Okay, great. Can you guys hear me? Great. Good afternoon, everyone. Welcome to day two of the Cantor Healthcare Conference. My name is Olivia Brayer. I'm one of the Senior Biotech Analysts here at Cantor, and we're really excited to have with us the CEO of Tectonic Therapeutic. We've got Alise Reicin. Thank you so much for joining us.
Thank you for having me.
A lot going on these days at Tectonic Therapeutic, but also in the relaxin space, so to speak. Maybe I'll give you the floor, you know, given Eli Lilly's update and their data over the weekend. How are you guys thinking about that data release, and then just maybe contextualize it with your program and some of the nuances and differences, and why you all think that you have a real shot at success here.
I think our program and the way we're going about testing the relaxin hypothesis is quite different from what Eli Lilly did. I do feel like we've had triple jeopardy, however, with this one trial from Eli Lilly has impacted us three separate times. I think what I said from the beginning when I knew very little is very similar to what I've said now, although now there's even more information, which is that they went into a very different patient population. They took patients with decompensated heart failure, preserved ejection fraction heart failure, and who had just been discharged from the hospital within the last two weeks. I think there are several things about that patient population. It's a really tough patient population to treat in general. So many studies have failed in that patient population.
The patients with decompensated heart failure tend to have a tendency for sodium avidity and fluid retention. You put them in the hospital and you start treating them with IV diuretics and they get even more sodium added. On top of that, because these patients had just been discharged from the hospital, they were all fluid overloaded, likely, or many of them were fluid overloaded. Now you give them relaxin, which at least one of the mechanisms is it's a vasodilator. What do vasodilators do? They've been shown to, if you vasodilate the vessels around the kidney, the glomerulus sees lower pressures, reads that as, oh, has blood pressure dropped, and it tends to retain sodium, and it tends to retain fluid. You took your highest risk patients, and then you gave them a drug that's going to make them retain a little bit more fluid.
Number one, they can't handle the excess fluid because they're already fluid overloaded. They may have had a tendency to retain even more fluid than they might otherwise have done. The other thing before I go to how it compares with our patient population is this was a potentially very sick treatment-resistant population. First of all, they had class four, I mean, class four patients in it, not just class two and three. There was low use of MRAs. Only about 40% of patients were on MRAs. In our phase 1B and HFpEF patients, 80% were on MRAs. That could have been a, could, that could have counteracted the increase in sodium retention and fluid. and also their mean ejection fraction was 58%, which means many of the patients were likely over 60%. Those tend to be a treatment-resistant patient population. Now you switch to our patient population.
They have to be stable at baseline. They cannot have just been discharged from the hospital. We knew that relaxin can be associated with a small amount of fluid retention because we know there's a compensatory increase in renin. Going in, we've been telling our investigators, make sure your patients are not fluid overloaded before you put them into this study, that they're euvolemic, that their fluid status is balanced. We will continue to emphasize that with them. There's some good news that came out of the study. It's a little hard to see that.
Not to cut you off, but before we get to the positive spin on it, were you surprised to see the Lilly data? I mean, obviously we knew that they had discontinued the program, right? To your point that this is now the third punch from them. What was maybe the biggest surprise from the Lilly data?
To be perfectly honest, I was surprised they hadn't just said up front six months ago what they saw in the study. They had been a little quiet about it, and I was surprised by that. The KM plot on the heart failure hospitalizations, given the fact that they had said in multiple meetings there wasn't a safety issue, was surprising. I think there's the potential in the study that there may not have been balanced randomization, so it may have exacerbated what they saw, that male to females weren't balanced. I asked them if they stratified for how long they'd been out of the hospital and they did not. You may have been enrolling patients in varying degrees of acute heart failure and they didn't do anything to try and stratify that. With small studies, you certainly could have gotten some imbalances.
That wouldn't explain everything, but it could have exacerbated that type of signal.
What did we learn from the data set that is maybe a positive, right?
If you, just to, if anyone remembers what happened, Eli Lilly data came out, our stock plunged, and two days later we came out with our phase 1B data in group 2 pulmonary hypertension in the setting of preserved ejection fraction heart failure. There was, I think, a lot of reassurance with that data because it was so positive. We saw a 35% reduction in pulmonary vascular resistance, close to 20% reduction in pulmonary artery pressure, a reduction in wedge pressure, and an increase in cardiac output over the first eight hours after giving drug. The obvious question at that point was, how do you know there's not tachyphylaxis? This study answered that. There is not tachyphylaxis. They looked at what they called total peripheral resistance. It's sort of similar to what we looked at, which was systemic vascular resistance, and there was a persistent reduction in that.
They saw an increase in estimated GFR that was maintained, as well. That's telling you that the vasodilatory properties are maintained. They didn't look at pulmonary artery pressure. They didn't look at pulmonary vascular resistance. If the systemic vascular resistance reduction was maintained, I think there's a good chance that the PVR, the pulmonary vascular resistance, and the pulmonary artery pressures were maintained. I think if anything, it makes me feel good about the patient population that we're emphasizing, which is combined pre- and post-capillary pulmonary hypertension, CP-CPH, and we are specifically enriching for a higher PVR patient population. 70% of the patients in our phase 2 study have to have a pulmonary vascular resistance greater than 3 WU units, and the primary endpoint of our study is in that 70% of the population, whereas CP-CPH, the diagnosis is PVR greater than 2 WU units.
We'll have that in about, probably 85% to 90% of our population. In those patients, exercise tolerance, which is one of the key things we're going to, we're going to have a six-minute walk on our phase 3, is driven not just by low cardiac output or high wedge pressure, but by that high pulmonary vascular resistance, which prevents enough blood from even going into the left side of the heart. I think if we can bring that PVR down, I think we've got a chance of improving exercise tolerance in these patients.
What about your PH-ILD indication? I mean, what are the ramifications of the Lilly data on PH-ILD?
I actually think it's a nice orthogonal study to have with another shot on goal because I don't think the amount of fluid retention they actually saw in the study was not huge. It was about 250 cc, about 8% to 9% of plasma volume. Patients without heart failure should be very easy to deal with that. They're not sodium avid in that same way. In those patients, it's all about bringing their pulmonary vascular resistance down. We actually had decided on that before we saw this data, but it's a very nice shot on goal where you don't have to worry as much about the wedge pressure.
AstraZeneca obviously has another relaxin program.
Actually, I have to tell you, the fact that AstraZeneca has an ongoing program and where they are in that, which I'll explain, provides me a lot of reassurance. It helps me sleep at night. They have a phase 2 study that's just completed with their biologic, relaxin biologic in group 2 pulmonary hypertension. They had a right heart cath like we do at baseline, a right heart cath after six months, and they'd had an interim analysis when 50% of the patients had had that six-month right heart cath and the study progressed. If they had seen major evidence of congestion, and you can see that on right heart cath, you'll see they would have seen patients' pulmonary capillary wedge pressures go up. I can't imagine that they would have been continuing with the study.
They also have an oral, and they've just completed enrollment in chronic heart failure, HFpEF and HFrEF, 375 patients. That study hasn't been stopped early either. Yeah, that's reassuring. We're about, a little bit over a third of the way enrolled. Blinded data only, nothing on safety that I've seen to date that has me concerned. We have a data safety monitoring board that will be looking at unblinded data. They next meet in two to three weeks. You can be sure we'll make sure they've read the Lilly data so they can be sure to be focusing on the right things.
Why don't you give us a brief overview of the phase 1B data set that you guys have out today? What are some of the highlights from the data so far, and maybe just highest points of confidence in this program?
Yeah. That was in group 2 pulmonary hypertension and preserved ejection fraction heart failure patients. We'd have about 20 patients. We had set a goal of seeing a 15% to 20% decrease in wedge pressure and a 15% to 20% decrease in pulmonary vascular resistance. What we found was we had, in the high PVR patient population, a 32% to 35% decrease in pulmonary vascular resistance. It was, I don't know, almost one and a half Wood unit reduction.
Can you contextualize that? Just because that to me seems like a very big %.
In PAH, if you get a 20% decrease in PVR, that about corresponds to a 30 meter increase in a six-minute walk. You don't have that data in group 2 pulmonary hypertension. When I go over the rest, I'll come back to what we do have in group 2. We saw a three millimeter drop in pulmonary capillary wedge pressure that was close to a 20% drop, about an 18% drop in pulmonary artery pressure. At rest, we saw an increase in cardiac output, which was somewhat surprising to us, almost a 20% increase. We were really, really thrilled to see that. The fact that we decreased the pulmonary vascular resistance means you're sending more blood into the left side of the heart. Typically, that would increase the wedge pressure because they can't accommodate that excess fluid.
The fact that we did that, and not only did the wedge pressure not go up, the fact that it went down was really what created so much excitement. In terms of what does that mean for a six-minute walk test, there have been two studies that have both been done in patients with CP-CPH and a PVR greater than six, so very severe patients. They did experimental surgical techniques where they saw a 20% decrease in the pulmonary capillary wedge pressure and a 30% decrease in the pulmonary vascular resistance. On the line of what we saw, they saw a 70 meter increase in a six-minute walk, which is double or triple what you see with PAH drugs. That's not my bar. I think.
Just to be clear, you're not setting that bar.
I am not setting that bar. In our phase 2, where we're not fully powered, I think if we see a 15 meter increase in a six-minute walk, we'd be happy.
Yeah, I mean, to me, it seems like your drug is doing exactly what it's supposed to be doing on hemodynamics, but I know there is pushback out there around it being a vasodilator. What do you say to that?
It is a vasodilator. I don't walk that back. It's not the only thing it is. What I would tell you is not all vasodilators are created equal. If you ask my KOLs, have you seen a vasodilator that's done every one of these things and hasn't dramatically dropped blood pressure? They would tell you no. Some vasodilators dilate the systemic circulation more than the pulmonary circulation. Some do the pulmonary and don't do systemic. It just feels like what we have is a little bit of a Goldilocks effect. What we saw in our phase 1B data was quite reassuring for what we're trying to do. I think the Lilly data says that we may get a little bit of fluid retention.
Our hypothesis is it won't be as exaggerated as it was in the acute heart failure patients they went into, that they can accommodate it, and all of the rest of the benefit will offset that. That's something that we and the investigators are going to have to follow closely.
Is there anything that you can implement to try to mitigate some of that fluid retention beyond patient enrichment?
I think it's really trying to emphasize that patients be on the right meds at baseline. They had very little MRA use, aldosterone inhibitor use. In that study, it was only about 40%. In our phase 1B, it was about 80%. I think we're going to really emphasize, make sure they are maximally on maximum medications, really make sure they're euvolemic at baseline, and continue to monitor their fluid status during the study. We're in the process of speaking with our KOLs to see if there's any protocol changes that they think would be helpful or whether all of this is, you know, just around advice and judgment calls. I can't, we may make some protocol changes, not quite clear.
If there is a protocol change, what could that look like potentially? Or too soon to comment?
You could mandate that they're on certain meds. It's a soft mandate. If they can't tolerate them, if they're not available, you might. Those are some of the things that at least we're discussing. I don't know what we will or won't do.
Okay, understood. You do have some data coming up. You are talking about your phase 2 as well, the APEX trial, I believe it's called. Maybe just walk us through what are the next steps. When can we start to see more data out of your program?
The next data set out of our program is going to be second half of October. We'll be sharing similar phase 1B data as we had in HFpEF. This is in a group 2 pulmonary hypertension patient population with reduced ejection fraction heart failure. That's ejection fraction less than 40%. Those are typically patients who've had heart attacks and they have this sort of flabby heart muscle that doesn't pump, as opposed to HFpEF or HFmREF. MREF is moderately reduced. That's ejection fraction 40 to 50%. HFpEF greater than 50%. We've been studying 40% and above. Those are typically thick and stiff ventricles that don't relax enough during diastole and therefore can't fill with blood. The HFrEF data comes in just about two months.
Depending on how that looks, I mean, what I gather is that HFpEF is the clear strategic priority, but how important does HFrEF then become?
It doubles the patient population. It remains an unmet need, so it's certainly something that we'll consider. Lilly's study is in both HFrEF and HFpEF. I think our study may put some of that into context. Lilly's study and their data will be important in that regard as well. They're not enriching for the higher PVR patients like we are, but based on what we're seeing right now in enrollment, I think we can anticipate that the majority of their patients will have PVR greater than two.
Okay, understood. You guys have talked about phase 2 data sometime in 2026.
Yeah.
Any more granularity on timing beyond 2026?
We're going to see how we're right now. Recruitment's on track. We're just entering that acceleration phase. I think how we do over the next few months is going to be important.
That is a 24-week study in HFpEF patients?
In group 2 pulmonary hypertension patients with HFpEF, they all have elevated pulmonary artery pressure, and 70% of them will also have a high pulmonary vascular resistance. CP-CPH means combined pre- and post-capillary pulmonary hypertension. The post-capillary component is the heart failure component, backflow of high pressures on the left side of the heart to the pulmonary circulation. The pre-capillary component is similar to PAH, and those are the patients that have the high pulmonary vascular resistance.
Can you talk about the importance of enriching for that CP-CPH pulmonary hypertension population?
Our hypothesis has been that the greatest benefit will be in those patients. A regular heart failure patient, why do they have a decrease in exercise tolerance? They can't get their cardiac output up enough when they exercise, or their wedge pressure goes up when they exercise, and they get leakage, and they get short of breath. In PAH, pre-capillary pulmonary hypertension, why do they have a decrease in exertion? They can't get enough blood into the left side of the heart, and therefore they can't get their cardiac output up enough either because you can't get enough in. One is you can't get enough out. The other is you can't get enough in. In CP-CPH, they have both.
In order to adequately treat them, you want to decrease that pulmonary vascular resistance, open those arteries in the pulmonary circulation so you can get more blood into the left side of the heart. You have to have the left side of the heart be able to handle that blood and increase cardiac output. We think relaxin helps both sides of the equation, so you're taking full advantage of everything that relaxin does.
Have you seen other programs enrich for this CP-CPH? I know Merck, for example, has talked about it a lot with sotatercept and they have some data coming up. I guess it's a two-part question, right? Is other companies that are out there that are talking about this CP-CPH population? Maybe as a follow-up, what do you make of sotatercept? We're getting data either by end of this year, early next year. It's taken a while to get that data set from Merck. Any thoughts into those data?
Yeah, so I mean, it just shows you there's an opportunity that is there. It's a pretty large patient population. We conservatively have sort of said 400,000 to 700,000 patients in the U.S. alone. It might even be bigger based on some more recent epi data. They are enriching for pulmonary vascular resistance greater than four. Anecdotally, we've heard that people have used sotatercept off-label in these patients and have seen evidence of efficacy. How great for patients if it's a successful study. I think it's actually a net positive for us. They'll be about a year, a little bit more ahead of us. It means they can make the market open there because you have to identify the patients and there's no approved therapy, so people don't actively try to identify them now. The other thing is, they've said they're not changing their price point.
They're at a very high price point, I think one that's much larger, much higher than you would have anticipated in CP-CPH. It sets a nice bar there. It is a complicated enough patient population with enough that there's room for multiple mechanisms. I think there's ways for us to differentiate. They've only gone into the ejection fraction greater than 50% of the patients. Our study is in the 40% to 50%, the greater than 40%. That adds about a third more patients that they wouldn't address.
The difference between 40% and 50% is about...
...is about a third more patients. You know, 50% to 60% of the patients in our studies have had atrial fibrillation. Those patients are on anticoagulation. We know that sotatercept has a bleeding risk. I think there may be a preference to use a non-sotatercept mechanism in patients who are on anticoagulation.
Right, right. Okay. I know you touched on enrollment for your phase 2. I know you said you're just starting to see an uptake, or an acceleration, I should say. Anything you can tell us in terms of progress of enrollment or any numbers you can put around it at this point?
I think what I've said is we're over a third enrolled right now.
Are you stratifying so that the two arms are balanced?
We are stratifying for PVR greater than 3. Yes, we definitely are. AstraZeneca is stratifying, I think, based on pulmonary artery pressure greater than 25. To the best of our knowledge, they're not stratifying by PVR.
Okay. As you think about a potential phase 3 design, I know this will be a good problem to have down the road. Any thoughts there? What realistically do you think Merck's path forward may look like in this indication?
Merck's path forward?
Merck, yeah.
Yeah, six-minute walk test is the primary endpoint. I'm going to guess that Merck, because they already have an approval in another form of pulmonary hypertension, probably just has to do one study.
Okay, maybe I'll ask it a different way. Do you think six-minute walk distance is enough for this patient population, or do you think there's a need for some sort of composite around?
I think for regulatory approval, six-minute walk is enough. Okay, I'm sure Merck will be looking at, and as would we, is there a way to have a composite endpoint in there as well? Cardiovascular death, cardiovascular hospitalization, maybe just, you might even be, depending on if they're only doing one study, they probably wouldn't be powered for that. You know, adding in a deterioration in six-minute walk, that's often done as a composite. That's one possibility. If you have a large enough program, you may be able to just look at hospitalization and mortality.
Okay, understood. Maybe just in the last few minutes, I would love to shift gears a bit to PH-ILD. You know, what can you tell us at this point about the phase 2 that you're planning?
Yeah, we're still in planning phase for that. I don't want to get ahead of ourselves. We're just in the sort of final stages of talking about the protocol and interviewing CRO. Once we have a CRO on board and really have a protocol in place and have a better sense of how long, how many sites, how long it's going to take to enroll, we'll get out with more specifics about that. It's a small study. It's 20 patients. Unlike the phase 1B, where we just did a single dose and looked at hemodynamics over eight hours, this is going to be a multiple dose, 16-week study, hemodynamics at baseline and at 16 weeks. Right now, the thought of it is that it's a single arm study, because PVR doesn't go up in these patients.
If we see a 15% to 20% reduction, we can be assured it was a treatment effect. We're still finalizing that protocol. It's about 20 patients.
Where do you think you all could fit into the current commercial landscape? I mean, it has evolved some over the years.
PH-ILD.
There's really only one mechanism, and it's treprostinil. They're inhaled, and the patients hate inhaled therapy. They cough a lot, especially with PH-ILD. We think that it could be the first systemic therapy. I think we're going to start in patients who are on no background meds, but if we see evidence of efficacy there, we'd probably test on top of treprostinil so we could go into the widest number of patients possible.
Would that phase 2 encompass all of that, or phase 2 would likely just be monotherapy?
Right now, let's start with monotherapy, prove there's some efficacy, that the safety is good. One of the things you want to disprove early on is that it doesn't cause what's called a ventilation perfusion mismatch, VQ mismatch. That's what was seen with the systemic prostacyclin, which is why they went to inhaled, but wasn't seen with other PAH drugs. They didn't see a decrease in oxygenation, which gives us some confidence that we could move forward. It's something we're going to want to monitor closely.
Is there any work and presumably preclinical work that you guys have done that would suggest that you could see an additive benefit on top of sotatercept?
We haven't done anything on top of tricostanol yet, but our preclinical work shows we've got good antifibrotic effects and remodeling effects in the pulmonary vasculature, which, you get this muscularization that narrows the lumen of the pulmonary vessels, and that leads to the increase in pulmonary vascular resistance. We've seen remodeling preclinically.
Okay. I know we don't have the phase 2 design just yet, but safe to assume that it could look similar to other phase 2 designs we've seen in the space? Sixteen weeks, you know, PVR, will you measure six-minute walk?
You got it. You know, we'll probably measure it, but it's open label, 20 patients, so I'm not sure you're going to see much of that. It'll be mainly looking at PVR at 16 weeks and safety.
Okay, great. Any closing thoughts? I know it's been a really busy week.
We do have a second program that's about to enter the clinic. We haven't announced what the target is yet because it's a novel target, but we're going into another disease with no approved therapy, hereditary hemorrhagic telangiectasia, which is the second most common genetic bleeding disorder.
Okay, great. We're out of time. We'll wrap up there, but thank you so much.
Thank you.
Really, really appreciate it.