Great. Good morning, everybody. On behalf of Leerink Partners, it's very much my pleasure to welcome the CEO of Tectonic Therapeutic, Alise Reicin. Alise, thanks for joining us today.
Thanks for inviting me.
Thank you for being here. I thought we could maybe have you just start off with, you know, a framework for your vision, for the company and for TX45.
TX45 is the lead program. A lot of emphasis on us inside the company and outside the company as well. I really think it could be a transformational product for Group 2 pulmonary hypertension in the setting of HFpEF, and in particular in that subset of patients that not only has left heart failure but has narrowing of the lumen of their pulmonary arteries with a high pulmonary vascular resistance. That's the cpcPH population. We've enriched for that population in our phase II because we really think the greatest benefit of a relaxin compound will be in that population. I'll be thrilled if it works in the overall population. I think there's a chance of that, but I think the best shot is in that population. If we're just in that population, even there, it's 400,000-700,000 patients in the U.S.
If the drug works similarly in HFpEF, and I have reasons to believe it will, and we're exploring that now in our phase I-B, you'll almost double that patient population. It is a large, multi-billion dollar opportunity.
Wow.
We've actually had a lot of investors, based on our phase I-B data, encourage us to think about other indications, which we're just starting to think about now. Beyond that, hopefully less than a year from now, we'll be in the clinic with our second program, which is for hereditary hemorrhagic telangiectasia, another white space opportunity, second most common genetic bleeding disorder, no approved therapy.
Excellent. Excellent. Regarding the phase I-B results, they were quite impressive. Could you just remind us about those and what to watch next for TX45?
Just to remind, it was a small single-arm study, 19 patients with Group 2 pulmonary hypertension, both ipcPH, those are patients who have normal pulmonary vasculature, normal pulmonary vascular resistance, and cpcPH, the patients with high PVR. Patients came in, we did a right heart cath, we got baseline measurements, we gave them a single dose of TX45, and then we did hemodynamics over an eight-hour period. We had pre-defined that we wanted to see a 15%-20% decrease in the pulmonary capillary wedge pressure, which is really a measure of left heart function. In the cpcPH population, a 15%-20% decrease in the pulmonary vascular resistance. Our belief was that for a drug to show efficacy in Group 2 pulmonary hypertension, you have to both improve left heart function and improve pulmonary hemodynamics.
We saw a 17% increase, almost 18% increase in pulmonary capillary, decrease in pulmonary capillary wedge pressure. We saw, instead of a 15%-20% decrease in PVR in the cpcPH population, we saw over a 30% decrease. We were really gratified to see at rest, we saw an increase, about an, I think it was about an 18% increase in cardiac output, so another measure of left heart function. We brought pulmonary artery pressure down, and then in addition, we brought something down called TPR, total pulmonary resistance. Think of it as the high pressures that the right ventricle is seeing, and we brought that down in the overall population by 26%. In Group 2 pulmonary hypertension, what typically kills patients is right heart failure. The right ventricle, after seeing high pressures for a prolonged period of time, fails.
The fact that we could bring that TPR, those pressures down by 26% in the overall population, I think, over the long run could be quite beneficial for patients.
Excellent. We're gonna also see data in HFpEF, PH HFpEF patients later this year. Could you talk about that?
Reduced ejection fraction heart failure, those are patients who typically have had multiple large heart attacks and their heart muscle just doesn't contract well. Similar, we're doing a similar study, we may have added a Part B to enroll probably about 10 patients with Group 2 pulmonary hypertension in HFpEF, and we'll look at hemodynamics and we'll hope to have data second half of this year.
Excellent. Obviously this data that you just released is, you know, very short duration data.
Yeah.
Could you talk about the durability of effect that you're anticipating?
Yeah.
Just, you know, what supports your expectations?
It's the right question to ask. It's a question that I'm asking. What are the data points? There are actually a couple of data points, including some new ones that provide me reassurance from that. We know that relaxin increases cardiac output, decreases systemic and pulmonary resistance in pregnant women to increase cardiac output to accommodate the increased demands from the fetus, and pregnancy is nine months, okay? It's not eight hours. We know from, I'll just take as an example, even the Lilly study phase I, they looked at renal blood flow out to 30 days. We did something similar. What you're looking at in renal blood flow is the vasodilatory effects. That's maintained out to day 30.
There was a study with scleroderma, in scleroderma patients that was done with the old Novartis short-acting compound where they gave continuous IV infusion for six months, and when they abruptly stopped that infusion at the end of six months, their renal function got worse because of the fact that they'd accommodated to a larger, to an increased renal blood flow. There was just a recent study that AstraZeneca published where they used their relaxin in an elderly monkey model of reduced ejection fraction heart failure, HFpEF. It was a 21-week study where they gave weekly dosing, and not only, and they looked at ejection fraction, cardiac output, stroke volume, systemic vascular resistance, and not only were those maintained over the 21 weeks, ejection fraction, cardiac output, all, all went up, continued to go up over that 21-week period.
We did do echo in our phase I-B study at day two, so right within that first 24-hour period, day 15 and day 30, and I had very low expectations for it because it's only 19 patients, echo can be quite variable. Let's just say there were some interesting hints that came from that that will show when we release the phase I data. Not every endpoint that we looked at, could you see anything? A lot of them were noisy, but there were a couple that were intriguing.
Excellent. Excellent. Yeah, it's very exciting. Obviously, you could very much have a pipeline within a product here, but we'll wait for you to share more over time as you think about further development. With respect to, you know, some of the data that we've seen, there was a minor decrease in blood pressure that was observed post the IV dosing. Could you just touch on that and whether that's of any concern in the initial phase I-B data?
It was five to, on the order of 5 to 10 millimeters, if that's what we see in the animal models as well, it matched that. It really lasted the first 24 hours, and by day eight, their blood pressure was basically up to normal. None of the patients were symptomatic, none of them were considered adverse experiences. Again, in this AZ study, what was so interesting is the blood pressure was really maintained over that 20-week, 21-week period, but the systemic vascular resistance was decreased over that whole period. I think that's one of the things about relaxin that's a little bit unique is that you can get this sustained decrease in systemic vascular resistance without having a large decrease in the blood pressure.
Excellent.
Not all vasodilators are created equal.
Yes. Yes. Maybe we could pivot to fatigue. You know, four participants in the three mg per kg cohort reported fatigue the evening of day one. What do you attribute that to and any, any observations?
Yeah. The first thing is it was all on day one, all at the end of the day, and the longest one of those lasted was three hours. By the next day, when they clearly had drug levels on board, patients fell back to their baseline. It really feels, and none of them were considered drug-related. It really feels like procedure-related, long day in the cath lab. I'm sure, you know, sympathetic tone a little bit up from being in that type of environment. The other thing, you say, why are they all at three mgs? What, what, three milligrams? How, it looks like there's a dose effect. One thing, all three of the doses we had, over that eight-hour period, you were fully agonizing the receptor.
One of the things, you know, I've got a very diligent clinical group, and early on in the study, they noticed that the stoic Eastern Europeans were not complaining of any adverse experiences, and they were a little concerned that no adverse experiences were being reported. They wanted to make sure, and they coached the site, you cannot wait for a patient to complain of something, you have to ask them questions so that you do not miss anything. I think that probably happened around the time that we had dosed up to about 3 mg per kg. I think that is probably why those happened, only at the 3 mg per kg dose.
Interesting. That's very helpful context. So then turning to the phase II APEX trial, are any learnings from phase I-B being incorporated? Could you talk about that?
What we had said is we would certainly look at our enrichment strategy, for cpcPH. Did we still want to enrich? Did we not want to enrich? I think the phase I-B confirmed enrichment, and says, basically in the end, confirmed what we were already doing. So we are, I'm not gonna give you the exact percentage, but we're highly enriched for, not only a cpcPH population, but a pulmonary vascular resistance greater than three Wood units. You might look at the phase I-B data and say, why do that? The PVR was reduced by 32% in the PVR greater than two, and by 35% in the PVR greater than three. Why enrich for the PVR greater than three? You'll hit on your primary endpoint. We agree, but I'm really enriching the PVR greater than three for the six-minute walk test.
I really think those are the patients where you're gonna see the greatest benefit.
Got it. Okay. That makes a lot of sense. Thank you. And then with respect to the, you know, that trial, could you just remind us, I think the timing is a potential readout second half of 2026, is that right?
Right now, we've just said 2026. I think as we get further along in enrolling, we'll get more specific about when. Right now, we've just kept it at 2026.
Got it. Okay. Maybe just to summarize, what are you, you know, what are you hoping for? What are you hoping to show? What would be a successful outcome?
I think we wanna see hemodynamic changes again, evidence that we're improving left heart function, evidence that we're improving the pulmonary hemodynamics. A key secondary for us is six-minute walk test. That's the approval endpoint. We're not fully powered for that in the same way most studies in Group 2 pulmonary hypertension are run, but we will want to see a numeric trend there.
With respect to, you know, background therapy, et cetera, how are you handling that for the trial?
All background therapies are allowed. We are on top of standard of care. We're not going head to head, and that was the way our phase I-B was run as well.
You just, you know, planted a balance, use.
Yeah. You know, the study's large enough, you should have pretty balanced use. I can tell you, you know, we had SGLT2s in about 40% of patients in the phase I-B. We saw very consistent results. We showed that data at, when we presented at a medical conference, the wedge pressure went down in virtually every single patient. The PVR went down in every patient with high PVR. So regardless of whether, what background therapies those were on, you have to be on a stable dose of background therapy before you come in the study. You really want patients to be at a stable baseline.
I think that that may have been, I don't know, it's a hypothesis that may have been an issue with the Lilly study where patients had to have been released from the hospital two weeks or within two weeks for a heart failure exacerbation. It worries me a little bit that you're not at a stable baseline and therefore a change from baseline becomes a little bit more difficult to show.
Interesting. Yeah, I'd like to come back to that in a moment. One other question just on this trial. With respect to pulmonary capillary wedge pressure, what, you know, is your enrollment plan, you know, what is the hurdle to enroll in the trial?
You have to have a pulmonary capillary wedge pressure of greater than 15.
Okay.
Interestingly, you know, in HFpEF, you can have a normal wedge pressure at baseline. The way you figure out they have HFpEF is you exercise them, and then if your wedge pressure goes, I think it's above 25 with exercise, you get the diagnosis of HFpEF. In our studies, you have to have a wedge pressure greater than 15.
Got it. Okay. Great. Just going back to the Merck sotatercept trial, maybe you could just talk at a high level about scenarios of outcomes and implications.
Which one? The Merck trial?
The Merck sotatercept trial in cpcPH that's supposed to report out late this year.
Yeah. It's either later this year, we've heard two things. One person said fourth quarter, the other said first quarter. I think they're pretty much done, they're very close to being done with enrollment. Listen, if all sotatercept does is remodel the pulmonary arteries, I don't think it'll work. I think time and time again in Group 2 pulmonary hypertension, you have to improve that left heart function, as well. They do have a hypothesis and some clinical data that's supportive of the fact that sotatercept could remodel the left ventricle. I think we'll have to see if it works great for patients. I think it's actually a positive 'cause you can show that drugs can work in cpcPH. I think that that is a positive.
We may get data from them that then, you know, is there a correlation between, changes in wedge and PVR in six-minute walk test? If they're positive, I think that there's still a lot of room for us to compete with them. First of all, it's a complicated disease. You know, heart failure doesn't just have one class of drugs. There's no, gonna be no problem with that. We're also in a larger patient population. They're in ejection fraction greater than 50%. I don't think they have a hypothesis around going below that and pulmonary vascular resistance greater than four. Were our initial studies in ejection fraction greater than 40%? As you know, we're going into the HFrEF population as well. That 40-50 and the, less than 40, I think is a place they won't be.
We're gonna be enriching for PVR greater than three. The PVR greater than four, you really start to get into a smaller population. We're gonna be in a larger population. I also think patients are likely to feel better quicker with our drug because of those acute hemodynamic effects. It's gonna take a few weeks to a few months for sotatercept to work. The last is, which may be one of the bigger areas, we're gonna differentiate on safety. 60% of the patients in our phase I-B study had atrial fibrillation. Most of those patients are on anticoagulation. I think there's gonna be an issue with anticoagulation and the telangiectasia and the bleeding that you get with sotatercept, as well as the fact that some patients may drop their platelets.
I was speaking with an old colleague from Merck yesterday, a very senior person, and I said to him, how about anticoagulation? He's like, not a good idea with sotatercept. That and sotatercept can lead to increases in blood pressure, which is not an issue in PAH patients who often run low. I'm not sure it's the best thing for patients who develop HFpEF often because of longstanding hypertension. I think if they're successful, great for patients. I think it's great for the field, but I think there's still ways for us to be very successful.
Excellent. It seems like a wait and see, in terms of what those results show. With respect to your expectations for phase II for your trial, how would you frame the hemodynamic changes that you're anticipating? You know, obviously you had this, you know, phase I-B data, just, you know, essentially with eight hours of dosing, but how should we think about it in phase II? Do, do the, you know, do your expectations change with longer duration trial results?
I'll tell you, it's a little hard to handicap it because on the one hand, I think if we're right about the remodeling, you should, if anything, get greater effects. On the other hand, you're going from a small phase I-B study at three centers to a much larger study, probably over 50 centers, you're gonna end up adding variability. It's hard for me to tell you whether we're gonna look the same, better or, you know, even just a little bit worse. It'll certainly be in the same range though, and it could be better.
Great. Phase II isn't powered to detect clinically meaningful change in six-minute walk distance, or at least statistically significant change in six-minute walk distance. How would you sort of set the bar there for what you'd hope to see?
Our KOLs tell us that a 20-meter increase is clinically important in this patient population. I'd say if we saw anything in the 15-20 range, we'd be thrilled.
Great. Okay. Maybe we could pivot to a competitive drug, AstraZeneca, as a competing long-acting relaxin. That's a different trial, but could you just describe that and set the stage ahead of them disclosing results?
Yep. Like us, they have an Fc- fusion. They didn't re-engineer those to bring the isoelectric point down. We did. Our half-life in normal healthy volunteers looks about double what their half-life is. We are testing every other week and monthly dosing. All of theirs are every other week dosing in their phase II study. They have a more heterogeneous patient population than we do. They have both HFpEF and HFrEF, and they enriched based on pulmonary artery pressure. 85% of patients in their study have to have a pulmonary artery pressure greater than 25. They didn't enrich based on PVR, which is the way we are enriching.
Now, based on Epi data or data that we've gotten from KOLs, if you've got cpcPH, you probably have a pulmonary artery pressure greater than 25, but some ipcPH patients also have a pulmonary artery pressure greater than 25. I think one of the, and PVR is their primary endpoint as it is ours. They're doing six-minute walk test. It's a six-month study. I think one of the critical things for looking at their data, if it works in the overall population, great for all of us, right? And to me, if it really does have that efficacy in ipcPH, that would be great. If the data aren't as striking, it's gotta be what did, what did it do in the cpcPH population? 'Cause that's sort of really where we've, that's where our hypothesis is that you're gonna see the best, efficacy.
The reason for that, in heart failure, what limits your exercise tolerance? When you exercise, your wedge pressure goes way up, right? You get very high pressures. In cpcPH, in, or let's say in PAH, what limits your exercise tolerance? It's your high PVR, which prevents you from sending enough blood into the left side of the heart. In cpcPH, we think it's both. If you can decrease the PVR without increasing the wedge, and actually decreasing the wedge and increasing cardiac output, we think in the , which is what we showed in our phase I-B study, we think the cpcPH population will have that much greater an impact on six-minute walk test.
There was one little intriguing piece of data that I may be overinterpreting, I'll be honest about that, which was in our phase 1b study, as the baseline PVR increased, the cardiac output effect increased. It was like 16% in the normal PVR patients, 20% in the greater than two, 25%, or 24% in the greater than three. Is that reflecting the fact that as the PVR is going down, you've got more blood going into the left ventricle and therefore cardiac output is going up? We'll have to see if that bears out in the phase II study or not.
That's great. Just for AstraZeneca's trial, have they disclosed the mix of PH HFpEF versus PH HFrEF patients that they've enrolled?
No, they had a design paper that they published, which was very useful, but they did not say whether they limited it in one way or another.
Got it. Okay.
That'll be another important thing to look in. It's one of the reasons we're getting the phase I-B data so that, you know, when that data comes out, we can put it a little bit into perspective.
Excellent. We're almost out of time. Maybe you could just touch on, sort of where the company's cash position is and the runway that you've mentioned.
You know, before we just did a recent PIPE. Before that, we had said that our runway was into mid-2027. We just brought in $185 million. When we do our 10-Q, we'll put in a formal runway extension, but you can imagine it is quite substantial.
Excellent. Excellent. This has been great. Thanks so much for taking the time with us and being with us here today.
Thank you.