Tenax Therapeutics, Inc. Study result

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 PH-HFpEF. The primary endpoint did not reach statistical significance. The difference between groups in six-minute walk distance at week 12 was 3.5 meters with a P value of 0.63. The evidence we will share with you today impresses us. Levosimendan's impact on key objective biological targets directly translates 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 HELP 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 heterogeneous HFpEF population. The trial did not meet its primary objective. 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 one inclusion criterion 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 PH-HFpEF 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 set 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.

Here's 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 PH-HFpEF population. 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 hear from Dr. Sanjiv Shah, Professor of Medicine and Director of the HFpEF program at Northwestern University and LEVEL's Principal Investigator. I will close by discussing where our phase III program goes from here. 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 revise forward-looking statements except as required by law. 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.

Is chronic oral levosimendan safe 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 HELP were unprecedented in Group 2 patients, but were they reliable? Would we be able to validate the treatment effect we saw in those 36 advanced PH-HFpEF 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 eight meters or three and a half meters. The placebo-corrected improvement below the median is 26.3 meters, with a 95% confidence interval of 6 to 47 meters and a nominal P value of 0.0112. Above that line, healthier placebo patients out-walked healthier levosimendan patients by 17.6 meters. It's not hard to find patients with limited exercise function in 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 six-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 trials. Capping the walk at 450 allowed less advanced patients to be enrolled. Our median baseline walk came in about 50 meters higher than in HELP, and roughly half our population, based on that measure of severity and several others associated with it in our pre-specified analyses, ended up being patients healthy enough that the placebo arm improved on its own. In this one aspect, the study design permitted the inclusion of patients with moderate disease. The learning lies right there. We did not fail to find a 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 pre-specified 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 U.S. and Canada randomized a patient. 241 patients were randomized 1 to 1. Dosing was an oral capsule, 1 milligram twice daily for 4 weeks, and then 1 milligram 3 times daily through week 12. The primary endpoint was change in six-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 HELP. While we enriched on hemodynamics, based on that evidence, we had no basis to enrich the minimum or maximum baseline six-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 an 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 2, and 54% were functional Class 3. This was a contemporary, well-treated HFpEF population, which is what we set out to enroll. 60% qualified on provoked hemodynamics rather than at rest. As to the baseline six-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 endpoint. Patients on levosimendan improved their six-minute walk distance by least 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.