Welcome, everyone. It's my pleasure to host this fireside chat with Regulus Therapeutics. I'm Joe Schwartz from the Leerink Partners Biotech Equity Research team, and it's my pleasure to be joined by Jay Hagan, CEO, Preston Klassen, Head of R&D. Thanks so much for being here to give us an update. Thanks for having us. Yeah, absolutely, Jay. Maybe we can have you start us off with a quick level set of your recent accomplishments and goals for 2025, and then we'll dive into all the parts and pieces. Sure, yeah. We've been reporting out on an ongoing phase I-B clinical trial of our oligonucleotide designed to inhibit miR-17 called Farabursen, otherwise previously known as RGLS8429. We're wrapping that up and preparing for the initiation of a pivotal study on the heels of a successful end-of-phase I meeting we had with FDA at the end of last year. All right. Goals for 2025? Get that. Get that study started. Get that study started. Cool. What is that going to entail in terms of gaining FDA alignment? I know this is not the first time you've been thinking about this, but where are we in terms of FDA buy-in on the phase III? Yeah, so we have buy-in on the heels of that meeting. I think what's evolved is this division's acceptance of total kidney volume as an appropriate surrogate, reasonably likely to predict clinical benefit, and one that you can get accelerated approval for so long as you show in the post-marketing setting that it has an impact on clinical benefit in the form of GFR. These patients experience this prolific growth of cysts in the kidneys that ultimately leads to renal failure. By slowing the growth of the kidney, it's been shown, it's been correlated with a number of data sets now that accrues to clinical benefit. Yeah, that's a great segue to my next question. Seems like the FDA believes in this relationship. Have they, to what extent have they considered whether that's being seen in this study, or are they just basing the construct of accelerated and full approval based on kidney volume and GFR, respectively, on other data sets? Yeah, it's other data sets. It's the tolvaptan pivotal program, although that didn't go under, that wasn't approved under accelerated approval, but that is a large phase III program that demonstrated both changes in total kidney volume and changes in GFR. There have been two other longitudinal clinical trials, one called CRISP, one called HALT, that also demonstrated changes in total kidney volume relate to changes in GFR. All three data sets, those are probably the three predominant ones, actually have relationships that look pretty similar in terms of if you look at each one compared to the other, and the correlation is around 0.7 for those two variables. That's what the FDA has used to combine with the fact that it's a clear unmet need, an orphan drug, all of those additional things that help. It is very clear that they are committed to an accelerated approval pathway on the basis of changes in total kidney volume. They are very interested in and concerned with getting to the GFR answer at the end of the day. A company that comes with volume data for an accelerated approval needs to also show that they are well underway, if not completely enrolled for the GFR component to make sure that that actually crosses the finish line as well. Yep. Okay, great. Can you just summarize for us what you've seen in terms of the kidney volume and the GFR changes and the relationship between the two? Yeah, sure. Just real quickly, in our ongoing phase I-B study, we've got about 10-14 active patients per each cohort. We've tested three weight-based dose cohorts, 1, 2, and 3 mg per kg. We've also, we're in the process of testing the final cohort, which is 300 mg as a fixed dose. The first three, 1, 2, and 3 mg per kg, those are the dose-ranging cohorts that are placebo-controlled. In that, we demonstrated that the highest dose, 3 mg per kg, had the greatest impact on urinary polycystin. That's our indirect mechanistic biomarker. That shows where we can get in terms of mechanistic activity. We've shown that you basically kind of peak out at your ability to block miR-17. 3 mg per kg is the right dose. 300 milligram then is a fixed dose that best reflects, we think, that 3 mg per kg level. In terms of kidney volume, although the study was not powered to detect changes in kidney volume, it's relatively small, relatively short treatment duration, just three months of therapy. Despite that, now we've seen with three separate cohorts, 2 mg per kg, 3 mg per kg, and more recently an interim analysis of the 300 milligram fixed dose, we've seen notable mean reductions in the growth rate of the kidney. Essentially, we think we're somewhere near basically halting kidney growth over at least a four-month period of time. The MRI is taken at baseline, and then it's taken at four months later. That's after three months of therapy and one month off drug. That's actually, I mean, getting near no change in kidney volume over that period of time is, if we can continue that and really show that in our one-year study, that would absolutely be a game changer in the space. I think importantly, placebo grew, as you would predict based upon the larger studies that have been done with placebo arms, about 6% per year. You would expect around 2% growth over four months, and that is a deeper push. Yep. Okay. Very helpful. How is the phase III designed? Yeah, just very simply, it's a two-year study where during the first year, we check an MRI for total kidney volume at baseline, six months and 12 months. That 12-month data combined with the six-month data and the baseline will be used to determine that volume endpoint. That would be the primary endpoint for accelerated approval. Patients continue in the study for an additional year. All during the two-year duration, every eight weeks at least, we're checking GFR. All of that totality of data every eight weeks over two years in each patient will contribute to the GFR endpoint, which is the primary endpoint for full approval. What, so you're hoping to see like a 6% decrease in GFR over that timeframe. How about, can you talk about how the trial is powered in terms of what you hope the drug to show? We're essentially using the tolvaptan. Tolvaptan is the one drug approved on the market today. In its phase III program, it demonstrated over an annualized period of time, a 50% reduction in the growth rate compared to placebo. I think, as Jay mentioned, untreated patients in this moderate to severe disease category one, which is Mayo Class 1C, 1D, and 1E, tend to grow at around 6% per year. Tolvaptan-treated patients grew at about 3% per year. GFR decline tends to be around 3-4 ml per minute per body surface area per year down. In the tolvaptan-treated group, this decline was reduced by about 33%, by about a third. That's a delta of about 1.27 ml per minute. Our powering is that. We assume a 50% reduction in the growth rate of the kidney over a year and a 1.25 ml per minute decline in the, or reduction in the decline in GFR annually, but over a two-year period of time. That gets us the sample size of around 325-350. Right. Okay. You can also do some interim analyses. Can you talk about that? We wouldn't do an interim analysis where we and everyone else would look at the data because we can't do that kind of interim along the way in terms of biasing the study before it gets to its endpoint. However, unless we wanted to do an interim look for early efficacy where we'd spend alpha, etc., and that's not what we're currently considering. Importantly, though, we can use our Independent Data Monitoring Committee to look at the accumulating data along the way and do a sample size re-estimation just to make sure we've enrolled enough subjects. Things are looking pretty good. They're going in the right direction, but we might need some more subjects for some reason. We could be alerted to that. We'll do that at two specific time points. One for volume, and that would be when about half the subjects have accumulated that six-month total kidney volume analysis, so their MRI. We'd look, or the independent DMC would look and just give us a sense check, are we enrolling the right number. The second point would be GFR-related. When all of the subjects have completed one year of the study, we'll look at the one-year GFR, again, the Independent Data Monitoring Group, and then do a conditional probability assessment for when at two years, just as a sense check, are we headed in the right direction? Okay. How did you decide on the right dose to take into phase III? Predominantly based on the urinary polycystin response. The idea is that if you're blocking miR-17 on its own, an increase in miR-17 will bind to PKD1 messenger RNA, which makes polycystin-1, and PKD2 messenger RNA, which makes polycystin-2. If you're blocking miR-17, it's no longer able to bind to PKD1 or PKD2 mRNA. You should make more of those two proteins, and therefore more of those two proteins should show up in the urine. We don't get to test it. We don't get to take out pieces of the kidney in a kidney biopsy in these patients because of the bleeding risk related to the cysts. What we can do is measure what's in the urine. We showed very clearly a dose response increase in urinary polycystin until we got up to about 3 mg per kg. That seemed to be kind of hitting that asymptotic flat part of the curve. That was confirmed or has been confirmed so far in our interim look at the 300 mg fixed dose, where some patients, based on their weight, body weight are actually higher than 3 mg per kg. We have not seen any further increase. We really like the response seen at that high dose, 3 mg per kg. We think that 300 mg as a fixed dose is the right approximation of that 3 mg per kg dosing. Okay. That backtracks to all the efficacy data in the animal models where at 30 mg per kg, we're kind of maxed out both in terms of miR-17 inhibition and then ultimately the cyst index and other measures. That equates to roughly 2.5 mg per kg. We're on that flat part of the dose response curve. Okay. Great. We had some subjects that were upwards of 4.5 mg per kg in cohort four in the 300 mg fixed dose, just based on their body weight. No discernible differences in polycystin or volume changes. Right. So you've already done a pretty comprehensive response exposure analysis. Yeah. Got it. How long do you think that the phase III will take to enroll? We're planning on 18 months. It could come in quicker than that, but that's our base planning assumption. Okay. 80-100 sites around the world. Okay. I mean, there's so many of these patients. How are you going to select them? It's essentially kind of relatively simple. It's a Mayo Class of 1C, 1D, and 1E. It's what we use to include patients in the current study. That equates to moderate to severe disease. That's about 2/3 of the diagnosed patient population is 1C, 1D, or 1E. We'll have a broad GFR criteria, 25-90. It's pretty much all comers as long as you've got moderate to severe disease. We believe, particularly given that there's not much else out there from a competitive trial perspective in terms of mid to late-stage development, we know that the patient community is definitely looking for something additional. We do believe that our enrollment goals are very appropriate. What about background therapy? Will you be allowing tolvaptan? Yeah, we will not be allowing tolvaptan for a couple of reasons, probably the most important of which is that it's hard to find patients who are on kind of the indicated dose, full dose BID, for example. Many patients start and stop therapy. Over the course of two years, if you're on a background therapy that can, has been shown to impact the endpoints you're looking at, but they're going on and off that therapy, that could be a problem. We thought this is from a logistical perspective and potentially impacting efficacy. We didn't think that was right. From a safety perspective, obviously they've got a black box warning for fatal liver tox. Although that's a low-frequency event, of course, we didn't want to have that kind of confounding from a safety perspective. We did not propose including patients on tolvaptan, and we got no pushback from the FDA on that. We have done some initial payer work too and do not see that being a big barrier for us, even despite the fact that it is going generic this year. Yep. Okay. Great. That's very helpful. You mentioned that there's not a lot else in development, certainly late stage. When thinking about the commercial rollout, do you think that back to tolvaptan, do you think that patients would have to step through generic tolvaptan? I know this is looking at the future. Depending on their plan, there have been a lot of patients who've tried and discontinued because of tolerability. They're going to have that medical history already. It will be as much administrative as anything. We'll obviously have the right patient assistance programs in place to enable access to the medicine. Okay. If I could go back to the regulatory line of questioning, as far as Europe goes, where are you in terms of speaking with the European regulators? You've aligned with them. Does this fit all of their needs as well? Yeah, we certainly believe it will. We haven't had formal engagement with them to this point. We're planning on a scientific advice procedure over the next coming months. I think the key question there is whether it, so their accelerated approval analogy would be conditional approval. They've been less clear about ADPKD and conditional approval versus full approval and the requirements versus the FDA has been very public about this. We'll have that conversation, but I think it's also important to recognize the reimbursement landscape in Europe, of course, is different than in the U.S. It may well be that in terms of getting appropriate reimbursement, you actually do need that full approval with GFR data in order to do that. We're still making that assessment. It could be very easily the case that it just makes most sense to go for the full approval as opposed to conditional, which in our case would just be one year beyond the volume endpoint. We would have both volume and GFR data, and that could be sufficient for what we need in terms of reimbursement. There is still some work to do on that, but plenty of opportunity. Okay. Great. I guess how are you thinking about, I mean, this is such a big market opportunity, but you obviously have, it's an oligo, which is a, and it's a new modality. It's a new way of using. New target class, yeah. Yeah, exactly, with the microRNA. Would there be any precedent for this kind of a medicine, this kind of an agent to, I know it's orphaned, ADPKD, but it's such a big market opportunity. I'm just wondering how you're thinking about whether there's precedent for companies like yours to be able to bring an oligo like this to the masses. I think the tools that we use, right, are incorporated already into approved products, right, using Ionis and Alnylam chemistries. The notion of the oligonucleotide itself, the drug, is established, right? It's the target class. As far as that goes, it speaks to all the steps you would do in normal drug development to have the safety, tolerability, toxicology data, and so forth that support chronic dosing. We've completed our chronic tox studies. The top doses are in the NOEL. We don't, from a novelty standpoint, haven't identified anything that would suggest that it doesn't warrant pursuing the target. There are two other companies that are pursuing mid to late-stage development of products targeting microRNA, Novo bought. Cardior. Cardior, miR-132, and heart failure for a good chunk of change last year. That data was pretty interesting, the phase II-A data. They are advancing that. There is the small molecule approach targeting. miR-125. Yeah, miR-125 in UC and Crohn's. That's a company called AbbVie. AbbVie, yeah. Right. Yep. Okay. Yeah, that's encouraging. The other thing, just from a commercial perspective, a small company can do this. As you said, it's orphaned. We've done definite research on who are the prescriber base, how to grow that prescriber base, and it's something the small company can take on. Yeah, it's definitely a concentrated current writer base. You want to grow the writer base because there's quite a few physicians who tried once and didn't have a good experience, or their patients didn't, and then haven't prescribed since. There is a market growth opportunity here, but in terms of initial uptake, you can reach the top seven, eight deciles of writers with a very focused effort. You're not going to have share of voice challenges either, right? There's no other competing dialogue out there in terms of tools available for patients. They're pretty well organized too. Yeah, I would imagine. Foundation and. There's some good pull. Yeah. Yep. That makes sense. You've shown that you can do a lot of the heavy lifting yourself already on so many aspects of the development and the design. How about if we go back to the clinical setting with the measurement of height-adjusted kidney volume? Is that something that gets done routinely or would need to be if Farabursen makes it to market? I guess before that point, just in phase III, do you need to train sites in order to be able to do this, or are there enough sites out there that. It's fairly standard. I mean, it's an MRI. You go in the machine, you get your scan. I think the key part is the software that's used, and it's now very much AI kind of driven in terms of the measurement of the total kidney volume. Right now, our current study is being read centrally, read in a blinded fashion by the group at the Mayo Clinic, and they're at the forefront of all of this. They'll definitely be involved, not as a primary vendor, but as kind of the quality control vendor for aspects to our imaging vendors for the phase III program. That's not a rate limiter in terms of that. It's a fairly standard imaging process. Okay. Interesting. Will you be developing an auto injector? Yes. For this? The initial development feasibility work is underway. Yep. When's the right time to introduce that? At launch, you have to do a BE study, bioequivalent study, but that's pretty straightforward. Yep. What. Yep. What. Right now we're packaging in prefilled syringes for the pivotal study. Okay. Good. And then what's IP like? 2043, I think it is, yeah, without any extensions. Okay. Anything I didn't ask you? You should have. We should? Yeah. No, I think it's, I'd say that I think there's a growing appreciation for the unmet need here. There's been obviously a lot of progress in adjacent spaces like IgAN that I think will continue to accrue to ADPKD, which is much needed. There has been very little, right, until that then, and then there's been a number of pretty high-profile setbacks. Yeah. Yeah, it makes sense. Is ADPKD at all a disease that, like these GLP-1 drugs, continue to take share? No. In the now situation. It's not a metabolic. No, it's very much a genetically driven issue within the kidney. It's not cancer, but it's got a lot in common with cancer biology. It is a hyperproliferative cell-transforming disease, and it's driven by the mutations that drive it, trigger transcription factor signal pathways like c-Myc, c-Fos, c-Jun, etc. They drive an increase in the family microRNAs, miR-17, that adjust gene expression across a number of different genes, including PKD1 and PKD2 through this messenger RNA, and drive that hyperproliferative cell-transforming state. By blocking miR-17, you essentially put that back to normal. I would say that. Does it correlate with body mass or? No. Nope. No. I mean, what you do hear anecdotally from patients and physicians who are caring for them, though, is abdominal pain because of the size of the kidneys. To the extent you lose weight, and that creates a little bit more space, then perhaps you might be able to address some of the side effects of the disease. Even premature satiation also is another issue just because there is not that much room. It is as if you are on, I talked to one patient back home who describes the need to be very careful with his calorie selection because it feels like a permanent lap band because there is no room. To the extent you have some benefit there in terms of impacting patients' overall size and theoretically, but not with respect to anything disease-modifying. Maybe one more question. It's rare that you can address such a big market with such a reasonably sized phase III trial. How much is this trial going to cost? Because it does not sound like it's a huge study. Yeah, so 300. It sounds like it's fairly involved. We're in the process of getting quite close to signing up our, we've selected our CRO, and now with the protocol near complete, we're getting much more accurate quotes. Historically, we've used a benchmark. I know we've shared with you that $300,000 to $350,000 per patient was sort of a benchmark. We talked to other renal companies that you know. The estimates are coming in lower than that now. All in, the trial is probably going to cost about $100 million, maybe a little less, $80 million. Okay. How's the company funded, and what levers does it have to pull to get this done? Yeah, so we ended Q3 with $87 million, burning about $12.25 million. We'll have our K filed, I think, soon, but that's the rough math. Obviously, that's not enough money to fund a two-and-a-half-year study. We're actively in discussion with both investors on the one hand, as well as strategics, to see if there's something more compelling to do there with the program than just straight equity dilution. What I've said is we will capitalize the company before we start the trial. I've got every confidence that we'll be able to do it. Okay. Great. I think that's about all the time we have. Thank you so much for the update. Thank you very much. Keep up the great work. Thanks. Cheers. Appreciate it.