be targeted, and at this point in time, we feel quite confident that the mTOR pathway is one of them.
Are you limiting any background medicines in your phase II study, or do you really expect-
No
to have a broad-
Yeah
implication for mTOR?
Yeah, we
in the future.
We'll allow background therapies. They must be on them for at least 90 days, stable doses for 90 days, and they have to be symptomatic despite the background therapy. That's the key. In our prior study, everybody was on background therapy. All the PH-ILD patients were on background treprostinil, and frankly, triple background therapy. We'll just stay the course.
Okay, great. Can you talk a little bit about your phase IIb trial design?
How did you select the doses to move forward, and ultimately, what do you think a successful study will end up looking like?
Yeah. We're studying the 100 microgram dose, which we studied in the prior study. We've layered in a 200 microgram dose, really because regulators always suggest that you study multiple doses, and based on the tolerability profile across populations so far, we don't really feel a need to study a lower dose than 100 micrograms, so we've layered in a 200 microgram, and then a placebo arm. As a primary endpoint, we'll be measuring the change in PVR over the course of 24 weeks. The only difference from our prior study is that we will allow some Functional Class II patients in the study, but everybody will need to have, going into this, a PVR greater than four. That's quite consistent.
Okay.
Yeah.
How do you think about what a placebo arm should
Yeah
look like and perform, just given that you are looking at multiple background therapies?
Yeah. What we've seen in these various, they're not that many studies. What we've seen in the studies thus far is that a placebo arm will show an increase in PVR. The riociguat study that was just presented, I think it was a 6.6% increase. There was a small Corte study that was published many years ago that showed a single-digit increase. That was with bosentan. There was a riociguat study that Nathan published, I think it was in 2019, that one showed a double-digit increase in PVR in the placebo arm. I know they may be on background therapies, but I would imagine they're going to be symptomatic, and my guess is they'll be increasing. What we're powered for, you asked that question, or what we'd like to show,
we're powered to show a 20% delta versus that placebo arm.
Okay, helpful. Any thoughts on how long enrollment may take in a study like this?
At this point, we are looking to have our data set in the first quarter of 2028.
Okay. Great.
Yeah.
As you think about, we've talked about BOS, we've talked about PH-ILD, you do have a third indication that you're looking to move forward with, SAPH. Maybe just talk about SAPH, the decision to add that as your third indication. What work have you done in SAPH, just to give you confidence in moving forward with that one?
Yeah. There are many indications where the mTOR pathway is implicated, many pulmonary indications. I should say, there's a lot of interest to study in other pulmonary disease states. SAPH in particular, we did allow one patient with that in the study that was presented at ATS. That patient did well. We feel comfortable targeting the pulmonary hypertension component-
of pulmonary sarcoidosis, which is what we're doing. We're looking at the pulmonary hypertension. One thing that's very interesting to note is that the underlying disease state, sarcoidosis, is characterized by these granulomas. And it's been elucidated over recent years that those granulomas are mTOR-driven, and there are animal models that have shown this. But importantly, when you treat humans who have, let's say, the cutaneous form of sarcoidosis, so you get very visible lesions. When you treat them with an oral mTOR inhibitor, like in many patients, you see complete clearance of these lesions.
It's implicated in the underlying biology of sarcoidosis, and it's also, as we know, implicated in that hyperproliferation of the pulmonary arterial smooth muscle cells that are characteristic of pulmonary hypertension. So we think we, at a bare minimum, will benefit the arteries-
as an anti-proliferative agent, and who knows? We might see a benefit on the granulomas. But again, we're not looking for that.
Yeah. I know it will be some time before we have phase II data from that program, but are there things that you can learn from SAPH that maybe you can not learn from an indication like PH-ILD or BOS to then use as forward learnings for future indications?
I honestly think it is quite similar.
Yeah.
In PH-ILD, we saw a benefit on the pulmonary vascular resistance. That is obviously the anti-proliferative effect of the compound. We also saw a benefit on FVC, which is showing that we are benefiting the background disease in an anti-fibrotic manner, that fibrotic lung parenchyma. In the case of SAPH, if we see something like that, it would be similar learnings. Different diseases, mTOR pathway leading to different things. But again, very clearly an mTOR-driven disorder.
Mm-hmm. You brought up fibrotic lung diseases. Is that something that you think down the road, as you have maybe gotten a little bit more clinical validation, is that an area that you want to move into ultimately?
Well, we are looking at FVC in an exploratory manner in the ongoing PH-ILD study. If we continue to see the benefit that we have seen, yeah, it would be the right thing to do for those patients to move it forward in that disease state. But again, a little premature because we need to see what that study shows.
Yeah, sure. Okay.
Yeah.
Then as investors are thinking about BOS versus PH-ILD and then ultimately SAPH, how do you think about the opportunity set that you have across the three? I do not know if you are willing to rank order them, but just in terms of the commercial upside or the revenue opportunity that you could have across those three indications.
Yeah. Well, if you look at this on a purist basis, patient numbers, the PH-ILD market is the largest of the three.
SAPH and BOS. That said, the BOS market, these patients are all known. They are all known by these transplant centers across the globe. It will be much easier to find those patients than to find patients in some of the other categories. They are quantitatively, in terms of patient numbers, PH-ILD is the largest. Obviously, our next data set's BOS, and we think they're equally exciting. In the case of BOS, there's just nothing for these patients.
SAPH, it's a little early. We have to see some more data, but if it continues to pan out, again, another wide open market.
Yeah.
So.
Given that BOS is, to your point, a wide open market at this point, as you think about we'll get data next year, but next steps, designing a registrational study, when you think about the concentration of these patients and the sites.
Does that make it easier, or does it make it more challenging as you think about putting together site activation and ultimately a registrational program?
Well, the easier part of this, again, is these patients are all known by these transplant centers. Even if the transplant happens at the transplant center, and even if these patients are doing well, and they move back to the community, as soon as there is a problem, they are back at the transplant center, and BOS is a problem. We will. In a way, it's easier because we're going to be focused on a limited number of locations globally.
The hard part, of course, is that there are fewer of them.
Yeah
We'll just have to be patient and enroll over time.
Yeah.
But I don't think it will take forever to enroll the patients.
Okay, fair enough. We've got about a minute left, so I'd love to hear, over the next six or so months, we'll get BOS data, you'll have some enrollment progress in PH-ILD. As you think about positioning the company for long-term success, what are maybe the biggest drivers for you all going forward? Do you think about it as an indication specific?
Do you think of it as more of a de-risking of your program in totality and the mTOR pathway as you get more of these data points under your belt?
At present, I think every time we get another data set in a disease state, assuming it's positive, that's going to lend even more credibility to our drug's ability to target these other disease states, where we know the pathway's implicated. I think right now, it's obviously being looked at as a data set on a data set by data set basis. But I think as we move along, I think there will probably be a much more clearer understanding that this drug will likely work in very many diseases that we can target via this mode of action. I think it will evolve, honestly. I think it's being looked at a certain way right now, and I think it will evolve over time.
Sure.
Yeah.
Okay, great. Well, Brigette, Keith, thank you so much.
Yeah. Thanks.
Great discussion.
Thanks, Olivia.