We'll just get started. Hi, everyone. Welcome to our fireside chat with 10x Therapeutics. My name is Jennifer Kim. I'm one of the biotech analyst here at Cantor.
And I'm excited to welcome Chris, president and CEO and Stuart Rich, CMO. Thanks for being here with you guys. Maybe to kick things off, can you both do a quick introduction and give us a brief overview of the company?
Yes. I'm Stuart Rich, Chief Medical Officer of 10x Therapeutics.
And I'm Chris Giordano. Thanks everyone for your time today. Thanks for coming. I'm the Chief Executive Officer 10x. A quick overview of the company.
So we're consumed with our focus right now on the Phase III development of oral, which was submitted for group two PH patients with an injection fraction greater than 40. We're working with a drug that's been approved in 60 countries, started twenty five years ago for a different indication. Our phase two trial served as a proof of concept that this product can improve the exercise tolerance in these patients. It was actually the first trial to ever show an improvement in sixty minute walk distance for any patient with HFpEp. So that's what's focusing us all day long right now.
We have an ongoing Phase three trial. We plan to start by the end of this year, a second Phase III trial of oral elixir.
Okay. Maybe can you give us a broad level overview of what is PHF test and sort of frame the unmet need in market opportunity?
So, pulmonary hypertension is a disease of an elevation of the pulmonary pressure in the lungs. It's been categorized in five different subgroups, kind of like cancers. All cancers are different. Group two defines pulmonary hypertension that's associated with left heart disease, and within that category, it's HFrEF, HFpEF, and valvular heart disease. So it represents about fifty percent of all of the heart failure patients who have FF and who develop pulmonary hypertension as part of that disease content.
Okay. I'll give you an idea of the market size real quick. I think investors are starting to see with a lot of companies doing development or two estimates of the American heart failure population. So 2020, about six point seven million Americans. We expect by 02/1930, around eight point five million Americans have heart failure.
About half of those patients, more than half of the new diagnosis in March, are patients with greater than a forty percent ejection fraction. And then the prevalence data, and this is all prevalence data, especially in Group two, there's no drug approved here. So prevalence data suggests that between half and eighty percent of those patients with HFpEF have pulmonary hypertension. So even using conservative estimates, dollars 10,000,000,000 addressable market is pretty easy to come to.
That may partially answer my next question of why I go after PHF. But for those who are less familiar, you touched on this, your LUB program is an oral formulation of a fairly well established drug. Walk us through the development history there and maybe the mechanistic rationale to go after PHF-five.
Probably going to leave mechanistic rationale to Doctor. Rich here. Why go after it? Certainly the prevalence, but it's a progressive disease, it's debilitating and it's often fatal. Ultimately, the underlying conditions that can lead to pulmonary hypertension when they do lead to what is likely a fatal diagnosis with regard to the group.
So But really, why did we start down this path? A group of academics in The US came to the company because we have the rights to develop the drug and said, We believe that this drug could be useful to patients with group two. And we said, Well, what do you mean? And they said, Well, show us all your data. And one of them is Stuart.
He was at Northwestern at the time. Others are now and have been for years scientific advisors in the company. So we gave them all the data and they came back and they said, You have a wedge pressure drop. You discovered oil in your backyard, as we would often say. So the help product got developed, etcetera.
We just came back from the ESC, and when we shared that story with European investigators, the KOLs that we're relying on right now, they they
yeah. Yeah. That's probably about it.
We've known that for twenty years. So I I I like the fact that we kind of came across that and the company took the direction from academics. But in Europe where this drug is used all the time, patients who are hospitalized with heart failure, they know that it has that effect. And so that's encouraging for us.
And then Yeah.
So when I approached 10x as a consultant with interest in levocimendin and saw what Chris just referred to, that this drug has a tendency to dramatically lower an elevated wedge pressure in heart failure patients, they agreed for myself and my colleague, our SAB, to develop a phase two program. And so the question we asked ourselves, what are the possible mechanisms by which a drug can lower the wedge pressure in this subgroup of patients? And there wasn't a lot, but clearly one of them was if we could prove the compliance of the left ventricle, that might be a target. More likely the data was pointing to us that if we could dramatically load the volume overload, the preload, so be it, that these patients all suffer with, that's another potential mechanism of action. Especially with a drug that's called having vasodilator property.
So the phase two HELP trial was a mechanistic study. And in that trial, all of the patients who we enrolled had a rest exercise right heart cath because it's the exercise physiology really that drives the symptoms of these patients, and we needed to know what the drug's effect would be during exercise. So they all had a baseline, were admitted, got a twenty four hour infusion, came back the next day, and we we explained it. And that's where we saw the dramatic fall in the pulmonary wedge pressure at rest, legs up and exercise, and the right atrial pressure, which I tell you is equally as important for the preload. The same thing happened.
Then we measured all possible mechanism of action. Inotropin, no change in elastin, which is a measure of contractility, no change in cardiac output, no change in ejection fraction. It was not working on the left ventricle. Preload, stress blood volume, we measured it dramatically. Right atrial lung uptake.
So now we add our answer to the mechanism of action. Then we were able to tie that back to what is causing the excess preload, the splicing of circulation that releases all of the blood volume into the heart. So in Dan Burkoff's lab, they went and measured it, and sure enough, that's where it was. So we kind of, that's how we got to where we are from the science side.
Awesome. Stuart, you skipped a little ahead on the health study, but maybe we can take a step back and thinking more broadly about your drug, is there a rationale for what you're bringing to the table that could perhaps help circumvent some of the development challenges other drugs have, whether recently or not, in PHF? So specifically, what are you asking? Like, what, how are you leveraging learnings from other efforts to develop in this indication? And then what are you looking for?
Well, there's a lot of legacy data about levosimendin out there.
Think of the pulmonary vasodilators as well. Yes. They are to come from one entity.
Right. Chris mentioned. So we have all that legacy data except that none of it in HFN. Then, we looked from my experience and my colleagues' experience in terms of group one, we knew that group one drugs would only work if they relax the pulmonary arterial side and leave the wedge pressure alone, which that's what they do. So we knew that was not what we wanted.
We wanted something basically that would lower the wedge pressure, even if it left the pulmonary artery pressure alone. So that was helpful as well. Again, it was really the mechanistic help trial that kind of filled in the question marks of all of these things to us. And then from the drug development regulatory side, the numbers are great, but unless you can show that the patient is better off, either because of how they feel or how they function or survive, the drugs will not get approved. So it was the six minute walk that we included in our Phase two trial that pushed us ahead.
And are there particular phenotypes within the patient population where your approach might make more sense?
Well, that's an interesting question. The phenotype in The United States is pretty well set. It's equally prevalent in men and women. We are an obese population, so the BMI is higher. The cognitive diseases of diabetes and hypertension are there.
It's it's it's really characteristic of a phenotype, so there's no surprises there. Within that group, our phase two data is too small to say that there is a distinct phenotype of better responders. On the other hand, eighty five percent of the patients in the uprowload responders. It seem to be across the whole board. Our my opinion at this time is that if you have pH half pep and an elevated wedge pressure, you will respond to this drug. Okay.
Fair enough. I guess on the latest note, one approach that also targets spontanek vasoconstriction is FEVM. And there was the Rebalance HF study that didn't show a static benefit on wedge pressure. What read throughs are lack there?
Question. So Rebalance is a study that look at using a nerve ablation catheter to block permanently the splaychnic ganglion which would have the same effect as our drug. The big difference, Jennifer, is when you ablate a nerve, it's all or none. Either you got it or you didn't. What's important in my view in cardiovascular is the biofeedback that your your physical state is always changing, and you need to have the ability to adjust to it.
So the problem in rebalance was too much hypotension, And I believe you can explain that to say that there are states that a patient has where they need that's like the blood increase because they're trying to climb the stairs or they're trying to do something and it's permanently blocked and so you can't adjust to that. Where with this pharmaceuticals, you can't. You can kind of overcome it. And so we had none of this problem in our health trial at all. In fact, the warning of hypotension, we didn't have to come even close.
The blood pressures stayed stayed around one twenty over 80 throughout the trial. It doesn't appear to be an issue in terms of the ease and level. So I think that's the biggest difference about saying that a pharmaceutical in this instance is probably a safer approach than a a surgical approach.
And so HEALTH was maybe the defining point that led to confidence events and prevent the ongoing program. Can you just summarize your key takeaways from the HEALTH study and how you've sort of leveraged learning from that program?
Well, key takeaway, number one in health, is that since no drug has ever been able to show the lower exercise blood pressure that if we could, we did, that this drug has promised. And then luckily, the legacy data on label submitted over the years told us it's a safe drug, it's well tolerated drug. The general hemodynamic effect on blood pressure target is that are well known, there weren't a whole lot of mysteries compared to any chemical entities. So we kind of went fast to say, all right, we're pretty comfortable with the drug because of the changes we saw in the health trial combined with the legacy data and then getting license to the oral, that changed the world for us because developing a phase three program with permanent IV and home refusions would work, but not appealing for lots of reasons. So it was a straight shot, I think, from our development side that once we got the oral drug and that that was clearly the way to go. Remember, we we did a transition study of the patients in the open label extension of health. That means they were on a home IV for fifteen years and transition them to the oral formulation with great success. So all of that just kind of gave us feeling of security that we're really in the right path.
I was going to see the next question which is what aspect of health support your confidence in these selected oral formulations and the dose, and can you walk into the the final aspect of the program?
Okay. So as far as the oral, there have been some legacy studies on oral. A med study back when Orient was developing the drug, some chronic trials. There was a trial called PERSIST, which was orally was amended for six months in PEPRAP patients. There was a big phase three trial in ALS that was twelve months on oral.
So we had all of that legacy data. When we did our transition study, we took them off the IV and then escalated them every two weeks from one to two or three milligrams a day. We did efficacy and safety measurements. We felt that the three milligram a day of dose made the most sense because if you try to extrapolate from IV, the patients were getting about twenty one milligrams of levothyroxine per week on a late stage. And so three milligrams a day for seven days is twenty one milligrams per week.
So all of that, it's kind of gave us confidence that we were at the at the best dose for this group of patients. And in terms of level, do you want to comment on the level?
So, we're currently enrolling the level protocol. I'll review level two as well. It's very similar. But in level, we're enrolling two thirty subjects. They're randomized one to one, either placebo or three milligrams of levocement.
It's a twelve week endpoint. They're on two milligrams a day for four weeks. They go up to three for the next eight weeks. And then they can go straight into an open label extension for up to a total study participation period of two years. So I think the key thing there is twelve week endpoint.
That's where the six minute walk primary endpoint will be taken. We're also, of course, looking at KCCQ for patient satisfaction, lowering the BNP change in New York Heart Association Heart Failure Classification, a few other things. In Level two, which we intend to start this year, we'll enroll a higher number of patients and they will be the primary endpoint, again, six minute walk, validated, accepted endpoint. It's the endpoint used for every PH trial that's led to an approval. This will be twenty six weeks instead of twelve weeks.
That's the primary difference in the protocols. The populations will be different, and it'll be interesting to see years from now when both trials have completed how a much more European and global population looks level. The level is a US and Canada trial. Level two will also include The US, but probably another 15 countries or so. So a slightly different population, that'll come out in the wash. We'll see And what that looks
Level, first study, what does that power to show, and what would characterize the success?
So the power calculation is the same for both studies. We're expecting, you know, it's based on a 25 meter treatment effect. With the increase from a 150 to 230 subjects, greater than 90% power at a 55 meter standard deviation. So that'll be the same in the two studies.
And is there anything you can say in terms of what you've seen so far in blinded reviews of
the data in the below e? So what we've released so far is that we have not seen any sign of a new safety signal in level. We continue to see high levels of participation in the OLE, and it's reassuring. And that's really all we're able to say at this point in my mind.
And what are you able to say on enrollment and timing for level?
So we've we expect that we will enroll 230 subjects in level in the first half of next year. And that's a a recent statement in our earnings a couple of weeks ago. I think it's best to keep investors focused on a six month window for that. And and we don't feel comfortable that we're gonna have 230 enrolled by JPM. So we we said, let's go for a six month window here.
Fair enough.
But we're comfortable with the way enrollment is going. And again, the participation in the OLE is at least reassuring.
And the trial design for Level came out a couple of months ago. I believe there's a blinded sample size reassessment planned. Can you just walk through the possible outcomes of that blinded assessment and could we see that update sometime this year or hard to say?
So, what the paper shows is that when one hundred and fifty subjects have completed their treatment, either they've been to their twelve week visit or they've withdrawn consent essentially, a patient could die, right? I mean, but, you know, assume one hundred and forty eight or one hundred and forty nine patients will complete their twelve weeks. At that point, a blinded assessment by a statistical team of the standard deviation will take place to question the assumptions we use in the power calculation. If the standard deviation is greater than what was included, we will enroll up to a cap, and it's a cap that the FDA has accepted. And it's a the FDA wants to be able to replicate this calculation in the cases where they agree a company should do this.
Right? This is typically a move that's done when the power calculation is based on a small trial, and that's what we have with with help. We have a small trial, creating the power calculation, and this is a good way to check if it's ready or not. So we're at this point, all we're saying is that we expect to enroll two thirty in the first half of next year.
Is it fair to say that would that blinded the assessment impact plans for level two?
No. No? No. Because remember, the basis for the blinded assessment level was the small health trial from which we had to extrapolate the power of the central time. We will have the results of level known during level two.
And if there is a need to make an adjustment based on the level trial, of course, we would recommend that the agency that we do that. Otherwise, we just stay the course.
You mentioned just on the back of ESC, the second phase three trial. Is the plan still to initiate that study this year and then we'll select to get it up and running?
Yeah. So we're we're in the site selection and initiation phase globally. We are selecting the national leads who are helping us select those sites. I think overall, the timeline for enrollment of that trial is gonna be driven by the careful selection site who can perform a lot of Reichard cats in these patients who can and often do perform it with exercise and who can translate that to screens. That's the learning of level when it comes to enrollment, and that's gonna apply in different ways across the globe in terms of the consistency of the use of the Bright Heart CAT.
So the national leads that we are selecting really advisers to the company at a strategic level who have an operational role driving enrollment, etcetera, Phenomenal support from across the globe, from Asia, from Latin America, from Europe. So those guys have got it. Most countries select a lot of sites in order to get that national application. And so that's the stage that we're we're in.
Okay. And so leveraging learnings in terms of studies by selection, what does that mean in terms of your expectations for the pace of enrollment for level two versus level three?
Yeah. So I think it means that we will get into we will get into enrollment in that trial before we start predicting exactly when it's gonna finish. I think we've gotta see really, you know, in Spain and in Italy as an example, there are sites just coarse. Of course, that's what we do all day long. And then we look at trials they're participating in now and we can see that that's true. Other sites in those same countries will say we don't do as much better.
So really getting into that level of specificity and understanding, can they tell you how many they've done in the last month? Can they tell you the names of the people who send in the patients from the cath lab? Or do they do it themselves? That's really the the key.
Do you have a sense of what the overlap between trial sites will look like between the two trials?
I think our best US sites and of course enrollment is a big piece of that, but our best US sites will be invited to participate in the next trial. It won't have the kind of requirement that phase three programs often do, which is to get a minimum of twenty percent of your patients in The US. Don't just go all over the world and not get a bunch of American. We'll have this level. Level is almost exclusively US patients.
So, I think the best US centers will will carry on. This isn't a a population in which you sort of run out of patients. That's not that's not what would hurt enrollment at good centers. I think it's a it's a popular it's a it's a site dynamic. The the folks who participated in help, for example, who are in level in some new sites we've added, you've mentioned the rebalance trial, you know, the Duke site.
The the the investigator caps her own patient. It's easy then. And when we have that phenomenon in sites around the world, will be our best sites.
Okay. Then maybe one last question just thinking about the pivotal program. Any differences or ways you're thinking about those differences between health and the phase three program either usage of SGLT2s in some of the patients or an enriched population, any differences there?
So, I think it's fair to expect that the centers we will use now in level and over the years to come in level two will treat at least half of their patients with SGLT2 inhibition. It's basically consistent with what you'd see in published data, and then just add a little to that because we're talking about great academic centers and patient health clinics. SGLT2 use is getting more and more consistent. I think if anybody saw the Bull and Relaxin publication as an example, they recruited hospitalized HF patients for two years up until this year and about forty percent of those were on. Three years ago, zero percent were on.
So the uptake has been pretty dramatic. GLP-1s, I would expect it's much less than that in the in The US, and I'd expect it will be even less in a Hemp and Hemp population in Europe based on what KOLs tell us. Other than that, I mean and the BMI difference that you'd associate underlying that, I think will be pretty simple. They've got to meet the same hemodynamic criteria and when they fail to randomize today, it's probably because they don't they don't appear to be the same population we got at health based on hemodynamic.
I think we're out of time, but maybe a quick thirty seconds. Can you just remind us what the balance sheet looks like and key value drivers to look out for?
So we've announced we're funded through '27. Key value drivers, I mean, last last patient in clarifies the remaining timeline and top line data. First patient in for level two, and just hitting that. But I think it's millions of patients worldwide, zero approved therapies, fatal diagnosis, and the potential for a drug that makes them feel better. I think that's the value driving the size of the it's the size of the unmet need and the severity of it.
Looking forward to the progress. Thanks so much for joining us.
Thank you so much for
having me. Sorry we were late.