Tenax Therapeutics, Inc. (TENX) Earnings Call Transcript & Summary

Good day, and welcome to the Tenax Therapeutics Phase III level top line results conference call. [Operator Instructions] Please note this event is being recorded. I would now like to turn the conference over to Chris Giordano, President and Chief Executive Officer. Please go ahead.

Good morning, everyone. Thank you, Betsy. Thank you, everyone, for joining us. I'm Chris Giordano, President and Chief Executive Officer of Tenax Therapeutics. This morning, we released top line results from LEVEL, our first Phase III trial of oral levosimendan in patients with HFpEF. The primary endpoint did not reach statistical significance. The difference between groups in 6-minute walk distance at week 12 was 3.5 meters with a p-value of 0.63. But the evidence we will share with you today impresses us. Vivo Cemento's impact on key objective biological targets directly translates to benefit from pulmonary pressure and BNP lowering to functional improvement in the more advanced patients we treated. We believe we have a drug for the many patients who need it. And there are millions of them around the world. Our Phase II Health results found a new target population for this unique drug. LEVEL was always intended to validate the efficacy shown in that study, more precisely measure the treatment effect and establish the right patients who benefit in this very heterogenous teste population. Trial did not meet its primary objective, but when it comes to sizing and locating the treatment effect in these patients, the trial has achieved very important goals. We received data only last week. In beginning to dissect it, we see evidence of a very responsive patient population in LEVEL. And we also see the reason their response is obscured in measurement of the primary endpoint. We see clearly where 1 inclusion criteria, let this drug down in this study. What I will tell you today is this, our therapy works very effectively in a large, common, easily identifiable population of PHS patients, and they need it. We are not in a situation where the drug and the placebo groups are indistinguishable in our data or a situation where drug exposure or adherence was inadequate in the trial, at least not in the full analysis that we're looking at. On the contrary, our results define the population of high responders coherently and the adjustment we need to make in our Phase III program is crystal clear. LEVEL was a well-conducted trial. It was executed on time, randomizing 241 patients in about 24 months with a reassuring 2% rate of missingness on the primary endpoint, very high patient retention and therapy adherence and no site-specific problems or six-minute walk test performance anomalies we're going to point to as a culprit behind the primary miss. We have invaluable information from LEVEL, and we intend to use it. So here is how we will use our time this morning. Dr. Stuart Rich, our CMO, will take you through the complete top line data set, the primary and secondary endpoints, the safety profile, the biomarker and hemodynamic results that yield important information about the efficacy of levosimendan in a well-defined PHF population. And then the subgroup analyses, which will guide the direction of our program from here. so that the drug's effect is not obscured a second time. We will then hear from Dr. Sanjiv Shah, Professor of Medicine and Director of the HFpEF program at Northwestern University and LEVEL principal investigator. I will close by discussing where our Phase III program goes from here. Then we will open the line where Stuart, Dr. Shah and I will be joined by Doug Randall, our Chief Business Officer; and Tom Staab, our Chief Financial Officer. Before we go further, we will be making forward-looking statements on this call, including statements about our clinical data, regulatory plans, our future trial designs and our business operations all of which are based on management's current expectations. Actual results may differ materially from those indicated on this call due to inherent risks and uncertainties described on this slide and in the company's SEC filings. Please read them accordingly. Although we may voluntarily do so, we undertake no commitment to update or rises forward-looking statements, except as required by law. Now before Stuart walks through the results, let me tell you how we are reading the evidence we have. So you have a frame for what he's about to show you. Let's start with what this trial confirmed because it is much more than people may assume from the headline. LEVEL started out with several key questions still outstanding. This chronic oral levosimendan state in the population tested? The answer is yes. Do we have a clear and robust set of evidence of a dose that is biologically active, with NT-proBNP and pulmonary pressures, both responding in the way this mechanism predicts they should. Yes, the Phase II efficacy results from Health were unprecedented in Group II patients, but were they reliable? Would we be able to validate the treatment effect we saw in those 36 advanced PHS patients? Again, yes. Can the sites and the clinical operations team execute Yes. The reason those answers did not convert to a win on the primary is apparent, it actually jumps off the page at us in the first hours of our review of the data. Tenax did not anticipate the impact disease burden would have on the treatment response. In patients whose baseline walk is below the median of 333 meters, the result is not 8 meters or 3.5 meters, the placebo-corrected improvement below the median is 26.3 meters with a 95% confidence interval of 6 to 47 meters and the nominal p-value of 0.0112. Above that line, healthier placebo patients out walked healthier levosimendan patients by 17.6 meters. Now it's not hard to find patients with limited exercise function and HFpEF practices in clinical trial sites. A patient's track record on this standard assessment is one of several markers of advancing disease their cardiologists follow closely over time. In the results we have reviewed thus far, these markers of severity align in predicting exercise improvement levels from levosimendan and we are moving forward, knowing the 6-minute walk distance at baseline in particular, highlights patient responsiveness to our mechanism of action. We know much more clearly the right patients to enroll. LEVEL has taught us how impactful this particular baseline characteristic is on drug response in these patients. We set the ceiling for the baseline walk at 450 meters, which has been the ceiling for all of the successful PAH trial, but capping the walk at 450 allowed less advanced patients to be enrolled. Our median baseline walk came in about 50 meters higher than in health and roughly half our population based on that measure of severity and several others associated with it in our prespecified analyses ended up being patients healthy enough that the placebo arm improved on its own. In this 1 aspect, the study design permitted the inclusion of patients with moderate disease. The learning lies right there. We did not fail to find the treatment effect in LEVEL. We diluted one. Stuart will show you exactly how Stuart?

Thank you, Chris, and good morning. LEVEL was the largest randomized controlled trial completed to date in PH-HFpEF. As Chris summarized, this study has already taught us several important things nobody knew a month ago. I'm going to take you through all of it, including the prespecified subgroup analyses that elucidate the route we intend to take to bring levosimendan to the many patients who will benefit. Let me begin with trial design. The LEVEL study was a Phase III double-blind, randomized, placebo-controlled trial, 41 sites in the United States and Canada randomized a patient. 241 patients were randomized one-to-one. Dosing was an oral capsule 1 milligram twice daily for 4 weeks and then 1 milligram 3 times daily through week 12. The primary end point was change in 6-minute walk distance at week 12. Patients completing the double-blind period were eligible for an open-label extension of up to 2 years, which is ongoing. Every patient underwent a right heart catheterization and had to meet qualifying hemodynamic criteria either at rest with passive leg raise or with bicycle exercise. That was our enrichment strategy, and it came directly from the hemodynamic profile of the patients who responded to intravenous levosimendan in health. So while we enriched on hemodynamics, based on that evidence, we had no basis to enrich the minimum or maximum baseline 6-minute walk distance, which I will come back to. Baseline characteristics were broadly balanced. As you see on this slide, Mean age 69, 71% female, BMI 33, 72% were on an SGLT2 inhibitor, 28% on a GLP-1 receptor agonist, 60% on MRA and 87% on diuretics. These are the drugs that have shown benefit in patients with HFpEF and are considered the standard of care. 45% were New York Heart Association Functional Class II and 54% were functional Class III. This was a contemporary well-treated HFpEF population, which is what we set out to enroll. 60% qualified on provoke cabin dynamics rather than at rest. Now as to the baseline 6-minute walk distance, 319.5 meters with a standard deviation of 85, the median is 333 meters. I'm going to come back to the 333 number many times. The primary end point. Patients on levosimendan improved their 6-minute walk distance by lease squares mean of 14 meters at week 12. Patients on placebo improved by 10.4 meters. The treatment difference was 3.5 meters with a standard error of 7.3 and p-value of 0.63. Using the mean, patients on levosimendan improved by 17.7 meters compared to 9.8 meters for patients on placebo, with a treatment difference of 8 meters. The key secondary endpoint KCCQ total symptom score did not reach statistical significance. Levosimendan improved 6.6 points and placebo 6.5 points with a treatment difference of 0.1 points, standard error of 2.2. New York Heart Association function class improvement was 24.1% on drug and 22.5% on placebo. Adjudicated clinical worsening events were evenly split with 3 in each arm. Now on to safety. The oral form of levosimendan demonstrated a favorable safety profile in this population. Adverse events occurred in 86% of levosimendan patients and 72% of placebo patients. Treatment-related adverse events were 38 against 17%. Discontinuations due to an adverse event were 8.3% against 1.7% and dose reductions were 15 against 4. The following effects are characteristic in previous studies with oral levosimendan, headache, palpitations and hypertension. They were largely mild to moderate, and they were manageable and they were handled mostly by reducing the dose rather than stopping the drug. Serious adverse events, 10.8% against 10.7. adjudicated clinical worsening events, 2.5% in each arm. On arrhythmia, among patients with no preexisting evidence of atrial fibrillation or sustained ventricular, there were no new events detected during the randomized phase with repeat Holter monitoring. There were 2 deaths during the double-blind phase, both in the levosimendan arm, both unwitnessed both determined to be unrelated to the study drug by the patient's position. To remind you, the annualized mortality rate reported in HFpEF populations of this age and severity is on the order of 15%. Those are the top line results and allow me to show you exploratory endpoints and prespecified subgroup analyses. There are -- these are the findings that give us confidence that there is a clear path forward to a successful Phase III program and approval. The biologic thesis behind this program is that levosimendan potassium ATP channel activation mechanism reduces the chronic constriction of the vessels in the Spintec circulation. This constriction leads to volume overload and dilating the planting circulation will lower the patient's central and pulmonary venous pressures. This reduces strain on the heart and lowers pressure in the lungs. Those patients whose pressures are going down would be expected to demonstrate this through improved exercise. New evidence in this trial not only prove that thesis, it demonstrates an impressive and what we expect replicable treatment effect. NT-proBNP is a highly reproducible measure of cardiac wall stress. This is called strain on the heart, I just mentioned. Levels of this protein were markedly elevated at baseline in our overall population as expected. We observed a 49% reduction in the patients treated with levosimendan compared to placebo, which was robust. This biomarker is not a subjective measure. It correlates with the severity of heart disease and pulmonary hypertention in a multitude of studies and is trusted by physicians for diagnosis and treatment. A treatment effect of this magnitude has been associated with improvement in outcomes and is a reliable indicator of treatment efficacy. Treatment effect of the magnitude of levosimendan in LEVEL is larger than any I have seen in a large HFpEF trial. What about pressures in the lungs, as I just mentioned. We measured with echocardiography, the recontribute systolic pressure, or RVSP, also sometimes reported as PSP pulmonary artery systolic pressure. But just realize this is the pulmonary artery pressure that you are used to seeing in pulmonary hypertension trials. We observed that the PA pressure was reduced with levosimendan by 3.6 millimeters of mercury, whereas the placebo patients had an increase of 0.5 millimeter for a treatment difference of 3.5 millimeters of mercury, which was also robust and with a nominal p-value of 0.0045. In patients below the 333-meter median at baseline walk, the PA pressure dropped 4.9 millimeters nominal p-value 0.009. The pulmonary vasodilators that have been approved for Group I PH demonstrate the similar reductions in PA pressure in those patients. Lowering pulmonary artery pressure is the most important biologic objective in a therapy for pulmonary hypertension. Population studies in patients with pulmonary hypertension have shown a reduction in the pulmonary artery pressure is associated with a survival benefit. A paper published just this week by Zalan Lindenfield and others, demonstrated that a 3-millimeter mercury reduction in the PA systolic pressure delivers a 20% reduction in heart failure hospitalization. The fact that levosimendan was able to markedly reduce BMD and reduce the pulmonary art pressure with this drug in this population is a critical important finding. When we look to have a better understanding of which patients benefited most from levosimendan, we first look at the baseline 6-minute walk distance as a measure of disease burden. The lower the walk distance the higher the disease burden. Our first step was to look at those patients who walks were above and below the median, which was 333 meters. And those with a 6-minute walk below the median, in blue on this slide, the treatment effect was 26.3 meters with a 95% confidence interval and nominal p-value of 0.0112. However, when we looked at the patients with a baseline walk above the median baseline in red, the final 6-minute walk distance in the levosimendan patients showed a treatment difference of negative 17.6 meters. So here's what's happening. The drug is helping sicker patients more. What we became aware of in this population is that patients who were less sick and on background therapy did not show treatment benefit from 3 milligrams daily of levosimendan. But those with a higher burden of disease, we're very responsive despite being well treated on the latest recommended medical therapies for HFpEF with a very meaningful clinical response. The 6-minute walk test was reliable and conveying to us the patients with Group II PH respond best to this drug. When we look by age in the oldest tertile above 74. The difference was 37.6 meters, 95% confidence interval and nominal p-value of 0.0013. Look at the confidence in over there in the older patients in this trial, in patients at or above the median age of 71, the difference was 27.1 meters, 95% confidence interval nominal p-value 0.0021. This compared with patients below the median age of 71. The difference was negative 19.2 meters, 95% confidence interval, nominal p-value 0.0972. This finding about age persists whether we look at median tertiles or quartiles. We also look at natriuretic peptide as a biomarker of disease burden, the higher the BNP, the more severe the patient. Patients who came in above the median baseline NT-proBNP improved 16.7 meters against placebo that is the same ingredient again, arriving from a completely different direction from a blood test rather than a walk test or a birthday. Thus, these 3 markers of disease burden exercise capacity, age and natriuretic peptide point us to our responder population. I remind you, these are nominal p-values. They are not adjusted for multiple comparisons and the multivariable work that is still running, but they do provide answers to questions that were specified in advance rather than derived from data review afterwards. There is a practical finding sitting inside this that I don't want anyone to miss. The 6-minute walk distance turns out to be both our endpoint and our best tool for selecting patients. We do not need to go and find a new biomarker to identify who responds. We need to take this measurement and screening and use it to decide who gets into the trial. We relied on change in 6-minute walk as a solid primary endpoint in our studies and these results confirm its trustworthiness. The biologic measures of improvement parallel to clinical efficacy benefits in the results bearing this out. So in summary, we believe that levosimendan has now proven itself as a safe and effective therapy in patients with PH-HFpEF who have more disease burden. And those patients who had lower baseline walks, NT-ProBNP was higher to start with and it came down dramatically on therapy. This very impressive clinical treatment effect demonstrated here is of a scale we trust would satisfy regulatory authorities for product approval. There was not enough HFpEF literature to rely on when refining the upper range of this criteria. We also had to rely on PAH literature. Remember, in any HFpEF study, many of patients have PH that may not be described. So it's very difficult to tease out in these databases how much the pulmonary hypertension versus the HFpEF is driving walk response. We just don't have a trove of successful Group II trials to guide us. On the other hand, in PAH, FDA guidance suggests drug developers use a range of 165 to 450 meters, and that guidance draws on libraries of successful PAH trial databases. So in Group II PH, we now have a very clear indication where to set the ceiling. The 10x team is exploring now whether an amendment to the ongoing level of study would generate a data package that when submitted to authorities will bring this therapy to patients. Keep in mind that LEVEL 2 was sized based on the safety database requirements and is already powered above 90%, even with the 55% standard deviation and an assumed dropout rate more than 4x what we saw in the shorter trial. LEVEL randomized 241 subjects. LEVEL 2 currently aims to enroll more than double that number. we are optimistic about our ability to modify this trial once regulators have reviewed our LEVEL results and hurt our proposal so that we can generate a successful data package and get this drug to needy patients. And with that, I am very pleased to introduce Dr. Sanjiv Shah. Sanjiv, we would avail your thoughts about the meaning of these results.

Thank you, Stuart. It's really a pleasure to be here and discuss my thoughts on the trial result as the academic principal investigator of the trial. I've been taking care of these patients for the past 25 years and in the past 20 years and directing the Northwestern HFpEF program. And as you are well aware, this is the dominant form of heart failure now. We think that based on the current data, 60% of patients in the United States alone have a preserved injection fraction greater than equal at 50% at the time of diagnosis. And of those, we think that 75% to 80% have pulmonary hypertension. So it's extremely common and there are no approved therapies for PH pet. So of course, for the past 2 decades and longer, we've been looking for drugs that can improve this patient population and it's been littered with neutral trials or even some trials that harm the patients. And it's been a really challenging patient population. We have had successes recently with SGLT2 inhibitors, GLP-1 receptor agonist, nonsteroidal MRAs. And that's been a great advance and some may say, well, maybe we don't need to do anything more for HFpEF. But clearly, we do. Even in these trials, even on patients with all of these medications, they're still quite debilitated and they still have high morbidity and mortality. And those who develop pulmonary hypertension and the more severe the pulmonary hypertension is are the ones that really suffer and the ones that need above help. Now in the past, we have tried with pulmonary vasodilators to see if we could help these patients with PH-HFpEF like we've helped patients with pulmonary atrial hypertension. And it's been a universal no, not an improvement at all. And what's consistent about all of these trials is that NT-proBNP didn't come down. In fact, it either stayed the same or went slightly up on the treatment. This is the case for drugs like [indiscernible] in the recent trial that was published last year. PD5 inhibitors with endothelin receptor agonist, SGC antagonists and SGC stimulators. And so there's a clear signal there that there is not an improvement of congestion. There's not an improvement of wall stress and those trials were neutral and didn't improve the patients. Now we look at the recently published CADENCE trial, which was in patients with a pulmonary vascular resistance of greater than 4 which is quite high and is the minority of patients with PH-HFpEF, but we do see those patients there quite sick. And the CADENCE trial did reduce PDR and seem to improve other markers, including NT-proBNP came down, but not nearly as much as we see here with levosimendan, which is a much easier to administer oral medication that seems to be better tolerated. So while I felt that 6-minute walk distance, if we could show it with this number of patients in a wide proportion of patients with PH-HFpEF sort of a broadly defined patient population we would have a major advance. And sometimes we get lucky and it's easy and it's simple. Here, what we saw was what we often see in HFpEF that it's not simple that it is a heterogeneous patient population. And what we see here is that thicker patients really are the ones who benefit. And that's the most important finding because those are the ones that we need to treat. If we have a patient who has a 6-minute walk distance of, let's say, 375, 400 meters, 425 meters with PH-HFpEF that they're doing pretty well, and we have treatments for those patients. We have SGLT2 inhibitors, we have GLP-1 receptor agonists, nonsteroidal MRAs. And those are not the patients that are having the events that like heart failure hospitalizations and higher mortality. So the ones that we want to treat are the ones with the lower 6-minute walk distance with the higher NT-proBNP in the sense that those are the ones that are at highest risk for heart failure hospitalization and debt, those are the ones that are costing the health care system so much and are really the ones where the disease of HFpEF and pulmonary hypertension is driving the patient's journey. And in those patients, in particular, is where we found the benefit in the LEVEL trial, those with the lower 6-minute walk distance, those with the higher NT-proBNP and so I think that these findings, while they're not a slam dunk and an easy win for us that will quickly move us forward on the path. I think that what they show is actually better than we would have expected. Based on these data, I feel like we have evidence here that levosimendan will reduce heart failure hospitalizations in PH-HFpEF. And I say that because of the reduction in NT-proBNP there's sort of a linear relationship across all trials, not just the big large outcomes trials, but all trials that have looked at this. And that linear relationship suggests that the reduction in NT-proBNP that we see here, which by far is the biggest reduction in proBNP in any PHS for HFpEF trial ever done will reduce heart failure events dramatically and of course, that needs to be proven. We need to do that trial. But to me, that is really compelling. You couple that with the fact that those with 6-minute walk distance at baseline less than 333 meters, did quite well, 26-meter improvement compared to placebo. I think it gives us the whole package there and it tells us that this drug really has a future. I'm still a big believer in the drug and I've done many of these trials in HFpEF and I take care of many of these patients. We see that in the open-label extension that patients feel well and are doing better. And so I'm still quite positive about the drug and think that we really have a lot of work cut out for us. But I'm very positive and hopeful for our patients based on the results that we've seen here today. Thank you.

Thank you very much, Professor Shah. I know that in a few minutes, we'll have questions, and we'll probably be directing a few of them to you. We appreciate your support, but we also reminding everyone that there will be data coming out in the future in publications and in presentations and we're not going to steal too much of your thunder here today. So we're looking forward to hearing more about that linear relationship between BNP and heart failure events, but we'll wait for the late breaker, et cetera. So all right. So with the last few minutes of the call, we want to do 3 things: tell you what we know now, tell you what we are going to do about it and tell you what we cannot answer yet today. What we know. We have a drug candidate that lowers filling pressures and pulmonary pressures in this disease at a dose we no longer have questions about, with a safety profile consistent with over 25 years of clinical use in study. We have an efficacy signal above 26 meters in the patients who aren't walking near the normal range, and we have several ways to identify those patients before they enroll. The question that kicked off the PH-HFpEF program at 10x in 2018 was what might levosimendan do in a totally new group of heart failure patients without a drug and with high unmet need. Numerous health findings led us straight into Phase III. In LEVEL, a question so many of you asked was whether oral levosimendan at the 3-milligram daily dose would transfer those benefits. That question is now retired. What is left is a trial design problem and a new challenge our team will overcome to deliver this drug to patients. Trial design is the kind of problem we know we can solve. And our aim will remain shortening the time patients have to wait. I want to be clear about that 26-meter signal because I worry it will get lost beneath the headline. 26 meters is not a rounding error. We are trying to talk our way into. It showed up in the patients who have the most to gain. It moved with 2 independent biological markers that dramatically improved in this population and it is about the same magnitude help produced in about the same kind of patients. In the patient with highest indications of disease burden and level, we saw effects in the 30- to 40-meter range. The RVSP and BNP improvements are profound. Those improvements are evident across all quartiles of levosimendan patients we studied and they are undetectable in the placebo patients. We have pressure tested these observations already with the data we have so far, and I can tell you our pathway is very clear. So what are our next steps here? 10x will request a Type C meeting with FDA to present these findings in our recommendations. We are seeking in parallel scientific consultation from EMA. We will go into these meetings with a complete data set, including the multivariable analysis we don't yet have, and with our scientific advisory board and regulatory advisers aligned behind a recommendation. Our statistic experts are working on the right strategy to construct criteria for an impressive level 2 based on several disease severity factors they and the medical team are analyzing now. Their goal is to create a correlated set of factors, preserving as much of the population as possible on the way to a positive result. They will avoid overfitting by using modeling techniques that repeatedly test our rich new level data set through these filters. Axis statistics leaders inform us, we have strong evidence, undergirded by impact on BNP that is clearly translating to exercise improvement for designing a successful next trial. The predefined analysis reveals demonstrable levosimendan effects in those with higher disease burden at the start of the study. The prespecified analyses consistently show this positive effect. This is not exploratory. I should pause for a second here to thank the incredible data management team at Medpace and the biostatistics team at Lucent, who've worked tirelessly to get us where we are this morning. Dr. Shah plans to present the level of results at ESC, where the community will next learn quite a bit more about level, and then he and the steering committee intend to continue presenting and publishing their findings. The one thing I will commit to this morning, something that doesn't require a validated staff output or regulators input. We are not intending to enroll another patient into this program whose baseline 6-minute walk distance sits in the range at diluted level. In the COPD, heart failure and PAH literature, there is an association between a walk of less than 350 meters and increased mortality. In ATTR cardiac amyloidosis, a walk less than 350 carries at [ 2.2-fold ] higher mortality risk. There is plenty to support lowering our ceiling to something in this range. So we're finalizing the exact threshold quickly based on our new level data and when that number is fixed in the coming days, the steering committee will communicate it to every active Level 2 site. Now what can I not tell you today? We have yet to decide whether the right vehicle is simply an amendment to Level 2, which is enrolling now or an amendment and the addition of another trial built from the ground up for this population. Several options are under consideration. We may limit the walk ceiling or we create a combined disease severity score to avoid enrolling patients who are a few years ahead of the point in disease progression where levosimendan is going to help them. Amending Level 2 preserves what we have already built, initiated sites around the globe, a highly functioning group of national lead investigators a running supply chain, delivering IT, training, ethics and site approvals and randomizations, a continually building footprint is active across 4 regions. A trial population built on the findings of LEVEL could enroll at a reasonable rate, and we would not be starting from scratch on site activation. These are key decisions that we're going to make with the FDA rather than ahead of them, and not on today's call a few days after we were unblinded. We believe the agency will see that what levosimendan does what we said it would do. at a dose we know is driving big improvements. In patients who are heart failure physicians clearly recognize in their practices and who our sites will now identify before they ever enroll and with an FX size larger than the one we powered level to detect. The FDA wants therapies for the millions of Americans suffering from PH-HFpEF. The data we have shown you this morning tells us what needs to get done. We intend to develop and ultimately deliver an authorized oral levosimendan to these patients because this drug has proven itself to us in our data. To everyone at 10x, thank you and keep going. To the investigators and the coordinators, thank you.

We are very grateful to the patients making this research possible. So thank you for listening, and Betsy, we will take questions now.

[Operator Instructions] The first question today comes from Olivia Saunders with Cantor.

I wanted to ask, what is your best explanation for why those higher baseline patients, AK, the third and fourth quartile on walk score are seeing such a pronounced worsening effect versus placebo. And is that something that you also saw on KCCQ scores or is that just a 6-minute walk distance phenomenon? And then also wanted to ask about how each arm did in that lower disease burden patient population and whether those patients on TNX-103 actually saw a decline versus baseline 6-minute walk or whether the placebo patients maybe just improved disproportionately or maybe it was some combination of both?

That's a great question, Olivia. I'm going to hand over to a great set of questions. I'll hand over to Stuart. Let me just mention to everyone a couple of things. The 10x team was unblinded by our staff team last week. So we have been pretty much heads down through today with our effort to get the data where you saw it, so that it's in front of you and everything is clear. So there are going to be detailed questions we can't answer. There are also going to be a really important conceptual conversation topics like the one you just brought up that fit in that category. But if we can't be certain here today that we can quickly lay our hands on accurate data, we may punt on a few of those things. Second, again, please remember that sort of analysis is a great question for the SAB to answer in upcoming presentations and published topic. So it's an open one. I'll hand it off to Stuart here, and then maybe if Sanjiv has comments on those topics. So it's KCCQ. It's the patients with the highest walker baseline who we seem to go the wrong direction.

Thanks, Chris. So Oliver, that's a lot of questions. And let me kind of go through 1 at a time, and I may have to ask you to repeat some of them. You have to imagine the 1 thing that I focused on right from the get-go was why the ones who are less sick and received levosimendan did so poorly because we have convincing data that they were taking the drug, and we have convincing data the drug had a biologic effect on their BNP. In this population, where these patients have congestion, we talk about the preload effect on the heart and lungs, which means the blood volume coming to the heart and lungs in these patients. And as you know, we talked about our mechanism being to reduce that blood volume. There is some literature suggesting that in these patients, if you reduce the blood volume too much, they actually develop worsening symptoms, and it's a term preload insufficiency, which is relatively new and being talked about a lot in the literature, but to come up with something that makes sense, and I'm not saying this is actually going to pan out is that the drug worked too well in these patients. It dropped their preload to a point that they didn't have enough filling. And again, if you don't have enough filling that will limit your ability to walk. So that fits the drug's mechanism. It fits the disease and may turn out to be the answer to the question. But as we've already alluded to, our drug would not then be the ideal treatment for these patients at this time. If they get worse over time, then it's a different story. Okay. Next question, Olivia.

Very helpful. Yes. And then the other question was just around KCCQ scores. Whether you saw maybe more pronounced benefit on KCCQ scores in those patients that do have the higher baseline 6-minute walk or higher disease burden, however you all are categorizing it? .

Here's what we'll tell you about KCCQ at this point along the lines of the topic you just raised. One of the things that we can do in looking at the patients in each group, on each treatment over time and their responses, which right there, you're talking about a multivariable analysis, right, is also look at their KCCQ and see it in those patients that Stuart just described, who we made discovered here were not preload dependent, et cetera, that their KCCQ expresses what their walk expresses. We know that the patients in that group who walk high at baseline. Well, you know what, let me ask 1 that Sanjiv, you -- are you still there? And do you have a theory on this?

Yes. I mean -- so first of all, they are great questions, and we still have a lot of work to do to analyze all of this, but I would say a few things. So first of all, I think what Stuart said is very possible. The patients who walk are at baseline and have lower filling pressures they are different type of patients, and they may sort of depend a bit on the sort of blanket vasoconstriction during exercise to help them get to that walk distance and you remove that are you less than that and they can't do that. So that's something physiologic that we'll have to figure out and take a look at. But also, the -- when you look at the quartiles, the 95% confidence interval at the higher end of lot distance, levosimendan versus placebo IP crosses Unity. And so like we're not as confident at that higher range as we are at the lower range, where it is very much the confidence rules don't pass and you see a very statistically significant improvement. And I think the last point is that you made is sort of like is the issue that these patients are really worsening or is the issue that the placebo is getting better. And from my analysis of the data at that last is seemingly what's going on, where the -- that it's not that levosimendan is harming these patients in some way. I mean it's just that the that these placebo patients when they're already doing quite well, they kind of did a little bit better over time. And is that a fluke or something, I don't know. But in the ones with the lower 6 minute walk distance, those are the ones that -- where it really does seem like there's a clear improvement on levosimendan. So I think there's still a lot that we have to unpack here, and I'm hoping that by the end of the month, when I presented it, yes, we'll have a lot more of these answers.

The next question comes from Dave Risinger with Leerink Partners.

Yes. So I guess, Dr. Shah to follow-up. So regarding Slide 13. Do we need to wait for ESC to understand the absolute figures behind the calculation so that we can assess to what degree the above median and below median performance was driven by the placebo responses. That's my first question, and then I have another one, please.

We'll try to go to 13 now all I think people will remember it's the blue and the red walk or graph. Dr. Shah can address it in a second. Let me address it in 1 way, Dave, it's a great question. Let me just share a little bit of the observed data over time that sits behind this bar graph, right? What we're looking at is 12-week data. Let me give you the walk distance in observed data. This is raw data, not statistically adjusted, et cetera, but these are just the numbers that we have at 4 weeks, 8 weeks and 12 weeks. In the Levo patients below the median baseline at entry into the study, the improvements are 19, 21 and 27 meters, right? They went up -- they're on 2 milligrams. They walk 19 further. They go up to 3, they go to 21 and 27. Do they stay there? Do they go up? Do they go down after week 12, your guess is as good as mine, we, of course, have the OLE data. What about the placebo patients who walked less than the baseline, their walks are negative 1, 4.8 and negative 3 tight clustering of unimpressive numbers. The same trends are available in different analyses, and that's part of the data that we're looking at initially here. That points to the same conclusion that, that's our divider. So Professor Shah, we're not showing all the data behind this now because we're still getting through it. But what would you expect one we'll see, I think.

Yes. I mean I think that that's right. It's not that the patients who benefited like let's look at the lowest quartile of baseline 6-minute walk distance. I think the question that we just heard is, is it that the levosimendan patients are truly doing better or is it that the placebo patients in that group are just doing a lot worse and we're preventing worsening. It looks like the levosimendan-treated patients are actually doing better. which is really kind of amazing to see because a lot of times when we have really sick patient patients like ATTR cardiomyopathy, we're just sort of preventing or slowing worsening. But here, I think we're seeing an improvement. And again, we've got to really dive into those data and tease it out. But that's what Chris had just mentioned, that's what we're seeing placebo remains flat and the levosimendan group improves over those 12 weeks.