Good morning, everyone. Welcome again to day three of TD Cowen's 45th Annual Healthcare Conference. My name is Tyler Van Buren. I'm a senior biotech analyst here at TD Cowen. For our next session, very excited to have a hybrid presentation and Q&A discussion with Tectonic Therapeutics. And it's my pleasure to introduce Dr. Alise Reicin, President and CEO of Tectonic. Alise, it's a privilege to have you here. Thank you very much for joining me.
Thank you for inviting me.
I'll go ahead and pass it over to you to kick off the presentation.
Perfect. Our standard disclaimer language and getting right into the presentation. For those who do not know, Tectonic, we are leading the way in the discovery and development of biologics for GPCRs, which has been a real challenge in the field. The company was founded in 2019 by Andrew Kruse and Tim Springer, and we went public via reverse merger in June of 2024. We have an unusually experienced and successful leadership team. Between us, we have led teams that have resulted in the approval of over 20 novel drugs, lots of life cycle management approvals as well across a variety of therapeutic areas, which enables us to choose what we think are the highest probability of success targets regardless of the therapeutic area.
The focus today is going to be on our lead program, our long-acting Relaxin program, for which we are now in phase two with very supportive phase one B data that we'll discuss today. Our initial indication is for group two pulmonary hypertension associated with preserved ejection fraction heart failure. I may refer to that. I've got a lot of acronyms in this talk, PH-HFpEF, with an emphasis on a subpopulation that you've probably not heard of unless you've heard my talk before, but I'll describe it, called CpcPH, combined pre- and postcapillary pulmonary hypertension. Our phase one A study in normal healthy volunteers confirmed that we had an active compound that was safe and has the potential also to be a best in class.
The phase one B data, which I'll show you today, I think really increased the probability of success of our phase two study, which is ongoing. We considered multiple indications for TX45, our lead program, including the larger preserved ejection fraction heart failure indication. We chose PH-HFpEF enriching for CpcPH because we think it has the highest probability of success with the greatest benefit for patients because the mechanism of action of Relaxin, as I'll describe later, really matches the pathophysiology of the disease. Furthermore, PH-HFpEF is a large population, over a million patients in the U.S. alone, and there are no approved therapies with a very high unmet need. The five-year mortality is close to 50%. We're not alone. AstraZeneca is exploring both PH-HFpEF and PH-HFrEF. The latter is pulmonary hypertension associated with reduced ejection fraction heart failure.
We actually just expanded our phase one B also into the latter population, PH-HFrEF, which should almost double the patient population. I'm not going to spend a lot of time today on our second program, our TX2100 program, where we're targeting hereditary hemorrhagic telangiectasia, the second most common hereditary bleeding disorder, about 70,000-75,000 patients in the US, and again, no approved therapy. We've demonstrated efficacy in a preclinical model of the disease, and that has shown translation into the clinic historically. We are well capitalized. We just completed a $185 million private placement. In terms of pipeline catalysts and the Relaxin program, we'll have our phase one B data in the PH-HFrEF, the reduced ejection fraction population, second half of this year. Our proof of concept study in PH-HFpEF, preserved ejection fraction, is ongoing. We'll have data in 2026.
We're about to start IND enabling studies for TX2100 and hope to be in the clinic either later this year or early next year with efficacy studies about a year later. Let's talk a little bit about group two pulmonary hypertension for those who don't know a lot about it. It's hypertension in the pulmonary vessels associated with left heart failure, whether it's HFpEF or HFrEF. There are two subtypes: IpcPH, isolated postcapillary pulmonary hypertension. What does that mean? Because of the heart failure, you get elevated pressures on the left side of the heart that backflow into the pulmonary circulation. Their pulmonary circulation is normal. Over time, those elevated pressures on the pulmonary circulation lead to right heart failure, which is often what kills patients. If you have longstanding IpcPH, eventually those patients develop CpcPH, combined pre- and postcapillary pulmonary hypertension.
You have that same postcapillary component, the backflow from the left heart, but in addition, their pulmonary vasculature is not normal. It starts to look like they have group one pulmonary arterial hypertension, where you get a narrowing of the lumen of the pulmonary arteries. As you're trying to send the same amount of blood through a narrowing of the pipe, you get an increase in your pulmonary vascular resistance. That's how you differentiate them from IpcPH. People define that increase as either a pulmonary vascular resistance greater than 2 Wood units or greater than 3 Wood units. You'll see we present data using both. On the left, you've got some of the epidemiology: 4 million patients in the U.S. with HFpEF. 1.4 million have elevated pulmonary pressures and therefore have group two PH.
Of those, depending on how you define CpcPH, you have 700,000 to 1 million with IpcPH and 400,000 to 700,000 with CpcPH. If you add in the HFrEF population, you can almost double that. Relaxin has multiple modes of action. What I am going to describe on this slide is how that addresses the pathophysiology of the disease. First, it is a vasodilator. It is both a pulmonary vasodilator and a systemic vasodilator. In doing that, it decreases afterload. The pressures that the left side of the heart and the right side of the heart have to pump against are brought down by that. In addition, it is an active relaxer of the left ventricle during diastole.
That is really important in HFpEF because the pathophysiology of HFpEF is that you have a thick and stiff left ventricle that does not adequately relax during diastole and therefore does not adequately fill with blood. Relaxin actively relaxes that, fixing the diastolic dysfunction. That might be especially important in the CpcPH population because as Relaxin would decrease the pulmonary vascular resistance, you can send more blood into the left side of the heart. If you are actively relaxing the left side of the heart during diastole, the left side of the heart can take that blood in and then increase stroke volume and increase cardiac output. We also think with long-term use, it acts as an antifibrotic and a remodeler via inhibition of TGF-β.
Our phase 1b study, since it's a short-term study, is really only measuring the vasodilatory and the lucitropic effects, the active relaxation effects of the drug. We do have competition, as I said. We have an Fc- fusion. We have a subQ formulation. Half-life is 14-20 days in normal healthy volunteers. We think that monthly dosing should be adequate, although we're also testing every other week dosing. Our phase 2, as I said, is in PH-HFpEF enriched for CpcPH with pulmonary vascular resistance as the primary endpoint. AZ also has an Fc- fusion. Half-life in normal healthy volunteers is shorter, seven to nine days. All of their dosing is every other week. They're going into both, as I said, HFpEF and HFrEF with PVR as the primary endpoint.
They also have a small molecule indication that they're going into a broader heart failure indication. I'm going to show you data today from our phase one B study in PH-HFpEF patients. It's an interim, the first and only interim analysis we did. It's based on we've completed dosing in all 19 patients. The data I'm going to show you today is in 16 of those 19 patients. We've seen data on the last three, and I can tell you it's highly consistent. We'll be presenting the final data set at a medical conference later this year. Patients got admitted to the unit. They had a right heart cath put in. You put it into the right ventricle, and you go into the pulmonary circulation. We had measurements, two of them at baseline. We averaged those for the baseline measurements.
They got a dose of drug. We measured hemodynamics again over the next eight hours and averaged the measurements during that time for the change from baseline. In terms of baseline hemodynamics, they are consistent with the patient population that we were enrolling, PH-HFpEF. Therefore, you had patients who had elevated pulmonary artery pressures and also elevated pulmonary capillary wedge pressure. Many of these patients have hypertension. I can tell you they were treated with standard of care medicines for their heart failure. Depending on how you define CpcPH, if it is PVR greater than 3, then we had 11 patients with IpcPH and 5 with CpcPH. If it was PVR greater than 2, then it is 7 with IpcPH and 9 with CpcPH. The data met or exceeded our goals.
We said what we wanted for a drug to work in group two pulmonary hypertension. It's got to both improve left heart function and improve the pulmonary hemodynamics, including in CpcPH patients, the pulmonary vascular resistance. We've clearly demonstrated that here. What I'm showing you in the middle column is change from absolute change from baseline. On the right, the average % change in the parentheses are the 95% confidence intervals. Just to remind you, if the 95% confidence intervals exclude zero, that means it would have had a p-value of less than 0.05. I can tell you the zero was excluded. These all have a nominal p-value that would be statistically significant. The first row, pulmonary capillary wedge pressure in all participants. Pulmonary capillary wedge pressure is the gold standard for measuring left heart function.
It goes up when your heart failure gets worse. When you diurese and give patients drugs to treat their heart failure, it goes down. We saw an 18% decrease in that. We pre-identified that we wanted to see a 15%-20% decrease in PVR, pulmonary vascular resistance, in patients with high PVRs. That is the CpcPH population because we did not think you would see much in the IpcPH population. You can see we saw a pretty dramatic 32%-35% decrease. We also were really encouraged that even at rest, we saw an increase in cardiac output of about 18%. That was driven by an increase in stroke volume, not heart rate, which is exactly what you want to see. We also saw in the overall population a decrease in what is called TPR, total pulmonary resistance, of about 26%.
This is the pressure that the right side of the heart is seeing over time, which causes it to fail. That was really another important measurement. Lastly, pulmonary hypertension is defined by elevated pulmonary artery pressures. We decreased pulmonary artery pressures as well. This slide, we're just looking at effects both in the overall population in white and in the CPC population in blue and orange. You can see the wedge pressure we saw in all the subpopulations overall and in the CPC, IPC as well. PVR, on the other hand, in the overall population, the reduction was only about 12% because we really didn't see any effect in the IpcPH populations who had normal PVR at baseline. That's what we anticipated. There is something intriguing about cardiac output.
There was a numeric trend for cardiac output to get higher as the baseline PVR got higher. That could just have been a statistical slew. The 95% confidence intervals were overlapping. It is intriguing. Something we will look for in our phase two study because this may be another evidence that the drug is likely to have its greatest benefit in patients with CpcPH. Drug was well tolerated. There were no SAEs, severe AEs, drug-related AEs, immune-mediated events. The most common AE was fatigue, which was in four patients. They all occurred at the end of day one when patients had been in the unit for a very long period of time. They were considered more procedure-related, I am putting that in quotes, than drug-related. They had resolved within three hours when drug levels were still high. There was no evidence.
We heard one person ask if they were associated with drops in blood pressure, and they were not. We did see transient mild drops in blood pressure on day one. On target, we expected this. We saw this preclinically of about 5-10 millimeters. It's really not drug. It's not you can go up to very high concentrations, and it maxes out at about 10 millimeters of mercury. It's basically resolved by the later visits. Six-minute walk test is the approvable endpoint. What everybody wants to know is, are there any data that ties the hemodynamic effects that you've seen to six-minute walk test? The reality is, because there hasn't been that much drug development in this field, there's very limited data.
What we do know is decreasing wedge pressure in these patients alone is expected to improve exercise capacity to some extent because pulmonary capillary wedge pressure at rest is the one hemodynamic measure that does correlate with six-minute walk test. We know that the SGLT-2 in one study decreased pulmonary capillary wedge pressure by about 20%. In another study, that was associated with about a 20-meter increase in six-minute walk test, which our KOLs tell us is clinically significant in this population. Based on our understanding of exercise physiology in patients with CpcPH, exercise is limited both by their left heart function and their wedge pressure, but also by their PVR because of the high PVR. When you exercise, you just can't get enough blood through the pulmonary circulation into the left side of the heart.
Therefore, in CpcPH patients, it appears that decreasing both the wedge pressure and the PVR sort of leads to added benefits. The data consistent with that comes from one study, which was done in pulmonary artery denervation, an experimental surgery where a 20% decrease in wedge pressure and a 30% decrease in PVR led to almost a 70-meter increase in six-minute walk. I do not think that is what we are going to get in our program. This was a very high PVR CpcPH population. It gives us some evidence that if you address both of those, the benefit will be even greater. TX45 is well tolerated. We showed evidence that it works both to improve left heart function as well as pulmonary hemodynamics. I think the data also support that we have enriched for CpcPH. Phase two design, real quickly, right heart cath at baseline.
Patients get randomized to either 300 Q2 or 300 Q4 week of TX45 or placebo. Hemodynamics at the end. Change in PVR is the primary endpoint. Of course, we'll be looking at wedge pressure, cardiac output, and importantly, six-minute walk test as well. I'll wrap it up so we have some time with Tyler for Q&A. Tectonic, basically, we have two pipeline candidates, both addressing very high unmet need populations with no approved therapy and very significant market potential. We have a steady cadence of inflection points in 2025 and 2026. We have a really well-experienced leadership team who have shown we can execute and will execute, hopefully, in the future as well. Thank you.
Okay. Great. Thanks very much for that presentation, Alise.
As you noted, TX45 reported stellar data in the phase 1 B recently, the first kind of real meaningful clinical data set to come out for this class of drugs. Just going to follow up on some questions that we've gotten from investors. What gives you confidence that TX45 is differentiated from, say, systemic vasodilators that have been tested previously in HFpEF?
I think there's a few things. First of all, and I'll start and I'll end with it, we think it's more than just a vasodilator. Even within vasodilators, all vasodilators are not created equal. You've got some that preferentially dilate the pulmonary circulation. If they do that to an extent that's far greater than the systemic circulation, you will end up sending more blood into the left side of the heart, and you will make their heart failure worse. Okay?
Those are vasodilators as well, but they actually make heart failure worse. Then you have other very potent systemic vasodilators, which can increase cardiac output. You bring down the systemic vascular resistance. It will bring down cardiac output. It will bring down the wedge pressure. It can bring down, if it is that potent, even some pulmonary pressure. Very typically, the blood pressures drop. You cannot use those chronically in patients. You can use them when they are at bedrest, maybe, but they are not sent out. My comment to that is show me another vasodilator that works exactly like this where patients' blood pressures are maintained because most, and here, as I said, you cap that first day, 10 millimeters is the most. Most of the vasodilators, you keep increasing the dose, and your blood pressure goes even lower.
To say it's just a vasodilator, they come in all flavors. There's something, there's a little bit of a Goldilocks approach. Then you add on the fact that we think there's the lucitropic effects in HFpEF where that would be important, the active relaxation and the antifibrotic effects. That becomes even more promising as well. In fact, there was just an AZ study that was published this week looking at their long-acting relaxin in a monkey model of HFrEF. You could see the cardiac output, ejection fraction, stroke volume got better and better and better over three or four months. That's not a vasodilatory effect. I think that's evidence of the remodeling effects. How long do you think it might take to see potential antifibrotic effects? You know, we don't know.
I can tell you sotatercept, which also works via inhibition of the TGF-β pathway and people really believe has antifibrotic effects in the pulmonary circulation, weeks they start to see some improvement in six-minute walk test, I think earlier than people thought. I think it probably takes a few months. Certainly, it gets better over time. Again, the magnitude of improvement on wedge pressure, PVR, and all the other endpoints was far exceeded expectations. However, it was an eight-hour time point, right? What gives you confidence that this effect will be durable based upon everything you know about TX45 and the data you've generated today? There are multiple data sets that give me reassurance until we get our phase two data. The first is pregnancy. What does relaxin do during pregnancy? It acts as a vasodilator.
It increases cardiac output so that the pregnant mom can increase cardiac output to accommodate the growing fetus. Pregnancy, I was pregnant three times. It was about nine months, not eight hours. That gives me confidence this is a sustained effect. Number two, both us and Lilly looked at renal blood flow in our phase one study, which is one of the effects of relaxin. You get an increase in renal blood flow. That was maintained out to a month. Actually, this AZ study is quite encouraging as well. In a monkey model of heart failure, if anything, over six months, you saw the effects improve. Now we've got to do the phase two study to prove that that's the case in PH- HFpEF as well.
Great. Lilly discontinued their program recently, which caught people's attention. Can you elaborate on the differentiation with TX45 between your program and Lilly and Astra and how we should think about that?
It is Lilly. Different molecule, different indication, different endpoints. I am going to put the different molecule at the bottom because they did what we did in phase one. They did renal blood flow. They have an active molecule. There may be some differences that I could articulate about ability to penetrate tissue. I really am going to put that at the bottom of the list. Different patient population. They went into broad HFpEF. In order to get enrolled in their study, you had to have recently been discharged from the hospital for acute heart failure. We have heard from physicians that was a really sick patient population.
Number one, these are patients who probably were not stable at baseline or might not have been stable at baseline. It is really hard to see a change from baseline if you do not have a stable baseline. I can tell you for our phase two, we want patients to be euvolemic because I do not want changes in fluid status to interfere with our ability to measure this. Get them optimized and then start treating them. That is the first thing. The other is they are in a broad HFpEF population. I told you we considered HFpEF. Because of the multimodal action, we really think the greatest benefit is going to be in the PH-HFpEF patients.
Our bet is even in the CpcPH patients because bringing both improving left heart function and bringing the pressures down, the pulmonary vascular resistance down, we just think you're going to get a greater benefit. There would have been very few of those patients in that study. They did not do right heart cath, so they could not even find those patients. The endpoints—they did echo. It is a really, really tough endpoint for a multicenter study. They used a novel endpoint called left atrial strain. It has been shown to be very good for a personal prognosis. The only multicenter study we found, it was used in patients that had mitral valve repair. Their heart failure got better. Their left atrial strain did not. I think they have an active drug. I really believe we have chosen a better patient population.
Having right heart cath is the gold standard.
Okay. Very helpful. Multiple things to consider there. You were very nice by putting the difference in the molecules at the bottom. I just have to follow up on that. Is there any difference in potency between your molecules? What have you observed?
Yeah. All relaxins have something called a high isoelectric point. They're highly positively charged. What happens with biologics and proteins that are highly positively charged is they get bound to negatively charged heparin sulfates lining the blood vessels. There's less free drug to penetrate the tissues. There's a theoretical long because I think you can get over that with very high doses. I do think we lowered our isoelectric point. None of our competitors did.
I think that's why we have the longest half-life because you're not losing the drug acutely as much. There's a theoretical argument that you might get better tissue penetration and therefore maybe better antifibrotic effects. I don't have data to support that. That's not my base case. There are differences there that could theoretically have an impact. Is potency the same between the two? That's the difficult thing. What we found with high PI compounds is in vitro potency is disconnected from in vivo potency. Whereas when we lowered our isoelectric point, the in vivo and in vitro potency match identically. It's hard for me to tell you. When we have tested a high PI compound to a low PI compound, what we found is in vitro, the high PI compound looked 10 times more potent.
In vivo, it looked 10 times less potent. We haven't done it versus the clinical compounds that they have.
Fair enough. Acceleron back in the day sold for a very high number. Sotatercept consensus estimates, I believe, last I checked, are $8 billion ± $1 billion or so. In terms of this market opportunity, group two PH- HFpEF relative to PAH, can you just elaborate on the magnitude?
Oh my gosh, yeah. PAH 25,000-50,000 patients in the U.S. I don't know, 12 marketed drugs, I think four different mechanisms. Yet, sotatercept, they think, is going to be an $8 billion drug. Here, even if let's just assume we're just in CpcPH because that's possible, 400,000-700,000 patients just in HFpEF and then almost double that if you have HFrEF. That's just in the U.S.
These are much larger indications.
I want to end with HFrEF since we're going to get data there later this year. What's the expectation? You all have helped me create a couple of great analogies or you provided them, rather. I'll help everyone in the audience who doesn't remember the difference between HFPEF and HFrEF. HFPEF is that stiff balloon. You're relaxing it with a relaxin agonist. HFrEF is a saggy bag. Why do you need to relax a saggy bag? Help us understand what expectations should be.
HFrEF, the saggy bag, right, it's basically typically in patients who've had multiple heart attacks. You have a really weak muscle. I don't think the relaxing effect, the lucitropic effect, is going to be important in those patients. Decreasing the systemic vascular resistance, the HFrEF patients are much more sensitive to that.
Think about it. You're trying to push a really heavy piece of furniture over a thick shag rug, right? It's really hard. There's a lot of resistance. You're weak. You can barely push it. You now take that same piece of furniture and you put it on a shiny floor. Even someone who's weak can very easily push it without the resistance. That's similar to what if you decrease the systemic vascular resistance, you decrease that afterload, the heart can pump out much easier.
Great. We're over time. Maybe I'll just end by asking you what you believe is the most underappreciated aspect of the Tectonic story by investors right now.
I don't think people know enough about what's coming next in our pipeline. We really have a platform that enables us to go after GPCRs. GPCRs, a third of all drugs target them.
There are only 10% that have been targeted. I think there's a whole variety of mechanisms that we can now go after that have been very difficult to drug in the past. There is a lot more that could come in the pipeline from that.
Wonderful. Alise, thank you very much.