Welcome everyone to our next session here. It's very much my pleasure to welcome two members of the leadership team of Tenax. I thought we'd actually kick off and assume that not everyone has read your bios. Maybe just very briefly, Chris, if you could just describe your background. Then you, Stuart, I thought that would take up most of the time. No, I'm just kidding. I think it would be nice to set the stage, right, because you both have very complimentary experience to execute. Anyway, obviously we have CEO Chris Giordano and Stuart Rich, Chief Medical Officer. Chris.
Thanks, David. I'm Chris Giordano. I joined the company almost four years ago when it was described to me as an opportunity to lead a company with a phase three ready asset. My background is in clinical development. I basically have been managing clinical trials at large CROs for a little over 20 years, much of it in the cardiovascular space. That's what brought me to Tenax.
I am an academic cardiologist. Started my career in 1980, starting with pulmonary hypertension and heart failure, and have been involved in the development of drugs, understanding the disease for over 40 years. I also had a time where I was a standing member of the FDA Cardiovascular Renal Advisory Committee, which gave me a lot of training in clinical trials as well. Developed an interest in levosimendan before I joined the company, had a conversation with them about testing it in this space, PH-HFpEF. Did a phase II trial, which was successful. COVID came, and I decided to leave the medical center and join Tenax to be the Chief Medical Officer.
Excellent. Excellent. Well, congrats on your recent corporate updates. Chris, maybe you could just discuss the key news that you disclosed last Wednesday, and then we'll take it from there.
Great. We have an ongoing phase three trial in group 2 PH. We aimed to enroll 152 subjects, and we recently announced that with FDA's input on our protocol amendment that we proposed, we're going to increase that to 230 subjects. We now anticipate enrolling 230 subjects in LEVEL by the end of this year. They also reviewed a protocol for the second phase three trial we need to complete in order to file for approval, and we're going to start that now. With the funding that we've raised in the last year, we're in a position to aggressively move forward with both of those studies, a larger LEVEL and the initiation of LEVEL-2. We anticipate enrolling a patient in LEVEL-2 this year as well.
Excellent. Excellent. Maybe you could just touch on the market opportunity, right, which obviously is quite significant assuming the drug succeeds. Could you speak to that?
Sure. Sure. The market opportunity, we're designing this program and really developing levosimendan as an oral product specifically for patients with PH that results from HFpEF. Group 2 PH includes PH from HFrEF, PH resulting from valve disease, and PH- HFpEF. We're very specifically targeting PH HFpEF. We think somewhere between 2.2 and 3.7 million Americans at around the time that we would launch. That's the prevalence. We think that the total opportunity, if we look at the addressable market, is at least $6 billion and could be upwards of $10 billion. It's an enormous market opportunity. Of course, there's not yet a drug approved for patients with Group 2 PH. It's an exciting opportunity. I think the investment in the area in the last year or so has shown real interest and a real acknowledgment of the size of the potential market.
Excellent. Stuart, maybe you could just give us some background and perspective on IV levosimendan. Some of the questions that we receive are, well, how is it possible that Tenax is developing this drug when the IV formulation was not ever developed for PH-HFpEF and it is actually off patent ex-U.S.? How should we think about it for such an old drug that is now been reformulated as an oral?
When levosimendan was discovered and developed, this is 1998, the target for the company Orion, which is a Finnish pharmaceutical company, was acutely compensated heart failure. Drugs at the time that were popular were inotropic drugs to take patients with heart failure in intensive care units, make their ejection fraction go up, cardiac output go up so that they could survive over the short term. At the time, they also described the drug had a potassium ATP channel activating property. Potassium channels regulate all of the circulation in the body. In this case, when it's abnormal, it downregulates. The activator property puts it back to the normal level. They even did preclinical work that described site-specific activity on the splanchnic circulation, which is your abdomen where all the blood kind of sits most of the time, and saphenous veins, et cetera.
That was not their purpose of developing the drug. Twenty-five years later, it's been used in over 2 million people in 60 countries, but never in the United States. It is off patent. It's still being used actively in Europe. When I approached Tenax regarding levosimendan, it was not my interest in IV levosimendan as an inotrope. It was my interest in pulmonary hypertension and other properties that it might have. At the time, Tenax, which licensed the drug from Orion, only had the license for IV. As you know, we put together a phase two trial which tested IV that was successful. Subsequent to that, we got the license to oral. That kind of shifted everything to a really viable product that a patient could take on a daily basis.
A lot of advantages of going to oral include you don't need an IV line permanently put in, which can thrombose or get infected. You don't need to stay home for an infusion at home. You can take a pill every day. Equally as important is you get a steady-state blood level of a metabolite. They're always on active drug, whereas during the HELP trial, their levels would go up and then kind of come down towards the end of the week.
Could you speak to the surprise that led to the U.S. Patent and Trademark Office issuing patents and really creating an important inflection for the company?
The surprise, that's the one way to put it. It was novel and not obvious. The novelty was that no one had ever used this drug in patients with PH-HFpEF or even HFpEF. Why? Because the drug was designed to increase ejection fraction. Why would you do that to someone whose ejection fraction was normal and does not need to be increased? In fact, considered counterintuitive was the non-obviousness that when I was trained as a cardiologist, we were told never to give an inotropic drug to someone with a normal ejection fraction. It could be dangerous. That is what really convinced the patent examiner that we qualified for a patent. The patent is for the use of the drug. It is not a composition of matter patent because that expired previously.
Yes. The duration of your protection?
Oh, it goes into 2040. If PTE is used, it would go to 2042. It covers all doses. It covers combinations with other drugs. It covers the IV as well as the oral.
Excellent. Excellent. I would love to get into a little bit more on the update that you provided last Wednesday. Maybe, Chris, you could just speak to what the patient experience has been in the LEVEL trial to date and during the open label extension?
Sure. Sure. Patients in LEVEL are randomized for 12 weeks. At the end of that, they go in, of course, knowing at the end of that, they have the opportunity to get into an open label extension, which will take them through a two-year period. They enter that knowing that they're now moving on to therapy if they've been on placebo, staying on it if they've been on it. They do have to, as they come in, start again with 2 milligrams and move up to 3, right? That way, as patients are coming on, they undergo the same experience with the active drug that they would have had if they had been randomized to therapy in the first place. Enrollment has gone well. We have seen encouraging signs in terms of the tolerability of the drug in the ongoing open label extension.
I think in an OLE, you can possibly see signs of perceived efficacy, and you can possibly see signs of tolerance issues. We have been very pleased that while we know patients are coming in and probably willing to undergo a lot for 12 weeks, it's not that long of a period. If they're thinking, "I'm going to be on placebo for a while, but then I can go on the drug," it's always good to see that they stay on. We have had very, very little dropout or withdrawal from use of the therapy in the randomized phase. Almost every patient has gone into the OLE, and of those, almost everyone has stayed on until now. We started randomizing patients a little over a year ago.
Randomization obviously picks up over time as more and more sites come on, but there are more patients now in our open label extension than we had in our phase two study, for example. That was a six-week study. We are now, and we continue to walk them every month. The burden on patients to continue to come into a hospital is substantial, and they are staying in the open label extension. That is, again, you can infer what you want about efficacy. What you probably would be more likely to see would be a problem once people know, "I'm on a drug. If I'm now having AEs, I might want to stop." We just have not had any concerns in that category at the moment. We will keep watching that. It will be interesting to compare with a later trial at 26 weeks.
Do people have the same tolerance to be on the placebo control for a longer duration? There is no drug approved in these patients, so I think we're in good shape.
Excellent. With that release and describing that, obviously some of the trial sites are already experiencing this, but will that help you accelerate enrollment just simply disclosing the figures that you've disclosed, the over 95% adherence?
Yeah. I think as we talk to investigators at the start of the trial about the mechanism, about the hypothesis, they pretty quickly understand what we're doing. As we talk to prescribers today and present them with a, as part of market research, present them with a target profile, they pretty quickly get a sense, "Okay, you're going after this underlying cause of PH-HFpEF and HFpEF." I think they sort of get it. I do think that when you see a trial is randomizing well, you might like to contribute to it randomizing well. When you see patients tolerate it well, and I do think people look at OLE experience in that way, I think it's worth putting out there because it can help. We always like to imagine that if we get a really positive result here with another trial ongoing, it'll have that impact.
I've run clinical trials in a class before. I was running a big phase three of a Factor Xa inhibitor when the rivaroxaban ROCKET AF data came out, and the trial enrollment picked up substantially at that point. When people see that a class works, it can help.
Makes sense.
Yeah. People are worried about putting a patient in a trial. Patients are worried about being a guinea pig, right? When you can show them, "Look, it's well tolerated so far," it makes an impression.
Excellent. I wanted to pivot to PH-HFpEF specifically. Stuart, since you're here with us, I thought it's a nice opportunity to hear from you how PH-HFpEF is different than PAH, why you think historically PAH drugs have failed in HFpEF to date. After you comment on that, just bring us back to oral level.
Sure. As you know, there are five groups of pulmonary hypertension described, and those groups were created in 1998 to define the targets for physicians to create therapies. That was really what drove behind that WHO classification. Group 1 is what was known as idiopathic, no known real cause. It was just an elevation in pulmonary pressure. All of the drugs developed and approved in that group are drugs that lower the pulmonary pressure. Group 2 was associated with left heart disease, in which case the target would be the heart disease if you can reverse it. Specifically with HFpEF, the target is the wedge pressure. That defines the disease. The way we distinguish between Group 1 and Group 2, PH HFpEF, is with a heart catheterization. Both have elevated PH pressure. One has a normal wedge pressure, Group 1. One has an elevated wedge pressure, Group 2.
Otherwise, it's hard to distinguish between the two. Group 3 is lung disease. Group 4 is thromboembolic disease. Thromboembolic disease, you would remove the clot. That's the target there. It helps define your target when you're trying to do a therapeutic development.
Excellent. Bring that back to oral levo in terms of why you believe this is the right mechanism that is likely to succeed in phase three.
Sure. As I mentioned before, it's an inotropic drug through its calcium sensitization property. The teaching in my day as a fellow was that inotropic drugs can lower the wedge pressure because as they raise the cardiac output, the ventricle empties and the high pressure can drop into the ventricle. That is the conventional thinking. However, when I started to work with Tenax and I asked for all of the clinical trial data that they had available, I saw on every single trial that the wedge pressure came down first and then the cardiac output went up. Totally the opposite direction, which then raised the question, "How is this wedge pressure coming down?" As I told the company, "No drug drops the wedge pressure directly.
There is some property to this drug I want to investigate because Group 2 made up half of my clinical practice, and it was the worst patient I could see to say I have nothing to offer you. That kind of just drove us into the design of the HELP trial, which was mechanistic to measure ejection fraction, cardiac output, pulmonary pressure, wedge pressure, elastance, which is contractility. The results showed very effective in lowering the wedge pressure at rest and with exercise, which is really difficult to do, translating fortunately to a clinical benefit of improved exercise walk.
Excellent. We have gotten the question about how to think about the fact that oral levo does not lower PVR and whether investors should be concerned about that. Can you comment on that?
Yes. It's a big source of confusion amongst investors and even physicians. You can't measure the resistance in the pulmonary circulation. What was done is to create a ratio of pressure over cardiac output, which is what we call resistance, developed really because of congenital heart disease in the 1950s, where you were correcting these shunts and you wanted to know where things were flowing and how the pressure was responding. Applied to group 1 because the wedge pressure is normal in Group 1. All you're really looking at is the change in pressure over flow. For those not familiar, it's an equation. The numerator is the mean pulmonary pressure and the wedge pressure. The denominator is cardiac output.
You can make that number go down if you raise the cardiac output, the denominator, or if you lower the numerator pressure, which is the goal in Group 1. In Group 2, the target, as I said, is that wedge pressure. What happens is the denominator actually changes and becomes smaller, and the cardiac output doesn't change, so the calculation is a higher number. If the PVR should be lower, then why is it going higher? That is the confusion. It goes in the opposite direction one might think unless you understood the elements that go into that equation. All I would say is, and what I've done even when I was teaching residents, I tell them, "Look at the individual factors that contribute to the equation, and you can understand better if the PVR goes up and down what's driving that.
Got it. Thank you. Maybe we could pivot to the news flow over the next year or two. If you could just speak to what you've said about the expected timing of the LEVEL top line phase three results and then how you see the LEVEL-2 trial getting started and ramping up.
Okay. Before we started initiating sites in LEVEL, we predicted we'd recruit 150 subjects by the middle of this year. We reiterated this week that we're on track to do that. I think the big target will now be 230 at the end of the year. At that point, people will know that we've got our final patient. We then need 12 weeks to prepare that final patient's second walk or final walk, and then probably a month to two months to do any if it's a slower patient, right? There's a little window there. Clean and lock the database. When we do release the top line, there's an onus on Tenax to release a bit more than just that we met our primary endpoint because I think the investors will need to know more than that.
They'll have to have a few more analyses than just the duration improvement or reduction as the case may be. That will be sort of mid next year. For the LEVEL-2 trial, I think what we'll end up announcing is that we've started enrolling in the U.S. at some point this year. We will probably have many of the best recruiters and sites overall from the current trial roll into the second one once that enrollment is complete. I think fall or late in the year, we should have sites across a number of countries start in LEVEL-2. We are planning for that to be a global trial. That's the neneedle-moving news flow that matters.
Excellent. Let me pause there and see if there are any questions from the audience. All righty. Maybe you could just speak to the recent capital raise and just highlight who your key investors are in the company.
Sure. Sure. Back in August, an investor called BVF led a big round. They helped us target a raise of $70 million. We ended up getting $100 million. They were joined by T. Rowe Price, Janus Henderson, Venrock, Vivo, Adage, Vestal Point, a number of great healthcare investors. Recently, with the news that we released last week, we also announced a single investor, RTW, has joined that group, and they've had an interest in the company for some time and have done a lot of work in understanding the disease and understanding the mechanism. We are thrilled to have RTW also join the group and are in a great position now in terms of our funding. We expect, again, top line data from LEVEL in the middle of next year, but we're funded all the way through the end of 2027.
That includes with all the funds that we expect to put progressively into the second trial. We are in a very different position than we were before August of last year, and we are thrilled to have such good support.
Excellent. Maybe we could pivot to looking ahead. A little bit over a year from now, you'll be releasing the top line results. Could you talk about specifically the LEVEL's powering now post the expansion, the endpoint, and just contextualize for us how clinically relevant 25 meters of six-minute walk distance really is, etc.?
Okay. I'll talk about the powering. You could talk about clinical relevance and meaningfulness. We are now powered above 90% to show a treatment effect of 25 m with a standard deviation of 45, sorry, of 55 m. Our standard deviation could potentially be larger now when we maintain 90% powering. We are powered at over 95% if the standard deviation is 45 m or less. Those calculations all assume 10% of the patients are non-available, and we are nowhere near that at present. That is a positive. In terms of the 25 m treatment effect, we are conservative there. When we look at health in the phase two trial, we had a 29 m effect.
We always like to remind people that at the time that we designed that study and even well into the open label extension, the plan at Tenax was to conduct phase three trials and eventually launch a weekly IV product. We didn't have the rights to the oral at that time, which we do now. The FDA requires trough data if you want to move forward in a situation like that. The measurement of the six-minute walk and the third right heart cath occurred in patients at six weeks at trough. We got an improvement of 29 m at trough. In the case of LEVEL and LEVEL-2, obviously patients will be on a daily oral and at steady state. 25 m as a treatment effect will be super meaningful to me, but I'm not one of these patients.
We think that we have a pretty conservative estimate there. Please talk about meaningfulness.
Yeah. So just for clarity, six-minute walk has been used in PAH, recognized by the agencies as a reliable endpoint. 30 m has been where a line has been drawn to say this is clinically meaningful. Keep in mind, those are younger patients, usually with only one disease, the PAH. In group two, they're older. They have a lot of comorbidities, including diabetes and other diseases. The expectation is that they will not improve as much as they got in PAH Group 1, even though we hit 29 in the phase II trial. We were conservative in downsizing their treatment effect to 25. Feedback we've gotten from KOLs is some say 15 m or even 10 m would be a meaningful improvement. Some have said anything, even one meter would be better given how miserable they are with this disease.
I think it's to be determined, but we're in a sense going to define that because we're the first trial using a six-minute walk that's already shown that it works in that regard. I think we're just going to have to build from there. I'll just add by saying I know that it works because my patients have told me that they feel better and walk farther. That's not science, but it feels good.
Excellent. Excellent. Could you just add a little bit of color on your engagement with the FDA sort of in recent years and then most recently? Just to, I guess, take us a little bit behind the curtain in terms of the engagement with the FDA that you've had.
I particularly had a very close relationship because Norman Stockbridge and Ellis Unger even considered friends because, as I say, because being on that advisory committee, you really got close to these people very much so. I'm assuming people know widely that Dr. Stockbridge retired at the end of last year. The current director was the former deputy director, Aliza Thompson. She's a nephrologist. In years past, she would kind of take charge of the nephrology products, and Norman would take charge of the cardiology projects. Now they have a new deputy director who's in charge of cardiology. It's a woman who I don't know. I've not met personally. Everyone says she's capable and competent, and I truly believe that's the case. It is a new administration. Personally, I'm reassured that they will continue on the path they've always been on before.
We sent our revisions to our current trial, which we released in the press release about upsizing with the one and starting the two, etc., etc. The feedback we got was consistent with all of the feedback we've had before. There's been no request or changes in the trial sizes. They confirmed that the safety database still has to meet for 300 patients exposed for six months and 100 exposed for a year. I think we're aligned. There are other questions that we raise, and we will probably be contacting them in the future about some of those questions, but I think we're sitting pretty well with them right now.
Excellent. Maybe if you could just connect the dots. We see this with a lot of companies, but obviously the market opportunity is tremendous. You're talking about millions of patients, but it takes a while to recruit just 230. Could you help bridge that for us?
Look, we've met our projections for enrollment in LEVEL.
Yes.
Going to Europe with a LEVEL-2, in many ways, may even go faster because of the reputation that some of these European centers have by being able to enroll faster. They're a little later to start. I think the real advantage is that we can cherry-pick from LEVEL those centers that have been super performers, and we have several of those, and then involve them into LEVEL-2, and that will help the enrollment as well. I think our projections regarding the completions are very conservative and realistic.
Yeah. Yeah. I mean, we have inclusion-exclusion criteria. We're not looking for anybody with PH or anybody with HFpEF, right? I would say the constraints within the academic medical system, constraints about which the heart failure academic leadership have been pretty explicit for many years, are a bigger factor than anything else. It takes many, many months to get contracts and budgets approved. The focus of academic scientists is not singularly supported in terms of clinical research by their management, right? There's just a different world that they operate in. I know that within heart failure, the leaders have always been asking for more of a focus on the research because it's so important. Those are the constraints, I think, that keep us from just running one of these trials in just a year.
I think if we can recruit phase three trials in under or around two years in cardiovascular, I think we can feel pretty good about that.
I might add that the conduct of the trial of LEVEL-2 is identical to LEVEL with the exception of the duration from three months to six months. The feedback from the big sites, they say it's a very easy-to-enroll trial.
Excellent. On that specific point, how should we think about these patients that you're enrolling? Are they quite similar to the ones that were enrolled in HELP? Given their comorbidities and other issues, how do you set the appropriate inclusion and exclusion criteria?
The HELP patients were sicker. If you look at functional class, there was about 75% were functional three in HELP, where it's about 50/50 in LEVEL. That's very typical of all of the HFpEF trials that have been published to date. What was the other part to hear?
Just ensuring the appropriate enrollment in the trial considering the comorbidities of these patients.
Right. Okay. We enriched HELP by doing a right heart cath, 24-hour infusion, and repeat right heart cath the next day to identify responders. It's a great way to enrich a trial. You give them the drug, and they respond, then you randomize them in the trial. The baseline hemodynamic data that got you into that group in HELP is identical for the level trials. That will give us an enrichment strategy of about 90% precision. I can't do much better than that for a trial. That was kind of easy to do. I would say it appears that we got the right patients coming in the trial, just looking at baseline characteristics right now.
In terms of comorbidities, right, there's an approval for SGLT2 inhibitors in HFpEF patients that didn't exist when we started the HELP phase two. A lot of these patients also have diabetes, obesity, so GLP-1s are along with drugs like empagliflozin becoming more commonly used in this population. We've had some great input from KOLs, great input from our sites, and we've tracked data carefully, and we're making sure that the use of those drugs will have a balance, if any, effect on our population. We're pretty confident that the mechanism we're going after shouldn't conflict in any way with the therapies that HFpEF patients are on. We're in good shape.
Excellent. I think we are out of time. This has been great. Thanks so much for being with us here today, coming down to Miami for this meeting.
It was great. We appreciate the invitation.
Yes. It was literally our pleasure.