Good morning, and welcome to the Regulus Therapeutics program update. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your touchtone phone. To withdraw your question, please press star, then two. Please note, this event is being recorded. I would now like to turn the conference over to the company's CFO, Cris Calsada. Cris, please go ahead. Thanks, operator. Good morning, and thank you for joining us for this special update on top-line results from the first cohort of patients in our Phase 1b multi-ascending dose clinical trial of RGLS8429 for the treatment of autosomal dominant polycystic kidney disease. Before we begin, I'd like to remind you that this call will contain forward-looking statements concerning Regulus Therapeutics' future expectations, plans, prospects, corporate strategy, and performance, which constitute forward-looking statements for the purposes of the Safe Harbor Provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our filings with the SEC. In addition, any forward-looking statements represent our views only as of the date of the webcast and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. Joining me on today's call is Jay Hagan, Chief Executive Officer, and Dr. Preston Klassen, President and Head of R&D. I will now turn the call over to Jay. Jay? Thanks, Cris, and thanks, everyone, for your time and attention this morning to discuss the results of the first cohort of our ongoing Phase 1b study of RGLS8429 in patients with ADPKD. Hopefully, everyone can see the slides that we will walk through to guide the discussion. Before we get started, though, I want to remind everyone about our program. RGLS8429 is an antisense oligonucleotide designed to recognize and bind to a specific microRNA called miR-17. miR-17 has been shown to be upregulated in the kidneys of both mouse genetic models of ADPKD, as well as in patient kidney samples. Part of miR-17's role is to control the expression of its target genes, PKD1 and PKD2. Our molecule is designed to preferentially distribute to the kidney, bind miR-17, thereby allowing gene expression through de-repression. miR-17 has other proliferative biologic roles, thought to contribute to its efficacy in a variety of disease models. RGLS8429 is our next-generation molecule that has been designed to eliminate the off-target effects seen with our first-generation compound, RGLS4326. Importantly, though, the combined data set of our anti-miR-17 program indicates consistent pharmacodynamic responses, which Preston will walk through in a minute. This approach has demonstrated significant anti-cyst activity in disease models, as well as preservation of kidney function. By targeting miR-17, we have now seen consistent pharmacodynamic responses in the form of increased polycystin production, the protein product of the genes we're trying to regulate. Today, we're talking about the results from our first cohort, dosed at 1 mg per kg every other week for 3 months. Our second cohort at 2 milligrams per kilogram is fully enrolled, and we expect data in the first quarter next year. Finally, the third cohort, which will be dosed at 3 milligrams per kilogram, will commence enrollment next month. Hopefully, you all have had the opportunity to listen to our investor event from a couple of weeks ago. We gathered several leading academics in the field of ADPKD to discuss the unmet need and treatment paradigm, the genetic drivers of the disease, and the role of miR-17, as well as new imaging biomarkers taken from MRI samples to set the stage for our data release on the program today. If you've not had the opportunity to review those materials, they're available on our website. In summary now, before we get to the data that Preston will walk through, there's a huge unmet need in this disease with only one approved therapy. There are over 160,000 diagnosed with the disease, caused principally by a mutation in either the PKD1 or PKD2 genes. Our approach represents a novel mechanism to design, excuse me, designed to address the genetic drivers of the disease, and we're excited to share the results from our first cohort. With that as background, I'll turn the call over to Dr. Preston Klassen. Preston? Thanks, Jay. We can go to Slide 3, and I'll just set the stage with a few key messages, then we'll dive in. So we have solid study conduct in this Phase 1b trial, including enrollment, and incorporation of MRI measurements into site activities. RGLS8429 at this first dosing cohort of 1 mg/kg was well tolerated and no safety concerns were observed. There's clear evidence of polycystin increase at 1 mg/kg. This is consistent with what we've seen with our first-generation compound. Our polycystin-1 increases were a bit greater than seen for polycystin-2. And overall, the polycystin pattern is consistent with what we believe is the renal tissue pharmacokinetic profile based on non-clinical studies. When we examine all clinical dosing across our first-gen, RGLS4326, and this current second-gen, RGLS8429, we see an emerging dose response that does suggest an opportunity to demonstrate greater polycystin responses at higher doses in subsequent cohorts, which is exactly the purpose of this dose-ranging study. As anticipated, we saw no evidence of impactful changes to renal function or MRI measures of kidney volume or cystic architecture. This, of course, is in a setting of short treatment duration, small patient numbers, and measurement variability. But running the experiment has been very useful to us in preparation for a more extensive and pivotal Phase 2 trial, and we will have the ability to collect additional exploratory measures as we gather more subjects in this study and more information as we combine the groups together. So overall, cohort 1 clearly meets our expectations and continues to establish polycystin as a valid pharmacodynamic marker for this dose-ranging trial. Now we'll cover this in just a bit more detail. Going on to the next slide. Just a brief reminder of the study design. This is a Phase 1b, multiple ascending dose trial, enrolling ADPKD patients with a Mayo Classification of 1C, 1D, or 1E, and an estimated GFR of 30-90 mL/min. 12 subjects randomized 3 to 1 active to placebo and dosed every other week for 7 doses or 12 weeks. polycystin was measured at months 1, 2, and 3, with additional measurements during the follow-up month to characterize the PK/PD relationship. We examined a variety of renal function measures as well as baseline and post-treatment MRI to evaluate the kidney for total size, as well as novel measures of cystic architecture. We spent significant time covering these novel measures at our recent R&D Day, so I'm not gonna cover the details here. Let's go to the next slide. Baseline characteristics were evenly distributed for what we would expect, with 9 active and 3 placebo. Overall, a mean age range of 42-52. Equal gender split, mean GFR in the low forties, and in the 9 active patients, the Mayo classification distribution is what we would expect. It's a bit harder to see that same distribution across only 3 placebo patients, and really nothing unexpected in terms of the baseline genetic mutation. Let's go on to Slide 6. Safety was benign. RGLS8429 was well-tolerated, with treatment-emergent adverse events in the low to moderate grade and only one SAE, which was a case of appendicitis not related to study drug. There were no significant changes to labs, vitals, or ECG, and all subjects completed the study. Now, the PK results were similar to what we have observed with the first generation, RGLS4326. No accumulation in plasma or urine. AUC plasma exposure in patients with ADPKD is greater than in healthy volunteers in a manner that is consistent with a reduction in renal excretion due to the underlying reduced GFR from ADPKD. And our modeling suggests that one milligram per kilogram is on the lower half of the dose response curve, and we'll talk a bit more about that in a moment. But let's start to get into the polycystin results at Slide 8. So again, just a brief background in terms of polycystin. We know that polycystin is reduced specifically in ADPKD as a direct result of both the germline mutation and the upregulation of miR-17. And we see that lower levels of polycystin do correspond with greater disease severity, shown here with polycystin-1 on the left and polycystin-2 on the right. And you don't see reductions in polycystin among either healthy volunteers or patients with chronic kidney disease due to conditions other than ADPKD. And it's not shown here, but it's also clear that in ADPKD patients, lower levels of polycystin correlate with reduced renal function as measured by eGFR. Slide 9 shows the top-line results for polycystin-1 and polycystin-2 at 1 milligram per kilogram. For polycystin-1 on the left, we have three measurements that constitute baseline: screening visit one, screening visit two, and then day zero prior to dosing. After dosing starts, we see increases in the first measurement at one month and sustained increases while dosing occurs, followed by a drop-off after the 12 weeks of dosing. You can see from the error bars that the variability is a bit larger in the active patients compared to the three placebo. We think this may be because we're actively driving changes in polycystin expression, and the response may be more variable when that happens. The increase was approximately 36%-41%. Looking at the end, at day 85 and day 86, this is changes from baseline, I think, to the end of 12 weeks of treatment. These are statistically significant as a change from baseline and as a reminder, we're qualitatively characterizing placebo here on the slide, but we're not going to perform statistical testing until placebo has all 3 dosing cohorts combined for a total of 9 placebo patients, to then compare to 9 in the other active groups. And with polycystin-2 on the right, we see some greater variability, and that's particularly evident during those 3 baseline values. That's screening 1, screening 2, and day 0. And overall, a bit of a lower response, which is consistent with what we saw with the first-generation compound, RGLS4326. These numerical increases did not reach statistical significance, which again, is not surprising at this lowest dose level, given the variability and the small sample size. What we're really looking for here, and particularly demonstrated in this slide, is the overall curve of the response. We want to see that it makes sense, and we want to get a solid view that we're beginning to impact polycystin at this lowest dosing cohort, and the results clearly accomplish that. Let's go to Slide 10. When we combine the totality of existing clinical data in patients across both our first-generation RGLS4326, which was tested at 0.3 mg per kg and 1 mg per kg, along with the current 1 mg per kg data from the second generation, RGLS8429, we believe we are seeing an emerging dose-response relationship and this further encourages us that we've got strong opportunity to increase the polycystin response at higher doses. These two graphs examine Cmax on the left and area under the curve, AUC, on the right against polycystin-1 levels. Now, obviously, by definition, the regression line between two points is linear. We'll have to see the true nature of that PK/PD relationship, whether it remains linear or is less than linear, as we accumulate more data from the 2 mg per kg cohort and then the 3 mg per kg cohort. Let's go to Slide 11. As I mentioned at the top, we saw no significant or notable changes in either renal function measures or in renal imaging measures by MRI. We looked at all the usual suspects in terms of renal function measures, and with MRI, we focused on total kidney volume and a handful of more novel cystic architecture measures. The bottom line is that renal function and renal imaging studies are likely to take 12-24 months of treatment in hundreds of patients, and so it makes sense that we haven't seen any patterns yet in nine patients over 12 weeks of dosing. But we did learn what we needed to in terms of incorporating MRI measurement into the clinical trial execution, as again, that's going to be a very important part of our Phase 2 pivotal trial. And what we do expect to do is continue with these exploratory analyses like these for each cohort, and of course, once we have all groups combined at the final data set at the end of the study. In summary, on Slide 12, we just covered the top line results from the first dosing cohort in an ongoing Phase 1b multiple ascending dose trial of RGLS8429 in patients with ADPKD. 8429 dosed at 1 mg per kg once every two weeks over 12 weeks was well tolerated with no safety findings. Statistically significant increases from baseline in PC1, or polycystin-1, were noted at 12 weeks of dosing, and increases from baseline were also observed in urinary polycystin-2 at 12 weeks. However, the changes did not reach statistical significance. As expected, renal function and renal MRI measures did not demonstrate meaningful changes over the short-term 12-week dosing. Importantly, urinary polycystin continues to exhibit all of the appropriate PKPD correlations to serve as an important pharmacodynamic biomarker in ADPKD, and the data suggests the opportunity to demonstrate increased urinary polycystin response at the higher doses that are planned in subsequent cohorts in this Phase 1b study. We're quite pleased that this first cohort has met expectations, and we look forward to seeing future results from the ongoing trial. Cohort 2 is now enrolled and is being dosed at 2 mg/kg, and cohort 3 will initiate enrollment next month and will receive 3 mg/kg. As we complete this weight-based dose ranging, we are planning to run at least one additional cohort as a fixed dose as we prepare for a fixed dose in a pre-filled syringe for Phase 2 and eventual commercialization. Now I'll turn it back over to Jay. Thanks, Preston. And with that, we're ready to open the line for questions. Operator? We will now begin the question and answer session. To ask a question, you may press star, then one on your touch tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. Again, it is star, then one to ask a question. At this time, we will pause momentarily to assemble our roster. The first question comes from Whitney Ijem with Canaccord Genuity. Please go ahead. Morning, guys. Congratulations on this data. Very, very exciting to see. First question, I guess. Have you talked about, in terms of the... You presented this data in terms of PC1 and PC2 as change from baseline. Have you characterized, or can you, the level of PC1 and PC2 that were achieved relative to normal or healthy volunteer levels, in this first dose cohort? Sure. Yeah, I'll go ahead and take that and see if Ed has any additional comment. So, you know, very clearly these levels are reduced as you saw in that background slide in ADPKD patients generally compared to the normal population. And so what we're showing is, you know, an increase in change from baseline. When we look at, because we sometimes get asked, well, how much do you want to increase it? You know, we're not trying to push it up necessarily into the quote, "normal range." All of the preclinical evidence demonstrates that changes in the order of around 50% or higher have significant impact, and so we'll see where, you know, where we can go. But obviously, what we'd like to do is be pushing the levels up as high as possible. Ed, do you have any additional comment? No, I don't have any additional comments. Okay, thanks. Got it. Okay, that's helpful. I appreciate that it's small numbers here, but any early indication of a difference in response based on underlying mutation? Yeah, the short answer is just too small numbers really to tell. So we look forward to being able to kind of group everything together and see. But, you know, even in that setting, as you well know, these kinds of, you know, real stats, once we get into Phase 2, it's going to be, you know, several hundred patients, to be able to tell those kinds of analyses a little bit better. Yep. Makes sense. All right. Thanks very much. Congrats again. Thanks, Whitney. Again, if you have a question, please press star, then one on your touch tone phone. The next question comes from Yi Chen with H.C. Wainwright. Please go ahead. Hi. Congratulations, and thank you for taking my question. So, with respect to the renal function parameters and MRI parameters, how soon do you expect to see a change? Go ahead, Preston. Yeah, so you know, essentially all of the studies, particularly when you're talking about renal function, like estimated GFR, those studies tend to be two years in duration. So, you know, the plan for our program is, you know, most of the studies, there haven't been many of them, but most of them that have looked at total kidney volume, using MRI, have been 12 months or 18 months in duration. Generally speaking, we're planning on a 12-month evaluation to look at that in our pivotal Phase 2, and then we would have to follow that up once we get approval and are in the, you know, commercialization setting. We run a post-approval additional study to confirm clinical benefit, looking at the focus on eGFR, and that would likely be a two-year duration study. And so, you know, again, it's just not surprising that we're not really seeing a whole lot of movement here at 12 weeks across 9 patients. ... Yeah, and further to that, Yi, you know, in terms of total kidney size, you know, the historical data for large data sets run by the one approved drug suggests an annual rate of increase in a larger sample size of around 6% in total kidney size. And so over three months then, if you just do some simple math and assume it's somewhat linear, you know, you're looking at about 1.5% in three months. So an ability to detect any changes in such a short period of time with a small sample size is highly unlikely. And that's consistent with what we saw here. And importantly, the data set, when we look at the change in total kidney volume across the 12 subjects that we randomized here, it's largely consistent with that background rate. Thank you. When you increase the dose of 8429, do you expect to see the increase in PC2 to become significant as well? Yeah, I'll take that, to start off with. You know, the short answer is yes. I mean, we do expect to see greater increases as we increase the, you know, the dosing, the weight-based dosing, to up to 2 milligram per kilogram and then 3 milligram per kilogram. As I showed on one of the slides, you know, all of our evidence suggests we've got that, that right kind of relationship that's demonstrating that ability. I think what we've seen, you know, from the first-generation compound as well, is that the PC2 response seems to be a little bit more muted compared to PC1. That, frankly, is all right. You know, the primary genetic mutation is PKD1, 85% compared to PKD2, and PKD1 tends to be a bit more severe. So if anything, our focus is a bit more on PC1, but we'd like to see both, both come up. And with respect to, you know, any specific group and statistical significance, I mean, sure, that's great, but this is a Phase 1b with nine patients. You know, that's not the intent. The intent is really to demonstrate that overall pattern, make sure that we believe that we're seeing the right kind of response, and enable us as a team to be able to pick the right dose moving forward into Phase 2. And then once you get into the pivotal Phase 2, well, yes, statistical significance becomes, you know, much more important. Yeah, and further on that, Yi, you know, we've done extensive work in terms of assessment of pharmacokinetics across multiple species, as part of this program, which has enabled us to be able to model dose and exposure and translate that into humans. And as Preston alluded to in his prepared comments, you know, we believe we're in the lower half of the dose-response curve here, and likely, you know, under 50% inhibition of the target of miR-17. So, you know, the next cohort should boost us above that sort of mid-range in the dose response, and we look forward to those data. Thank you. Last question, just for clarification, the day 85 and day 86 are pre-specified time frame for the evaluation of the biomarkers. Is that correct? Yeah, that is correct. Okay. Thank you. The next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi, thanks for taking our questions. Looks like for PC1, the increase peaked at day 57, it's but not so for PC2. Is that just due to variability? Do you think, for this dose, the peak level has been achieved at some point, or it could continue to go up with further dosing? A couple things on that. First of all, the short answer is absolutely, we believe it's due to variability, right? That's, that's, you know, quite clear. Again, with 9 patients, you see the error bars, you know, this is, you know... We're seeing the right response, you know, from the get-go, you know, in terms of polycystic, and particularly, it's more clear with polycystin-1. Again, that's got a little less variability than the results we're seeing with polycystin-2. To your other question about, you know, how long, if you kept dosing, would polycystin continue to go up? You know, we haven't done that yet. We don't know. Based on what we think, you know, is the tissue-based half-life from our non-clinical studies, we would think that we're getting into the steady-state range by week 10, certainly by week 12. And so it might be the case that if you continue dosing further that those changes would kind of be locked in at that level. It might, they might accumulate a bit further. Ed, do you have any additional comment about that? No, I think the preliminary data suggests it's the same kind of response around, steady state. I'll just further add that we were encouraged with seeing the drop-off in polycystin post cessation of dosing that we've demonstrated here, which is consistent with what we saw. It's not shown here, but at 0.3 mg per kg with the first generation, supporting our view that this is a clear sort of pharmacokinetic response here. That the PD follows the PK. Right. Maybe a follow-up on the drop-off after cessation of dosing. It looks like placebo group also dropped off after dosing. Could you explain what might be underlying that? Yeah. Well, really what you see is kind of that one, that one time point. But then again, with 3 patients, it may just be, you know, kind of random variation. So I, I don't, I don't know that there's a whole lot to make of that. What we'll do is, at the end of... Once we've got these, these 3 dosing cohorts, 1 milligram, 2 milligram, and 3 milligram per kilogram, you know, completed, we'll pool all of the, the, you know, 3 each. Each cohort has 3 placebo patients, so we'll be able to get to 9, with that. Then we'll take a kind of a, a more close look, at what we're seeing in terms of, active versus placebo. Great. Lastly, do you have any prediction for what the PC1, PC2 increases might be at the next dose level? Thank you. You know, that's kind of why we're doing the experiment. We'll see. You know, as Jay mentioned, based on the PK/PD modeling, we think we're in the lower half of the response curve, so I would expect it to be, you know, relatively robust, but we'll need to see. You know, we're looking forward to getting those data. We've completed enrollment in the cohort. It's obviously, you know, three months of dosing, another month of follow-up, and then it takes a bit longer for all of the urinary polycystin measurements. They're not, you know, it's not quite as simple as just, you know, measuring something in plasma. You know, we're looking forward to sharing those results in Q1. Got it. Thanks for taking our questions. Thank you. This concludes our question-and-answer session. I would like to turn the conference back over to Jay Hagan for any closing remarks. Thanks, everyone, for your time this morning, and we look forward to providing additional updates as the program advances. Thank you. The conference has now concluded. 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