Innovation Conference. I'm Seamus Fernandez. Really pleased to be joined by Retension Pharmaceuticals. To my left, in order, are Eric Keller, CEO and Co-Founder, Chief Medical Officer Alison Schecter to his left, and then to her left is Alex Schwartz, CFO. Thanks, everybody, for joining us. Maybe just to kind of kick everybody off and orient folks to the story, because you are a very new, recently minted IPO. Eric, if you just want to kind of tell the Retension story, and then we'll jump into Q&A.
Perfect. I know we have a lot of questions to get through, so I'll give you the speed dating version of this. We are Retension Pharmaceuticals. We are focused on a single asset, RTN-001, that we are developing for hypertension, resistant and uncontrolled hypertension, as well as other cardiovascular diseases. The asset, RTN-001, is a second-generation PDE5 inhibitor. What we mean by that is it's not incrementally better than previous PDE5 inhibitors. It's something fundamentally different, and it's different in that we get it to the tissues of relevance for lowering blood pressure and controlling cardiovascular disease. PDE5 is this The lore behind PDE5 is well-known, right? This is VIAGRA, sildenafil, was originally developed by Pfizer to be a hypertension asset and a heart failure drug. It was put in the original studies. It didn't work very well.
They closed the angina study, asked for the drug to be sent back. The women sent it back, and none of the male patients sent the drug back. They found out it had this unexpected side effect, but it's an on-mechanism side effect. It's doing what the PDE5 was supposed to do, which is targeting the nitric oxide cyclic GMP axis. Inhibiting PDE5 preserves cyclic GMP, which potentiates nitric oxide, and that allows you to maintain normal healthy vasodilation and normal healthy vascular health and function, even with decreased nitric oxide. That's what it's doing in erectile dysfunction, but it's doing it in the penile arteries. It's allowing for normal vasodilation to happen. What we have figured out is how to get it to the central vasculature, and that's why it works differently, and it does lower blood pressure, where the first-generation PDE5s don't lower blood pressure.
Got it. Perfect. That's really helpful. In terms of just the journey, the origins of 001, can you just remind us where the drug come from? I think Surface Logix is a sort of originator of the technology. What is it about the asset and the technology that allows for this modification and impact of the PDE5s?
Thanks, Seamus. That is right. Surface Logix is a Boston-based company. It was founded out of George Whitesides' group at Harvard, and the idea behind it was to use George's surface chemistry tools to control in vivo tissue distribution. My co-founder, Paul Sweetnam, was the original CSO at Surface Logix. He came from a long background in small molecule development at pharma, including that he started DrugFinder at Pfizer. He was head of research at Bayer, and he was there for the early development of sildenafil and then vardenafil at Bayer. What Paul saw was the Pfizer rule of five, the Lipinski rule of five, used for drug development, which allowed for the development of small molecule drugs to be bioavailable on the theory that if you get it to the bloodstream, you get enough PK, you will get an effect where you need it throughout the body.
His idea was to take this Whitesides chemistry platform, go a step beyond that, and control, not just get it to be bioavailable, but control the protein interactions in vivo—
Yeah.
—to get the drug where you need to get it. This was the perfect, actually, initial project to validate that concept. Could you take a PDE5 inhibitor scaffold, and he started with something very similar to the vardenafil scaffold, and using this Whitesides Modulon platform, allow the drug to get to tissues it did not otherwise get to? The way they did that was by controlling the way that the small molecule interacted with particularly elastic proteins. When you think about the structure of the blood vessels in the body, the penile arteries are these really thin vessel walls, and there is a single cell layer between the smooth muscle and the endothelium, and it is easy to get drug into that.
But when you get to the central vasculature, you get to the aorta, you get to the heart, you get to the central vascular tree, these are thick vessels.
Yeah.
They are loaded with elastic proteins. The first-generation PDE5 inhibitors cannot get through that because they are sticking to and binding to these elastic proteins, laminin and tubulin and actin. What Paul was able to do with this Surface Logix platform is allow, significantly reduce the binding to these elastic proteins, allow the drug to get in there. It is one of three drugs that was developed at Surface Logix, all to phase II. ARCH, Venrock were backers. Back then, you had to run a CVOT for a hypertension asset. There was no appetite to run a seven-year CVOT. The company was going to actually shut down after the crash of 2010 timeframe.
I was running a sister Whitesides company, acquired Surface Logix, out-licensed the assets to Kadmon Pharmaceuticals. Kadmon focused on a different asset Paul had developed, which was the ROCK2 selective kinase inhibitor.
Yeah.
Developed using the similar platform, but to get a ROCK2 that was bioavailable and to the right tissues. That was developed into REZUROCK. When Kadmon was looking to sell to Sanofi, really to get access to REZUROCK, I was able to go in and license this asset back and start Retension.
Got it. That is super helpful. Why choose vardenafil in particular?
Paul used vardenafil because it was the most potent of the first-generation PDE5 inhibitors.
Got it. Purely.
But what we knew was that this was not a potency problem, it wasn't a PK problem, it was a tissue distribution problem. Starting with something that was essentially best in class, not having to better it in terms of selectivity and potency, then allowed him to focus just on the tissue distribution aspect.
Got it. Perfect. And just hypertension in general, ultra-common medical condition, maybe just remind us the unmet need.
According to the WHO, the World Health Organization, 1.4 billion people worldwide have high blood pressure. 120 million adults in the U.S., nearly half of the adult population. It is the most common chronic disease, and it is the single largest modifiable risk factor for cardiovascular death.
Yeah.
In fact, cardiovascular events usually occur between 7:30 and 8:00 A.M. in the morning, so I appreciate you putting us on first. All the people who are here, so that in taking the risk during this highly vulnerable time of day. Hypertension is a space where there is lots of approved anti-hypertensives. Many are generic. There has been a dearth of innovation for the last 20 years.
Yeah.
The main reason for that is really twofold. One is, the cardiology world sort of thought they had the problem solved. Plenty of agents, we can keep people on it. What happened is, the guidance kept going down. It was lowered from 160 mmHg to 150 mmHg to 130 mmHg in 2017.
Yeah.
Now, many patients are targeting 120 mmHg, and the ALLHAT study has validated that even small drops, 5 mm drops in mercury, translate to a 10% improvement in cardiovascular events. The guidance has moved down, and there is a realization that the existing agents are not sufficient, because you have 120 million people with hypertension in the U.S., and 80% of them do not have it at goal. So there is a need. Second is that you used to have to run a CVOT, and nobody wanted to run a seven-year outcome study.
Right.
There was no new development. What opened the gates is this recognition for a need for additional additive blood pressure-lowering agents that work well, play well with others, don't add to the side effect or safety burden, and are easy to take. Compliance is a major issue, so you want drugs that patients are willing to continue to take and stay on, and the ability to run essentially a six-month blood pressure-lowering study. CinCor and Mineralys are really almost the first out of the gate to take advantage of that new pathway.
Got it. Great. Let's talk about just the preclinical work that you've done just to prove out the drug delivery, ability to get 001 to the central vasculature in particular.
This was all done by my team at Surface Logix. Even though this is a new company, we have all of the history with this asset, so we know everything there is to do with it. The preclinical really breaks down into a couple of key areas. One is the platform chemistry. The Modulon platform allows for the creation of surfaces that mimic in vivo very well, and rapid screening and throughput. This molecule, with the various Modulon attachments, was screened against vardenafil and other first-generation PDE5 inhibitors. So we have the preclinical work that was done on the platform chemistry to show the significant improvement in reduction in binding to these elastic proteins.
Yeah.
That work was validated. Second is work in rats, where we looked at radiolabeled drug and actually tracked free drug between the vardenafil and 001 in the tissues of importance for blood pressure-lowering heart failure. We looked at the amount of free drug that gets to the aorta, the amount of drug that gets to the heart, and we see essentially an order of magnitude more drug with 001 than is reported with the first-generation PDE5 inhibitors. Then the third is, it was put into spontaneous hypertensive rat and showed better blood pressure lowering and dose responsive in those rats. The first generations did show blood pressure improvements in spontaneous hypertensive rats too. That's why they were pushed forward into—
Right.
—human studies. They just didn't translate. But the preclinical we have shows that each step of the way, we're validating and nearly order of magnitude improvement in each of those metrics.
Great. Let's talk about the phase II data that you have so far with the immediate release formulation.
Surface Logix ran these studies, and you're right, it was an immediate release formulation. The 001 was put into a total of nine clinical studies by Surface Logix, 265 total patients, 243 on drug. Seven of those studies validated the safety tolerability profile, which is very much in line with what you would expect to see with similar doses of a first-generation PDE5 inhibitor. No SAEs are seen, and mild, occasionally moderate transient side effects. Very similar to the first generation, headache, flushing, some chromatopsia that's occasionally seen in those first couple of days, and you dose through it. Nothing really different than you see with VIAGRA or LEVITRA or CIALIS. 2 of those nine studies were in hypertension patients.
There are two studies that were run, patients on zero to four other background meds, who still had high blood pressure, and up to 14 days of dosing, 12 days in one study, 14 days in the other. They showed clinically meaningful reductions in blood pressure that validate the blood pressure lowering ability of 001.
Great. Can you talk about the peripheral versus kind of central blood pressure lowering and the importance of that?
Alison will talk about the importance of it. What I will say is the two studies that were run, there was an 05 and an 08 study, 07, 05, 08. One of those two studies looked at central blood pressure lowering. It was a pioneering study. It was one of the first to look at central in a non-invasive way. Back then, you had to run a right heart cath to measure, and this was one of the first studies Ian Wilkinson, our KOL, pioneered the ability to measure central blood pressure using waveform analysis. What we learned from those two studies, the 05 and the 07, was twofold. I mean, these are proof of concept studies. It's why we're running a robust phase II-B right now.
They validated the tissue distribution story, and we did that with that 05 study where we measured central, because you can't lower central blood pressure, blood pressure through the aorta, unless you're getting drug to the aorta. So it validates that we're getting drug, because we see equipotent reductions in central and peripheral. No other antihypertensives do that. Antihypertensives that affect central, most of them do it through remodeling. So with an ACE or an ARB, you'll see reductions in central, eight to 10 weeks after you start on the drug. The fact that we're seeing blood pressure, significant reductions in central one hour after the initial dose means we have to be getting drug there. It's also better than you see with other vasodilators that act immediately on central, like amlodipine and some of the calcium channel blockers that lower central, about half as much as they lower peripheral.
We're seeing equipotent reductions.
Okay.
We are validating. The 08 study, and we will get into this a little more, gives us a look at the 24-hour blood pressure lowering across the study. Central for us in that study was validating, but it is also highly therapeutically relevant. Alison, I will let you talk about that.
Yeah. As people may or may not be aware, you do not die of hypertension, you die of end organ damage. The chief driver behind end organ damage is the pressure load that is seen from the heart. You have 8 L- 10 L of blood pumping through, and that hits the cerebral vasculature, it hits the kidneys, it hits the heart. If you can manage the central blood pressure and markedly reduce it without orthostasis, without peripheral edema, without nifedipine, which will drop your blood pressure and you have syncope, and without stealing blood from other organs, it is a unique ability. Now in the European guidelines, they are looking at vascular stiffness, central blood pressure, augmentation index, all these things that we are able to get through these Oura Ring-like cuffs that use algorithms and different mathematical modeling to be able to get those pressures measured.
I think just to add on to what Eric said, I think you cannot underestimate the uniqueness of the way pharma looks at bioavailability. We talk about tissue distribution, but the way drugs are looked at is they measure it about serum binding to albumin. We actually get not only into the extracellular matrix, we get into the cell. The only way you can, as Eric said, drop central blood pressure is getting into the smooth muscle cell and really impacting the cyclic GMP and vasodilating. You cannot do that unless you get intracellularly. That is the limitation of the first generation PDE5s. We have cracked that anatomical barrier through this very novel chemistry that Paul developed, and it is remarkable. Many companies have tried.
Right. As we think about the advancement into the phase II, which is already well underway, the modified release formulation, what about the modified release formulation is unique and what are you just seeking to accomplish?
Yeah.
Relative
What we learned from the two previous phase II studies—
Yeah.
—is that we effectively lower blood pressure at clinically meaningful levels, that it's sustained, it's sustained out to 14 days, that we're getting blood pressure lowering throughout the course of the day with a single dose immediate release. In the 08 study in particular, we have a really rich data set, and we also learned that there's a bit of a liability with the immediate release, which is that the blood pressure lowering that starts in the first six to eight hours, very robust with peak blood pressure lowering of between 10 mm and 12.5 mm of mercury, placebo adjusted. We're seeing that start to wane as you get out to 24 hours, because the half-life of the drug is between six and eight hours. That was something we knew we had to fix, but was fixable with formulation work.
It's not an exotic formulation, but with the modified release, what we're able to do is increase the concentration levels of the parent molecule, 001, at 24 hours by sixfold. So we're getting sixfold the amount of PK at 24 hours. We're also able to reduce the Cmax that's seen by about fivefold. What does that do for us? It allows us to have 24-hour blood pressure lowering coverage while reducing the Cmax-driven AE events. It's really optimized and tailored to a once-daily treatment for hypertension in particular.
Perfect. The phase II, maybe just walk us through the 280-patient phase II-B study, the key learnings from other hypertension studies, and what you're kind of laser-focused on here to really differentiate your product.
Yeah. So we had proof of concept data, and we knew that. What we had to do was validate that we're seeing robust blood pressure lowering with this modified release optimized formulation in a large number of patients. It's a registrational-like study of 200 patients. We believe 280, thank you. We believe that really that study is what will validate this asset as a real viable additive treatment for hypertension that's distinct from and outside of the RAS axis.
Yeah.
Really, all the innovation has been around that RAS modulation system, which is a particular system. Our goal, I'll step back a bit and then let Alison talk about the study. Our goal with Retension has always been not to be sort of an incremental alternative to other medications, but really be paradigm-shifting. Give cardiologists, give nephrologists, give primary care physicians a new tool to treat hypertension in their patients.
Yeah.
Really looking at differentiation, not being additive to, not being a redundant mechanism or just a replacement for something, but truly an independent orthogonal mechanism. In this nitric oxide cyclic GMP axis that we're targeting, that's the most therapeutically relevant way to treat hypertension. It's the way the body regulates blood pressure. Everything else is more indirect, it's downstream from that. So it's the potential to be a sort of core pillar in hypertension. The other is that differentiation we see in central blood pressure lowering. It really differentiates it as something that is directly targeted to the sequelae of high blood pressure, that end organ damage driven by the central. So really looking to change.
We've designed the phase II study to show that broad impact in a lot of patients, in a lot of patients on different background meds, who fit a lot of different use cases. Hypertension has never been a one-size-fits-all treatment. It's very much an individualized therapy.
Yeah.
We've also been able to take advantage of the work that has been done by others and adopt best practices into the study. Alison, I'll let you talk a little bit about how the study design is—
Yeah.
—put together.
I mean, it's all about, as you know, with all the blood pressure studies you've seen recently that have come out, it's all about execution. We're a four-arm, three doses and a placebo arm, using the best practices in real-world hypertensive patients. So you have to be on two or more antihypertensives, and 30% will be on three or more. It's a double, it's blinded RCT, where we're going out 12 weeks with the primary endpoint at four weeks. But what's important is that we have two run-in periods. We have the first run-in period where we make sure that you're eligible by having a blood pressure above 135, and you're on the medication, and we let eGFR down to 45, which is unusual. That's CKD class 3A, which is all the other ASIs or initial studies were at 60.
Then we have another run-in period where we put them on placebo for another two weeks, because people, once they sign informed consent, they have a come to Jesus moment where they all of a sudden become compliant, and that's where you get that placebo effect, the halo, and we didn't want to be another halo. So, it's about execution, but once the study starts, people are used to taking the medicine, and then we do, per Norm Stockbridge, who used to be at the FDA for cardiovascular, we do it four weeks because that's all you need to know. I think, and then we go out to 12 weeks. We're doing also ambulatory blood pressure monitoring. We have diaries. We'll be able to get some nocturnal.
We have biomarkers for urinary albumin-creatinine ratio because PDE5 has known salutary effects on the kidney, and we feel very confident in the execution. It's all done in the U.S. It's standard of care. So we're not going out somewhere where the standard of care would be different.
Got it. So we only have a limited amount of time left. I think one of the things that we haven't had an opportunity to cover is how this product really differentiates from the existing therapies today. I think one of the factors you just mentioned, Alison, is that sort of problem or the challenge of treating patients with existing and new therapies because of the risk of hyperkalemia. Can you just remind us why nephrologists and cardiologists, and certainly primary care physicians, would want to avoid hyperkalemia specifically?
I mean, I think this drug, as Eric said, is, if we had solved, as Pfizer and everybody tried to earlier, the bioavailability, the true bioavailability of getting it into the cell, this would have been a pillar of hypertension. There's no doubt, because it's a primary mechanism. We don't impact. We're fecally excreted. We don't have to worry about urine accumulation. We don't affect the potassium sodium channels. Hyponatremia is actually almost not a problem if you look at the ASI data as hyperkalemia, which is obviously could be life-threatening, even though you talk about percents. You have a bifurcated approach.
If you are primary care and you know that your side effects of seeing some blue vision, which is chromatopsia, or having some flushing, are going to end in two or three days in the 5% or 10% that have it, and never have it again once you have it. There is no drug, hypertensive drug, where the side effects stop. Every other drug, the side effects stop when you stop the drug, which is why people prematurely stop or are non-compliant. I think none of the. And the safety profile, bar none, as a cardiologist, and I am speaking as a physician, it is very comfortable to not be able to worry about orthostasis or syncope, having a fluid accumulation where people have to wear hose, nocturnal urination when people take diuretics and they have to go to the bathroom, and the potential to fall risk.
Not only that, when you are out in the sun, you have to modify your medication. What we are unique is that we have a plateau effect because we are a secondary messenger. We are not hitting a primary receptor. We are working in the cell that we have a plateau effect. We work best when your blood pressure is higher, but then we get to a—
Yeah.
—baseline.
If you think about nephrologists who do not have a lot of tools in their patients with hypertension plus CKD, because almost every antihypertensive affects kidney function and lowers eGFR. For nephrologists, the fact that we do not impair, further impair kidney function makes this a clear first alternative for those patients. Cardiologists, the lack of a requirement to continue to monitor.
Yeah.
For the hyperkalemia and the potassium levels makes it really comfortable. For primary care physicians who are going to be very wary of a new agent, they are very comfortable with this class.
Great. Well, definitely exciting times. Big data coming in the first half of next year, and really looking forward to what we think will be a successful clinical study alongside, I'm sure, your confidence as well.
We do.
Thanks so much.
Thank you.
Thanks for your first fireside.