Conference Transcript - TECX 2025-10-29

Operator

Good day, and welcome to the TX45 Phase 1B, Part B, PHFRAF Data Conference Call. After the speaker's presentation, there will be a question-and-answer session. To ask a question, please press star 11. If your question hasn't answered and you'd like to move yourself in the queue, please press star 11 again. As a reminder, this call may be recorded. I would like to turn the call over to Dr. Elise Rayson. Please go ahead.

Speaker 3

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 1B clinical trial, which evaluated the safety and hemodynamic effects associated with the 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 HEF-REF. 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 HEF-REF and to explore the 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? And 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 PHF-pest with evidence of improvement in both left heart function and pulmonary hemodynamics. And I can say unequivocally that the results met that goal. Similar to what we saw in PHF-PEF 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 HEP-REF patients, pending data from our ongoing APEX Phase II clinical trial in PH HEP-PES patients. And as a reminder, APEX is a 24-week clinical trial to evaluate the safety and efficacy of TX45 in PH HEP-PES. This study is highly enriched for CPC patients with a PVR greater than or equal to three wood units. In fact, we're aiming that 70% of the population have a PVR greater than three. And the primary endpoint of mean change from baseline in PVR in this PVR greater than three population is, that's the primary endpoint. Six-minute walk distance will be a secondary endpoint. And with that, I'm going to now turn the presentation over to Marcy Ruddy, Tectonics Chief Medical Officer, who would describe the rationale for us doing Part B of the clinical trial, as well as the results. Thanks, Elise.

Marcella K. Ruddy, Analyst — Other

Next slide. So, what was the rationale for exploring TX45 in PHF breast 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 visodilatory, lucitropic, antifibrotic, and reverse remodeling effects. Second, we were encouraged to explore TX45 in PHF-REF after we saw that meaningful hemodynamic improvements in PHF-PEF were consistent with what would be expected from the relaxant mechanism. Similar to PHS-PEF, 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 three wood units. Lastly, expansion into PHS PEP 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 three. Next slide, please. So although the left ventricular pathology for these two types of heart failure is different, the development of pulmonary hypertension and its consequences are similar. PHF-REF 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, PHS-PES, 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 CPCTH. They develop decreased cardiac output, particularly with exercise, and then eventually can develop right heart failure. Next slide. So the trial design of Part B was similar to Part A. Patients with PHF refs were screened by history and echocardiograms 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 who 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 per kg dose, the second 1 mg per kg. The rest of the cohort was dosed at 3 mg per 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. So 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 afterloads that the right ventricle needs to pump against. Elevated right ventricular afterload has been linked to poor outcomes in patients with pulmonary hypertension, 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 in concomitant medications were consistent with a pH-hef-ref population enriched for CPCPH. Patients had an average left ventricular ejection fraction of 34%, an elevated NT-proBNP of over 3,000 picograms per ml. The patients had expected comorbidities of hypertension, atrial fibrillation, and coronary artery disease. 57% of these patients had New York Heart Association Class 3. These patients have symptoms with minimal exertion. Only two patients in Part B had a PVR less than two wood units, five had a PBR between two and three wood units, and seven had a PBR greater than or equal to three. 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. So, the baseline hemodynamics were also consistent with the diagnosis of PHF rest. Mean baseline pulmonary capillary reg pressure was elevated at 31 millimeters mercury. The PBR of 3.26 wood units 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 preloads. 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 to 10 millimeters of mercury 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 millimeters of mercury, 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 PBR, in the PBR greater than or equal to 3 wood unit population. In a previous hemodynamic study in patients with PHF-REF treated with sildenafil, a 20% reduction in PBR was associated with a 29-meter increase in six-minute walk. In the PBR greater than two population, the mean percent reduction was 10.3%. As footnoted in the slide, the lower percentage change from baseline in this subgroup was driven by one outlier, as evidenced by the difference between the mean percent change of minus 10.3% and the median percent change of minus 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 preloads. Taken together, the concordance of these hemodynamic effects suggests that TX45 meaningly improves left ventricular function and pulmonary hemodynamics, both of which are necessary for an effective treatment in pH HEPRAP. Next slide. So 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 CAP-C over SPAP. This is an ECHO measure that is considered an inversely correlated surrogate for PDR, meaning that if PDR is reduced, we would expect to see TAPC over SPAP 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 PBR 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 percent at baseline to 35 percent at day 29 this change represents an improvement of approximately 20 percent these echo data are very encouraging as they suggest that the hemodynamic improvements seen on day one as measured by right heart cast 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 pulmonary vascula in the pulmonary vasculature in pH HEC rep. This is noted by improvements in pulmonary capillary wedge pressure, cardiac output, and left ventricular ejection fraction by ECHO, which demonstrates the improvement in left heart function, and reductions in pulmonary vascular resistance, total pulmonary resistance, and mean pulmonary artery pressure, along with the increase Syntaxi over SPATH by echo, which demonstrates improved pulmonary hemodynamics. The echocardiographic data suggests persistence of the TX405 effects out to 29 days post-dose. These data are consistent with what we observed in our pH-HESPATH cohort in Part A. So we are always asked about how these data would translate into changes in six-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 PHF-PEF and HFREF 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 afterloads. Reductions in right ventricular afterloads 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 PHF-REF, and we believe they support further clinical investigation in this population, pending results from our ongoing 24-week APEX Phase II trials in PHF-PEF. I will now hand it back to Elise. Next slide.

Speaker 3

Thank you, Marci. Before we turn to Q&A, I'm going to end with just a few company updates. With regard to the APEC 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 three, and we're now limiting recruitment to patients with a PVR of greater than or equal to three WUD units to enrich the trial for this patient population. By the end of 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 and pulmonary hypertension associated with interstitial lung disease, PHILD, 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 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 fourth quarter of 2028. I'd like to conclude just by thank you for your time today. Operator, we're now prepared to open the line for questions. Please go ahead.

Operator

Thank you. Our first question comes from Tyler Van Buren with TD Securities. Your line is open.

Frances, Analyst — TD Securities

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 HFREF?

Speaker 3

Oh, I think if we see evidence of good efficacy and safety, that would certainly give us confidence to move forward in HFREF as well. And I think we'll be looking for evidence of reductions on pulmonary vascular resistance, increased cardiac output. And while we're not powered fully for six-minute walk tests, we're going to be looking for strong numeric trends there.

Operator

Thank you. Our next question comes from Yasmeen Rahimi with Piper Sandler. Your line is open.

Yasmeen Rahimi, Analyst — Piper Sandler

Good afternoon, team. Congrats on the great data. I would love to understand sort of when we think about the hemodynamic and responses in the half-ref population, how that could translate sort of prediction on a six-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 half-pef population, but I appreciate color on how do we take this really strong data from part

Speaker 3

be to think about ethics? And I'll jump back in the queue. Yeah, we think that it's similar and 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. And 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. And that led to, you know, almost a 70 meter increase in six 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 HF-Peth and in HF-Ref. And then there was a pH HF-Peth, CPC-PH population for, and then there was a study by Lewis in 2007 done with sildenafil in pH HF-Ref. And in that study, they saw a 20% improvement in PVR, an increase in cardiac output. Wedge actually didn't go down that much. And in that study, they saw a 30-meter increase in six-minute walk. So I think the data that we've seen both in HEPF and HEPFREF suggests that if maintained over the six-month period, we should see clinically important improvements in six-minute walk.

Yasmeen Rahimi, Analyst — Piper Sandler

Thank you so much, Elise.

Operator

Thank you. Our next question comes from David Reisinger with Lyric Partners. Your line is open.

David Reisinger, Analyst — Lyric Partners

Yes, thanks very much. So congrats, Elise, 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 and then 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.

Speaker 3

Yeah, we didn't see any fatigue-related AEs. As Marcy 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. And when they came in on day two, they no longer had fatigue. Nobody thought that that was related to drug. But I think we heard there were some people talking about wondering whether the fatigue was the result of a lowering in blood pressure. We never saw a correlation there. And 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. You know, the issue when you do small numbers of patients is you can have one outlier that really impacts the mean. And what we saw was a difference in the mean and the median, as Marcy outlined, with the median more aligned with what you would have expected to see. And 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. And they started with a not very high PVR. And so the percent change ended up being quite large. And 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. And so, in the percent change in PVR, that one patient had sort of an outsized effect.

David Reisinger, Analyst — Lyric Partners

Got it. Thank you very much.

Operator

Thank you. Our next question comes from Oyer with Mizuho. Your line is open.

Oyer, Analyst — Mizuho

Hey, guys. Yeah, congrats on the great data. Thanks for taking our question. Elise, I think you indicated that, you know, you've met with the Data Safety Monitoring Board, and that it's given you pretty much a clean belt of health. Just wondering if, you know, if you could elaborate that a little more as to when was the safety data monitoring board, when did they meet? And was it, you know, were they sort of aware of the Lilly Phase II publications? And if there's anything else that can be shared, that would be great.

Speaker 3

Yeah, I'm going to have Marcy take that.

Marcella K. Ruddy, Analyst — Other

So we met with the DSMB after the Bowling Relaxment data was released, and we we told them about it and 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 and their examination of the unblinded data in mid-September suggested that there was no issues and they told us to continue the study without any alterations. Was there any hospitalizations, anything to that effect we've had one we've now had two patients hospitalized for heart failure but again remember these are patients with heart failure and so there's an expected rate of heart failure hospitalizations actually even in the placebo group in this trial so the rate we have now is completely

Operator

expected all right thank you thank you our next question comes from Corey Jubenville with Lifeside Capital. Your line is open. Thanks for taking our questions and congrats

Speaker 10

on this really exciting data. I guess just building off the previous question, we saw with the Volan Relaxin 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. I mean, 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? And similar to the DSMB update in APEX, is there any signs or any signs of congestion at all in those patients? We, you know, there were no AEs

Speaker 3

suggested of congestion. And 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.

Speaker 10

Very great. And 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, you know, 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?

Speaker 3

Yeah. If Marcy 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. Um, you know, it reminded me of the, um, monkey study done by AZ in a, in a monkey model of reduced ejection fraction heart failure were over five months, over that five month period, you saw the ejection fraction continue to go up over five months. And in our study, even over the day two to day 15 to day 29, we saw it go up, it sort of, you know, 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

Operator

you. Thank you. Our next question comes from Danielle Brill with CHUIS. Your line is open.

Speaker 10

Hey, guys. This is Alex on for 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 relaxing receptor agonism and additionally how your strategy compares to the current AZ approach and the prior Lilly trial and heart failure?

Speaker 3

So our 300Q2 dose at trough levels, we should be probably about between 90 and 95% of agonizing the receptor. At our 300Q4 dose at trough, we're probably somewhere between 75 and 80 percent at trough exposure. The volunrolaxin study, their lowest dose was already above, we think, 95 percent agonism. And then the other doses were on top of that. So we really think they were at the upper edge of the dose range. And, you know, 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 300Q2 dose, and their middle dose is probably more similar, maybe a little bit lower than our 300Q4, and their lowest dose, we don't even think gets to an EC50.

Martin Oster, Analyst — Raymond James

Great. Thanks so much for the color.

Operator

Thank you. Our next question comes from Martin Oster with Raymond James. Your line is open.

Martin Oster, Analyst — Raymond James

Thanks for taking my question, and congrats on the favorable, consistent hematomic effects shown today. I at least appreciated the clarity on the Phase II APEX enrollment and the disclosure on targeting 70% CPC-PH 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. I'm curious if that's sort of evolved or if that's always been sort of the team's thinking internally. And then also just wanted to check in on, you know, now that you've probably got most or all of the sites sort of up and running, in terms of screening failures and kind of finding eligible CPC-PH patients, does that do anything to sort of 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?

Speaker 3

It's been 70% since we wrote the original protocol, so there were no changes there. I don't know why I was being coy about sharing that data, and I finally said, you know, we might as well share it. So that was no changes there. We're seeing about 45% of when we were doing all comers, about 45% had PVR greater than three. I don't know, 70 to 80% had PVR greater than two. I think those were actually a little higher than we thought, and 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. And that's why I said by the end of first quarter of 2026, we'll be ready to narrow the guidance there.

Martin Oster, Analyst — Raymond James

That sounds great. Thank you.

Operator

Thank you. And our last question comes from Leland Gershaw with Oppenheimer. Your line is open.

Leland Gershall, Analyst — Oppenheimer

Oh, great. Thanks for squeezing me in. Congrats on these terrific data and, again, reiterating the consistency with the Part A data set. Just wondering, you know, with respect to the PVR, we saw, you know, it was a wider confidence interval for those measures in the HEF-REF versus HEF-PATH. 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 hard failure. And part two 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, but should we presume that you take 645 forward for HFREF, would you look to conduct a Phase II similar design with respect to PVR being primary endpoint and six-minute walk secondary, or how might it differ with respect to endpoints? Thank you.

Speaker 3

Yeah. So, 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 half-ref versus half-pef. We'll just need to study more patient numbers in order to get an idea of that. And with regards to the later, I think it's premature for us to say how we would move forward. We wouldn't necessarily have to do a standalone phase two. We could potentially go to a phase two, three. We'd have to get alignment with regulators on that. So, I think there's a variety of ways that we could incorporate HEF-REF into the program without delaying it too much.

Leland Gershall, Analyst — Oppenheimer

Terrific. Thanks for taking our questions.

Operator

Thank you for your participation. This concludes the question and answer session, and you may now disconnect. Good day.