All right, we can get started so we can make sure to get through all of our questions. But great to be here with Tectonic Therapeutic. We have CEO Alise Reicin. Great to have you here. Thanks for joining.
Thanks for the invitation.
Of course. Really interesting time for you guys. Maybe we can just start with a kind of like a brief overview of kind of like what's coming and kind of how you're framing it for folks.
We have a catalyst-rich 2027. It'll start with our TX45, our lead program.
We'll have phase II data by end of January. We will not be at JP Morgan, so you can expect it sometime between JP Morgan and, hopefully end of January. So that'll be data from our phase II study in Group 2 pulmonary hypertension and HFpEF. We are actively enrolling our PH-ILD study with TX45. We expect interim data from that study, which is a single-arm study of about 20 to 25 patients, second half of 2027. We are just about, between now and the end of the year, we will start our phase I-B study with our APJ antagonist, TX2100, in patients with HHT who require hematologic support.
We should have interim data from that study, so our second program in hereditary hemorrhagic telangiectasia, by the end of 2027. In early 2027, we will start our phase II study in moderate to severe, in patients with HHT with moderate to severe epistaxis.
Mm-hmm. Yeah, very busy time. Maybe we can just start with HHT, since you had some data recently. I think there is a lot of investor interest in HHT and sort of an appreciation that it could be a big rare disease market, but there is obviously a lot of companies and different mechanisms. So, maybe just kind of like set the stage on your mechanism, kind of this sort of like thesis behind it, and then some of the initial healthy volunteer data you have.
So, why don't I start with HHT, because not all investors know HHT yet. HHT is the second most common genetic bleeding disorder. It impacts about 75,000 to 80,000 patients in the U.S. alone, over 1 million worldwide, and it is basically a disease of dysregulated angiogenesis. It is mutations in the BMP9/ALK pathway. Anti-VEGF inhibitors, anti-angiogenic agents, have been shown to work in preclinical models of the disease, and that has translated to the clinic. TX2100 is an antagonist antibody to APJ, which is an anti-angiogenic agent.
But it's a more specific and selective approach to angiogenesis. So what we hope is to have the efficacy, or maybe even better efficacy than the currently used therapies, none of which are approved. Because we'll have a better safety profile, and then, as I said, efficacy as good as and maybe even better than those.
Yeah. Makes sense. And obviously it sounds like safety is the core part of that thesis and—
Yeah.
—in terms of some of the healthy volunteer data.
How do the VEGF inhibitors work? AKT and ERK are downstream. You inhibit a VEGF inhibitor, and you are inhibiting AKT and ERK, which we think are important in angiogenesis. It is expressed on a lot of different cells, and VEGF is also important in normal blood vessel homeostasis and many other things. It inhibits NO, it inhibits NF-kappaB, and so you get a lot of safety side effects. It is also important in normal vessel homeostasis, and if you inhibit it for a long period of time, you can actually get an increase in bleeding.
Which is why we think you get waning efficacy with the VEGFs.
Yeah.
What's downstream? First of all, where is APJ expressed? Mainly in endothelial cells. That's where the disease is, so you're not inhibiting things in every cell of the body. What's downstream of APJ? AKT, ERK, and also cyclic AMP. And we think all of those may be important in treating patients with HHT. So we think it'll be safer than, for instance, inhibition of AKT.
Yeah.
Where you're inhibiting AKT in every cell in the body. We think we can get to higher levels of inhibition of AKT, then we think that the cyclic AMP and the ERK may be important as well.
Mm-hmm. Great. Sounds like you're still very confident in sort of that pathology-specific selectivity hypothesis after the healthy volunteer data.
Right. In non-human primates, we went up to 100 mgs per kg. And we saw nothing. The safety looked It was a 13-week study that, the FDA is allowing us to go forward with six-month studies. Based on a 13—
Yeah.
—a 13-week study. There was no dose-limiting toxicity.
Yeah.
Our phase I study, which was single- dose, normal healthy volunteers, there was really no evidence of an emerging safety issue. We do have a multiple-dose cohort that's completed dosing, and the preliminary data also looks quite good.
Yeah. Makes sense. You mentioned confident in sort of like your dose selection kind of coming out of that healthy volunteer work.
We approached dose selection. Let's start with target exposure. We went at it two different ways and came to the same answer, which gives me confidence in it. What were the two ways? In two different mouse models of the disease, and these mouse models are much more severe than the human disease. They're homozygotes, in fact.
Yeah.
What was the exposure, the minimum exposure that provided maximal efficacy? That's one target exposure. Then in the normal healthy volunteers, we saw something, TMDD which can actually be, it's a measure of strong target engagement of our antibody targeting the APJ receptor, and you can infer receptor occupancy. We said, "Okay, we want to get to here on receptor occupancy." If we assume that, what would the exposure be? It was the same exposure that we saw, or very, very, it was in the same range of what we saw.
Yeah.
Now we know that is the target exposure, and then we use the single- dose data to develop a model of what doses would hit that. That would be the mid dose, then we would go to a dose higher, one dose lower, and the multiple dose cohort was being done just to confirm the model from the single dose. Again, very preliminary data available. Looks like we are in the right range.
Yeah. Great. Now you are moving into phase I-B, phase II. Maybe just kind of like help frame out what those studies are in terms of what you are trying to show in them.
Yeah.
And kind of what you think is clinically meaningful on these endpoints.
The phase I-B study, as I said, is in the severe bleeders. That can be bleeding from the nose, epistaxis, or GI bleeding. Many of them, in fact, will have GI bleeding. Why do I call them severe? It means that they can't keep their hemoglobin up without getting IV iron and/or red blood cell transfusions. We get the baseline, what's their hemoglobin, what are their transfusion requirements. They get put on therapy for six months, then we are looking for a reduction in the need for those transfusions and either stabilization with a reduction or an improvement. In the hemoglobin. You are looking for about a 30% reduction in the transfusion needs. If you are just looking at hemoglobin, you would get about 1 g.
You would want to hit those as the targets. Nobody else is looking at that at that patient population, there's a lot of interest in that study. About 20 patients will be in that study. I said we'll be looking at something called the hematologic integrated score, which integrates transfusion rates and hemoglobin. We'll look at hemoglobin, and we'll look at the hematologic support score as well. For patients who have moderate to severe epistaxis, we'll also get frequency, duration, and intensity scores. Some patients in that study may have mild epistaxis because most of their blood loss could be from GI bleeding.
That only has one- dose regimen. The phase II study is three dose regimens, placebo, run-in, a one-month run-in to get the baseline e-diary scores, because we'll look at intensity, frequency, and duration, then it's a 16-week on-treatment period. We're looking for a minimum of a 15% difference from placebo, treatment difference from placebo. If you look at the ESS, which is the epistaxis severity score, which cannot be used for phase III, but is a validated measure, about 0.71 is what's considered clinically meaningful on that score.
Yeah. Okay. That's really helpful. I think obviously, like the benchmark out there people look to is something like the Vaderis clinical data. Just curious how you think about that in the context of where you think kind of like this next wave of drugs is going.
That is about the minimum on efficacy. If you look on the ESS, they were about 0.6.
Yeah.
Just barely meeting that. If you look as a percentage base and placebo- adjusted, 10%-15% depending on the endpoint. For duration, I think they were 20% or 25%.
Yeah.
I think they were limited on dose by the toxicity. They get to about trough levels of 50% inhibition of AKT. We think if you can get higher, you can get more efficacy out of it.
That's helpful. Maybe just like in that context, there's AKT1- selective approach. There's a lot of different kinds of mechanisms out there now. Just be great to kind of like quickly kind of hear your perspectives on how kind of your approach fits in within sort of this broader landscape of these different strategies.
A couple of things. Number one, I think that because of the fact that you're not, I think AKT is important. Okay? It definitely is important in angiogenesis. But when you use an AKT inhibitor, you're inhibiting AKT in every cell in the body. I think there's toxicity that goes along with that. The question is, with the non-selective inhibitors, you can't get above 50%.
Yeah.
We'll have to see how far up on the dose curve they can get. With the more selective agents. That's one thing. The other thing is we think that there are other things downstream of APJ that will also impact HHT treatments, as I said. It's not just AKT. If you look at the AKT inhibitors in the preclinical models, they have good effects on AVM. Their effects on bleeding are not as good.
We think there may be some things downstream of APJ that are important in vessel architecture and stability. We've shown in the ALK1 model of HHT, it's an ALK-inducible model, the architecture of the endothelial junctions gets disrupted. You can imagine, you get leaky vessels, which can lead to bleeding. VEGFs don't fix that architecture, but APJ antagonists seem to.
Mm-hmm. Awesome. I do want to jump to relaxin because there's obviously a lot to talk about there. Anything else specifically to highlight on HHT that you think is important for people to understand?
Listen, it's a huge unmet need. There's no approved therapies. One of the things that gives me confidence in it is the models have been kind of translated to the clinic.
Yeah.
I think that that provides de-risking that you don't get in all diseases that you go into. We'll see. We're excited about it.
Yeah. Okay. Great. With relaxin, there's obviously so much has happened this year. Like relaxin, AstraZeneca had some readouts. Merck and Tenax have been in similar indications. I think, obviously, there's been a number of failures with relaxin specifically, and I think the biology is so complicated, the patient populations are different. There's so much to unpack. I guess my question to you is just, what are your takeaways from this year, and how you feel about your thesis?
I'm going to go back a year and a half to two years ago when the only data available was our phase I-B data, and Lilly had stopped their study.
Due to an increase in heart failure, right? We had our phase I-B data where, really, the hemodynamic effects were spectacular. They exceeded our expectations of them. The drug did everything we could have asked it to do. But what people said is it was a single dose. How do you know you don't have tachyphylaxis?
Looked by echo that things were maintained out to a month, but that was the data we had. Key question was the tachyphylaxis. And then the other key question was, look what happened with Lilly.
They had an increase in heart failure events. How is relaxin ever going to work in heart failure if it increases the heart failure events? When we saw the Lilly data, my hypothesis was the dose was too high and they were in the wrong patient population. It was a straight preserved ejection fraction heart failure population, no pulmonary hypertension, and the patients had to have been discharged from the hospital within the last two weeks for worsening heart failure. Those patients with worsening heart failure, they have fluid retention and sodium retention.
When you discharge them, they are usually still fluid overloaded. They also get treated with IV diuretics in the hospital. That makes them more sodium- retentive. That is not a patient population you want to put on relaxin, which can have some sodium and fluid retention associated with it. I really felt those two things are what caused that. Now here we are two years later. The two relaxin programs did not show an increase in heart failure hospitalizations. Our DSMB has met multiple times. There doesn't appear to be a safety issue. I think I was right. It was the dose, and it was the patient population.
Yeah.
If you look just at the oral relaxin data, there's no evidence of tachyphylaxis. Even in the HFpEF cohort that they had with their oral, you had sustained increases in cardiac output, sustained decreases in systemic vascular resistance out to six months. Those two things, I think, I'm not as worried about them. What the data has shown, though, dose is important.
Yeah.
Patient population is important. If you look at the oral relaxin data- the lowest dose was the dose that had the best efficacy.
Yeah.
I will not be surprised in our study if our 300 Q4 has better efficacy than our 300 Q2. We have a hypothesis that we have chosen a patient population where we are most likely to get the best efficacy. That is, patients with HFpEF and a PVR greater than three. That dose is important, and now we are just two months, three months away from getting that data.
Yeah.
To see if we were right.
Yeah, yeah, and I think maybe on those two points, patient population, dose, makes total sense. On the patient population, I think your sort of thesis around it being kind of the right test of the relaxin hypothesis is really interesting. Maybe just like expand on that a little bit more and why you think that is really the right patient population and some of the data points here that kind of give us confidence in it.
I think we are taking advantage of everything relaxin has to offer. So, in patients with CPC-PH, high PVR. Why do they have a decreased exercise tolerance? Well, number one, they have got heart failure, and when you have to increase blood coming into the heart and increase cardiac output for when you exercise, pressures go up in the heart, fluid goes into the lung, you get short of breath. In PAH, where you have a high pulmonary vascular resistance, why do you have a decrease in exercise tolerance? Because your vessels are narrowed, and you cannot actually get enough blood from the pulmonary circulation into the left side of the heart.
To increase your cardiac output. CPC-PH has both of those defects. We think relaxin. Our hypothesis when we went into the phase I-B is we wanted to see the pulmonary vascular resistance go down, and we wanted to see the wedge go down and cardiac output to go up. We saw all of those. You are taking advantage of everything relaxin has to offer.
Yep. Makes sense. I think in the AstraZeneca study, presumably they might have had some of these patients.
In the subcu study, yeah.
This kind of starts to tie into dosing, but what is your view on whether or not they even tested that CPC hypothesis and specifically PVR grade?
First of all, they included HFpEF and HFrEF. They included IpcPH, normal PVR.
Yeah.
CpcPH. Four different subgroups. There wasn't stratification on any of those subgroups.
You know, you can look at the baseline, you've got unequal distribution of patients, so that's one thing that really complicates this. The other piece is, in terms of PVR greater than three, in each treatment group, they only had about 30- 35, I think, patients that had CpcPH, that's PVR greater than two, and the PI told us only a third of those had a PVR greater than three. You're talking about 10- 15 patients in each treatment group, divided between HFpEF and HFrEF. Now, the hypothesis we are testing, which is in PVR greater than three in HFpEF, has not been tested yet.
Yeah, with relaxin, yeah.
But even there, if you look at their data, w here did you start to I have no idea where they are on the dose curve, by the way.
Yeah.
I'm just going to be honest about that. Where did you maybe see a hint of a signal?
You saw a PVR reduction in the CpcPH group, and you saw a PVR reduction in the HFpEF group at the highest dose.
Yeah.
I don't know. Maybe that was noise, or maybe it was telling you something. I don't know.
Yeah. Like you said, we don't know where they were on the dose curve. They didn't really disclose anything as it relates to their—
No, they didn't.
—dosing.
They never did renal blood flow. Lilly did renal blood flow, we did renal blood flow, so I feel very confident about how to compare myself to them. They didn't give us, for instance, the hemoglobin data. Which would have given us a look at whether there was any fluid retention.
Yeah.
Hard to tell.
Makes sense. Then just kind of like, so yeah, we have not seen the right test of this. What you are doing, we have not seen sort of the right test. As it relates to dose, we do not know where AstraZeneca was on the subcu. We know the oral, there was the inverse dose response. Maybe just kind of like talk about what you think is the right part of the dose curve and your confidence that you are kind of like in that sweet spot.
I am not going to get into a lot of detail, but based on what I am seeing blinded, as well as some phase I data and what AZ has reported, I think in terms of the fluid retention, we are probably, our 300 Q4 is probably about like their 20 mg or maybe in between their 20 mg and 80 mg. Our 300 Q2 is more likely to be between their mid-dose and their high dose.
So, I am guessing that if we see efficacy, it will be at the 300 Q4 dose. Then we plan to look at exposure response. If we see efficacy at the 300 Q4, we are going to look at exposure response and say, "If you go even to lower exposures, do you start to see even better efficacy?
Mm-hmm. It is all about threading the right needle here.
I think that is the way they have talked about it, and I think they are right.
Yeah. Okay. That's just the sort of lower dose, that's just your hypothesis in terms of like why maybe it's, as we've just learned more, it's probably maybe on the better part of the dose curve.
I think so.
Okay. I think, obviously, we've seen with your phase I-B data, there's a lot of interesting hemodynamic benefits. I think one of the more interesting things, as it relates to your patient population, is it got better as PVR went up. I think you addressed the tachyphylaxis question, but I think naturally the other question is like, okay, if we see those hemodynamic benefits and they're durable, will they translate into a clinical benefit? Maybe just help us understand what gives you confidence, or at least optimism, that that will translate.
Okay. If you look at PAH, there are hundreds of studies where you can, from all of those, look at a correlation between PVR and six-minute walk. We don't have that in CpcPH. Let's just be honest about that. I also think it's not just PVR. I think PVR is important, but if you have a reduction in PVR and you're sending more blood into the left side of the heart and you're not doing anything to improve heart function, you can actually make heart failure worse.
Yep.
We have to, at a minimum, keep the wedge pressure from going up.
Yeah.
As well. If you look, though, if you get about a 20% reduction in wedge in regular heart failure, you get about a 20 m increase in six-minute walk. If you get about a 20% reduction in wedge and a 30% decrease in PVR, which they saw in a very high PVR population in PADN with a surgical procedure called PADN, pulmonary artery denervation, they saw like a 60 m to 80 m increase in six-minute walk. In other words, that combination of bringing down the wedge and bringing down the PVR led to a very dramatic increase in the six-minute walk. That's not my bar.
Yeah.
It's not 60 m to 80 m.
Yeah.
That was unusual. Sotatercept, they brought down PVR, they brought down wedge, they saw about a 20 m increase in six-minute walk, and there was one single -center study with a PDE5 inhibitor that saw about a 20% decrease in PVR. They also saw an increase in six-minute walk. My bar is not, my bar is if I can see a 15 m. People say 15 m to 20 m is what's clinically relevant in this patient population. We're not powered for six-minute walk, but I want to see a strong numeric trend.
Yeah. I wanted to ask about Merck and sotatercept.
Yes.
That was in a CPC population. Like you said, it was improved wedge pressure, improved PVR, what you've kind of shown, and there was a real six-minute walk benefit. There was an inverse dose response, but in my overly simplistic view is that they decreased cardiac output.
I'm with you.
Is it that simple of why there was maybe an inverse dose response?
I think so. I don't know if I'm right, but I, like you, I said, "Huh, I wonder if that decrease in cardiac output just dampened the effect on six-minute walk." Our drug increases cardiac output.
Yeah.
So.
Is it basically like the low dose was, the benefits were enough to kind of overcome that decrease, but—
Exactly.
Okay.
They saw a really nice effect on time to clinical worsening, and that is now their primary endpoint in their phase III, which gives us some flexibility about how we think about our phase III. We had been focused on six-minute walk, but now we're like, "Well, let's look at the data on time to clinical worsening.
Yeah.
We can consider either one, figure out which one would be the most efficient study to run.
Yeah. Makes sense. I thought that was interesting. Maybe just, again, going back to kind of six-minute walk, PVR, wedge pressure independently are associated with six-minute walk benefit.
That's right.
The denervation study kind of has both. Sotatercept maybe has both, like all these things kind of showing a consistent improvement on six-minute walk. Tenax obviously also had data this summer. They think in, like, their more severe patients, there was a signal there. What do you make of that, and does that have any bearing on kind of like what you're doing or?
I don't think it does. I really think, other than the fact that we decrease preload too, but I think they have proven that their drug decreases preload. I think that was evident by the reduction in right atrial pressure. I think the reduction in NT-proBNP was driven by reduced preload, reduced strain in the heart. What it looked like is you had two very different patient populations. It was beneficial in one, and it was harmful in the other. I think what could have been going on there, they have already said that the ones that it was beneficial in were probably more fluid overloaded.
Yeah.
I think if you're fluid overloaded and you decrease preload, that's good for the heart, right? It's not as congested. It works, it functions better. On the other hand, if you are euvolemic and you decrease preload too much.
It is bad.
It is bad. I think their challenge will be in the clinic, who is it going to help, and who is it going to harm? It'll be very interesting to see if the FDA thinks that six-minute walk is going to be the way to do that.
Yep, makes sense. For APEX, I mean, just kind of like going to the study, 15 m plus kind of benefit would be a win, not expecting any sort of p-value. In the context of this time to clinical worsening, I guess like, one, are we going to have like any sense of that data over the course of the study, or is it too early?
We'll look at outcomes.
Yeah.
CV death, hospitalization for heart failure, outpatient diuretic use, and then the fourth component to that is 15% reduction in six-minute walk that's replicated. In the Merck phase II study and their phase III, I think they're doing it in their phase III too, if you have a 15% reduction, you're supposed to come in a week later to confirm that. We didn't do that in ours. We're going to have to come up with other ways of looking at that, like do you do it on two separate occasions? If you do, you know. We'll have an early look at that data.
Yeah.
In the phase II.
Yep. Makes sense. I guess just like in the context of them using this, like not using six-minute walk, is there a scenario where you have like really good hemodynamic benefits, like some signals on outcomes, but six-minute walk is noisy because six-minute walk is noisy?
Maybe we do what they're doing. We do time to clinical worsening in there.
Yeah. Okay.
Yep.
Yes, you're bringing
I mean, if you look at the PADN study also, they did. New England Journal had their phase III study, which was in a mixed Ipc/Cpc population. The phase II that I referred to was all CpcPH. The improvement in six-minute walk compared to placebo was not as big in this study, but they had a 50% reduction in time to clinical worsening.
Yeah.
It was in that. But they saw statistically significant improvement in six-minute walk. We're going to let the data drive our decision for phase III.
Yeah. Those kinds of takeaways here are, right dose, right patient population. We've seen these hemodynamic benefits be durable, and there's evidence to kind of tie that to clinical benefit. That's sort of the kind of summarization of the optimistic case.
We have a hypothesis. We're testing the hypothesis.
Yeah.
Hopefully not too long till we get the data.
Yep. Maybe just, I know we're a minute over, but just runway, cash runway, what does that take you guys through?
Cash runway to first quarter of 2029, which should really cover both getting through our APEX data and CpcPH, Group 2 PH, PH-ILD, and the phase I and the phase II for—
HHT.
—HHT. We don't talk a lot about it, but hopefully something else going into IND-enabling studies and into the clinic as well.
Sounds good. A lot going on. Thanks for joining.
Thank you.