Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yaz Rahimi. I'm a Senior Biotech Analyst at Piper Sandler. Excited to have the team from Tectonic Therapeutics here. It's been a great year.
It's been a great year.
Stock has done extremely well, especially in the back half of the year, really, and we just.
We were only public for the back half of the year.
That's right. Good job on crushing it to public markets. Yes. Exciting. And with the phase I data too, right? It's been a great amount. Lots to cover over the next 25 minutes, but maybe a good place to start off is to talk about, I think our investors listening are in the room, have a good feel about understanding what serelaxin does and its biological role. But maybe if we could touch on your compound and its differentiation versus the compounds that Lilly and Astra are developing. Let's maybe start there and then go into.
Do we have an hour?
Yeah.
Okay. So it's a little complicated because for many mechanisms or compounds, you just look at the in vitro potency assays and say, "Okay, well, this is how we compare." We don't think you can do that with relaxin. And that's because of the work that we showed that if you had a high isoelectric point, which native relaxin does, and we think the competitor compounds do, you tend to get stuck as other high isoelectric point compounds do to heparan sulfates that don't look like glycocalyx. And so what you find is that free drug is trapped, and there's a disconnect between the in vitro potency and the in vivo potency. It looks more potent in vitro than it does in vivo. For us, by bringing down the isoelectric point so it wasn't as sticky, we found there was really good concordance between in vitro and in vivo potency.
So when you ask about potency, I can't look at in vitro assays, which is the easiest thing to do. I can only look at in vivo data. The Lilly compound has renal blood flow data. And based on everything we know about that and our data, I'd say they're generally similar potency. And you can probably tell that even by the doses that we think they're going after. It's a lower dose because they're dosing weekly. They'll get some accumulation, but it sort of gets you in the same range on a monthly dose once you take accumulation. So I think potency-wise, we're probably on par with Lilly. It's really hard to say versus the AZ molecules because they didn't do renal blood flow data.
Okay, and then I think.
Selectivity, did you say?
Selectivity, yeah.
Yeah, selectivity. So I think the biologic compounds are all very similar. They're essentially native relaxin, so they signal in the same way. The oral drug by AZ has some off-target activities at high enough doses. We'll have to see if that becomes an issue in the clinic. And we know there may be some drug-drug interactions with that compound as well. And we know it doesn't signal in the same way. It binds to an allosteric site, so the signaling may be a little bit different.
Could you also talk about half-life and how it can differentiate?
Our PK data, if you compare apples to apples, which is normal healthy volunteer data, we appear to have the longest half-life. Both AZ and Lilly's biologics are on the order of within a week, a little bit over a week in normal healthy volunteers, and we're between two and three weeks. And I think that translates to the dosing schedules that you're seeing being evaluated in phase II. We're evaluating monthly and one every other week dose. We think the monthly dose will give full efficacy, but we're doing the every other week just to make sure we don't leave any efficacy on the table. AZ appears to be dosing every other week, and Lilly appears to be dosing weekly. And then with their oral AZ, the half-life is three to six hours.
Their phase I data was all with BID dosing, but now they're dosing daily in their phase II study.
Okay. There's two catalysts. Your data are coming from your phase I- B study, which is expected end of one Q, early two Q, and then also the phase II- B study from Astra, which is expected also in two Q.
That's when the study will complete. When they go public with it, I don't know.
So the likelihood is your data is going to come out first.
We anticipate that our data will come first. I've said 2025 may be the year of relaxin. You're going to have our phase I-B data, which we think will be out first. Then AZ data with their biologic, that'll be done in second quarter, end of the year. They'll get phase II data from their oral, and Lilly also should have phase II data from their biologic. When they actually share that data, given that it's large pharma, is a little bit harder to know.
I think when we had the opportunity to speak with you during another Fireside Chat a few weeks back, I think you noted sort of the bar for success there. Could you maybe repeat for our investors, what do you hope to gain from the I- B study?
Just to remind people, this is basically a disease that starts with left heart failure. And so fundamentally, we think you have to have an agent that improves left heart function. And one of the best ways to look at that is what's called the pulmonary capillary wedge pressure, which in essence is measuring pressures in the left atrium. And if you improve left heart function, you should bring the wedge pressure down. So across our entire population, we're hoping to see somewhere in the range of a 15%-20% decrease over the first eight hours of dosing with the drug. I think we anticipate that over a longer term, you'd get even a greater effect because the remodeling effects will come out. So that's one thing. And then in the CpcPH population, and remember, Group 2 PH has two categories of patients who get elevated pulmonary pressures.
One's called isolated postcapillary pulmonary hypertension, IpcPH. They basically have elevated pressures, as I just talked about, on the left side of the heart, that backflow into their pulmonary circulation. Their pulmonary vasculature on path looks normal, and their pulmonary vascular resistance is normal. On the other hand, you've got a subset that have what's called CpcPH, combined pre and postcapillary pulmonary hypertension. They have that same postcapillary component, the backflow, but in addition, their pulmonary vasculature looks more like they have PAH. They get a narrowing of the lumen of the arteries, as you're trying to push the same amount of blood through a smaller pipe, they get an elevation in their pulmonary vascular resistance, and in that subset, in the CpcPH subset, we want to see a decrease of about 15%-20% in their pulmonary vascular resistance.
Remember, PAH also has an increase in pulmonary vascular resistance, and if you can bring that PVR down, that has translated into an increase in exercise capacity.
So with the data in early 1Q, end of 2Q, let's say you achieve that bar of 15%-20% reduction in PVR, how much de-risking is it from the APEX s tudy that is obviously enrolling? If you could just talk about that because I think that's going to be sort of.
I can give you a one-to-one correlation. PAH, people have taken, there's been so many successful studies done where they've looked at reduction in PVR and translated that to Six-Minute Walk Test. You can almost look at the reduction and see how it translates. No one's done this in group two pulmonary hypertension, so what I would say is we know that elevated wedge pressures lead to a decrease in exercise tolerance. So if we can bring the wedge pressure down, we should increase exercise tolerance, and we know in PAH, like in CpcPH, if you can bring the PVR down by about 15%-20%, that also has an effect on exercise tolerance, which is why we say it partially de-risks the phase II study.
I wish I could point to a - if I get this exact, it will translate to this on the Six-Minute Walk Test, but that data isn't available to us. So what it's telling us is, number one, the drug is doing what we expect it to do in this patient population. And also, remember, hemodynamics is going to be the key thing we look at in the phase II study. So the fact we're looking at hemodynamics in the phase I- B, that should translate to the phase II. And then Six-Minute Walk Test is a key secondary in the phase II where we want to see at least a numeric difference.
Okay. And then given that the phase I-B is small, right? It's 20-25 patients. It's a combination of ICP and CPC population. And there's inherent variability in heterogeneity in the disease. How informative or clear do you think the data readout will be? That's a question in terms of just the nature of the time.
And so we hope to be able to look at both CpcPH and IpcPH. I get asked, "Well, what if you see a 14% difference?" I'll be very happy. If I see no effect on wedge pressure, which is not my expectation at all, that obviously would make us take a step back. But we're fairly confident we're going to see the type of effects we've spoken to because those are the types of effects that were already seen with Relaxin in acute heart failure, but nobody's now tested it in the chronic Group 2 PH population.
Is your distribution the same in CpcPH and IpcPH between the I- B?
Oh, between the I-B? I'm not going to comment on exactly. So what I would say is we're trying to get an almost even distribution of CpcPH and IpcPH in the phase I-B because it's such a small study. Whether we get 50/50, I doubt we'll get 50/50 because you can't know that they have CpcPH until you put that right heart cath in, and then you're dosing them right away.
Be balanced.
We're trying to get close to a balance. My guess is we'll have more IpcPH than CpcPH, but we want to make sure we have in the range of more than eight or something like that with CpcPH.
If you think about the Group 2 PH population, what is the distribution between CPC and?
Oh, that's a great unknown. Really hard to get at those numbers. And it depends how you define CpcPH. So it was always defined as a PVR greater than three Wood units. More recently, the guidelines have taken it down to two. But as you speak with the KOLs, there's still a lot of discussion about whether it should be two or three. So if you're talking about a PVR greater than three, I don't know, 30%, maybe 30%-40%. 30% is sort of an assumption. And if it's a PVR greater than two, it's probably going up to about 40%.
We're doing some more work on that, and we'll have better numbers, but until somebody studies it in a large enough patient population, because if you just rely on right heart cath studies, you'll probably get a higher percentage, because who's going for the right heart cath are the patients who have been more difficult to treat.
Is it easy to understand from a mechanistic perspective of serelaxin whether there could be a differential effect in CPC versus?
I really think it's going to work in both.
Yeah. There's no reason to believe that one could be well suited or.
The only reason we decided to study it, to try and enrich for CpcPH, was twofold. Very often, in sicker patients, it's easier to see a signal. The other thing is the PDE5 inhibitors, which activate the NO pathway, have looked in some studies like they work in CpcPH, whereas they don't work in IpcPH. And one of the pathways that Relaxin activates, in addition to many others, is the NO pathway. So we thought maybe you had a higher probability of success. And then the other is you might just see a bigger effect size because you're doing two things for the CpcPH population. You're both improving their left heart function, but you're also dilating their pulmonary arteries, and that might lead to a bigger treatment effect.
Okay, and we talked quite a bit around expectation on PVR. Any other hemodynamic and other measures that you hope to see in the 1B in terms of?
There's been a lot of talk with Tenax about CVP, so we'll probably look at CVP. I don't have any predefined notions of what we might or might not see there. We'll look at cardiac output, but I don't expect to see large improvements in cardiac output at rest because PEF patients have normal cardiac output. We'll look at pulmonary artery pressure. And the other thing we'll look at, remember I said for CVR, we're really going to focus on the. I'm sorry, for PVR, we're going to focus on the CpcPH population. Across the whole population, we'll look at something called TPR, which is total pulmonary resistance, and that should go down, we expect, in both the CPC and the IpcPH populations.
Okay. Very helpful, and then for post that, the next readout, obviously, Astra and Lilly are going to have their readouts, and I don't know if you have a view on how the data could unveil or what you're hearing.
Listen, I'm hopeful that they'll all be positive. For AZ, we don't know that they're enriching in CpcPH, and they have both HFrEF and HFpEF. I actually think there's good reason to believe this drug would work in reduced ejection fraction heart failure, HFrEF, as well as in preserved ejection fraction heart failure, HFpEF. Our study focuses on HFpEF, but I think they've got a good shot in working on both, which just widens the opportunity, but clearly, when they present data, we'll be very interested in understanding what the efficacy looked like in each of the populations. We'll be interested in IPC versus CPC, and then I think the key thing for AZ is understanding the doses that they chose. They didn't do renal blood flow, which I still believe is the best biomarker, although they did just start a renal blood flow study using a PET ligand.
And so hopefully, maybe there'll be some data from that around the time of their efficacy study so that we can put whatever data they have in context, make sure that they had doses that were fully efficacious.
Okay. And then with APEX, what is your timeline perspective in terms of enrollment completion, top-line data?
Right now, we've just said 2026, and we haven't been a lot more specific. As we get a handle for how well enrollments go, we'll beef up and narrow that timeline, sort of as we've done with the phase I- B.
Okay, and I think another question that comes up is what is the regulatory path going to look like in group two?
I think it's pretty clear.
HFpEF, like Six-Minute Walk Test.
Six-Minute Walk Test is an approvable endpoint for it. And so going in right now, that's our hypothesis. We will probably in phase II start to explore some composite endpoints looking at outcome-type things. We'll look at change in New York Heart classification. Do you go from class three down to class two or class one? And we'll look at KCCQ, so a quality of life measurement and things like that.
Then before we go on to 2100, you are going to be hosting a KOL event , and when are you and what do you hope to share?
Yeah, it's going to be. There'll be a press release out later this week with the date and the time. I think it's the 12th at 4:00 P.M. Yeah, 4:00 P.M., where I needed to help with that. We have two terrific KOLs. A KOL is really an expert, Benza from Mount Sinai here in New York, who's really a Group 2 PH expert. I've learned a lot from him about Group 2 pulmonary hypertension and John Teerlink, who was the PI for the serelaxin program and really knows a lot about relaxin, and both of them are really excited about our program as well.
Okay. So there'll be two speaking about. You're not unveiling any new data. It's more like getting.
There's no new data.
There's no new data, but more the two clinicians' views on serelaxin as a mechanism of population.
One will really be sort of a teach-in on Group 2 pulmonary hypertension by Ray Benza. And then John Teerlink will talk about his experience with serelaxin and why he's a believer that this could be an ideal mechanism for Group 2 pulmonary hypertension.
Okay. And then, team, I guess at least one of the questions that we get is a lot of investors that are new to Tectonic will have looked at the stock performance and really seen a skyrocket straight line over the last few months. And they know the phase I-B data, but then they're like, "What am I missing here?" So there's been a tremendous FOMO associated with wanting to be—so could you maybe capture—you guys have had a tremendous amount of investor discussions, from starting the company to the sentiment that exists right now. Yeah.
Yeah. You know, first of all, no one knew what Group 2 pulmonary hypertension was. And it took a lot of time for investors to get used to understanding the pathophysiology of the disease. And then the other thing you had to sort of get people over is, "Oh yeah, relaxin, that failed." And then I think the more people have heard the story and why we really think the mechanism of action of relaxin so matches the pathophysiology of the disease, we really think it can improve left heart function and treat the pulmonary vascular changes, especially in the CPC population, as well as improving kidney function. Just the story makes a lot of sense.
I think the fact that there's two really well-respected large pharma that are clearly going into this and doubling down, AZ has two programs, Lilly now has two phase II and two different indications ongoing. I think people have realized there's something really interesting here. And for a new molecule, a new target in an indication with no approved therapy, there's a lot of data that suggests there's a chance for success here.
What's the market opportunity in Group 2 PH?
It's really big. I mean, I think these are very large multi-billion dollar opportunities. And there aren't so many multi-billion dollar opportunities with no approved therapies.
Yeah. No, that's very helpful. So you have the opportunity to embark on the orphan in a Group 2 or go broader.
I don't think any of them will be orphan indication there, but sort of the pricing will end up being dependent, as you might expect, based on which population you're in.
Okay. Maybe as we have like two minutes and 40 seconds, could we talk about TX 2100, where you are in terms of what's the rate limiting step on completing IND enabling studies and getting it ready for market?
Yep, so we've started manufacturing. Things have been going incredibly well with that. Once we have a drug that comes out of the cell line that we've made, we can start the IND enabling studies, and so then it's just finishing the CMC, getting the final formulation, getting the final path on the IND enabling studies, and then we're hopefully off to the races, so we hope to be in the clinic either at the end of next year, so a little bit over a year from now, or the beginning of 2026.
Okay. And I think you have a core GPCR technology as well, and we love GPCR. So is there other platform work or partnership or other activities ongoing at the firm?
There are. The platform actually is performing incredibly well right now, and we've got some earlier programs in discovery that are really interesting, but not ready to talk about them yet.
Okay, and then maybe last question: what is the cash and the cash runway, and where does it get you to APEX readouts?
Yeah. So as of end of September, it was $159 million, and we said it gets us into mid-2027.
Okay. Perfect. All right. I think this was my first Fireside Chat that I can give a minute back to you. Thank you so much, Alise. It's been a pleasure covering you and on a great sort of trajectory of the last few months and great 2025 ahead of us. So let's say thanks to Alise.