Good day and welcome to the TX45 Phase I-B Part B PH-FrEF Data Conference Call. After the speaker's presentation, there will be a question and answer session. To ask a question, please press star one one. If your question has been answered and you would like to move yourself from the queue, please press star one one again. As a reminder, this call may be recorded. I would now like to turn the call over to Dr. Alise Reicin. Please go ahead. Thank you. Good afternoon and thank you for joining us. Today we'll be reviewing the top-line results from Part B of our phase I-B clinical trial, which evaluated the safety and hemodynamic effects associated with a single dose of TX45 in patients with pulmonary hypertension associated with reduced ejection fraction heart failure, and we'll be referring to this as PH-FrEF. Next slide, please. Attached is our disclaimer information regarding forward-looking statements that will be made today. Next slide. This 14-patient clinical trial was designed to evaluate the safety and tolerability of TX45 in patients with PH-FrEF and to explore the hemodynamic effects of TX45 in this patient population. I've been asked several times over the last few months, "What do I hope to see in this trial?" The goal was to observe hemodynamic effects that were directionally similar to what was seen in Part A of this clinical trial in patients with PH-FpEF with evidence of improvement in both left heart function and pulmonary hemodynamics. I can say unequivocally that the results met that goal. Similar to what we saw in PH-FpEF patients in Part A, TX45 was well tolerated and demonstrated improvements in all hemodynamic measurements that we evaluated. The data from Part B of this trial support further clinical investigation of TX45 in PH-FrEF patients pending data from our ongoing APEX phase II clinical trial in PH-FpEF patients. As a reminder, APEX is a 24-week clinical trial to evaluate the safety and efficacy of TX45 in PH-FpEF. This study is highly enriched for Cpc patients with a PVR greater than or equal to 3 WU. In fact, we're aiming that 70% of the population have a PVR greater than 3. The primary endpoint of mean change from baseline in PVR in this PVR greater than 3 population is the primary endpoint. Six-minute walk distance will be a secondary endpoint. With that, I'm going to now turn the presentation over to Marcie Ruddy, Tectonic's Chief Medical Officer, who would describe the rationale for us doing Part B of the clinical trial as well as the results. Thanks, Alise. Next slide. What was the rationale for exploring TX45 in PH-FrEF patients? First, TX45 is a long-acting relaxant. This mechanism appears ideal to address the disease pathology in both types of heart failure associated with pulmonary hypertension, given its vasodilatory, lusotropic, antifibrotic, and reverse remodeling effects. Second, we were encouraged to explore TX45 in PH-FrEF after we saw that meaningful hemodynamic improvements in PH-FpEF were consistent with what would be expected from the relaxant mechanism. Similar to PH-FpEF, there is a significant need for new treatments for these patients. In both types of heart failure, patients have worse exercise capacity and increased mortality if they develop pulmonary hypertension compared to those who do not. This is especially true for those with combined pre- and post-capillary pulmonary hypertension, or CpcPH, and a pulmonary vascular resistance, or PVR, greater than or equal to 3 WU. Lastly, expansion into PH-FpEF represents a significant potential market expansion. There are approximately 1.1 million people in the U.S. with this condition, of which approximately 300,000 have CpcPH with a PVR greater than or equal to 3. Next slide, please. Although the left ventricular pathology for these two types of heart failure is different, the development of pulmonary hypertension and its consequences are similar. PH-FrEF is defined by an ejection fraction less than or equal to 40%. It is most commonly due to myocardial wall infarction, often referred to as a heart attack. This results in a dilated, weakened ventricle with a decreased ability to pump blood during systole. In contrast, in PH-FpEF, the ejection fraction is normal or near normal. It is typically seen in patients with a history of significant hypertension, diabetes, and/or obesity. These patients have a thickened, less distensible left ventricle, which has difficulty relaxing for maximal filling during diastole. In both forms of pulmonary hypertension, the impaired function of the left ventricle leads to elevated left atrial filling pressures, which is manifested as elevated pulmonary capillary wedge pressure. In some patients, these elevated pressures backflow into the pulmonary circulation, leading to elevated pulmonary artery pressures that is then pulmonary hypertension. As this condition persists, patients develop elevations in pulmonary vascular resistance, or CpcPH. They develop decreased cardiac output, particularly with exercise, and then eventually can develop right heart failure. Next slide. The trial design of Part B was similar to Part A. Patients with PH-FrEF were screened by history and echocardiogram to meet our entry criteria, and then they were admitted to the trial. The day one procedures are outlined in the center of this slide. After a right heart cath was inserted, baseline hemodynamics were obtained. Patients were then given an IV infusion of TX45. The TX45 doses administered are described in the top blue box in the schematic. To assess the tolerability of TX45 in this population, the first patient received a 0.3 mg/kg dose, the second 1 mg/kg. The rest of the cohort was dosed at 3 mg/kg, a dose that was expected to have an efficacious trough exposure through day 29 post-dose. Hemodynamic measurements were then obtained repeatedly over the next 8 hours post-infusion, and results were pooled and compared with baseline measurements. Next slide, please. To orient you to some of the hemodynamic measures we will be discussing, I have a short primer here on this slide for your reference. I've already talked about pulmonary capillary wedge pressure as a measure of left atrial pressure, and this is a key marker of the pressures on the left side of the heart. PVR, or pulmonary vascular resistance, measures the resistance to blood flow in the pulmonary arteries. This is a calculated measurement that subtracts the pulmonary capillary wedge pressure from the mean pulmonary artery pressure divided by cardiac output. Total pulmonary resistance, or TPR, measures the afterload that the right ventricle needs to pump against. Elevated right ventricular afterload has been linked to poor outcomes in patients with pulmonary hypertension, especially including Group 2 PH. Cardiac output is the amount of blood that the heart pumps over time, and stroke volume is the amount of blood ejected from the ventricle per beat. Next slide, please. In this trial, the baseline characteristics and concomitant medications were consistent with a PH-FrEF population enriched for CpcPH. Patients had an average left ventricular ejection fraction of 34% and elevated NT-proBNP of over 3,000 pg/mL. The patients had expected comorbidities of hypertension, atrial fibrillation, and coronary artery disease. 57% of these patients had New York Heart Association Class III. These patients have symptoms with minimal exertion. Only two patients in Part B had a PVR less than 2 WU, five had a PVR between 2 and 3 WU, and seven had a PVR greater than or equal to 3. Patients were well treated for their heart failure. This is reflected in the high percentage of patients on each key category of HFrEF standard of care. Next slide, please. The baseline hemodynamics were also consistent with the diagnosis of PH-FrEF. Mean baseline pulmonary capillary wedge pressure was elevated at 31 mm Hg. The PVR of 3.26 WU is consistent with the majority of this cohort having CpcPH. The total pulmonary resistance, a measure of right ventricular afterload, was elevated, as was the mean pulmonary artery pressure. Notably, the right atrial pressure was also increased, suggesting that these patients also had elevations in right ventricular preload. Next slide, please. In this clinical trial, TX45 was well tolerated. There were no serious or severe adverse events, discontinuations, infusion-related, or drug-related adverse events. The only treatment emergent adverse event was mild to moderate procedure-related back pain, which resolved after completion of the right heart catheterization procedure. There were no clinically significant changes in vital signs, ECG, or lab values. In some patients, we observed transient asymptomatic decreases in systolic blood pressure of approximately 5 mm Hg- 10 mm Hg over the first 24 hours. We saw a similar effect in Part A, and this has also been previously reported for the relaxant mechanism. There were no signs or symptoms of congestion or worsening heart failure, and there were no TEAEs of fatigue. Next slide, please. In this trial, TX45 resulted in improved left heart function and pulmonary hemodynamics. This slide represents the data as the mean change and the mean percent change from baseline, along with 95% confidence intervals. The values highlighted in green are those values for which the confidence intervals do not include zero, meaning changes are consistent with a nominal p-value of less than 0.05. Notably, the wedge pressure in this population decreased by greater than 6 mm Hg, which translated into an impressive 29% decrease from baseline. Many studies have shown that lowering wedge pressure alone improves exercise capacity in both patients with heart failure as well as heart failure associated with pulmonary hypertension. There was a meaningful, approximately 20% reduction in PVR in the PVR greater than or equal to 3 WU population. In a previous hemodynamic study in patients with PH-FrEF treated with sildenafil, a 20% reduction in PVR was associated with a 29-meter increase in 6-minute walk. In the PVR greater than 2 population, the mean percent reduction was 10.3%. As footnoted in the slide, the lower percent change from baseline in this subgroup was driven by one outlier, as evidenced by the difference between the mean percent change of - 10.3% and the median percent change of - 18.3%. For the other hemodynamic measures, there was less variability, and the mean and median assessments were similar. Importantly, we observed an increase in cardiac output of approximately 17%, and there was a marked decrease of approximately 29% in total pulmonary resistance, consistent with a meaningful effect in right ventricular afterload reduction. We were encouraged by this because, as I just mentioned, elevated right ventricular afterload is associated with increased mortality and poor outcomes. The mean pulmonary artery pressure decreased by 19%, and the right atrial pressure decreased by 29%, suggesting an important reduction in right ventricular preload. Taken together, the concordance of these hemodynamic effects suggests that TX45 meaningfully improves left ventricular function and pulmonary hemodynamics, both of which are necessary for an effective treatment in PH-FrEF. Next slide. We included echo assessments in this trial to capture persistent effects of the single dose of TX45 out to day 29 post-dose. We did this because the constraints of our clinical trial design did not allow us to conduct a second right heart catheterization at that time point. These data demonstrate sustained improvement in markers of left ventricular function, pulmonary hemodynamics, and right ventricular function. In the first panel on the left side, the echocardiographic data demonstrated change from baseline in left ventricular ejection fraction from 34% at baseline to 40.3% at day 29, representing an improvement in LVEF of approximately 19%. The middle panel demonstrates the improvement in TAPSE/ SPAP. This is an echo measure that is considered an inversely correlated surrogate for PVR, meaning that if PVR is reduced, we would expect to see TAPSE/SP AP increase. We observed a change from baseline from 0.3 to 0.4, representing an increase of approximately 36% at day 29. This finding provides further confidence that TX45 had a meaningful effect in PVR in this population. In the far right panel, the treatment with TX45 increased right ventricular fractional area of change, a measure of right ventricular ejection fraction. We saw a change from 29% at baseline to 35% at day 29. This change represents an improvement of approximately 20%. These echo data are very encouraging, as they suggest that the hemodynamic improvements seen on day 1, as measured by right heart cath, are persistent through day 29 after a single dose of TX45. Next slide. In summary, these data met our goals. Our Part B data presented today again demonstrate that single doses of TX45 are well tolerated. TX45 demonstrated hemodynamic improvements in both left heart function and in the pulmonary vasculature in PH-FrEF. This is noted by improvements in pulmonary capillary wedge pressure, cardiac output, and left ventricular ejection fraction by echo, which demonstrate the improvement in left heart function and reductions in pulmonary vascular resistance, total pulmonary resistance, and mean pulmonary artery pressure, along with the increase in TAPSE/ SPAP by echo, which demonstrates improved pulmonary hemodynamics. The echocardiographic data suggest persistence of the TX45 effects out to 29 days post-dose. These data are consistent with what we observed in our PH-FpEF cohort in Part A. We are always asked about how these data would translate into changes in 6-minute walk distance. It is difficult to give an exact answer to this question, as there have been no approved therapies for pulmonary hypertension associated with heart failure. However, the magnitude of the reduction in wedge pressure and PVR demonstrated in our PH-FpEF and FrEF cohorts have been associated with meaningful changes in exercise tolerance in previous clinical trials in the PH heart failure population. TX45 demonstrated improvements in total pulmonary resistance, a measure of right ventricular afterload. Reductions in right ventricular afterload have been shown to be associated with improved outcomes and a reduction in mortality in patients with pulmonary hypertension due to left heart failure. We are encouraged by these data in PH-FrEF, and we believe they support further clinical investigation in this population pending results from our ongoing 24-week APEX phase II trial in PH-FpEF. I will now hand it back to Alise. Next slide. Thank you, Marcie. Before we turn to Q&A, I'm going to end with just a few company updates. With regard to the APEX study, the study is now just over 50% enrolled, and to date, there have been no safety signals of concern. We've completed the recruitment of patients with PVR of less than 3, and we're now limiting recruitment to patients with a PVR of greater than or equal to 3 WU to enrich the trial for this patient population. By the end of the first quarter of 2026, we plan to update and narrow guidance for the top-line readout of the APEX phase II trial, which is currently guided for 2026. As we look to 2026 for the TX45 program, we will also be initiating a study to evaluate TX45 in pulmonary hypertension associated with interstitial lung disease, PH ILD, with the potential to further broaden the patient population for TX45. Our second program, which is targeting the treatment of patients with hereditary hemorrhagic telangiectasia, remains on track to enter the clinic in the first quarter of 2026. We're really excited to be exploring the potential of TX2100 in this patient population with a high unmet need and no approved therapies. Financially, the company is sound with a runway into the fourth quarter of 2028. I'd like to conclude just by thanking you for your time today. Operator, we're now prepared to open the line for questions. Please go ahead. Thank you. Our first question comes from Tyler Van Buren with TD Securities. Your line is open. Hi, this is Frances on for Tyler. Congratulations on the data. It's great to see the consistency of the effects across the two populations. I'm just curious, what in the phase II APEX trial would make you feel confident moving forward in later stage trials for PH-FrEF? I think if we see evidence of good efficacy and safety, that would certainly give us confidence to move forward in HFrEF as well. I think we'll be looking for evidence of reductions on pulmonary vascular resistance, increased cardiac output. While we're not powered fully for a 6-minute walk test, we're going to be looking for strong numeric trends there. Thank you. Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Good afternoon, team. Congrats on the great data. Would love to understand sort of when we think about the hemodynamic and responses in the HFrEF population, how that could translate sort of prediction on a 6-minute walk test or a functional improvement in the population. You guys have done a really nice job educating us on hemodynamic correlations to the HFpEF population. I appreciate color on how do we take this really strong data from Part B to think about APEX. I'll jump back in the queue. Yeah, we think that it's similar in that what you want to see is a reduction in the pulmonary capillary wedge pressure, a reduction in the PVR that also leads to an increase in cardiac output. If you look at the studies that have been done, there was a surgical technique, PAN, that was associated with about a 20% decrease in wedge and a 30% decrease in PVR. That led to almost a 70-meter increase in 6-minute walk. That's a high bar. I don't think that's the bar we're aiming for. That was in a very, very high PVR population, but it gives you a sense of, and that study was done both in HFpEF and in HFrEF. There was a PH-FpEF, CpcPH population. There was a study by Lewis in 2007 done with sildenafil in PH-FrEF. In that study, they saw a 20% improvement in PVR, an increase in cardiac output. Wedge actually didn't go down that much. In that study, they saw a 30-meter increase in 6-minute walk. I think the data that we've seen both in HFpEF and HFrEF suggests that if maintained over the six-month period, we should see clinically important improvements in 6-minute walk. Thank you so much, Alise. Thank you. Our next question comes from David Risinger with Leerink Partners. Your line is open. Yes, thanks very much. Congrats, Alise and team, on today's results and on the strong progress in enrollment in APEX. Could you comment on the lack of fatigue in Part B relative to Part A that was seen? Also, just discuss that patient outlier in a little bit more detail that drove the difference between the mean and median hemodynamic results. Thanks very much. Yeah, yeah, we didn't see any fatigue-related AEs. As Marcie said, the only AE we saw was procedural back pain, and the patients felt better when they got up off the table. In Part A, we saw fatigue only at the high dose, which we think was by chance, and only at the end of day one. When they came in on day two, they no longer had fatigue. Nobody thought that that was related to drug. I think we heard there were some people talking about wondering whether the fatigue was a result of a lowering in blood pressure. We never saw a correlation there. I think the fact that we didn't see it here just speaks to the fact that it was related to the time in the cath lab more than anything else. You asked about the one outlier. The issue when you do small numbers of patients is you can have one outlier that really impacts the mean. What we saw was a difference in the mean and the median, as Marcie outlined, with the median more aligned with what you would have expected to see. That patient had a very, very large drop in pulmonary capillary wedge pressure that was larger than their drop in pulmonary artery pressure, which meant that their PVR went up. They started with a not very high PVR, so the percent change ended up being quite large. When you do percent change from baseline, you don't take the absolute value of the mean and figure out the percent change. Instead, for every single patient, you figure out their percent change, and then you take an average of those. In the percent change in PVR, that one patient had sort of an outsized effect. Got it. Thank you very much. Thank you. Thank you. Our next question comes from Uy Ear with Mizuho. Your line is open. Hey, guys. Yeah, congrats on the great data. Thanks for taking our question. Alise, I think you indicated that you've met with the Data Safety Monitoring Board, and that they've given you pretty much a clean bill of health. Just wondering if you could elaborate that a little more as to when was the Data Safety Monitoring Board, when did they meet, and were they sort of aware of the Lilly phase II publications? If there's anything else that can be shared, that would be great. Thanks. Yeah, I'm going to have Marcie take that. We met with the DSMB after the volume relaxant data was released, and we told them about it. We specifically asked them to look at the unblinded data to see if they saw anything of concern. There was nothing in our blinded data to suggest any issues. Their examination of the unblinded data in mid-September suggested that there were no issues, and they told us to continue the study without any alterations. Were there any hospitalizations, anything to that effect? We've had one. We've now had two patients hospitalized for heart failure. Remember, these are patients with heart failure, and there's an expected rate of heart failure hospitalizations, actually, even in the placebo group in this trial. The rate we have now is completely expected. All right. Thank you. Thank you. Our next question comes from Cory Jubinville with LifeSci Capital. Your line is open. Thanks for taking our questions and congrats on this really exciting data. I guess just building off the previous question, we saw with the volume relaxant data presented at ESC last month that they saw a significant increase in plasma volume as early as three weeks post-treatment, which is what they thought contributed to some of the adverse outcomes. You pretty encouragingly reported no signs or symptoms of congestion. Can you just quantify the magnitude of change in plasma volume, if any, you observed following the treatment period? Similar to the DSMB update in APEX, is there any signs or any signs of congestion at all in those patients? There were no AEs suggested of congestion. If you looked at hemoglobin and hematocrit, which is how you get at plasma volume, there was nothing suggested that we saw an increase in congestion. Very good. Just as a quick follow-up, can you help us contextualize the clinical significance of some of these echo parameters? Specifically, if my math is right, you're bringing the average ejection fraction above 40% and out of that HFrEF range in these HFrEF patients, essentially changing some of these patients' classification from HFrEF to heart failure with mildly reduced ejection fraction. Is that meaningful at all, or is that predictive of potential cardiac remodeling or outcomes that might occur down the line? How should we take it? Yeah, I'll see if Marcie knows of data. I'm not aware of data, probably because there aren't too many drugs that do that, that link an increase in ejection fraction to outcome. I'd have to go back to look at the literature. I think it's positive. You know, it reminded me of the monkey study done by AZ in a monkey model of reduced ejection fraction heart failure, where over five months, over that five-month period, you saw the ejection fraction continue to go up over five months. In our study, even over the day 2 to day 15 to day 29, we saw it go up. It sort of raises the question of what we, you know, are we seeing a remodeling effect? Why is it taking time to go up over time? It's interesting. Very helpful. Thank you. Thank you. Our next question comes from Danielle Brill with Truist. Your line is open. Hey, guys. This is Alex from Danielle. Thanks for taking the question and congrats on the data. I'm just going to zoom out a little bit and ask a more philosophical question about your dosing. Can you just remind us where you are in the dose range as it pertains to relaxant receptor agonism and additionally how your strategy compares to the current AZ approach and the prior Eli Lilly trial in heart failure? Our 300-Q2 dose at trough levels, we should be probably between 90% and 95% of agonizing the receptor. At our 300-Q4 dose at trough, we're probably somewhere between 75% and 80% at trough exposure. The volume relaxant study, their lowest dose was already above, we think, 95% agonism. The other doses were on top of that. We really think they were at the upper edge of the dose range. That may have had an impact on their study. The one endpoint, and I don't want to make too much of this because I've heard two competing views of this. At the lowest dose, they did see a significant improvement in left atrial strain, and then you lost that at the higher doses. Some people have said that they think that could signify that a little bit of a lower dose was better. I don't know whether to make too much out of that. AZ is probably testing the widest dose range. We think their top dose is similar to our 300-Q2 dose, and their middle dose is probably more similar, maybe a little bit lower than our 300-Q4. Their lowest dose, we don't even think gets to an EC50. Great, thanks so much for the color. Thank you. Our next question comes from Martin Auster with Raymond James. Your line is open. Thanks for taking my question and congrats on the favorable, consistent hemodynamic effects shown today. I at least appreciated the clarity on the APEX phase II enrollment and the disclosure on targeting 70% CpcPH patients. I was wondering if you could comment on if that's sort of been the consistent plan throughout. I know previously you just said it was going to be sort of generously enriched. Curious if that's sort of evolved or that's always been sort of the team's thinking internally. Also, just wanted to check in on, you know, now that you've probably got most or all of the sites up and running, in terms of screening failures and kind of finding eligible CpcPH patients, does that do anything to adjust the rate of enrollment going forward? Are you still pretty confident that you can, you know, sort of benefit with all the sites up and running now? Thanks. Yeah. It's been 70% since we wrote the original protocol. There were no changes there. I don't know why I was being coy about sharing that data. I finally said, you know, we might as well share it. There were no changes there. We're seeing about 45% of when we were doing all comers, about 45% had PVR greater than 3. I don't know, 70%- 80% had PVR greater than 2. I think those were actually a little higher than we thought. I think we'll have a better sense. We want to give it a few months with just enrolling the PVR greater than 3 until I can give you more clarity on timing for ending the study. That's why I said by the end of first quarter of 2026, we'll be ready to narrow the guidance there. That sounds great. Thank you. Thank you. Our last question comes from Leland Gershell with Oppenheimer. Your line is open. Oh, great. Thanks for squeezing me in. Congrats on these terrific data. Again, reiterate the consistency with the Part A data set. Just wondering, with respect to the PVR, we saw it was a wider confidence interval for those measures in the HFrEF versus HFpEF. Just wondering if that is incidental to this part of the study or if it may be a function of the different nature of the heart failure. Part 2 of my question, which I guess relates to that, is as you look to contemplate next steps in development for HFrEF, it sounds like we won't see that until the APEX data are in hand. Taking should we presume that you take TX45 forward for HFrEF, would you look to conduct a phase II, a similar design with respect to PVR being primary endpoint and 6-minute walk secondary, or how might it differ with respect to endpoints? Thank you. Yeah. We saw a little bit more variability on PVR than we did in the first cohort, not completely unexpected. I don't know that I can say that's because it's HFrEF versus HFpEF. We'll just need to study more patient numbers in order to get an idea of that. With regard to the latter, I think it's premature for us to say how we would move forward. We wouldn't necessarily have to do a standalone phase II. We could potentially go to a phase II-III. We'd have to get alignment with regulators on that. I think there's a variety of ways that we could incorporate HFrEF into the program without delaying it too much. Terrific. Thanks for taking our questions. Thank you for your participation. This concludes the question and answer session, and you may now disconnect. Good day.