I'm Whitney Ijem, one of the analysts on the biotech team here, and it is my pleasure to be joined today by Regulus Therapeutics. We've got CEO Jay Hagan, as well as President and Head of R&D, Dr. Preston Klassen. I will leave it, turn it right over to you guys to dive in. Thanks, Whitney. Thanks to the folks at Canaccord for having us today. I appreciate the opportunity to give an update on our ADPKD program. It's not gonna be there. Oh, yeah. Just take a look. Sorry. Thank you. We will be making forward-looking statements. Actual results may differ materially from those implied today. We encourage you to read our risk factors in our SEC filings, including our 10-Q filed last week. Just in terms of investment highlights, Regulus Therapeutics is a company focused on ADPKD or autosomal dominant polycystic kidney disease. We're in the midst of a phase 1b multiple ascending dose study. We've completed 3 weight-based cohorts and are in the midst of enrolling a fourth cohort, which is open label, studying a fixed dose, 300 milligrams, in patients with the disease, where they're dosed every other week, for 3 months. And what we're primarily looking at is, obviously, safety and tolerability for this stage of development, as well as looking at imaging biomarkers and urinary biomarkers of target engagement. The study will read out a cohort data early next year, from a significant number of participants in this final cohort, and then wrap up in the first half of next year. Importantly, though, the company is on track for an end of phase 1 meeting with FDA, towards the end of this year, where we intend to present the protocol that we wanna pursue for accelerated approval. The timing of that then sets us up to be able to start that study in mid-2025. I can't read it from this angle here, interestingly. We have initiated a number of activities to get ready for that pivotal study, including the manufacture of drug substance. And we recently completed a PIPE financing in March of this year that extends our cash runway into the middle of 2026. So I'm gonna turn it over to my colleague, Preston Klassen. You might wanna angle over here- Yeah. A little bit 'cause of glare. We'll just run over a couple of quick slides, talking about the mechanism of action, the disease state, et cetera, then get into some, some Q&A. But we really like the ADPKD market. Obviously, it's an orphan indication. It's actually one of the more common monogenic disorders. It's the most common hereditary disorder in the kidney. But from a prevalence perspective, at least in terms of diagnosed patients, we think it's more than that in terms of a significant undiagnosed population, but the diagnosed patients is about 160,000 in the U.S., and so that does lend itself to orphan status. There's only one drug on the market today, tolvaptan. It is limited by significant concerns on the safety and tolerability side, so overall market penetration for that compound is less than 10%, we believe, of the addressable population, and yet it did $1.3 billion last year. So this is a really great market. The orphan status affords us some regulatory streamlining. It obviously supports a price point as well. Clear unmet need. This is ADPKD causes inexorable loss of renal function, leading to dialysis. So it is very significant, and the available therapies today are quite limited. So this is a great area to be developing in, and we happen to be the only mid- to late-stage program in clinical development. Just briefly in the mechanism, the disease pathogenesis on the far left, even though it's just a single gene that's mutated, that single gene mutation kicks off widespread gene dysregulation. Thousands of genes are impacted in gene networks. Some genes go up in expression, some genes go down in expression. It turns out that a lot of that, those changes in gene expression, and I'll show this in a second, are driven by abnormal upregulation of a microRNA called miR-17. It's a family of microRNAs. And so that kicks off all of that gene network dysregulation, and then our mechanism of action is simply to block that microRNA. So it is no longer able to bind to messager RNA, and stop the protein translation. And so for all of the gene network dysregulation that, that miR-17 would promote, you can—if you can block miR-17, then that will not happen anymore, turn to a more normal pattern of gene network regulation. Why do we know that miR-17 is important in disease? We take an animal on the far left and knock out either their PKD1 gene or their PKD2 gene, and you see an upregulation immediately in the expression of this microRNA, miR-17. In human tissue samples, in patients with ADPKD, miR-17 is also upregulated. Maybe more importantly, you can take a mouse as the far right. You can take a mouse that is normal. It does not have the PKD genotype, doesn't have a mutation. All you do is you transgenically overexpress miR-17, and they start to develop a PKD phenotype. Renal tubular epithelial cells hyperproliferate, and they turn into cystic epithelial cells, and you get the formation of cysts only because miR-17 is around. I talked about widespread gene network dysregulation. Let's cover this very briefly. You can look at comparative differential gene analysis to take a look at a diseased animal, PKD diseased animal, and see what changes in gene expression do you see compared to a normal animal. Then take that same set of animals with disease and treat them and see how those same genes move. Maybe to cut to the chase here, the green dots represent thousands of genes that are impacted, both in disease, they're moved by disease, and then they're also moved by therapy. If therapy completely reversed the changes that you saw in disease, the green dots would have a slope of -1, and the slope is very close to -1. More specifically, you can look at the gene sets of genes. Here, they're clumped into networks, gene networks, that are most impacted either by disease or both by disease and by treatment, and what kind of genes are they? The first third here are all hyperproliferation genes, and this first column pink to red represents an increase in gene expression, and light blue to dark blue represents a decrease in gene expression. So you see the first third up here, most commonly hit targets are all hyperproliferation genes. c-Myc targets, beta-catenin, mTOR, et cetera. So genes that promote proliferation are increased. The middle third are all inflammatory genes that help express inflammatory or immune mediators, TNF-alpha, IL-6, JAK-STAT, etc. Again, increased. The only group that's decreased is a group of genes that deals with oxidative phosphorylation in mitochondria, PPAR-alpha, PPAR-gamma. That actually helps to control proliferation, but those genes go down in disease. And now you see, when you actually take diseased animals and treat them with RGLS8429, this is in a dose-dependent fashion, so the highest dose, 20 mg per kg, is this column here, just focus there. Every gene expression change you see that happens in disease is now reversed when you treat with miR-17. I'm sorry, with that anti-miR-17 therapy. So you block miR-17, these gene expression changes do not happen. So then that translates in animals into significant amelioration of disease. You can really delay or slow the progression of disease in these animals. So three models here. PKD1 flox/RC, the far left, that's the most clinically relevant animal model we have, where the PKD 1 allele is completely knocked out at the flox, and then another one is made hypomorphic, which is the RC model. So that most represents clinical PKD in humans, and you see significant disease amelioration. Also, PKD2, the other gene that can be impacted in disease, complete knockout. You also see... It's a very severe disease model, but you do see amelioration of disease with therapy. And then on the far right is another renal cystogenic disease that actually has nothing to do with the PKD gene itself, but it's another hyperproliferation renal cystogenic disease where miR-17 is upregulated. You block miR-17, you help fix the disease. So that's all the background in terms of the mechanism. It really resets the... It's directly addressing the genetic basis of the disease and reversing all of the genetic changes that you are-- many of the genetic changes that you see in the disease. So where are we, where are we from a clinical development perspective? We're in this ongoing Phase Ib MAD study, as Jay mentioned. We've completed all the weight-based cohorts. Those are the placebo-controlled. We'll show the data in a second. That helps us define our dosing range, and, and then we move into next, middle of next year into essentially a pivotal registrational program. We call it Phase II, Phase III. Typically, it's phase III that's registrational, but in this case, because it's an orphan indication, a clear unmet need, and an acceptable surrogate endpoint in kidney volume, the agency allows accelerated approval pathway, where you can do a single study to get approval by showing changes in kidney volume. We'll talk about kidney volume in a second. And then you need to keep following those patients for an additional time. That's called the phase III component for the true clinical benefit endpoint, GFR. But you can get approved on kidney volume, and then in the post-approval setting, you wrap up the phase III component with GFR to get to full approval. These are a phase Ib study. We've got four cohorts. The first three are weight-based, placebo-controlled cohorts, 1, 2, and 3 mg per kg, so low, mid, and high dose. Then again, as Jay mentioned, we're in an open-label, 300 mg fixed dose, kind of to get us practice into a fixed dose in phase II. Safety, we have seen, no concerns, on the safety and tolerability, to date. We have somewhat of an increase in injection site reactions, at the highest dose. We're continuing to track that very carefully. We haven't seen any, dose-limiting aspects of this, so we're not concerned at all about the safety and tolerability profile, and it far exceeds the profile you see with the currently available therapy today, tolvaptan. In terms of dose ranging, this slide basically summarizes the main thing we needed to see, which was an increase in evidence of mechanistic activity. So we measure urinary polycystin. It's a protein that should go up if you're blocking miR-17. It's a protein product of the PKD gene itself, and you indeed see increases in the percentage, a change from baseline in both polycystin-1 from the PKD1 gene and polycystin-2 from the PKD2 gene. You see that we're starting to hit what we believe is the asymptotic, kind of flat part of the curve at 3 mg per kg, which completely is supported by our non-clinical data, suggesting we should be hitting the optimal levels of miR-17 target engagement. S o everything in patients looks like what we had expected based on our mechanistic non-clinical work. The table below just shows that it's statistically significant compared to placebo at the 3 mg per kg level. So we really like that 3 mg per kg level generally in terms of picking a dose. And now we also looked at the kidney volume. So you do an MRI at the beginning. In this case, we did an MRI at four months, so it's three months of therapy, one month of follow-up, then you do the repeat MRI. Small number of subjects, pretty short treatment duration. We hadn't necessarily expected to see a whole lot in terms of kidney volume, and yet at both 2 and 3 mg per kg, the average level, average change in terms of kidney volume from the group was actually a decrease, a regression. That has not been seen before. Tolvaptan does not stop growth. It does not reverse growth. It slows the growth by about 50%. So instead of growing 6% per year, kidney size, you're growing 3% per year. This is a, on average, a mean reduction in kidney volume over... In a small number of patients over a short period of time, repeated in two doses. We think that's pretty important and generally de-risking for what we're going to do next. This slide just shows that it's more recent exploratory analysis, kind of, cutting the data by baseline Mayo Imaging class, which is how you measure disease severity, so moderate to severe disease. You see the same general effect size across all three groups, which is great. And the GFR looks good. We don't expect to see changes in GFR compared to placebo in a short study over a small number of patients. It's gonna require a couple hundred patients over probably two years to detect that, but we do measure it for safety and have seen no, no issues from a GFR perspective. So that's the summary. We've definitely shown clear evidence of mechanistic activity. The fact that we're starting to show impact on kidney volume, which is the next thing we need to show for approval, is highly de-risking, and it's a great market to be in. Thank you so much. So just to start, and going back to the kidney volume changes, the decrease in kidney volume that you saw, that was kind of what was surprising and the wow factor for us in cohorts two and three. So you've done it twice now. And there are, you know, a few we call them super responders, patients who had kind of very meaningful reductions. Any early learnings or thoughts on those patients, either what you've been able to see or mechanistically, what might be driving some patients to respond? Yeah, because it's relatively small numbers, about 10-12 subjects per group, treated, we haven't done those kind of slicing and dicings. It literally would be, you know, one or two, you know, patients, and looking at their characteristics. I do think that when we and as we get more... The 300 milligram fixed dose is more, it, it will be more patients overall. As Jay mentioned, we'll be reporting out on a significant number of that early next year, and then the final In later in the first half. And it may be the case that we can then combine 2, 3, and 300 milligram, and really start to take a look at some of those things. But to date, we haven't seen anything. We haven't done those work, those analyses, other than the one slide I showed, which is baseline Mayo Imaging Classification. 'Cause you would wanna know, are you seeing all the effect in the most severe, or all the effect only in the, in the least severe, the, you know, moderate disease? The answer is no, it was very uniform across all, which is great. Right. Right, important. Okay, noted. And then just going back to the idea that nobody's been able to show this before, declining kidney volume. I guess, does that even make sense, like mechanistically, how could that be happening? And I think there's maybe some preclinical data. Yeah, you know, it totally makes sense because Dong and Somlo in 2021 published a paper where they essentially were able to turn off the PKD gene in an adult animal. They developed disease, and then they're able to turn the gene back on, right? So you're kind of fixing it. You're totally fixing the genetic basis of the disease. And when that happened, you actually saw a regression, kidney, the, the cells and the renal cystic epithelial cells themselves started to transform back into normal renal tubular epithelial cells. And so everything started to change back towards normal. And so that was a situation where you completely fixed, reversed the actual genetic change. What we're doing is maybe one step, you know, removed from that. We're reversing essentially the widespread gene network dysregulation that you do see. Even though it's a single gene that gets mutated, it causes increases and decreases, abnormal, you know, increases and decreases in gene expression across thousands of genes, and much of that appears to be controlled by miR-17 going up. And so by blocking that, you're normalizing the gene widespread, you know, gene network regulation. You're putting it back to normal. And so that would make sense that you could then maybe start to see, you know, some real disease modification, possibly even a regression back towards normal. Okay. And in terms of the time course as well, it was much sooner than anticipated. I guess, what's happening in the kidney or, like, why would it be happening that quickly? Does that make sense with sort of what the cysts are and kind of the- Well, I do, I do think it speaks to the strength of the mechanism. From a time course, you know, no one's ever really looked this early. Most of the time when you're doing a clinical trial, probably the earliest it's been looked at before is about, about 9 months, you know, and then 12 and 18, and that kind of thing. And so it is a little surprising to us, but I, I think it just speaks to the strength of the mechanism. Yeah, no, I was gonna say in that publication that Preston referenced, you know, they saw reversal within two weeks of reexpression of polycystin. So we know we're seeing increases in polycystin. They're coming up within four weeks of treatment, and so perhaps there's something that holds that together there. Yeah. Okay, makes sense. In terms of dose, you had the 2 mg per kg cohort, 3 mg per kg, and now you're doing the fixed dose cohort. Can you remind us, where does the fixed dose kind of slot into the- Yeah. Based on everybody's body weight, 'cause that's obviously a distribution, the vast majority of folks will be at 3 mg per kg or a little bit higher. That's got... You have to pick a, you know, you have to pick a fixed dose. If you wanna go with the fixed dose, you gotta pick it, and so there's gonna be some spread in terms of the weight base. We wanted to make sure that based on what we saw, that we were, you know, in that realm of 3 mg per kg, and in this case, we'd elected to test so that pretty much everybody's at 3 mg per kg or higher. And then as long as that's safe and, you know, well tolerated, then that, that would make sense. But we also, I think, have room if we, if we did, you know, look at the data and believe we needed to bring the dose down a little bit, we got plenty of room in terms of where we sit, both in polycystic and on volume. Fair enough. Fair enough. Okay, so similar dosing then as we go into Cohort Four. Excuse me. And so can you, I guess, how can you set expectations into Cohort Four data? I mean, similar dose, you've kind of shown similar things from Cohort Two to Cohort Three. Should we just be looking for more of the same, or what are you guys, what's the plan? I think in terms of 3 mg per kg, you wanna see, you know, more of the same. We're not. We're definitely not looking for more mechanistic response at higher, you know, weight-based dosing We will have some patients, upwards of 4 mg per kg, who we'll be able to take a look but our expectation is that based on what we've seen, we're kind of at the top, top part of the curve. We'd love to see volume, you know, impact as well. Again, that shouldn't really be considered table stakes by folks who are following the company because it's small numbers over a short period of time, but, I mean, we didn't expect to see anything. And so the fact that we've now shown it twice, you know, it'd be great to show it a third time as well. But I think what we've demonstrated to date is pretty de-risking for what we have to do next. For sure. For sure. Yeah, no, just to, just to amplify on that, you know, we really wanted to get experience with the fixed dose prior to the Phase II. Given that that study is likely registrational, then you have to introduce your commercial format, right? And so we envision this being a product that can be administered at home by patients. And not only will we be able to do that in the Phase II study, which will streamline the execution of it, but obviously, that's a much more preferential product profile versus a, you know, vialed product that's physician administered. Fair enough. Fair enough. Okay, perfect. And then on the safety side, can you characterize the injection site reactions? Like, what is, what is, what do those look like? Yeah, most of the majority of folks who've reported, again, it's only been a handful, but the majority of folks report it as pain or tingling at the site of injection for 5-10 minutes. ... after the injection... hasn't stopped anybody from taking it. Right. Yeah, so. And just, it's an injection, so that- Yep. It happens with injections. Okay. So we're, we're not concerned about it. It is important because oligonucleotides that are subcutaneously injected, you know, can... You know, they all report some form of ISRs, all the way from kinda like cytokine release symptoms. You feel like you've got the flu for a couple of days, down to, "Oh, it's a needle prick in my arm." We're, we're at that end of the spectrum. Right. We're not seeing anything that we're concerned about right now. Right, right. Perfect. Okay, and then on the GFR side, what you've shown, the data, everything looks good. What would not good look like on the GFR? Well, you would wanna make sure that you're not having any evidence of acute deterioration or evidence of acute tubular, you know, ischemic injury. It's why we measure KIM-1 and NGAL and all of that, and everything from a safety perspective looks good. We know, we did get some questions. How, you know, if you're seeing changes in volume, are you seeing changes in GFR? Like, hold on now. Right. We're at a good place with the FDA because they're willing to accept kidney volume because it tracks so well with GFR, but getting to GFR takes hundreds of patients over, you know, two years of time at least. Right. Some of the programs go out for three years. We're kind of thinking we could probably show it in two years. But that means that 10 or so patients over 4 months is not, you know, not gonna be able to really- Yeah. If you shouldn't expect to see evidence of benefit there. Yeah, or be fooled by what you see. Right. 'Cause I think, you know, we included in previous updates historical data sets from tolvaptan against placebo, and you can see even at four months, you know, GFR is jumping ±40 units, and it just shows the inherent variability of that measure. So you need as many data points as you can have to really understand what the true slope is. Right. Right. But we're super excited with where we sit because, again, volume is the way to get approved. We've demonstrated that we're impacting volume. Certainly looks like that. And we know that volume tracks with GFR over the long run, but that's why there's accelerated approval, 'cause you gotta go, you're gonna have to go do the longer studies to get there later. Right. The FDA gets that too, hence the accelerated. Yep. Yeah. Yeah, no, we're. It's a good place to be in. Yeah. Awesome, okay. In terms of the timing, I guess, as you said, data from Cohort 4 is not lagging. You're moving forward with the FDA meeting. What are the key questions or points of discussion left with the FDA? I mean, ultimately, it's a lot of little things, you know, not little. It's a lot of things to get to the point of what you're really trying to do is get agreement that it's okay to move forward into a pivotal phase 2, 3 program. Here's what the protocol looks like. Everybody's aligned on it, all of that. So that's the main goal. Our goal is to have that happen as quickly as possible because that kinda sets the clock for when you can start enrolling patients. Typically, industry standard, you need to get to final protocol, so you have to have agreement with the FDA. Once you get to that final protocol, it's generally speaking, about six months to really kicking off with enrollment. Talking to all your vendors, you know, all of that planning work that goes into it. And so that's why we're definitely, you know, interested in getting to the FDA by the end of this year, so we can, by the early, early next year, wrap up that final protocol and then, and then get in midyear into being enrolling in the pivotal program. Okay. At the end of your meeting, you'll be taking a data cut from cohort four, whatever you have at the time- Yep ... to discuss as well. So that will be when you- Yeah, that'll mostly be focused on safety and tolerability. Yep. You know, most likely, but then we'll show all the data that we do have. We talked about that, you know, early in the year. And then the final, you know, analysis from all the patients when they're completed. That'll be, you know, later in the first half. Okay, noted. Noted. And then in terms of timelines and next steps, because you're seeing kidney volume changes so early, assuming that continues to hold, how should we be thinking about timeline of endpoints? I guess historically, what have people done, for tracking TKB? Historically, volume's been measured over either 12-18 months. We certainly think 12 works for us. Historically, if you base it off of the tolvaptan demonstrated effect size and other programs like Sanofi's venglustat program before it got stopped, you know, midway through, but it was around 300-ish subjects for a year to 18 months. I think Sanofi actually did 18 months as a plan. So, you know, our planning will be relatively conservative, I think. It'll be based a bit more on what is the prior compound shown, tolvaptan. Again, we're showing, at least right now, far, far better than that. And so we'll probably build in some way to have a sample size re-estimation or some other way to think, "Hey, is there a shot at taking an early look for a win? But otherwise, our main expectations would be about 300 patients or so over 12 months of therapy. Okay. Okay. For the volume component And then GFR would be out two years, and it might involve more patients. Right. Right. Okay, perfect. So you mentioned Sanofi has tried here in the past. Otsuka obviously is here. There's others that have demonstrated interest in this disease. So I can imagine there's a lot of interest coming your way. How do you think about partnerships, or BD work and any goals on your side of the coin? Yeah, no, I mean, our first objective really is, you know, to obviously understand if there's interesting strategic opportunities to consider where we can accelerate the development of the product in a non-dilutive way. But importantly, this is the kind of product you can build a company around, and the team, you know, that we've assembled here at Regulus can easily execute on this U.S. study at a minimum. We talked about 300 subjects for a year, and so, you know, we're continuing to have conversations to see if there's something compelling, then just raising the incremental capital we need to keep the product unencumbered. So, that, that's about the extent of it, I would describe. Okay, perfect. That makes sense. Any last questions? I had a question just in regards to... You sort of touched on it, but, you know, in discussions with the FDA, and, you know, given what tolvaptan's not been able to do, I guess, and the variations in the results there. I mean, are they sort of keen to see consistency in results? Are they thinking like, you know, if they're gonna really focus on patient stratification, like when you look towards phase 2, 3, you know, just thinking about trying to show- No, I'd say the main aspect is really just that 1C through 1E is the moderate to severe disease, is the patient population that they're most interested in. But that's also a sponsor decision, you know, who we want to enroll. We think those-- that's the right population to demonstrate an effect in. And I wouldn't say that the FDA is specifically focused on other kind of stratification factors. In terms of tolvaptan use, that will be of interest, but they don't require it. That's, and that's an important distinction. So it's not like this has to be add-on or only in tolvaptan failures or only an add-on to tolvaptan. What they've said is, and they've said this to all sponsors: "We'd like it if you included some patients with background tolvaptan use, but it's not a requirement." So we're planning to have a small percent... First of all, frankly, it's hard to find patients that are on stable tolvaptan for a long period of time, because of the tolerability issues, but we do plan to enroll at least a, you know, a proportion of them and then stratify by that. Yeah, I mean, most of the market research would indicate those that are on stable tolvaptan are not at the top dose yet. Yeah, which is another factor. Yeah. Yet, or just they're gonna get there. Can't tolerate it. Yeah. Okay, perfect. Excellent. All right, well, thank you all so much for taking the time. This was very helpful.