Tectonic Therapeutic, Inc. (TECX) Earnings Call Transcript & Summary

Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 46th Annual Healthcare Conference for our next session. Looking forward to a hybrid presentation and fireside with Tectonic Therapeutics. And it's my pleasure to introduce Dr. Alise Reicin, President and CEO of Tectonic. Alise, it's a privilege to have you here. Thank you for joining me. I'll hand it over to you for the presentation.

Thank you for inviting me. In the next 10 to 15 minutes, I'm trying to give you a very high-level overview of what we're doing at Tectonic. Here is our forward-looking statement. And just to get started. Tectonic is focused for any of you that don't know, on the discovery and development of both agonist and antagonist biologics targeting GPCRs. We have a super experienced executive team. Between us, we've led teams that have resulted in over 20 first approvals drugs and many follow-up indications. Our focus to date has been on high unmet need areas with limited to no therapeutic options with multibillion-dollar market potential. When we started the company, our goal was to have a robust product pipeline that enables optionality and good data-based decisions. And as of today, we have 2 programs in the clinic covering 3 indications as well as a strong emerging preclinical pipeline. First, we have TX45, our long-acting relaxin, which is in Phase II for pulmonary hypertension associated with preserved ejection fraction and heart failure. You'll hear me refer to that as PH-HFpEF going forward as well as we just initiated a study in pulmonary hypertension associated with interstitial lung disease, otherwise known as PH-ILD. TX2100, which just entered Phase I is a potential first-in-class APJ antagonist being developed for hereditary hemorrhagic telangiectasia, otherwise known as HHT. I'm going to use a lot of acronyms here, and it could be used for other bleeding disorders associated with dysregulated angiogenesis. We have really good clinical momentum, and we're well capitalized to advance the pipeline. So in terms of pipeline-related catalysts, we expect to have results from our Phase II APEX Group II PH-HFpEF study in late 2026, maybe early 2027. And our Phase II study in PH-ILD was just initiated. As I noted, we're in Phase I with TX2100. We should have data from that by fourth quarter of this year, and we will be starting a Phase Ib in parallel with the Phase II very shortly thereafter. So first, starting with our relaxin program. There are 5 groups of pulmonary hypertension. Most of the product development has been in Group 1 PAH. But the 2 that we're currently focused on are Group I, which is pulmonary hypertension associated with left heart failure. This is the largest group, probably with over 2 million patients in the U.S. alone. Group III is pulmonary hypertension that's associated with lung disease. And specifically, as I said, we're in the PH-ILD population. The need in Group II PH is large and underserved. There's no approved therapy. And we estimate in the Group II PH-HFpEF population, so that's with preserved ejection fraction, there's about 1 million patients in the U.S. They have very long-term outcomes. The market is clinically segmentable, Group II PH has 2 subpopulations, IpcPH, and that's isolated post-capillary pulmonary hypertension and CpcPH combined pre and post pulmonary hypertension. Both are driven by elevated left -- pressures on the left side of the heart that backflow into the pulmonary circulation causing the pulmonary hypertension. And that's called the post-capillary component. In the CpcPH subpopulation, in addition to that post-capillary component, there is a pre-capillary component that's caused by abnormal pulmonary vessels where you have muscularization and a narrowing of the lumen, which then causes an increase in pulmonary vascular resistance as the same amount of blood is tried to be driven through a smaller pipe. We think that, that sub -- while we think the drug could work in both IpcPH and CpcPH, the CpcPH population has a greater unmet need, and we think the benefit could be even greater in that population. TX45 mechanism matches the biology. Relaxin results in pulmonary dilation, which should reduce pulmonary pressures and pulmonary vascular resistance. It also dilates the systemic circulation and improves diastolic relaxation. Both of those should improve left heart function. And lastly, its antifibrotic effects should both improve left heart function as well as the pulmonary circulation. We have supporting clinical evidence, which I'll show you from our Phase Ib hemodynamic study in patients with PH-HFpEF, which showed that relaxin could improve both left heart function and pulmonary hemodynamics. And lastly, we think we've got an efficient plan. You'll see we've enriched for patients with CpcPH in our Phase II study, and we think that 6-minute walk will be an approvable endpoint in Phase III, which means we wouldn't have to do an outcome study. Just real briefly, these are the results from the Phase Ib study in patients with PH-HFpEF. We took those patients. We put in a right heart cath. We measured hemodynamics at baseline. We gave them a single dose of relaxin and then we measured hemodynamics over the first 8 hours. And what you can see is we showed evidence of improvement of left heart function on the first row, you see there was almost a 19% reduction in the pulmonary capillary wedge pressure as a change from baseline. And then on the fourth row, you can see we also improved cardiac output by a little bit over 18%. We also showed evidence of improved pulmonary hemodynamics. That increase in pulmonary vascular resistance that I referred to was brought down by over 30% in patients that had an abnormally high PVR. And we also, if you look further down, brought down mean pulmonary artery pressure by about 17%. Our Phase II study, which is ongoing, is a 6-month study. Patients are brought in. We do a right heart cath at baseline. They then get randomized to either 300 milligrams Q4 of relaxin, 300 milligrams every 2 weeks of relaxin or placebo, a right heart cath is then done at the end of the study. The primary endpoint is change in pulmonary vascular resistance in the patients with a PVR greater than 3, and that's about 70% of the patient population. We'll be looking at other hemodynamics such as cardiac output, pulmonary capillary wedge pressure as well as 6-minute walk and secondary endpoints. Switching quickly to PH-ILD. As I said, these are patients with Group II pulmonary hypertension, secondary to interstitial lung disease. These patients tend to have shortness of breath and cough. And when they get pulmonary hypertension on top of their ILD, their exercise and tolerance gets even lower, and they tend to have lower blood oxygen levels. Like other forms of pulmonary hypertension, you make the diagnosis on right heart cath, where you see an elevation in pulmonary pressures and pulmonary vascular resistance. It's a very high unmet need population. The only approved -- there's about 60,000 patients in the U.S., and they have very high 3-year mortality. And currently, the only approved therapies are inhaled treprostinils, which can be difficult to tolerate because of cough and bronchospasm that can grow associated with that. Preclinical models in pulmonary hypertension support exploration of PH-ILD. And furthermore, the data that just showed you in Group II pulmonary hypertension, where we reduced the pulmonary vascular resistance as well as the mean pulmonary artery pressure go along with the ability to potentially do that in this patient population. It's a devastating disease that has a significant commercial potential. Just real briefly, the study, which just initiated is a 16-week open-label Phase II study, up to 25 patients. They'll have a baseline right heart cath and then another right heart cath after 16 weeks of therapy and the primary endpoint is safety and looking for a reduction in pulmonary vascular resistance. And lastly, just switching to our TX2100 program. Hereditary hemorrhagic telangiectasia is the second most common genetic bleeding disorder. It's caused by mutations in the ALK1 pathway. It's a serious disease with major effects on quality of life and life expectancy and a multibillion-dollar potential market with no approved therapies. It's an orphan disease. And while off-label anti-angiogenic agents are used, such as the VEGF inhibitors, and they are efficacious, they're limited by their toxicity as well as a lack of durability. Our approach to this is novel as APJ, the receptor for the peptide hormone Apelin is a selective and specific anti-angiogenic target. We don't have to prove that anti-angiogenesis works in this disease. That's already been done. Instead, we're going to improve on that because this approach is more tissue selective. It's really only expressed or mainly expressed in endothelial cells, and it's pathology biased, meaning that it's typically quiescent and only gets upregulated in the disease states. Further, we think there's the potential to expand into a broader group of bleeding disorders that are caused by dysregulated angiogenesis. TX2100 is a potential first-in-class subcu administered APJ antagonist, again, with the goal of achieving the type of efficacy you see with other anti-angiogenic agents but with improved safety. And our POS is enhanced by the demonstration of efficacy in 2 separate preclinical models of HHT that have previously been shown to have clinical translation. We're currently in Phase I in Australia. And I told you that we had efficacy in 2 mouse models. In the interest of time, I'm just going to show you data from one of those. This is -- these are mouse models where the ALK1 pathway is inhibited to reproduce the disease, and they do reproduce the phenotype of the disease. The data on this slide is from the most severe of those, which is the adult ALK1 inducible knockout model, where you can see in the white is a normal mouse. Next to it in blue is the inducible knockout mouse. And then in orange is TX1351, which is a mouse surrogate for TX2100 in orange and the VEGF antibody is in gray. And what you can see on the left-hand side on day 7 is you get a marked anemia in the knockout models that are rescued by both the anti-APJ and the VEGF. But if you take the model out to day 12, you still have persistent increase in hemoglobin in the anti-APJ animals but that's lost in the anti-VEGF animals, which may be showing us what happens in the clinic where there isn't durability of the effects in some patients. If you look at GI bleeding out to day 12, you can see that APJ inhibits the bleeding but the anti-VEGF does not. And so as I said, our Phase I study is ongoing. And the toxicity profile preclinically enabled us to go into animals. We dosed nonhuman primates up to 100 mg per kg. There was no signal whatsoever on safety in that finding and that enabled us to go into normal healthy volunteers. When that study is over, we will quickly start a Phase Ib study in severe HHT patients in parallel with initiating a placebo-controlled dose-ranging study, proof-of-concept study, Phase II study in moderate to severe HHT patients. And just lastly, as I said, we have 2 clinical candidates addressing untapped markets with significant market potential, expected data readouts from both our APEX study in either late 2026 or early 2027 and from our Phase I with TX2100, and we've got proven leadership and the capital, we think, to execute on this. And with that...

Good. Great. Thanks very much for the presentation, Alise. So we'll get into the fireside chat portion. So broadly speaking, at a high level, there's been updates from competitors recently, right? The Lilly discontinued last year. We saw some data in the fall. AstraZeneca had an update recently as well. So can you discuss your thoughts on some of that? Do you view it as noise? Or is there anything that could be learned from those updates? And what gives you confidence in TX45's design, dosing strategy, data target population?

So you've got 3 companies, and I think we all -- we've all gone about exploring relaxin in a slightly different way. I think a year from now, when we have data from everybody's programs, you will have learned a lot about what the right patient population is, what the right dose is. It's almost, I think, been a gift to the field that we've all done it in a slightly different way. We'll start with Lilly and their program. They went into patients with preserved ejection fraction heart failure, not pulmonary hypertension with that. And more importantly, they went into patients who had to have been discharged from the hospital within the last 2 weeks, okay, for heart failure exacerbation. What causes a heart failure exacerbation? Sodium retention, fluid retention, you admit patients in the hospital who are fluid overloaded and you treat them with IV diuretics. Turns out when you treat them with IV diuretics, you make those patients even more sodium retentive. What did they find in the Lilly study? They found an excess incidence of hospitalization for heart failure in the patients treated with relaxin. That's not good. And they saw evidence of about a 200 cc increase in plasma volume. Why did they see that? Well, relaxin, as I mentioned, is a systemic vasodilator. It dilates the vessels around the kidneys. And when the glomerulus sees less pressure, it thinks the patient is dehydrated and it holds on to sodium. That's not good for heart failure patients. Other vasodilators that are efficacious in heart failure do it. So it doesn't mean it can't have efficacy. We think what happened in these patients is they took the most sensitive patients. The patients were already fluid overloaded. Typically, you haven't completely gotten rid of the fluid when you discharge them. And they were likely even more sodium retentive than they typically are because of the IV diuretics. And I think that -- and if you look at the doses they used, we think they were really on the upper end of the dosing. And I think dosing may be important. So I can tell you in our study, obviously, because of the Lilly, we've been looking very carefully at blinded data. I think that you will get some sodium retention and some fluid retention. But looking at the blinded data, there's nothing that we've seen that suggests we're seeing what Lilly has. And our IDMC met in January, most recently, 40% of patient exposure. They had right heart cath data. They had safety data. They had plasma volume data, they had 6-minute walk data, and they didn't suggest any change. And you also didn't hear that about the AZ program. Now AZ, the subcu is a much more similar patient population to us. And I have to tell you, they gave so little inflammation. I don't know exactly what happened in that, but I can tell you they had a much more heterogeneous patient population. They had HFpEF and HFrEF, so reduced ejection fraction and preserved ejection fraction. Their PVR was their primary endpoint, and yet they included patients with normal PVR. You're not going to get a reduction in those patients. So it may have diluted the signal. I think we've got to wait for the data. The good news is they explored a very large dose range, even doses that I would have predicted would not be efficacious. And I think once we see that data, there'll be a lot to learn from it.

Got it. Okay. So I guess just a follow-up on the Lilly disclosure. So I guess it's possible to overshoot with the relaxin mechanism.

I think it is. And the Lilly data taught us that. I don't know before the Lilly if we would have expected that necessarily.

Got it. And -- so do you think there's the same -- relative to that population, do you think there's the same increased risk of pulmonary congestion in stable HFpEF patients? Or do you think it should be much lower?

I think it will be lower. That's my hypothesis.

Okay. And again -- is there -- how is that being managed in the ongoing Phase II?

Well, even before we saw the Lilly data, we were encouraging our investigators to make sure patients were euvolemic before coming into the study. If you're going to treat pulmonary hypertension in the setting of heart failure, they always encourage you to make sure fluid status is taken care of. We want patients on stable standard of care medicines. Part of the reason that you could get this increase in congestion is if renin levels go up. And many of these patients are on ACE inhibitors and MRAs, which should blunt that. And we've been encouraging the investigators just to make sure they're monitoring their patients for fluid, which is what you're supposed to do when you take care of a heart failure patient.

And how is enrollment progressing in the Phase II?

Enrollment has been going well. If you look on clinicaltrials.gov, we're supposed to complete the study actually in about November, which would put us really at the end of the year. And so we may go into 2027. We're sort of in the last several months of recruitment.

Okay. And I guess, should we expect updates? Will you tell us when enrollment is completed so we can do that math? Or how should we...

Yes. We will. We will.

All right. And in terms of the Phase Ib data that you showed, really exciting kind of first-in-class clinical data providing validation for the mechanism. How should we think about the ability for that to translate into a longer time frame of treatment? What evidence you have that suggests it will be durable?

So actually, in that study and a similar study we did in HFrEF, where it was just a single dose, we didn't echo out to day 30. And somewhat surprisingly, we actually, in both studies showed very reproducible evidence of maintenance of effect on a surrogate for pulmonary vascular resistance, which you can look at Echo called TAPSE/sPAP as well as evidence of improved right ventricular function. So it was showing some sense of durability out to day 30. If you look at the Lilly study, systemic vascular resistance goes down with relaxin, and they saw that was maintained out to 6 months. So that's telling you you're getting durability of effect. And if you look at 2 recent publications from AZ looking at a reduced ejection fraction model of heart failure in nonhuman primates, if anything, you saw effects on heart function go up over time over a 6-month period.

Great. And as we think about the primary and secondary endpoints of the Phase II, what do you need to show on those endpoints to claim success?

I think for PVR, it's somewhere around a 15% to 20% reduction in PVR. We'll want to show evidence that we're seeing improvement in left heart function. And while we're not powered for 6-minute walk, I want to see a numeric trend on 6-minute walk.

What -- is there any kind of -- to follow up on the trend comment, is there any sort of minimal improvement in 6-minute walk test that you think is necessary?

You probably -- the KOLs are very clear that a 20-meter increase is what's clinically relevant in this patient population. I think if we saw 15 to 20, that would be one.

Great. And how soon could you start the pivotal trial after data potentially if it's successful, which hopefully is?

I'm going to keep that as I'm torturing my team as soon as possible. I'm not ready to give -- but let's put it this way. I would hope that we could beat the median timelines in the industry.

Great. And the primary statistical analysis is focused on CpcPH patients, right? So can you elaborate on why you did that? What portion of total enrollment that is in the study? And also what you expect to see in IpcPH?

I think you could get efficacy in both CpcPH and IpcPH very clearly because it bring wedge pressure down and improved cardiac output, you could see an increase. Our hypothesis was if you brought down the pulmonary vascular resistance and improved, you'd see a greater increase. That's basically what the hypothesis was.

Okay. And so if you see positive data in IPC in the Phase III, would you envision a mixed population kind of like the Phase II or 2 separate studies?

I would envision we'd obviously have to speak to the FDA but I envision them both in one study.

Okay. And just more broadly with respect to the competitive landscape, in Group II PH. Curious to get your thoughts on Merck's sotatercept, of course, relative to TX45 and like the Tenax approach and just in general for others...

Listen, I think the fact that Merck had a positive study is a win for the field. I think there's plenty of room for more than one mechanism. They're in a more -- in a much -- in a smaller patient population, and they want to keep it small. They've said they want to keep their pricing the same, and they want to keep orphan status. So they're in a PVR greater than 4 population, an ejection fraction greater than 50% population. And we're expecting to see strong data based on what we're hearing. So I think that's exciting. And I hope we'll learn something about core -- are there correlations and what are the best correlations between hemodynamics and 6-minute walk. And I think there'll be learnings for the field. Tenax, I think, is interesting. Their hypothesis is that if you bring down right atrial pressure and wedge pressure that you'll have an effect on 6-minute walk. By the way, relaxin does the same. We bring down wedge. We bring down right atrial pressure. We'll have to see.

And switching gears a little bit to HFrEF. You mentioned the data that was pretty darn consistent with HFpEF. What are plans for HFrEF moving forward?

I want to see what HFrEF looks like in the AZ data sets. I think that and seeing our own Phase II and then we can make a decision. And I think if there is compelling data there, we could go straight to a Phase II/III and is one possibility that we could do in HFrEF.

Fair enough. And PH-ILD, you've guided to initiating a Phase II trial there. Maybe just -- you touched on it a little bit in the presentation but maybe you could just elaborate on that, that opportunity and why you've prioritized it over even HFrEF.

So it's a large unmet need. Almost all of the drug development that's going on in that area is inhaled. And inhaled can be difficult for these patients. We think there is room for a systemic approach that could come in there, and that could be a little bit differentiated as well. Our Phase Ib data in HFpEF really suggested you could have a large impact on PVR. And then the preclinical data and the fact that there is an antifibrotic element went along with that as well. The other thing is if fluid congestion is an issue, these patients will be less susceptible to any sort of fluid retention.

That's interesting. Last couple of minutes, we have to turn to 2100. My apologies for not spending more time on it. But you had a very interesting KOL webcast the other day that I encourage everyone to listen to, really hammered home the unmet need there, really quite horrible what some of these patients are dealing with and APJ seems like a very exciting target to go after. So can you elaborate on the development plan there, the Phase I healthy volunteer data later this year and what you hope to see from that?

Yes. So the Phase I, actually, we think it was because we had such a good preclinical safety package that we could go into healthy volunteers. And it means you can get dose escalation and get PK. It will mainly be PK and safety. Mechanism has never been in humans. So getting some initial safety data, I think we'll do some derisking for the program as a whole. And then we've got -- I'm going to put it in a surrogate for receptor occupancy that should help us additionally choose doses going forward. And then as quickly as we can, we'll get a Phase Ib started in severe HHT patients where we can look not only at epistaxis but we can look at hematologic support, i.e., the need for iron and blood transfusions as well as hemoglobin levels.

What sort of reduction in epistaxis would be meaningful in this population?

I can't give you a good answer to that yet because nobody knows the best way to measure epistaxis yet. The most commonly used measure so far has been an epistaxis severity score, ESS, which is a look back a month. That is not going to be the best way to do this. And on that scale, a 0.7 improvement is considered clinically meaningful. We're going to be also exploring a daily diary. I think that is the way the field is going to go. And part of what we're going to have to do in that is define what a clinically relevant improvement in that is. So I think people have to -- in this field, this Phase II, there's going to be learnings to define the best way to measure epistaxis going forward. It's looking from other groups that are doing this that it's some sort of duration and intensity, and that will be something that clearly we'll be exploring.

Great. So we're up on time but to wrap up, I'll ask you what you believe is the most underappreciated aspect of the Tectonic story by investors right now.

Probably right now, it's still -- no one really knew about the HHT program, and I think it's just starting to get appreciated by investors. And I think it's an important program for us.

Fair enough. Alise, thank you so much for your time.

Thank you.