Great. Welcome everyone to the next session here. Happy to be joined by the Tectonic team. I have Alise Reicin, CEO, and Dan Lochner, CFO. Obviously, a lot going on with you guys and some topical data yesterday. Maybe, Alise, you could just kick it off with a short overview of everything going on with Tectonic, and then we can jump into some Q&A.
Well, obviously we've got two programs in the clinic, and actually there's things behind that as well, which we don't spend a lot of time talking about. Lead program is relaxin, and as you know, we're in phase II in a randomized study in Group 2 pulmonary hypertension with preserved ejection fraction heart failure, and we've got a readout from that study coming in the next couple of months. We are really getting close there. We've also got a single arm phase II study in PH-ILD. Our second program is our TX2100 program, which is an antagonist to APJ for hereditary hemorrhagic telangiectasia. We just had our phase I readout, which was really safe, very well tolerated. We had a very clean preclinical tox package, and I would say the data to date in the normal healthy volunteers mirrors what we saw preclinically.
We'll be moving forward into a phase I-B, hopefully by the end of the year, in patients who require hematologic support, so really some of the most severe patients, as well as a phase II randomized dose-ranging study in early 2027. Very high level, hopefully. I'm sure we'll get into a lot more detail on both programs.
Yeah. No, definitely. Yeah, maybe we can just quickly touch on HHT, obviously very topical given the data yesterday. Like you mentioned, it looks like everything was safe. Obviously, we'll get full details soon. A key part of the thesis with this mechanism is sort of its pathology and tissue specificity as it relates to it being a safer version of just like a safe drug. Sounds like, again, we'll get more details, but it sounds like yesterday was an important de-risking step of establishing and confirming that mechanism.
It really was, because no one's ever taken an APJ antagonist into the clinic and into normal healthy volunteers. One of the questions, if you look at the preclinical data, people said, "Oh, are you going to get the hypertension that you get associated with the VEGF inhibitor?" We absolutely saw no signs of that. It was really very well tolerated. I get asked if we had a biomarker. The good news about this target, as you said, is it's selective. It also tends to be quiescent. It's hard to find a biomarker in normal healthy volunteers. It gets upregulated in patients. But we did have a biomarker in that we had TMDD. Which can be used as a surrogate for receptor occupancy.
It's a really strong signal that you're binding the receptor. By looking at inferred receptor occupancy levels, we could then say, "Okay, what are the exposures we're going to want to get to in patients?" That was one way we looked at that. That got us to exposure X. Then we said, "Okay, now looking at the HHT preclinical models, which tend to translate to the clinic, based on that, what exposures do we think we need to get to?" Two orthogonal ways, they sent us to the same place, which gives us confidence in the target exposures that we're going after in the phase I-B and the phase II study.
Yeah. Makes sense. That was going to be my next question. It seems like really confident in dose selection. Maybe just in the context of those studies, the phase I-B and the phase II, just sort of help us understand what a win looks like in those studies and sort of just how to frame what you're hoping to see in terms of obviously slightly different studies and just curious how you would frame it up.
I don't want to get ahead of myself, and I think what you have to understand is there's been so little research in this area. There's not a lot to go on. In the setting of moderate to severe epistaxis, which is moderate to severe nosebleeds, which many of these patients have, and these aren't the nosebleeds that are associated, like we think about schoolmates having when we were in grade school. By the way, some of those who kept having them probably had HHT. The disease gets worse as you get older, but these can really be severe nosebleeds that really impact a patient's quality of life. There's one validated measure of that. It's called the ESS score, the Epistaxis Severity Score.
There is what's considered a clinically meaningful change in that, which is about one point on that. So that might be something you'd like to get into the range, or maybe it's somewhere in the 0.7 to 1.0 range. The other thing that KOLs have said is they think a 30% reduction from baseline and a 15% placebo-adjusted effect on efficacy would be clinically meaningful as well. One of the things that all of the companies in this space are doing are validating daily diaries, and that's what will be used as your phase III endpoints. Because the ESS is like a one to three months look back, there's no way patients can remember.
I don't know about you, it'd be hard for me to remember how many episodes did I have two weeks ago on each day, how long did they last, how severe were they, and that's where the daily diaries are coming in. So, it's hard to say we want to see an X point drop on the daily diaries because they haven't been validated yet. That is where the 15%-30% range is coming from.
Yeah. Okay.
We want to see that the drugs are well-tolerated.
Yeah
The efficacy is maintained over time. One of the things that happens with the VEGFs that we hear about is the efficacy starts to wane over time, and we saw that preclinically with the VEGFs as well. Our APJ antagonist efficacy was maintained throughout the dosing period, and the VEGF seemed to fall off.
Yeah. Makes sense. I do want to get to relaxin, obviously the cardiometabolic day, but maybe just last question here on HHT, because I think it is a topical one for folks, is just there is so much going on in HHT now. There are different mechanisms. Just curious how you think about how apelin fits into that and sort of your confidence in that approach versus all the other mechanisms we are seeing out there.
Yeah. So, we are the only ones going after apelin. I feel really good about the approach. As you said, right now anti-angiogenic agents are used. VEGF inhibitors are used, bevacizumab, pomalidomide, and others. The problem is those were all developed to take care of patients with metastatic end-stage cancer, and they are not particularly well-tolerated. There is a lot of safety issues that either require patients to discon or reduce the dose of their drug. But they have demonstrated efficacy, and they have demonstrated efficacy in the preclinical models that have translated. So, we have had very strong efficacy that has matched those in the preclinical models or been better in terms of durability. But we think the safety profile of the drug will be much better. When you inhibit VEGF, you are inhibiting AKT, and you are inhibiting it in many cells in the body.
When you inhibit APJ, you are also inhibiting AKT and ERK, but you are only inhibiting them, or you are mainly inhibiting them in the endothelial cells. We have got three competitors going after AKT, and we know giving AKT inhibitors, you are limited on dosing by toxicity because you are inhibiting AKT in every cell in the body. So, the Vaderis compound, which is going into phase III, only got to a 50% inhibition of AKT. We think you need to be much above that, and we believe we can get there with an APJ inhibitor, so potentially better efficacy than you might see with an AKT inhibitor with better safety. Alnylam is not a disease-modifying approach.
Basically, it is going after the plasminogen pathway so that you stabilize clots. You should decrease the bleeding. I anticipate that they will get some efficacy, but you are basically not modifying the course of the disease. There are the other approaches. Diagonal has a very sophisticated approach. The genetic defect in this disease is mutations in the ALK1 and endoglin pathway, that inhibit that pathway. They are reactivating that pathway with a clustering antibody. I think there are some theoretical safety questions. It is a very well-controlled pathway if you are activating it broadly. Then I think there are also questions about whether patients get second somatic hits. Most patients are heterozygote, but are the vessels that bleed, do they become homozygous, and could that affect the efficacy in some patients? So we feel really good about the approach that we are taking.
Yeah. Makes sense. Super helpful. I do want to jump to relaxin to make sure we get to some of those questions. So much has happened in the last few years with relaxin and also just the Group 2 space in general. We've had a lot of readouts, including recently AstraZeneca, an oral small molecule. They had a sub-cu earlier this year. Merck's had data in this disease with a different mechanism, so many different paths we could go down in so many different questions. Maybe just set the stage in terms of one or two of the key learnings that you've taken from all of these updates over the last couple of years, and how that informs your confidence or your optimism around TX45 and APEX.
First of all, I think my confidence is increased compared to where it was, let's say, 15 months ago. Let's start there. Why is that the case? We had spectacular phase I-B data in the patient population. Relaxin did everything you wanted it to do. It improved so many elements of heart function in patients with PH-HFpEF. It improved the pulmonary hemodynamics. It was well-tolerated, and it was only a single-dose study, but some evidence of efficacy even on echo out to day 30. Right in that setting, we have the Lilly failure. What happened there, they went into a HFpEF population, not PH-HFpEF, in patients who had been discharged from the hospital within the last two weeks with worsening heart failure. How are those patients treated in the hospital? They're treated with IV diuretics. What does that do?
It makes them get rid of fluid, but it also makes them even more sodium retentive. Typically, patients are discharged, they're still not on baseline therapies, and they're still fluid overloaded. They took those patients, and they treated them with relaxin, and what did they see? Study stopped midway, mainly for safety. They had an excess of heart failure hospitalizations on relaxin and definite evidence of an increase in congestion. Probably at the time, we said our hypothesis was wrong patient population, the most susceptible to sodium retention, and they were too high on the dose curve. Why would you get sodium retention with relaxin? You're dilating the vessels around the glomerulus in the kidney.
The kidney sees less pressure, it thinks you're dehydrated, and says, "I have to hold on to fluid." Other vasodilators that are approved for the treatment of heart failure can do that, but they can still work in heart failure. You just need the right balance, and it seemed between their dosing and the patient population, they were on the wrong side of that. You can imagine it raised a lot of questions about the relaxin class for the treatment of heart failure. Now, a year and a half later, AZ's had two programs, neither of them saw an increase in heart failure hospitalizations or evidence of significant congestion. In our own program, based on the blinded data, we didn't see something that looked like that. The DSMB has access to both unblinded and blinded data. They last met in the summer.
We had 80% of the patient exposure, and they basically said, "Benefit-risk looks good. Continue with the study." I think that piece we have de-risked. I think the data we've seen to date, I think we put the pieces together when we saw the Lilly data. The other question about the phase I-B data was, well, it's single dose. How do you know you're not going to get tachyphylaxis? I think now there's also extensive data on that. Pre-clinically, there's evidence the drug worked for over six months. AZ had done several studies. Mechanistically, we know RXFP1, the receptor, doesn't couple with beta-arrestin, so the mechanism of tachyphylaxis doesn't happen with relaxin. But if you look now at the AZ data, let's take even just their most recent data with their oral, there's evidence of efficacy out to six months in the HFrEF cohort.
In the HFpEF cohort, which wasn't designed for efficacy, you saw evidence of target engagement. Systemic vascular resistance was reduced for six months. Cardiac output was increased for six months. So, I think we can put the tachyphylaxis piece to bed as well. Now, the last thing we have learned, and that got started with the Lilly and got confirmed with relaxin, dose is super important. If you go back to the Serelaxin data, their phase II data, and I must admit, I wasn't convinced by it. I thought maybe it was just noise, but it looks like there's an inverse dose response in that data. Now I think you're starting to see, and I think it relates to that fluid retention. You sort of have to be in a place where you're getting the efficacy part of it, but not too much fluid retention.
When we saw the Lilly data, I've always said I think there'll be some fluid retention. But the hypothesis is that you can get to efficacy, and you can tolerate a little bit. If you look at the oral relaxin data, based on the fact that hemoglobin decreased just a little bit, even at that 20 mg dose that had efficacy, you're having a little bit of fluid retention, but not enough to interfere with the efficacy. So, dose is important.
No, that all makes total sense, and I think is really interesting. To your point, safety feels like we have a lot of data answer that. We know dose is really important and therapeutic index. Again, you've done a lot of work, and your phase I-B is really interesting. I think the other piece of this, and it's sort of, again, all tied in, is patient population. I think, again, you guys have a really interesting thesis around the specific patient population you're testing with relaxin. Maybe just expand on that a little bit more versus what we've seen with AstraZeneca and with Lilly, and why specifically this type of Group 2 is probably or maybe the best suited for relaxin.
We always thought that there would be efficacy in straight heart failure, but we didn't think it was taking full advantage of everything that relaxin can do. We thought we might get enhanced efficacy if we went into a patient population that not only had heart failure but also had pulmonary hypertension. Not only on top of that, we've gone into the most severe patients within that subset. This patient population that's called They love acronyms in cardiometabolic. It makes everyone crazy. CpcPH, combined pre- and post-capillary pulmonary hypertension. What does that mean? The post-capillary component is the heart failure component. High pressures on the left side of the heart backflow into the pulmonary vessels, you get high blood pressure.
The pre-capillary component is, we think in patients that have had that for prolonged periods of time, you start to get remodeling in the pulmonary vessels. So that they start to look like they have PAH, Group 1, and you get a narrowing of the lumen of the vessels. As you're sending the same amount of blood through a smaller pipe, you get an increase in the pulmonary vascular resistance. Those patients tend to be the sickest. Their exercise tolerance is driven not only by their heart failure, but by their high PVR, which prevents enough blood from getting into the left side of the heart when you exercise. We thought relaxin can both improve the heart failure, but also bring that pulmonary vascular resistance down, bring the pulmonary pressures down.
You can send more blood into the left side of the heart, which could make their heart failure worse, but you're improving their heart failure, and you should almost get enhancement of the efficacy. That was sort of our hypothesis that we're testing [crosstalk].
Yeah.
On the clinical trial.
Yeah. No, it's really interesting, and feel like it maps really well in terms of the mechanism and some of your hemodynamic data look better in the higher PVR patients, which was an interesting sort of validation point for that. In that context, AstraZeneca's subq is maybe a little bit more similar to this population, but do we have a sense of what the patient overlap with your study is versus those [crosstalk].
Yeah.
Patients in that AstraZeneca study? Do you think they actually tested it?
Not a lot. First of all, they included both preserved ejection fraction heart failure and reduced ejection fraction heart failure in a single study. If you look, you can see randomization one isn't exactly equal. That's an issue when you interpret the data and you combine it all. In addition, as best I can tell, they had a CpcPH population, which was about half of their population, anywhere between 30 and 40 patients per group had CpcPH as defined by a pulmonary vascular resistance more than 2 Wood Units. We're enriching for pulmonary vascular resistance of more than 3 Wood Units, and from what we've heard from some of the PIs, that was only about a third of the CpcPH population. So maybe 10 to 15 patients had PVR greater than three, and that's divided by HFpEF and HFrEF.
The other thing about that, I have no idea where they were on the dose curve. They did not present any of the data that would've given us clues. We didn't see the hemoglobin data. We didn't see the renin data. They didn't show data on things like systemic vascular resistance. So, we don't really know where we are on the dose curve with that study, which did not have a safety issue, but also really didn't demonstrate much efficacy. Although, you saw a hint of efficacy in PVR reduction in that CpcPH group, and again in the HFpEF group. What you didn't have was CpcPH HFpEF. Yeah.
Yeah. Makes sense. Yeah, no, it's really interesting. So, it's like you have the right patient population, right dose. We've seen the right sort of hemodynamic benefits. We have evidence that those can be durable with this class. Safety seems fine. The other question naturally is just okay, how does that translate to six-minute walk?
Yeah.
What is sort of your confidence there that these hemodynamic benefits will translate to a true clinical benefit and just sort of help us think about what your expectations are for that.
Yeah. Unlike PAH, where you have hundreds of studies where you can actually correlate changes in pulmonary vascular resistance to six-minute walk, there's just limited data set. But there are some. The sotatercept data set shows if you decrease the pulmonary vascular resistance, you improve left heart function, you do get an improvement in six-minute walk. There have been studies with a specialized PADN, pulmonary artery denervation, in a very sick patient population that had similar effects on PVR and [uncertain] and saw very large increases in six-minute walk. The other thing if you see with sotatercept, they are actually deciding to do their phase III study, not a large study, only about 325 patients, looking at clinical worsening, which includes worsening six-minute walk, but also includes heart failure hospitalizations, need for IV diuretics. That is another way we could think about designing the study.
Yeah.
In the frame it kind of previously, the biologic relaxin data from AstraZeneca was a baseline PVR of about 2.25 Wood Unit, and what we disclosed previously in APEX for baseline was the overall population was 4.2 Wood Unit mean, and in the PVR greater than 3 Wood Unit was 5.2 Wood Unit. So, it kind of gives you a sense for the type of patients we have in our trial.
Yeah. No, that is really helpful. I think the sotatercept data was really interesting. Obviously, there was an inverse dose response, but that drug also decreases cardiac output. Help us sort of, again, different mechanism, but tie back to what we see hemodynamic.
I think it impaired their efficacy, and that is what drove that dose response. The 0.7 mg/ kg, you saw an increase in systemic vascular resistance, so you're increasing afterload, which you do not want to do. To be perfectly honest, wasn't unexpected. With that, the cardiac output went down, and the cardiac output went down more in the 0.7 mg/kg than the 0.3 mg/kg group, and I think it impacted the six-minute walk.
Yeah. Makes sense. Obviously, you guys increased cardiac output. So awesome. Well, we're just about up on time. Maybe just to kind of tie a bow on it, in terms of APEX, early 1Q next year, what are you hoping to see on six-minute walk that'd give you confidence to move forward?
Yeah. With six-minute walk, the prevailing, what you hear from the KOLs is it's hard to get large improvements just because they have osteoarthritis and so many other things that could impair it. If we saw something in the 15 m to 20 m, which was just sort of aligned with what Merck saw, I'd be very, very happy. That along with the reduction in the PVR, I think would put us in a good place.
Makes sense. Awesome. Well, exciting time for you guys. I appreciate you both joining and looking forward to the next few months, and thanks everyone for listening in as well.
Thank you.
Thank you, James.
Thanks.