Next up, we have Chris Giordano and Stuart Rich from Tenax Therapeutics. I'm going to turn it right over to you guys for an introduction of the company, where things stand today. Then we'll come back for some questions.
Great, great. Hi, I'm Chris Giordano. Thanks for attending. We're currently enrolling in a U.S. and Canadian phase III trial in patients with PH-HFpEF. We've been enrolling since March of 2024. We've guided that we expect to enroll 230 subjects the first half of next year with data in the second half. And we expect to announce the commencement of our second of the two phase III trials here in the next couple of weeks. So that trial will be a very similar patient. The endpoint will be 26 weeks instead of 12, and it'll be a global trial. So we'll probably go to around 15 countries for essentially a larger and longer trial.
I'm Stuart Rich, Chief Medical Officer. I was at the groundbreaking of this whole project when I was consulting for the company, constructed the phase II trial, which was the first successful trial ever for PH-HFpEF showing a clinical benefit of six-minute walk. COVID came. I left academia and became part of the company, and I haven't looked back since.
Awesome, awesome. Great introduction. All right, so let's actually just start on the commercial side and just how large the market is before kind of diving into some of the clinical data and endpoint considerations, which I think are a big part of the discussion. I think you've noted 2.2 to 3.7 million U.S. PH-HFpEF patients. How symptomatic are these patients, and are they actively diagnosed and managed in the system today?
They're very symptomatic. In fact, they seek out medical attention because their symptom affects everyday life, every activity they do. Getting up, cooking, going out to the store, playing with their children, et cetera, they are short of breath. So typically, in my clinical experience, they come seeking medical attention, "Help me, something's going on. I don't feel well," and they will often go to their internist to begin with. The typical response would be looking at risk factors. If you're a heavy cigarette smoker, they're going to think it's lung disease and look at chest X-rays. If they can't find anything pulmonary, they're going to do an echocardiogram. That report should be representative of PH-HFpEF. Labs are a little different in terms of what they print out, but that should then drive them to a cardiologist or pulmonary hypertension specialist to finish the workup.
Yeah, and I guess just this will be dependent on strength of the data as we look ahead. But for a lot of us who are kind of modeling and like to use analog analyses, is there any reason that future therapeutic penetration should be that different from what we see in PAH, for example?
There are some important differences. PAH is an orphan disease, not common, less well understood by physicians. The price tag on those drugs is very high. In order to be able to prescribe it, payers are insisting on seeing hemodynamic data to confirm the diagnosis. That won't really apply to this group. Again, more commonly here, they'll start with an internist and then go to a specialist. I will say that when patients can't live a happy life, they get very proactive. It's not your cholesterol, which you can't feel on a day-to-day basis.
That makes sense. All right, and maybe as we start to turn to some of the clinical considerations, maybe you can just run through the different patient populations that were studied in various prior trials.
For PH-HFpEF?
Yeah, yeah.
The definition of PH-HFpEF is straightforward. Elevated pulmonary artery pressure is the PH part. Normal ejection fraction with an elevated wedge pressure is the left ventricular part. There have been clinical trials testing approved pulmonary vasodilator drugs in this disease. They have all failed. I will explain they fail because they are targeting lowering the pulmonary artery pressure. We believe that the target is really the elevated wedge pressure. Our drug is the only one that I'm aware of that specifically will lower the wedge pressure because of site-specific action on the splenic circulation.
There is data we think sort of outstanding right now on two other Group 2 trials. So HELP and LEVEL have both tested our drug in patients with PH with left heart disease, but specifically from HFpEF. There was a Lilly relaxin trial recently that was a HFpEF trial, not necessarily PH. There is the CADENCE study with sotatercept. That is a smaller population. Think of it as a less sick population with pEF than we're looking at. And then there's the REFIRE trial, and that is almost all of Group 2. So HFpEF can underlie PH in that population. So those two trials have slightly different populations.
Yeah, perfect. All right, so you started to allude on this. Maybe you could just give us a little more detail on levo's mechanism. And I guess the specific question is your primary endpoint, six-minute walk, not PVR. Why is that the right measure?
Okay, so the problem in HFpEF is that there's excessive blood volume going into the heart and lungs. That may be a little hard conceptually to understand that, but if you think of the gas tank and when you hit the pedal to go faster, if you wake up in the morning and you want to jog, you need more blood volume to carry oxygen to your skeletal muscles to run. So where does that come from? You don't get a transfusion. That comes from your splenic circulation that gets constricted because your sympathetic nervous system says, "We're running," and that loads the heart. And then when you're done running, sympathetics go away and the blood goes back into your abdomen. It happens in everybody all day long, a little bit more, a little more, a little bit more.
In these patients, we have shown that this splenic blood volume is constricted 24 hours a day, even while you're sleeping. You don't need all that blood volume. And when you start to run and the sympathetics kick in, the filling pressures start going way, way high, interfere with your oxygenation, can't run, can't do very much. That just makes the best physiologic sense in terms of a target of reducing the overload filling, which lowers the wedge pressure. The two have to go hand in hand. If I lower the filling, it doesn't affect the wedge pressure, we're off course. If we lower the wedge pressure somewhat, but the volume doesn't change, we're off course. So we've linked mechanism of action to hemodynamic response, which is linked to six-minute walking better.
All right, perfect. And actually, I never asked you this before. That's on the venodilatory/vasodilatory effects of levo. There's also some inotropic component. How does that fit into the story?
So the inotropic component is actually why the drug was even marketed back 25 years ago when HFrEF was the dominant heart failure thing, and the perception was we have to improve the ejection fraction to make them better. In this disease, we studied the effect of the drug on left ventricular ejection fraction. There was no change. There was no change in contractility. So we've demonstrated that the left ventricle is not responding to the inotropic effect in that way. It is possible that the inotropic effect will work on the right ventricle because the right ventricle is being hurt by the pulmonary hypertension. Hard to measure. We were unable to measure the ejection fraction change in the HELP trial, but we now have some AI software that should give us a better look at it, and we're going to take a look at it.
Interesting. All right, so I have to ask the question. For what we do have of the CADENCE data, very little, what do you make of it? I guess there's a hypothetical, what if at ACC next year, and I'm actually not clear if they're showing the data at ACC in full yet, but let's say at ACC next year, they do show a positive clinical benefit, then their PVR translates to the clinical outcomes. Does that change how you think about anything that you just laid out?
Not at all. We're in phase III. I can tell you with high confidence this mechanism underlies all of HFpEF and PH-HFpEF. I can see other drugs being used, adding on to levosimendan when it's on the market to try to get a better efficacy. I don't see any of them replacing levosimendan because of different properties. Those are years away, but I can tell you from what I know about the disease and the physiology, this is fundamental to the problem. So if you're going to replace this, you're going to have to do better.
I think everybody's anxious to see that data and curious when we will. I think they quoted a clinically meaningful reduction in PVR. And when we look at previous PVR lowering PAH drugs in group two, we're not sure what that even means, but there will be clarity. There are a lot of great researchers involved with that study. Whatever conference it comes out at, we'll see it, and I think everyone will be really interested. I think we feel the same way with levo. Let's wait and see the data on some of these points.
Awesome. All right, maybe just a couple of quick questions about the previous HELP data. For the six-minute walk that you observed, did that correlate with any other efficacy outcomes or biomarkers like NT-pro, wedge pressure, et cetera ?
The wedge pressure at the end of six weeks was lower when we did the rest and exercise right heart cath. The correlation is lower wedge pressure for the group, better walk for the group. People ask us about is there a direct linear effect from one to the other. The answer is no. Humans are humans. Some people have long strides, small strides, et cetera. People also point out that the reduction in wedge pressure with exercise at the end of the trial was less than it was in 24 hours. Was the drug still working? The answer was absolutely. Look at the six-minute walk, which was also done at the end of the six weeks, and that treatment effect, which could be even larger in someone on an oral steady state.
The change in BNP that you referenced, so the data on reduction in BNP from oral levosimendan is really the data from the transition from IV up to one, two, and then three milligrams a day. It was a 23% reduction in BNP from the end of the IV use in patients in the open label extension to the three milligrams, and it's in the PRECIS trial. We tell folks who are interested in BNP, it's a great endpoint. The PRECIS trial with oral levosimendan in several hundred patients showed a significant reduction over about a year and then a return, an increase in BNP when they were taken off drug. So it is a well-established effect of even the one and two milligram doses of this drug in patients with heart failure.
Yeah, perfect. All right, so I wanted to turn over to the LEVEL study and just kind of ask what you're seeing at this point on a blinded basis that's kind of giving you confidence as you keep moving forward. So one of the first questions is, what's the baseline characteristics of some of the patients that you're getting in, specifically on six-minute walk from some prior studies? I think I had 300 meters, give or take, in my notes. Is it around that range? Is that what you'd expect?
In the HELP study, the baseline walk was 282 meters. The HELP study, 44 subjects willing to undergo three right heart caths in six weeks, so a symptomatic patient. It's right to expect that it will be higher in the LEVEL trial, but we haven't put that data out yet. Certainly possible that we could put the demographic data out there. Most heart failure trials do that in phase III. Not a lot of PH trials historically have done that, but it's possible that we'll put the demographics out there while folks are waiting for the database to be locked, et cetera. Other than that, we haven't really put too much demographics out there. It'll be more than 282.
That's fair.
You're right.
That's fair. That's reasonable. All right, what about the patients who are on SGLT2 GLP-1 inhibitors or agonists? Do you think that'll have any impact on the data also?
So the use of those drugs in our trial is consistent with the U.S. population overall. So none of the patients in HELP until the open label extension were on SGLT2 inhibitors. And when one of them was on a combination of levo and SGLT2, it led to a patent being filed. So they had a great response. So we don't know, but we will certainly be able to see in analyses after we finish LEVEL the effect of the drug on patients with and without SGLT2 inhibitors. GLP-1s in this population, because many of them are obese or have diabetes, is also increasing as time goes by, not as much as the SGLT2. Will it affect the data? We will certainly have enough to know.
Yeah, that's reasonable.
I do think it's important to note that we essentially require that patients be on a stable dose of either of those drugs for 30 days and that they have been on them for at least 90 days before they enter the trial, and the vast majority of these patients, when they enter, they're getting their right heart cath done at that time, so essentially, they've got to meet the hemodynamic criteria, which we think is so key to the enrichment of the study, despite any benefit they've had from either of those or either of those drugs.
Yeah. All right, that's a good point. Makes sense. What's your expectation for what the control arm is going to do on six-minute walk over this time period?
When we created the structure for the phase III trial, we anticipated they would be less sick because it doesn't require three right heart caths and it was oral rather than IV, so less sick patients will be willing to enroll, and that they might be on at that time, at least the SGLT2 inhibitors. The GLP-1s really weren't in vogue yet. So we decided to say no difference in the placebo group over time, and all of the benefit would be an increase in the six-minute walk in the active group.
Okay. And what effect size did you power the study for again?
So the study is powered for 25 meters.
Yeah. That's 25 meters with a 55-meter standard deviation. Have you seen where standard deviation is tracking right now versus your assumptions?
So the protocol has built into it a blinded reassessment.
Is it a sample size reassessment?
Yeah, it's a sample size reassessment, right? And the paper on the protocol explains that once 150 have been randomized and treated, that assessment can be run. And the deliverable of that assessment is the trial size can increase to ensure that we have 90% power up to a cap. So we haven't commented on the timing of that assessment. What we've done is just remind everyone that we expect to enroll 230 subjects the first half of next year.
Yeah. Are you planning to actually give an update once you perform the SSRE?
It's not required by the assessment itself. So there is quite a lot of research out there on how these ought to be done and what can be said about them.
We were talking to one company earlier, totally different space, but they're also doing a similar SSRE with actually a similar time frame as you guys. I think they're not disclosing it, but at the same time, I mean, you can see if the clinical trial page is updated to change the sample size. And in that case, it's kind of helpful to update investors sometimes, so.
That's a good thought. We're aware.
All right. That makes sense. That makes sense. I guess one consideration is going from or using the oral formulation in the study.
Yes.
You alluded to this before, but what exactly did you guys see on the exposure response analyses, also understanding there's a metabolite involved? And also, I guess one question is, when do you measure the six-minute walk relative to Cmax, Cmin, et cetera?
In the HELP study, by design, the walk and the final right heart cath and everything at the six-week visit were done at trough. The results we got were at trough with the IV. With LEVEL, the patient can come in exactly at week 12. They can come in day early, day late. They will have been on steady state of the drug for several weeks at that point. Part of our confidence in thinking about the result of this trial is that we got 29 meters at trough with the IV, and we believe that the concentration in these patients is going to be markedly better than that on a daily basis.
Of course, we're able to see what the safety of these patients looks like in the open label extension, obviously looking at blinded data during the randomized phase, but we feel like we're in a good place there.
Could you file based on the LEVEL study alone?
So we do get this question more and more, and I think it's because there's been so much interest in how the government and the FDA and the new administration are accelerating or talking about accelerating things. But our guidance has been that there's really no discussion we've had to date with the agency about filing on one study. In fact, we've talked to them for a couple of years now about the opportunity to do a single or two phase III. And the plan we've gone with is two phase III at p-value of 0.5. So yeah, so there's really no discussions we've had with them to date to suggest that that would be possible. And they're going to want a safety database that allows them, makes them comfortable approving a drug for a population of this size. It is really different, I think. Yes, high unmet need.
Yes, zero available drugs. Often a fatal diagnosis. Yes, yes, yes. But three million American patients, an addressable market of $20 billion, right, from one point of view, it's a lot of people globally who have HFpEF and could benefit. I think they're going to want to be really comfortable.
That makes sense. All right, maybe we can just kind of wrap up with cash runway milestones for next year since it's going to be a big one.
I think the milestones really are announcement of the end of screening or the last patient randomized at some point here in the near future, and then the start of the second trial coming up. There's just nothing like getting the trial up and off the ground, no matter how much planning you do, et cetera. Once you have a patient enrolled, it's a different status. And then data, the second half of next year is the current expectation for LEVEL. So a lot in the next year. We're funded, we expect we'll be more than 12 months past top line for LEVEL. We're funded through the end of 2027. We did the raise of $100 million a little over a year ago, and then this March brought in another $25 million.
And people who look at the filings closely can see that there is a little bit of funding coming in all the time from warrants that we've created this year, but also a lot of people should remember there were deals done before that with warrants that are now worth several dollars to a group of investors who are interested in that. So it's been good for us to be able to bring in some funding.
Awesome. Well, big next year. We'll be talking soon.
Yeah, let's get that.
Thank you, Gavin.
Thanks for doing this. All right.
Cheers.
Appreciate it.
Good job.
Good luck to truth as well.