Good morning. Welcome to the H.C. Wainwright 26th Annual Global Investment Conference. My name is Yi Chen. I'm a healthcare analyst with H.C. Wainwright. For this session, I have the pleasure of chatting with Mr. Jay Hagan, CEO of Regulus Therapeutics. Welcome, Jay. Thanks very much, Yi, for having us. I know Regulus is slated to have an end of Phase I meeting with the FDA before the end of this year. Could you tell us what could be discussed during the meeting with the FDA? Yeah, our plan is to get alignment on a protocol for a Phase II/III study that could enable accelerated approval for our drug, RGLS8429. Do you believe the data from the third cohort of the Phase Ib MAD study of 8429 has demonstrated sufficient evidence to advance 8429 into a pivotal study in ADPKD? Yeah, our intention going into this study was to define a dose response in the form of a biomarker we developed. Mm-hmm. -where we can measure urinary Polycystin, and we believe we've seen that now, based on our understanding of the efficacy in animal models and the dose and kidney exposure associated with that in miR-17 engagement, the target of the drug. And indeed, we saw that at three milligrams per kilogram, we saw an incremental increase in Polycystin-1 and Polycystin-2, and a more consistent response seen across that third cohort compared to earlier cohorts, where, in fact, three milligrams per kilogram- Mm -reached statistical significance versus placebo. What additional analysis was conducted after the cohort three data readout, and do those new data help you design the pivotal trial? We didn't. We did ultimately conduct an analysis of the GFR slope- Mm-hmm -seen, in all of the cohorts to date, placebo one, two, and three milligrams per kilogram- Mm -because there was some question about, the impact on GFR. Keep in mind, this is a very short treatment duration- Mm-hmm three months of dosing, followed by one month- Mm of follow-up, but nevertheless, we completed that analysis, and as expected, you see no impact on GFR over such a short period of time. Mm-hmm. We anticipate, with the target product profile that we're shooting for in this Phase II/III study design of having tolvaptan-like efficacy- Mm but being safe and well-tolerated without the black box warning, that it would take us approximately two years to measure statistically significant impact on GFR. Mm-hmm. That's a long answer to your question. With respect to additional analyses that we've completed, our going-in objective, as I said, with this Phase Ib multiple ascending dose study, was to demonstrate a dose response so that we could pick dose that achieved the highest levels of Polycystin changes and was safe and well-tolerated. Mm. We believe we've achieved that thus far. Are you suggesting that the dosing duration in a pivotal trial could be as long as two years? Yes. Mm-hmm. Yes. No, that is the plan, that you would study subjects enrolled in the Phase II portion of the study. Mm for one year for an impact on height-adjusted total kidney volume. So you'd unblind it one year, the TKV data, and submit if you hit your primary endpoint. Mm. Those patients would continue on, though, for another year of dosing, to look for the impact on GFR, and that would be- Mm -that would occur in the post-marketing setting. Okay. Got it. With respect to the fourth cohort of the MAD study, which has a three hundred milligram fixed dose, when do you plan to report data? And does that data going to have a very big role into, you know, the design of the pivotal trial? The main objective with the three hundred milligram fixed dose was to get experience with a fixed dose. Mm 'cause we want to migrate to that format. Right For the Phase II study design, for a couple of reasons. One of which is, we obviously, if successful, would be filing for approval, and so you need to incorporate your desired commercial presentation, at least your initial one, into your clinical trials. And so that's the main intention. The other intention of this was- Mm We had the clinical operation machinery up and going, and we had a period of time before we were gonna start that Phase II study, and a lot of interest in the compound from the community. And so, getting experienced, utilizing a fixed dose, and primarily looking at safety tolerability, we will get a bit of a dose response, too, because some subjects, you know, are going to weigh, you know, less than a hundred kilos, and so they'll be getting more than three milligrams per kilogram in this fourth open label cohort. Mm. That's the intention of this cohort. The data we'll have, because it's open label, we can look at any time. But what we've decided to do, just operationally, is to batch it. We'll have a batch of a substantial number of subjects from this fourth and final cohort available early next year. That we'll announce as part of a program update. Mm when we also have our end of Phase I meeting minutes. Mm-hmm. So we'd anticipate that- Mm early next year. Okay. So, the potential initiation of the pivotal trial could be later in twenty twenty-five, right? Yeah. The reason why we're working towards this end of Phase I meeting here by the end of the year is to get that final protocol established, 'cause then typically- Mm industry standard is it takes, you know, at least six months- M before you get to a position of being able to start Mm enrolling subjects. And so that's the sort of the gating item to getting going and why- Mm we've guided to mid next year to initiate that Phase II pivotal study. Got it. What is likely the efficacy endpoint in a pivotal trial? Height-adjusted total kidney volume. Okay. Is there a potential discrepancy between the efficacy endpoint required by the FDA for approval and the efficacy that the patients and doctors want to see? Ultimately, so, in terms of, clinical benefit- Mm-hmm. In this disease, it's preservation of GFR, kidney- Right. -a-as a- Yeah -as your surrogate for kidney health. Mm. Right? Your GFR declines to the point where you need to go on dialysis. And so, but FDA has adopted a view that an impact on height-adjusted total kidney volume is reasonably likely to confer a clinical benefit in the form of GFR, and sponsors have to demonstrate that- Mm-hmm, mm-hmm. in the post-approval setting, very similar to IgAN and FSGS categories Mm-hmm, mm-hmm. -where proteinuria or UPCR is used for accelerated approval, and then the, Mm sponsors need to confirm that clinical benefit. Mm in the post-approval setting. So we would expect, if maybe your question is, how will that be received in the community? I, physicians that deal with ADPKD know that these kidneys get- Mm very large, and so it's I think it's appreciated that if you can slow that growth of the kidney, it's gonna confer benefit, and ultimately, demonstrating that and having that in the label will further bolster physicians' and patients' confidence that it could have an impact on their disease. Got it. Got it. So how many patients in the U.S. could benefit from RGLS8429? And are these patients currently being treated by tolvaptan? Yeah, sure. I'll take that in the two parts that you asked that. Yeah. There are currently 160,000 patients diagnosed. Mm-hmm in the United States with ADPKD, roughly 80% of which have not yet progressed onto dialysis. So that's your starting population to think about- Mm from a prevalence standpoint. Of those, the ones that where the treatment imperative is are considered moderate to severe disease, and that's typically classified by the Mayo Classification system of 1A through 1E, with 1C, 1D, and 1E being moderate to severe disease. They're most likely to progress to needing to end-stage renal disease. Mm -and the need for dialysis or transplant. So that's 1C, D, and E are roughly two-thirds of that overall population, so you're looking at about 100,000, you know, that could theoretically be targeted with a therapy like this. Mm-hmm. Okay. And could you talk about the natural disease progression of ADPKD, and how fast do they progress if left untreated or inadequately treated? Yeah, and I didn't get to your second question. Yeah -about tolvaptan yet. We actually have recently completed a fairly extensive- Mm market research study in both U.S. and Europe. Mm to look at the patient journey and utilization of tolvaptan, and feedback on that product, as well as testing, obviously, our product profile, to get a handle on intent to treat. You know, of that, there have been a number of physicians who have tried their patients on tolvaptan. The vast majority discontinued due to the tolerability issues with the product and the polyuria associated with it. A little less so, the administrative hassle of complying with the REMS, where you need to have a clean liver function test each month to get your prescription refilled. Mm-hmm. It's the polyuria effect, and what we further found. Of the total potential addressable population, less than 10% right now appear to be getting prescriptions for tolvaptan. And of those, more than half of them are not at the recommended dose. Mm. They're at a lower dose to manage through the tolerability issues. So, it's, I think the takeaway of that is it's a high unmet medical area. Can you repeat the other question you had? The natural progression of the disease. Oh, the natural progression. Yes. Mm-hmm, mm-hmm. So it's a germline mutation in either the PKD1 or PKD2 genes. And while we don't, you know, typically, it goes undiagnosed until either you have a family history and get tested for it, or let's say, find out that your father or your uncle has it, and then you get a, you know- Mm The whole family tested to see if you have it as well. It's thought to be underdiagnosed because there was no therapy approved until the middle of two thousand and eighteen. Mm In the United States with tolvaptan. Mm. You know, genetic testing of this sort, when you have nothing to treat with, is done less so. Mm. We would expect to see, you know, continued testing done with more therapies. Mm -being available, like any market evolution. The females tend to be diagnosed earlier, if they have an incidental finding with an ultrasound due, when, they could be, pregnant, and whereas, men tend to present with flank pain. The kidneys get so large that you're, like, let's say, you're getting up or bending over, turning, and you can feel the pain in your sides. These get to be 10 times the size of a normal kidney. A kidney's supposed to be the size of a closed fist. And, so that germline mutation kicks off, a whole range of, you know, genetic changes that drive this cystogenesis and proliferation of cysts, in the kidney. And they not only multiply, they grow, over time. In fact, we've done some work looking at total cyst count through imaging techniques, and, you know, the patients that have been involved in our studies to date have, you know, eight hundred to a thousand cysts per kidney. Mm-hmm. Okay. Got it. So you mentioned that the treatment duration could be two years in the pivotal trial, right? Is it fair to assume the enrollment could take one, roughly one year to complete, and the entire trial could take up to three years to read out? So, our base planning assumes enrollment consistent with other rare renal diseases. Mm-hmm. where typically a site can enroll 0.25 patients per site per month. And so then you can layer on the speed at which you anticipate getting your sites up and going. And so our planning would suggest that for three hundred subjects, it would take us approximately fifteen months to enroll. Okay. Got it, got it. Do you believe the FDA would allow, you know, Regulus to submit ADPKD for approval with data from one single pivotal trial? Yes. Okay. They have indicated that? Yeah, we met with them in December of last year. Okay ... to confirm that the accelerated approval pathway. Okay -is available, based on the height-adjusted total kidney volume. Got it. Got it. Does Regulus need a commercial partner for ADPKD? We are in discussions with potential partners, because this is a global disease. Right. We certainly don't have any capabilities outside the U.S.- Mm Beyond our small team in San Diego. You know, in terms of us conducting the study, I believe our team is certainly capable of conducting a 300-subject, you know, one year and two year study. Very quite experienced. But we are in discussions with- Mm potential partners to see if there's attractive opportunities- Mm to be able to allow the drug to be developed and commercialized globally. Okay. Okay, got it. Are there any potential competitors for ADPKD? tolvaptan will lose patent exclusivity in the United States next year. Mm. And beyond that, in terms of what's in development from a competition standpoint, there are, if you look up on ClinicalTrials.gov, you'll see, you know, historically there was a J&J program, there was a Galapagos program. We understand that those are being deprioritized by each of their management teams. And, behind us, we do know that Vertex is in a Phase I study- Mm looking at a subset of patients with ADPKD. Specifically, we believe those with a missense mutation, which represents about, according to their math, about 10% of the diagnosed population. Mm. Those are the primary compounds- Mm that we see in development that, could be additional, important new tools in the treatment of ADPKD. Okay. But there are no other competitors, that are currently in late stage development? No. Okay, great. What are the issued patents for ADPKD? And what- We have a composition claim that goes to 2042. Okay. We have method claims that we developed in collaboration with UT Southwestern. Mm-hmm, mm-hmm around, targeting miR-17 for the treatment of ADPKD. Great, got it. Can you just give a brief overview of the upcoming catalysts within the next twelve to eighteen months? Yeah. So we're on track for this end-of-Phase I meeting, which we deem to be an important milestone to gain alignment with the agency on the trial design. We'll have a data... We'll have a program update related to that, as well as a substantial number of subjects- Mm ... from this, fixed dose cohort here early next year. Mm-hmm. Then we'll wrap up enrollment here, hopefully soon. Mm ... with this fourth cohort, which would put us in a position to read out the remaining subjects, likely in Q2 of next year. Mm. and then, you know, with the completion of the tox studies and submission to the IND, be on track to start the Phase II in the middle of next year. Mm. From there, beyond that, it's looking to get the trial substantially enrolled. Mm-hmm. Thank you. Does the company have sufficient capital to fund a pivotal trial? We've guided that we have cash into the first half of 2026. Mm, mm-hmm. So until we know and we align with the agency on the exact size and duration of that study, will we know exactly where we sit. Mm. But we estimate that if you just look at, again, industry norms for rare renal disease. Mm where you're doing, you know, these types of visits, as well as repeat MRI, that they run, you know, between $300,000 and $400,000 per subject. Mm-hmm. So with 300 subjects, you can do the math, that's $90-$120 million for the study itself. There'll be other costs, in terms of running the business, as well as because you can get approved on this, accelerated approval on a single Phase II, you'll have other commercial prep costs, to consider on top of that. That's the extent of our guidance right now. Mm ... in terms of, cash runway. Got it. So, I guess last question. What do you think is the key takeaway message for investors? Why should an investor pay attention to Regulus today? I think, you know, I think that, pay attention to Regulus because of the unmet need in- Mm autosomal dominant polycystic kidney disease. Mm. You know, it's not dissimilar in magnitude as other categories adjacent to us, like IgAN. And, you know, where I think there's a strong recognition of the unmet need there, and a lot more competition. With respect to our area, you know, a lot less competition, clear unmet need, supporting, you know, with an orphan indication, supporting attractive pricing and reimbursement. And, you know, for us, you know, what we've demonstrated to date, where at two milligrams and three milligrams per kilogram, we've seen not only an impact on Polycystin, and the dose response there, but now early evidence to suggest that we might be able to stop the growth of the kidney- Mm which is, could have a profound impact on patients. Got it. Great. Thank you very much for the informative chat, and thank you for your participation. Thanks for having us, Yi. Good. Best wishes.