Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yaz Rahimi. I'm a Senior Biotech Analyst here at Piper Sandler. Thrilled to have Tectonic here. Alise, wonderful to have you. This is our second year at our conference. Lots to cover over the next 25 minutes. 2025 was a big year, but 2026 is probably the key year for Tectonic, especially as the APEX study is going to be the
beginning of two years.
The beginning. Beginning of many key years.
But an important year. I think a lot of investors are very much excited and looking forward to APEX in 2026 reading out. Maybe give us an idea on how is enrollment progressing? At what point in 2026 would you be in a position to kind of fine-tune the guidelines? And then we'll ask some more additional questions.
You know, we had internal objectives to meet for recruitment. We had one for mid-year. We met that, and we are on track for meeting our end-of-year recruitment goal. We, in November, stopped recruiting all comers, and we're now only recruiting patients with a PVR of greater than three. And we want to have a few months to see the impact of that on enrollment to get greater confidence as to when we think enrollment will stop. So what we've said is by the end of first quarter, we think we'll be in a position to narrow guidance.
Okay, perfect. And then help us understand, as you guys are not obviously monitoring enrollment progress and giving an update in terms of the guidances, sort of the cadence of data safety monitoring committees you have. How often do they occur? When was the last one? What were some of the findings?
So they don't occur at a regular cadence. You know, sometimes you do set it up that way. In very large studies, you may say you want one. In general, this is going to be at the DSMB will sort of set the stage for it. The last one happened to be at the end of September. Some people thought we set that up after the Eli Lilly data. It was just timing was better. But we made sure that they were aware of the Eli Lilly data and looked at our data with that lens. And basically, what we heard from them was no safety signal, continuous plan.
What do they like when they say no safety signals? What are the type of things that they have previewed to?
They're going to have vital sign data, weights, labs, all of the AE data, and they will look at it in an unblinded manner. Whereas we, obviously, as a part of running a clinical trial, we always also monitor, but in a blinded manner, and have not seen anything of concern to us at this point in time.
I am assuming if they're checking vital signs, they assume also the spectrum of hospitalization rates, so it's like, is that so?
And the hospitalization rates have been low. I mean, you expect to see hospitalizations for heart failure in this patient population. In fact, you know, you're hoping to see some of them and see if you have any impact one way or another. We probably won't in a strong phase II . But in terms of the number of hospitalizations that we've seen, nothing has been of concern to us. We, of course, are blinded. And the next time the DSMB meets, they'll look at the data again in an unblinded manner.
Okay. And you noted that as of right now, you're just enrolling PVR greater than three.
We completed the PVR less than three subset.
Got it. And what percentage of the total population falls within the PVR greater than three?
70%.
70%
of the population.
Okay ,
yep.
What was the rationale for enriching this population?
I think that relaxin can work in both IpcPH, that's a normal pulmonary vascular resistance, and in CpcPH with a high pulmonary vascular resistance. But given the mechanism, I think that you'll see a greater benefit in the CpcPH patients. Why? In heart failure, what influences your exercise tolerance? Basically, when you exercise, you have to increase cardiac output to get more blood and oxygen out to your muscles. And as more blood goes into the left side of the heart, the heart has a hard time handling increasing cardiac output. Pressures go up in the left side of the heart, and you get short of breath. In PAH, Group 1 , what influences exercise tolerance? It's that because of the constricted pulmonary vessels and the high PVR, you can't actually get enough blood into the left side of the heart. And therefore, you can't get cardiac output.
In CpcPH, both of those are impacted. You can't get enough out, but you also can't get enough into the left side of the heart. And since we think relaxin improves both of those, it'll improve the function of the left side of the heart, but also decrease the pulmonary vascular resistance. So you get more blood into the left side of the heart, and the heart can actually accommodate that and pump the blood out. And so we think you'll see a greater benefit on six-minute walk tests.
Is there a phenotypic difference as the patient presents themselves with their symptomatology?
The way you make the difference between CpcPH and PVR.
Depends on PVR measures. Yeah.
It's really dependent on PVR. They tend to be the sicker patients also. If you looked in our HFpEF cohort, the higher the PVR, the lower the cardiac output at baseline. And actually, the greater the benefit on cardiac output after getting treated with Relaxin. So, you know, it's a hypothesis that we have. We will certainly look at the overall population as well. But for the primary endpoint, which is PVR reduction, we're focused on the high PVR, PVR greater than three. The new definition includes PVR greater than two. I think you'll see a reduction in that population as well. In the IpcPH, the normal PVR population, you've got a floor effect. And so you won't see much of anything there.
That's very helpful. And maybe help us understand, obviously, PH Group 2 with HFpEF is a pretty heterogeneous population. You've already enriched for CpcPH, which mechanics you just walked us through with a high probability of success. What are other elements incorporated in the study to just create more a homogeneous population that, you know, I think one of the findings that we will talk about that the Eli Lilly data is.
Mainly keeping to HFpEF.
Yeah.
Right? Preserved ejection fraction heart failure. And then enriching for that CpcPH patient. We are allowing obese and non-obese patients into the study. You'll have patients with hypertension, you know, diabetes. You need to, your six-minute walk, you don't want to be so severe that we don't think there's a chance that you can even improve it. But can't be so good that you hit a ceiling effect. So you have to have a six-minute walk between 150 and 450. We've tried to be pretty open to make sure we can recruit the study.
And what do you hope? What is the study power to show on PVR?
I have no exact p-value. What I can tell you is we saw a 1.3 millimeter of mercury decrease in PVR, which ended up being about a 30% decrease in our phase 1b. And we're powered for something much smaller than that because we anticipated we would get more variability.
Okay. And I know the study is not powered for a six-minute walk test, but help us understand sort of what is a clinically meaningful difference? And maybe also the correlation that exists between changes in PVR and a Six-Minute Walk Test?
In PAH, I think the accepted clinically important difference is about 30 meters. What we keep hearing from KOLs is in this patient population, in the heart failure population, they think it's about 20 meters. One KOL referenced the GLP-1 study in HFpEF where quality of life got better, and that was associated with about a 20-meter increase in six-minute walk. And we're definitely not powered for a 20-meter increase in six-minute walk in our study at this point in time. Neither is AZ and neither was Merck.
I think the idea would be to just see a trend, right? Like just to see a visual separation at the 24-week time point. Does APEX have an open label extension ongoing that patients could be eligible to track beyond the 24-week time point?
We don't have an open label extension at this time. Very possible that we will open one sometime in the future. Even if they've finished the study, they could then come in, but not at this time.
Okay. And is there, I think, in terms of when you look at the data, obviously you're going to look at the total population. You'll break it up like you did between CPC and IPC population to get an idea. Because ultimately, based on those results, then you can think about enriching for.
Or not.
Or not, depending on what you find in the study. Now, that's super helpful. Recently, you shared very, very compelling and strong data in HFrEF, which was the 1b. How much is that a key objective for 2026 to build a developmental plan in HFrEF? Or would you need to see HFpEF before embarking on that?
I'd like to see some more longer-term data before we decide how to move forward in HFrEF. I think that there are several options. We could decide to do a standalone phase II, or we could decide to go and do a phase II/III , and do, if the FDA agreed to this, a phase III in HFpEF and a phase II/III in HFrEF. I think there are options and optionality for us.
That's very helpful. And maybe one of the questions we get is, you know, I think investors understand there are your program, AstraZeneca has a relaxin program. They're going to get some sort of update still this year. And then Eli Lilly discontinued their program and they published the data. So first question is, what is the differentiation of TX45 based on your understanding of the competitors in terms of the construct and product profile? Or is it just a function of these studies are so differently run that it makes it difficult to compare?
I'm going to put the study design and the patient population as the highest, especially with Eli Lilly. Yeah, those patients were very, very different than the patients in our study and the patients in the AZ study. They were all half-half. They don't know whether they had pulmonary hypertension or not. So probably only a minority had pulmonary hypertension, probably few CpcPH patients. And they wouldn't know how to find them because they didn't do right heart cath. But most importantly, they weren't chronic stable patients. They had to have been discharged from the hospital within the last two weeks for acute heart failure. And those patients were like, I think, the canary in the coal mine for fluid retention. We know vasodilators can lead to fluid retention. That doesn't mean they won't provide efficacy in heart failure.
Hydralazine is associated with fluid retention, and yet it's approved for heart failure, and it does that probably by lowering the pressure in the kidney. The kidney views that as, oh, blood pressure is down, have to retain sodium, have to retain water, but those patients are probably at higher risk for all of those things. Why? First of all, they just got discharged for heart failure. Patients aren't completely dry when they're discharged from the hospital for heart failure. They're typically still fluid overloaded, and now they retain even just a small amount of fluid. It was only 8%-9% increase in fluid, and that can tip them over the edge. The other thing is they were treated with IV diuretics, which actually make you more sodium avid, and you often can become resistant to oral diuretics.
And so you're taking your most susceptible patients, and then you're adding on another drug that can lead to sodium retention. And I think that that exacerbated our study, the AZ study. You can't have been just discharged from the hospital. You have to be on chronic stable meds. And we've really been encouraging our investigators, make sure your patients are euvolemic, not dehydrated, not volume overloaded. And therefore, if you do have some fluid retention, we think the patient should be better able to accommodate it. And the positives of the drug should have a chance, we think, would negate the negatives. And I think the fact that the AZ study went to completion and wasn't stopped midway, as well as your study in chronic heart failure with their oral completed recruitment, something's different between what we're seeing here. So that's the patient population.
In terms of the molecules themselves, and we can get into AZ patient population next, but all of them are relaxin fusions. The Eli Lilly relaxin is fused to an antibody to albumin, and that's how it retains its long half-life. Could that mechanism mean it's got less potential for tissue penetration? Does it stay within the vascular space? And do you not get the antifibrotic effects? I don't know. I don't know. And I haven't seen any preclinical data that they did looking at the antifibrotic effects. So that may be one potential differentiator. Between we're an Fc fusion, AZ is an Fc- fusion. The only other thing we did that was different was we lowered the isoelectric point, which really improved the pharmacokinetics of the drug. High isoelectric point proteins and relaxin is one, and we think both of our competitors have a higher isoelectric point than us.
Highly positively charged, they get bound up by negatively charged proteins, including hyaluronic acid and the glycocalyx of the vessels, which sort of sucks them out of the blood, which is you get a very big drop-off in PK. So by lowering the isoelectric point, we markedly improved the PK, and we've got the longest half-life, which we think should enable monthly dosing. Eli Lilly was weekly, and AZ has gone with every other week dosing.
Maybe help us, since I think the Astra data is near term since they have continued to keep their guidance. So we will be waking up to some news that they have, whatever that news is. What do you see from ClinicalTrials.gov on how similar their patient selection is versus APEX?
A more heterogeneous patient population, so they have both preserved ejection fraction heart failure and reduced ejection fraction heart failure, HFpEF and HFrEF. It's pretty unusual in heart failure to include both subtypes in one clinical trial, and like us, they have IpcPH and CpcPH. They have not enriched for a PVR greater than three in the way that we have, and so I think their PVR greater than three population will end up, I don't know, somewhere between 30%-50% of the population, maybe. We'll have to see, and then they'll have some PVR greater than two in that study as well, so they've got four subsets. In essence, they've got CpcPH PH HFrEF, CpcPH PH HFpEF, IpcPH PH HFrEF, IpcPH PH HFpEF.
And do you, I think another data readout was the recent Sotatercept readout, right? And the Cadence study, which read out positive, they did not disclose the top line numbers. But they did, that was a study that's similar to APEX enriched for CpcPH. And they said that they saw statistical separation in PVR, which was their primary endpoint, and that they will be moving forward to phase III. So maybe help us understand through the mechanistic differences between Sotatercept. And obviously, Sotatercept has a very different risk profile than TX45. But what does that tell us from de-risking Sotatercept by understanding how Sotatercept works?
There is some overlap potentially. Now, relaxin is a vasodilator. We think it's a lusitropic agent in HFpEF. We think it actively relaxes the myocardium during diastole and helps with diastolic dysfunction. But with long-term use, based on preclinical data, we also think it'll act as a remodeler of the pulmonary vessels and the myocardium and is an antifibrotic agent via inhibition of the TGF-β pathway. And you see inhibition of phospho-Smad2/3 in a different way. Sotatercept also inhibits the TGF-β pathway and remodels the vessels. Now, and it does that by trapping multiple ligands for the TGF-β pathway, as we know. They don't have the vasodilatory effects. They don't have the lusitropic effects. And I think if they are seeing efficacy that is driving them to phase III, it means that Sotatercept not only remodels the pulmonary vessels, they must have improved left heart function.
If you just remodel the pulmonary vessels and you decrease the pulmonary vascular resistance, you'll send more blood into the left side of the heart. But if you haven't improved left heart function, you can actually make heart failure worse. So the fact that they're moving forward leads me to believe that they have some evidence that they saw an improvement in left heart function as well, which is really exciting.
Yeah. And I think it would be also exciting to see in that study. I'm sure, you know, the study was empowered to show a six-minute walk test, but what was that translation be between changes in PVR and the trend? And what trend embarked for them to move forward?
You know, I've had someone say, oh, isn't this bad news for you?
No, it's good news. Yeah.
It's a very large patient population. PAH, which is maybe tenfold smaller, has five mechanisms in it, 12 drugs. There's more than enough room. These are complicated patients. And I think there's ways for us to differentiate. First of all, we're in a larger patient population. Their ejection fraction is strict HFpEF, EF, ejection fraction greater than 50%. We include the 40% - 50%, which is now known as HFmrEF, moderately reduced. That adds about a third of patients. They've limited to PVR greater than four. Not clear to me that that would end up in a label. But maybe even more importantly is the potential. I don't think we could have an earlier onset of action because of the vasodilatory effects. Patients already have said they start to feel better within the first few days of dosing based on our phase 1b study.
But on safety, you know, we know there's the bleeding risk. If you look at their label, they say that the bleeding risk is exacerbated by anticoagulants. Well, 50%-60% of patients who have CpcPH have atrial fibrillation, which means they should be anticoagulated. And I think there will be some concern about putting those patients on Sotatercept. Sotatercept can also increase blood pressure. Not a problem in PAH. Could be a problem in patients who developed heart failure because of longstanding hypertension.
No, that's very helpful. I know we have only a minute and a half left. Would love to get.
I think that goes so quick.
I know, it gets so quick. TX2100. So obviously, you guys are on track to start a healthy volunteer study in 1Q. So maybe help us understand sort of where you are in the process and what would sort of a signal be in that study to warrant further development?
We are either today or tomorrow submitting our regulatory documents. So there's not going to be. We've completed our toxicology studies and we got to get, you know, regulatory approvals and drug to the site and we're ready to go. So we hope in early next year to start that study. It will be a normal healthy volunteer study. People have asked me why we're not going into patients. It just takes a lot longer to do dose escalation. We can do it really rapidly in normal healthy volunteers. It'll mainly be a PK and safety study. We'll have targets. There are some biomarkers we'll be looking at in patients. It's really unclear to me that we're going to see those. And then we'll go as quickly as we can from there to a phase II study in HHT patients.
Great, and then maybe just, I know we don't have Dan here, but cash and cash runway.
We have a runway into fourth quarter of 2028, and I think we had around $268 million in cash at our last quarterly earnings.
Great. Let's thank Alise for a great discussion and thank you so much for being part of the conference.