Okay, I think my name is David Risinger. I'm very much pleased to welcome Tenax Therapeutics to the Leerink Global Healthcare Conference. With us today, we have Christopher Giordano, the company's CEO, Stuart Rich, Chief Medical Officer. Without further ado, we should get rolling. The company had a very exciting press release this morning. Congrats on the earlier-t han- expected enrollment of LEVEL. Maybe Chris, you could just provide some high-level comments briefly, and then we'll go into additional questions.
Great. Thrilled to do that. Right, we announced this morning that we've achieved our target of 230 PH-HFpEF patients randomized in LEVEL. It took us right around two years to do that, a little bit ahead of expectations. We've been guiding first half. There are patients still in screening, but not for long. We will wrap up randomization for the study in March, and therefore, we've also been able to narrow our guidance on the results. We've been saying second half, and now, with it being a 12-week study, we can say third quarter. The other news in the 10-K, we filed the annual report today.
The liquidity has come up very nicely, essentially since the time that we did a PIPE, with you guys leading it a couple years ago, and that's obviously been helpful. We started the year with a little bit more cash, than we had a year before. Again, thanks to the kind of fund generation that's come from some of those warrants that we arranged back then. That's a good plus for the company. We're funded well past, you know, probably around 18 months past data at this point.
Excellent. Stuart, I thought it would be helpful for you to characterize why oral levosimendan is the right mechanism to treat PH-HFpEF.
Sure.
Now, that's a very simple question. I know the answer will be not that.
A little less simple.
Yeah.
Okay.
Not a one-sentence response. Yeah, I think that context is important because a lot of people don't appreciate this specific drug and what you see in it.
Understood. The principal concept of volume redistribution, where blood goes from your splanchnic circulation into your lungs to allow you to run and increase your cardiac output, was described in the 1960s. That's not a new discovery. What is more relatively new is the fact that patients with PH-HFpEF have an overstimulation of that mechanism to the point that their lungs are flooded with too much blood, and that raises the wedge pressure and the pulmonary artery pressure and the right atrial pressure. The proof of concept that that is the problem is demonstrated by a company that developed a balloon mechanism device that they can place in the vena cava and obstruct blood flow. If there's too much volume, then obstructing the blood flow should lower those pressures.
Sure enough, the right atrial pressure and pulmonary artery pressure and wedge pressure came down while the cardiac output stayed stable. The next question was, if this is from the splanchnic circulation, let's paralyze the splanchnic circulation and block that ganglion and see if, in fact, it is coming from the splanchnic circulation. Sure enough, same hemodynamic effects, right atrial pressure, pulmonary artery pressure, wedge pressure come down. Then we say, well, if our drug works on dilating the splanchnic circulation, let's see if, in fact, that is the case. Our HELP phase II trial showed not only the exact same findings of the reduction of the pressures, but if you put our hemodynamic results next to the splanchnic block data, they're identical.
I think we have now reassured that we have the right proof of concept of mechanism of action for this disease, and that, as we've shown in HELP, translates to walking farther, feeling better.
Excellent. Could you just provide an update on LEVEL? Specifically, you know, in the past, you've talked about retention in the trial, persistence, any additional commentary you can provide.
Yeah. At this point, obviously, we're blinded, but we look at safety data quite a lot. We look at and are reassured by a couple of key things just in terms of trial participation levels. We continue to have a very high rate of participation in the open- label. Patients come in, they're randomized for 12 weeks, and then they have the opportunity to enter the open- label. You don't wanna see a lot of people dropping out after a while. What we see is a very high retention rate. We also know that the consumption of capsules, remember, this is a three times daily regimen. Patients take 1 mg three times a day. The consumption is extremely high.
As Stuart just described, we have a drug that we believe addresses the symptoms of the disease. If patients feel better, we think consumption will reflect it, and you'd be wary if there were a real decline in consumption. We're very reassured by that. Then, of course, the number of patients who go into the OLE is well above 90%. We feel comfortable there as well.
Maybe you could recap just the patient experience that you've heard generally from investigators. Obviously, this study is blinded, but you know do have also patient experience from HELP. If you could just recap that and also talk about, and particularly Stuart, with your experience, you know, what do placebo patients experience, you know, in clinical trials? PH-HFpEF patients, what do they experience? Can they have a placebo effect?
Okay. That's a little complicated. Number one, the patients in HELP and the patients in open- label LEVEL feel better, and they're open about that. And, we get anecdotes of things that they're doing now that they claim they were never able to do before. I don't want to go too much into that because they're anecdotes, and you know, I don't want to overstate. The fact that the physicians tell us the patients like the drug, and they stay on the drug, and they're not dropping out because of AEs is very reassuring that the drug appears, at least from the distance, safe and effective. And as far as placebo patients go, it's very much dependent, David, on how sick they are when the trial begins.
Patients who are really sick are not gonna get better on placebo because they're so ill. If anything, they get worse, and that's what we had in HELP, a very sick group. Patients who are less sick might improve simply because it's a six-minute walk, and they want to exercise between visits, so they can perform well, et cetera. You have to be careful when you design your trial to make sure that everyone who is part of the administration of the six-minute walk test does it the same way, advises the same way. We have been a stickler on that in our trial. The fact that the variance that was discovered from the sample size reassessment was small n suggests we've been very good about that in keeping outliers out of the response group.
Excellent. Could you just talk about that enrollment in LEVEL relative to HELP? A little less sick.
Yes.
Characterize that some more?
Yes. A little less sick. I think, as we look at the baseline demographic data, it's just the right patient group that we were seeking in terms of how sick they are, what their ages are, if they're functional Class II and functional Class III. The HELP trial enrolled sicker patients for obvious reasons. They had to do three right heart caths. They had to go home on an IV therapy that had never been given out of an intensive care unit before. If you're gonna agree to do that, you're gonna have to be very symptomatic and want it. That was no surprise. LEVEL is addressing the population that is the dominant population of these patients out there.
Got it. Any figures on that? What proportion of the PH-HFpEF population that you'd estimate would meet the hemodynamic criteria in LEVEL?
A very high amount. Patients who are asymptomatic aren't ever gonna get in the trial, and they're not gonna go to their physician and say, "I need something." Patients that are critically ill and very sick are gonna be treated differently. There are papers published, primarily Barry A. Borlaug at Mayo Clinic, showing that even if the resting hemodynamics are not severe, the moment they exercise in the cath lab, their hemodynamics get very abnormal. Numbers out there are saying about 80% of patients with HFpEF have pulmonary hypertension. That might be true. It may be a little less than that.
There are a couple of issues here, right? Thinking about how many patients with HFpEF would qualify for this drug if approved in the future, right? That's where we tend to think that when a HFpEF patient is exercised during a right heart cath, they're very likely to reveal PH. I think that's where the 80% number comes in, right? How widely used would this drug be in a HFpEF population? A different question is really knowing what we recruited in the HELP study and what we're recruiting in LEVEL, so essentially, how enriched is this population, right? We'd encourage anybody to look at the design paper and take a look specifically at the pressure criteria that we extracted from the HELP study in order to create inclusion criteria for LEVEL, right?
It's not an all-comers population. This is a patient with elevated pressures because they clearly demonstrate PH. The reason for that is that we saw that about 85% of the patients exposed to an IV infusion of levo responded really well in HELP. We essentially looked at the characteristics of those patients when it comes to hemodynamic measures, and we made those the criteria for LEVEL. I remember you used to ask us, "Gosh, if there are 2 million patients out there, guys, why does it take you over a year to enroll the trial?" Now that we're finished enrolling, we could say we think it's a good thing that we are recruiting folks with elevated pressures who will demonstrate benefit.
At the same time, we think that a lot of HFpEF patients, when reviewed in the future if levo is approved, they're gonna have a PA pressure greater than 20. They're gonna have PH. They're gonna probably benefit from using the drug.
Yeah. It's an enrichment strategy that I think is gonna really carry the day here.
Excellent. Maybe we could pivot. Yeah, and this was an update late last year, but you obviously had a very encouraging update on the statistical analysis. Could you just provide a little bit more detail on that, and just how much that increased the powering of the study?
The sample size reassessment that you're talking about, which was blinded, was just to look at the standard deviation of the six-minute walk after 2/3 of the patients were enrolled in the LEVEL trial. That was part of our statistical analysis plan because, not knowing what that would be, we extrapolated from the HELP study a 45-meter standard deviation, which was based on very few patients, small trial, and so we put in our statistical analysis plan the opportunity to do this re-estimation of sample size. The agency agreed that that was a good thing to do.
We enlarged the trial, if you remember, to standard deviation of 55 and 230 patients evaluable. We were not allowed to withdraw the statistical analysis plan of doing it. It was still good advice, and we did it, and sure enough, what it showed was that, the standard deviation was considerably lower than 55, and so again, the power and that standard deviation kind of go hand-in-hand. Now the lower that standard deviation goes, the higher the power of the existing trial. We couldn't shorten the trial if we wanted to 'cause there's no alpha penalty here.
Yeah.
We're blinded to it, but now we are considerably higher than 90% power for the existing trial that's ongoing now.
Excellent. With respect to the expected improvement in six-minute walk, you know, I think in the past many have thought about, you know, a 20-meter improvement or more would be clinically meaningful, but could you also contextualize that by talking about baseline and percentage improvement, you know, and why a modest percentage improvement would still be so clinically meaningful?
We're asked that all the time. The first point I want to make is that there has never been a successful phase III trial in PH-HFpEF. Whatever our result is, that's gonna be the new standard to match. People look at the PAH trials and see a 30-meter improvement on average of a younger population with much less comorbidities, higher baseline six-minute walk. We are an older population with a lot of comorbidities and concomitant medications, so I think 30 meters is a stretch. We chose 25 meters as the targeted six-minute walk in LEVEL, and there's no reason at this point, David, for me to think that that was a bad choice. It's on the assumption that the placebo group has no difference, and all of the benefit comes from the active group.
If it turns out to be lower than that, then that's what it will be. I think when you ask KOLs, the numbers are all over the place, whether we're 10 meters, 20 meters. I don't like to get stuck on that, honestly 'cause it's more speculation, and I don't know that that's very helpful.
Got it.
Yeah, no, I think it's important to say, we talked earlier about here are some anecdotes from the open- label, right? Here are some things that physicians who've enrolled patients in the trials tell us about their patients' lives being transformed. You said it, that the patients are open about the fact that they're feeling better sometimes. We don't have 175 of those anecdotes. Like, but they're real, and like if a patient is feeling a lot better and they're able to do things, of course, we like to hear that. There are companies out there right now who maybe have completed a trial and who have their results and are gonna present them months from now, and they might provide kind of tips on what's coming. I like to be really, really clear. We are a small company, and we don't look at six-minute walk data.
Even having done a BSSR, it's a statistics team outside of our company who did a blinded review of basically two data points for 150 patients. We don't look at six-minute walk data, and people shouldn't. It's too risky. I say that now for investors, but also for posterity. Like small company, don't have the structure to have like special groups looking at some data. We have no idea what's going on in the six-minute walk data.
Very good. Maybe Stuart, you could talk us through the design of LEVEL. So blinded, washout, OLE, and then, you know, what you've learned, right, from the patient experience. Just continuing on with what you've heard anecdotally.
Good.
And in the open label, you know.
All right.
section.
During the trial, it's hard to interpret w hen a patient says they're getting better. When the trial ended, there was no real wash out, David. The blind remains. We don't know who was on active drug and who was on placebo in the LEVEL trial, but since everyone started the LEVEL trial at 2 mg a day for four weeks and then was increased 3 mg. everyone who went in the OLE was started again on 2 mg a day and went 3 mg. some of the patients who were 3 mg because they were on active in the trial got their drug dose reduced. We had heard that some of them said, "Hey, I'm not feeling as good anymore." When the drug was increased back 3 mg, they felt better again. That's what we've heard. I don't want to make too much of it.
It says that the drug was working so well that they were sensitive to going a dose down, and you may say, yeah, and that's why they take it three times a day. Because they're sensitive to it. Let's not read too much into that. As I say, everything that we look at, the general safety database, the AEs that occur, the compliance rate, the enrollment rate in OLE, all of those speak to the fact that patients want to be on the drug. Then why do they want to be on the drug? Because they tolerate it well, and they feel better.
Excellent.
Perfect. When patients may be responding, what are they experiencing clinically, or how do they describe feeling better?
The typical daily life comment is, "I can do things now I couldn't do before." They'll give their physicians, "Thank you. I can now go out to a restaurant. I can visit my children or grandchildren. I can participate in an activity." We've heard some crazy things about participating in a marathon or digging a cave or things like that. Again, let's not read too much into that. It's the medical goal is to restore their circulation towards normal, and the clinical goal is to restore their quality of life back to normal.
Excellent. With respect to the global trial, so pivoting to that, I would think that the updates you've provided would suggest maybe you could end up hitting, you know, enrollment completion before the end of 2027, but don't wanna get ahead of myself here.
Good. Thank you.
Could you just frame global for us, just where it, you know, the design of it, where it stands today, the investigator receptivity, et cetera?
Sure. We haven't enrolled a patient in LEVEL-2 at any of the LEVEL sites, right? We kept those sites very much focused on LEVEL, but we will soon see an uptick in screening in LEVEL-2 from some really good sites in LEVEL who some of whom, of course, are anxious to have the opportunity to continue enrolling. In the U.S. we expect, because we've got some great sites, we hope it'll recruit well again. I would expect, for example, that Argentina and Brazil will recruit more quickly. We'll be in at least 10 countries in Europe and the U.K. We'll be in Korea and Taiwan. That's the current plan. A much larger footprint, about double the number of subjects and 26 weeks treatment to the primary endpoint instead of 12 weeks.
I think it'll be a good long while before anything would convince us to adjust our estimation of two years to recruit. I think if we can get, you know, 240, 230 in the U.S. in two years, we ought to be able to get double that in 3x the number of sites globally. It takes, as you know, a little longer to get sites started outside the U.S., but they do tend to enroll quite a bit more quickly. We've got great pulmonary hypertension experts around the world involved, a lot of great HFpEF clinics across Europe. There are many sites who, I think, their understanding of how levosimendan works in these patients will evolve, but they use levosimendan all the time.
It's exciting for us to be opening centers in countries where levosimendan is a staple of acute heart failure care and where they're very excited to have access to the oral. They've heard about it from Orion's trials. They've heard about it from the PERSIST study, where several hundred heart failure patients were treated with 1 mg and 2 mg. It's exciting for us as kind of the new kids on the block, the Americans, to be going to Italy and Spain and Germany and France and the U.K. and talk to people who say, "Well, we can tell you exactly how it works." It's Q3 we'll have data, right? People who are listening to this and thinking, "I've been following this story.
Maybe I'll get involved, call some cardiologists in Europe who use levosimendan and just ask them how it works. Just ask them very open questions. How do the patients feel? What's your experience with levosimendan? I'd encourage folks to call anyone who treats acute heart failure in Europe and ask that question.
Just to add to that, remember, the results of LEVEL will be out shortly. That will only help enrollment into LEVEL-2 .
Yeah.
That will be another catalyst for us.
Excellent. Let's talk about that success scenario. Assuming that you have that positive news that LEVEL has succeeded in the third quarter, could you remind us about sort of the current baseline assumption for when you would have enough patient safety data to submit an application or the scenario in which you might be able to submit earlier, maybe a rolling submission?
Right.
Obviously, we don't really know who's gonna be where, when it comes to politics and the FDA, so things can change overnight. Still you may have a case to be made irrespective of who's running the FDA and who's, you know, writing a, I don't know, a paper about doing something differently.
Who's ending the dogma of the one trial? Yeah, I'd say this. The comments by FDA leadership and the two-page policy expression that we saw have led us to have conversations with our ex-FDA official advisors, our regulatory experts. That's about all that's happened, I would say, and that's about all that's changed. We've had more discussions about it, and we've thought about it more. What's proposed in the statement in The New England Journal is that people might start out their phase III with a single trial in mind. That wouldn't be new.
What's also suggested, although there's no discussion of p-values, is that people might go to the agency with a completed single phase III where the p- value's great and the treatment effect is good and present that, and say, "Do we really need to run a second trial?" That also would not be new. We know of circumstances, and our advisors shared several as well. Some of the pushback from current FDA, you know, members of FDA who are saying, "Oh, come on, this isn't the way we do policy around here," is because there's nothing truly innovative there, but there's certainly a different way of communicating, and a different posture being stated by the agency.
Again, to go to a really successful scenario, I think it's reasonable for investors, patients, the public in general to think that any pharma company with a really positive phase III trial would go and talk to the agency about it. The agency has told us for a couple of years now repeatedly, in discussions about our program, that they'd like to see 300 patients for six months and 100 for a year, and so they'll get more than that from our current program, and therefore our guidance remains that we anticipate running the two programs that are currently underway. I'll tell you, we're gonna generate a lot of safety data according to that program, and we like our safety data.
We want the agency to be in a very comfortable position when they look at our efficacy and our safety with this drug. It hasn't been approved in this country. It hasn't been tested at 3 mg a day. It hasn't been tested in PH-HFpEF patients. We feel really good about what we hope to get, but I like our safety data, and I want a lot of it to put in their hands and just see what they say.
Excellent. Maybe you could talk just a little bit more about, you know, how you've been operating the company, and, you know, that ramp of the second LEVEL trial. Obviously you have CRO partner, et cetera, but the ability to scale.
Yeah
you know, from a very small size.
Yeah. We've sort of tripled our number of FTEs, our employees since we raised, you know, $100 million-$125 million almost a year and a half ago. We've also added a lot of FTEs who aren't employees. I think what's gonna happen with what's happening now with a trial where we're going into so much new geography is that we're having to, you know, put in place employees and colleagues who will build relationships like we're able to build in the U.S., that are just too tough in terms of time and travel for us to build as quickly as we can in the U.S. Stuart is known worldwide as an expert in this area, and we have to leverage our data, the experience with levosimendan for over 25 years.
Obviously, a position that we have thanks to Stuart's presence in academic medicine, we wanna leverage that and so we're building a workforce that gets very involved with opinion leaders and investigators during a trial and builds the kind of relationships that drive recruitment and that drive open dialogue during the study about what's going on with patients. That's critical to good study execution. Obviously, that then is the seed for a much larger organization that we'll need when we look to globally commercialize the product because we've got. Actually, when we finished HELP, we had a license for the use of IV levosimendan in North America. We had no patents.
We have patents, we have cash for well over, you know, a year past data, and we have a global license and, you know, the patents, the license cover every formulation. It's a very different structure, but now we need a pre-commercial relationship management and medical team out there, and so that's a lot of company building.
Excellent.
Yeah.
Well, we are over time. This has been great. Thanks so much for being with us here in Miami.
Thank you.
Thank you, David. Always a pleasure.