Good day, and thank you for standing by. Welcome to the Regulus Therapeutics special update conference call. Today, all participants will be in a listen-only mode. Should you need any assistance during today's call, please signal for a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask your questions. To ask a question, you may press star, then one on your telephone keypad. To withdraw your question, please press star, then two. Please note that today's event is being recorded. I would now like to turn the conference over to Cris Calsada, the company CFO. Please proceed. Thanks, Operator. Good morning, and thank you for joining us for this clinical and regulatory update for the farabursen development program. 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 provision under the Private Securities Litigation 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 this 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. For today's update, we will provide a summary of our recent FDA meeting held to align on the suitability of our non-clinical, CMC, and clinical plans and data generated to date that would support agreement on the size and duration of our pivotal phase III study. I don't want to steal Preston's thunder, but we are happy to report that the meeting was very collegial, and our plans for a single pivotal study under the accelerated approval pathway were confirmed. We have also recently completed dosing for all 26 patients enrolled in our fourth and final cohort. This fourth cohort was designed to evaluate a fixed dose of our compound, RGLS8429, which recently received its official generic name, farabursen. So for today, we are pleased to report out interim data from this cohort, including safety and tolerability data on all 26 patients and efficacy data, biomarker and kidney volume results on the first 14 of the 26. Analysis of the remaining 12 patients' worth of data will be complete later this quarter or early next quarter. We will then wrap up the program update with where we go from here. Preston will walk through the specific elements of the phase III study design, powering assumptions, and a brief overview of the population we intend to enroll in this pivotal study. Before we get to those updates, though, I want to reinforce the unmet medical need for patients with ADPKD. Slide four gives you an idea of the market opportunity, showing last year's sales and penetration for the one approved drug. As you can see, despite generating over $1 billion in sales in 2023, it is not widely used, with roughly 7% penetration to the addressable diagnosed population. This is due in large part because of its safety and tolerability profile. We have heard resoundingly from physicians who manage this disease of the need for a new option that patients can tolerate. This would be a welcome addition to the market. This is important throughout this discussion in terms of how we intend to develop farabursen. Our market research indicates that a product with similar efficacy to the marketed drug, but one that was safe and well tolerated, would be widely utilized, as shown on the right graph on slide five, when tested with physicians who treat ADPKD patients. And this is a market prime for an innovative new therapy with good commercial coverage in place and with a concentrated base of prescribers making for an efficient market entry. These three elements laid out on slide five are just a few of the highlights from a recently completed market research study conducted with physicians and payers from both the United States and Europe that support the value proposition of farabursen's profile if successful. So with that intro, I'll hand the call over to Preston to walk through the rest of the update. Thanks, Jay. We'll start with a brief summary of the End-of-Phase 1 meeting we held with FDA last month. This meeting was intended to serve as the key regulatory interaction with FDA ahead of initiating the phase III program, and our objectives for the meeting were to confirm that the breadth of the farabursen development program was adequate in scope and that we were aligned with FDA on key aspects of a single pivotal phase III trial. Moving to slide seven, in the meeting with FDA, we did confirm that our CMC, non-clinical, and clinical pharmacology program plans are acceptable. Additionally, we have now completed the chronic toxicity program in two species, mouse and non-human primate, and in these studies, there were no adverse findings. As such, our No Observed Adverse Effect Level or NOAEL is the top dose in each study, which provides large safety margins relative to the planned clinical dose of 300 mg. Importantly, we do have alignment with FDA on the use of total kidney volume over one year as the primary endpoint for accelerated approval and estimated GFR over two years as the primary endpoint for full approval. Other key aspects of the phase III trial design were also confirmed: the use of a single active 300 mg dose with a two-to-one randomization, the inclusion criteria for enrollment, which I will cover later in the presentation, and that an overall trial population of approximately 336 patients, 224 of which would be on farabursen, is acceptable for safety exposure. This sample size provides appropriate statistical power, assuming that farabursen exhibits efficacy that is at least similar to that demonstrated in the tolvaptan phase III program. We'll cover more details of the phase III design in a moment after discussing the cohort four interim results. I do want to note that in our meeting with FDA, it was clear that the agency is very supportive of development efforts for new therapeutics in ADPKD, and we are very appreciative of the attention and the interest that the division has for the farabursen development program. And now we'll turn to the interim results from cohort four in our ongoing phase I-B multiple ascending dose trial in patients with ADPKD. On slide nine, as a reminder, this clinical development program is streamlined by the opportunity for accelerated approval. And the next study is planned as a single pivotal phase III trial that will support both accelerated approval based on total kidney volume, followed by full approval based on eGFR. And on the next slide, the ongoing phase I-B trial is conducted in patients with ADPKD who are Mayo Class 1C, 1D, and 1E, which corresponds to moderate to severe disease. Each cohort is dosed for three months by subcutaneous injection every other week. The first three completed cohorts comprise the placebo-controlled dose-ranging portion of the trial with exploratory evaluation of total kidney volume. After the weight-based dose-ranging cohorts at one, two, and 3 mg/kg, we elected to conduct a fourth cohort to test the 300 mg fixed dose that we intend to take into phase III. This fourth cohort is open label, and the objectives are to evaluate safety and tolerability, confirm the level of mechanistic activity using urinary polycystin-1 and polycystin-2 biomarkers, and again, examine total kidney volume as an exploratory measure. You can see in the study scheme at the top right of the slide, each of the first three cohorts had between nine to 12 patients on farabursen. And you may recall that after seeing a notable impact in total kidney volume in cohort two, we elected to expand cohort four, and ultimately, we enrolled 26 patients, all on farabursen. We did this to get a stronger read on safety and tolerability and greater clarity on any efficacy signal with respect to total kidney volume. Now that we have concluded the End-of-Phase 1 meeting with FDA and are working to finalize the phase III protocol, we've taken an interim look at cohort four to help us confirm aspects of our trial design. These data comprise the update today. We've got all 26 patients in cohort four that have completed the study. That's three months of treatment and one month of follow-up. We have complete safety and tolerability data and safety labs for cohort four. In addition, we have efficacy data analyzed for polycystin and total kidney volume for the first 14 patients. The remaining 12 patients in cohort four will have efficacy results available in the March-April timeframe. Moving to slide 11, I want to recap at a high level what we have learned from the first three cohorts, which we already covered in previous disclosures. Cohorts one through three demonstrated a favorable safety and tolerability profile with no adverse event findings of concern. Most AEs were mild to moderate, and injection site reactions were mild and not dose-limiting. Our dose-ranging test is based on urinary polycystin, and we saw a clear dose-dependent increase in mechanistic activity with a likely plateau of that activity at 3 mg/kg. On the basis of these results, we determined 3 mg/kg to be the preferred weight-based dose, and moving to a 300 mg fixed dose ensures that all patients will be at or near that 3 mg/kg dose level. In fact, at 300 mg as a fixed dose, the average weight-based dose is around 3.5 mg/kg. We also saw very encouraging results for total kidney volume despite the small number of patients and short treatment duration. The placebo group behaved as expected for an untreated ADPKD population, and at 2 mg/kg and 3 mg/kg dose levels, we saw a notable mean reduction in TKV growth rate, with similar effects seen across baseline Mayo Class score. This examination of TKV is exploratory, but the trend is encouraging. And now let's take a look at the cohort four interim results. On the next slide, we'll begin with the baseline demographics of the cohort four interim analysis group, which is in the far right column. Again, there are 14 patients out of a total of 26 who have complete efficacy data, and this group has a similar number of patients compared to all other treatment groups. Given the small sample size across each cohort, there are not really notable differences in terms of age, baseline eGFR, or kidney size, and the distribution of Mayo Class and PKD1 or PKD2 mutational status is relatively similar to the other cohorts. And if you look at the bottom of the column in cohort four, you see we did have more patients that did not have confirmed PKD1 or PKD2 mutation. Across all the cohorts, some of these patients that are categorized as neither are probably false negatives. However, when we look across the entire 26 patients in cohort four, no additional patient falls into this category, and so the overall proportion of neither actually goes down to 15%. So for all of cohort four, the number is similar to the other cohorts. The important message here is that overall, these patients enrolled in this trial have significant ADPKD burden and are representative of the patients that we intend to enroll in phase. Now on slide 13, we'll look at safety and tolerability across all 26 patients in cohort four, as I described earlier. There are no safety findings of note. Overall adverse events and treatment-related AEs are similar across cohorts. Patients taking 300 mg farabursen had no serious adverse events and no AEs leading to discontinuation of drug. In terms of injection site reactions, we've seen nothing concerning. Overall, cohort four shows a lower proportion of ISRs than we saw in cohort three, and when ISRs did occur, they were usually reported as pain or tingling at the site of injection for 5-15 minutes after administration. The majority of these ISRs were intermittent, occurring three or fewer times out of seven doses, again, with no drug discontinuations. We are pleased with the safety and tolerability profile that we see here with 300 mg of farabursen. Let's turn to efficacy on slide 14, with polycystin-1 response on the left and polycystin-2 on the right. 300 mg farabursen demonstrated a level of mechanistic activity that was as expected. As I mentioned earlier, we believe that 3 mg/kg, which is cohort three, is hitting a plateau for maximal miR-17 target engagement, and so we anticipated that a 300 mg fixed dose would look similar to what was observed in cohort three. And that's what we have seen, which is helpful confirmation that the 300 mg dose is likely to confer the optimal blockade of miR-17 in patients. I want to make another point here about the doses in cohort three and cohort four. Everyone in cohort three at 3 mg/kg falls within the weight-based dose range that you see when you give 300 mg as a fixed dose. For example, in the 300 mg fixed dose, the weight-based dose ranged from 2.6-4.4 mg/kg based on the weight of each patient, and of course, 3 mg/kg falls well within that range, so because polycystin response between cohorts three and four that you see here are very similar and at the top end of the dose response curve, and the weight-based dose ranges are overlapping, as you will see shortly, we will combine cohorts three and four for some of the analyses of TKV and kidney function in order to have a larger sample size. Now let's turn to the exploratory analyses of total kidney volume and kidney function. Slide 16 provides some background context on TKV and kidney function in ADPKD patients. We expect the untreated patient population to have a kidney volume growth rate of 5%-6% per year, which equates to around 2% over a four-month period, which is the time between our baseline and end-of-study assessments in this trial. Importantly, tolvaptan has demonstrated a 50% reduction in the annual growth rate of the kidney from around 6% per year untreated to 3% per year on tolvaptan. As Jay mentioned earlier, the target product profile for farabursen assumes that same 50% reduction. As I will discuss when we cover plans for phase III, we are also using the same 50% treatment effect assumption for powering and sample size calculations. Changes in total kidney volume growth rate correlate with the rate of change in kidney function. This has been demonstrated in the tolvaptan phase III program and other large longitudinal studies like CRISP and HALT. On average, eGFR declines around four mL/min per year in the patient population, and tolvaptan reduced its annual decline by approximately one-third. We know that the decline in renal function is correlated with the severity of Mayo Class, with the most rapid progression in patients with 1E disease. Because of the inherent inter- and intra-patient variability of eGFR, determining true differences between treatment groups requires many measurements over an extended period of time to define an accurate assessment of declining renal function. Thus, in the phase III study, we plan to collect eGFR every eight weeks over two years. We'll start with kidney volume on slide 17. Analysis of total kidney volume in the first 14 patients in the 300 mg fixed dose continued to suggest notable impact on TKV growth rate. Again, with the caveats of small sample size and short treatment duration, nevertheless, we've now repeatedly shown notable reductions in TKV growth rate compared to both placebo and also compared to what we know of historic TKV progression in untreated patients. You would expect that an untreated population will grow at 2%, around 2% over the four months during the trial, and at 2 mg/kg, 3 mg/kg, and now 300 mg fixed dose, patients are exhibiting mean rates of change that are nominally less than that. As I mentioned earlier, we then combine data from patients in cohorts three and four because of the overlap in exposure and evaluate the impact on kidney volume using the larger sample size. When we combine cohorts three and four, we get additional clarity on the potential impact to total kidney volume growth rate as the standard error bars tighten and now have less overlap with that of placebo. And finally, to estimate what these emerging data may mean for a treatment effect at one year, we take the observed data over four months in the trial and project that forward to one year, comparing it to historical TKV growth rates in untreated patients to calculate the conditional probability of a true treatment effect at one year. This assessment suggests that based on the data we are seeing now, the probability of a true treatment effect of at least 50% or more is very high. We've calculated the conditional probabilities of true treatment effects of approximately 75%, 90%, and 100%. And for reference, 100% would represent a halting of kidney growth. These analyses do make the assumption that changes seen over the first four months in the study will continue out to one year. We think that's a reasonable assumption, but it does need to be mentioned. Needless to say, we're very encouraged with the TKV results from cohort four, as well as these conditional probability analyses, and believe they further de-risk total kidney volume as a phase III endpoint for accelerated approval. Moving to slide 20, renal function is monitored for safety over the four months using a variety of markers, including KIM-1, which is a marker of renal tubule cell ischemia, blood urea nitrogen, and of course, estimated GFR. We have safety labs for all 26 enrolled patients. BUN and KIM-1 are shown here, and we see no acute changes with these markers of kidney function. And on the next slide, to have as large a sample as possible for eGFR because, again, it is highly variable. As we've done with kidney volume, we've combined cohorts three and four and looked at eGFR slope using a random coefficients model for both three-month treatment period and the entire four-month study period, including follow-up. Everything is as expected from a safety standpoint, and we certainly don't expect to see evidence of eGFR benefit at this point. And just to give a specific example of the inherent variability of the eGFR measure, when you just look across all the patients who were enrolled in this trial, eGFR was calculated at screening and then again at day one, and those are just a few weeks apart and before any study drug administration. We observed eGFR changes just between screening and day one as large as + 10 mL/min down to - 10 mL/min in just over those couple of weeks. And compare that to what we know is an average ADPKD decline of around 4 mL/min per year. So at first blush, that doesn't make sense. 10 mL/min over a couple of weeks versus 4 mL/min over one year. But we know that to really understand eGFR changes in a population, you need to be looking at a large number of patients with multiple measurements over a long period of time to get a true estimate of kidney change for that population. With this kind of variability, we're not able to make predictions about any long-term effect on kidney function based on what we have today, but across all of our kidney measures, we do see a reassuring safety profile. I'll just make a few additional points. First, we don't have any reason to expect acute changes in eGFR based on farabursen's mechanism of action, which does not involve hemodynamic changes or fluid volume shifts. We are also confident of the safety of farabursen based on the completed toxicology program, which demonstrates no accumulation or adverse findings in the kidney and has established large safety margins, and finally, the inability to determine the long-term effects on eGFR just using short-term eGFR data is an important reason why FDA accepts total kidney volume as a surrogate endpoint for accelerated approval because it does take a much longer time to see eGFR benefit. However, there is convincing evidence from multiple data sets that total kidney volume benefit does eventually correlate with eGFR benefit in the long run, so in summary, on slide 22, this interim analysis of cohort four confirms a selection of 300 mg as a fixed dose to take forward into phase III. We've seen a favorable safety and tolerability profile to date with no concerning adverse event trends. Injection site reactions are seen with all injected oligonucleotides, and it is important that ISRs seen with farabursen at 300 mg are mild, transient, intermittent, and do not limit dosing in patients. 300 mg performed as expected in terms of mechanistic activity, demonstrating similar increases in polycystin to what is observed with a 3 mg/kg dose. We are confident that we have reached optimal miR-17 target engagement based on our nonclinical work, the completed weight-based dosing cohorts one through three, and the results seen with this interim look at the 300 mg cohort, including the observation that patients with lower body weight in cohort four who received weight-based doses above 3 mg/kg demonstrate no further increases in polycystin. Dosing with farabursen also continues to show evidence of a notable effect on TKV growth rate, which has now been observed across three separate cohorts. And while not shown here today, we've also examined kidney volume changes by baseline Mayo Class, as well as the presence of PKD1 truncating and non-truncating mutations, and we see similar effects across all groups. Importantly, when we combine the two cohorts with overlapping doses, cohorts three and four, a conditional probability assessment suggests a high likelihood of success for a 12-month TKV endpoint in phase III. Kidney function as a safety measure looks unremarkable, and we see no evidence of acute impacts to eGFR, which is consistent with farabursen 's mechanism of action. We will need to dose for up to two years to determine any eGFR benefit, but we anticipate seeing that benefit should we be able to demonstrate meaningful impact to TKV growth rate over one year. I'll now turn to a brief description of our phase III planning. On slide 24, the pivotal program will consist of a single trial that is a total of two years in duration, with TKV serving as the primary endpoint for accelerated approval at one year and eGFR serving as the primary endpoint for full approval at two years. Approximately 336 patients will be enrolled in a two-to-one fashion, 300 mg on farabursen versus placebo. Key inclusion criteria will be a diagnosis of ADPKD with Mayo Class score 1C, 1D, or 1E. Baseline eGFR will be 25 - 90, although younger patients who are Class 1E will be allowed to have higher baseline eGFR as these individuals are at high risk for disease progression. Enrolled patients will not be on tolvaptan. This is because of the difficulty in keeping patients on that therapy due to tolerability concerns, as well as a black box warning for fatal liver toxicity with tolvaptan, which could confound the assessment of safety for farabursen. We will collect MRI for total kidney volume at baseline, six months, and 12 months for the primary TKV endpoint. eGFR will be collected approximately every eight weeks over the two years, and on my final slide, as mentioned earlier, our sample size estimates assume treatment effects on TKV and eGFR that are in line with the approved drug on the market, tolvaptan, so this means that we assume a 50% reduction in the annual growth rate of the kidney and approximately 33% reduction in the annual decline in eGFR. Again, the current data in hand do suggest that farabursen's impact on TKV may be greater than 50%, and so we believe our powering is appropriately conservative. We've performed a series of trial simulations using known estimates of the variability in TKV and eGFR based on published studies. And from these simulations, we estimate that a total sample size of at least 336 patients will provide adequate power for both TKV and eGFR to demonstrate the assumed treatment effects. As an additional confirmation of the adequacy of the sample size for the enrolled trial, we are planning two sample size re-estimation procedures. The first will be designed to confirm adequacy of the sample size for total kidney volume. When approximately 50% of enrolled patients complete the six-month MRI, the independent data monitoring committee will use those results to confirm appropriate conditional probability of success at one year. Separately, when all enrolled patients have completed one year in the study, the one-year eGFR data will be used by the DMC to confirm appropriate conditional probability of success for the eGFR endpoint at two years. As we work towards finalizing the phase III protocol, we may make modest adjustments to the design, but the primary components I described here today serve as the foundation of the trial, and we are pleased to have reached alignment with FDA on the endpoints, the opportunity for accelerated approval, sample size, and other key aspects of the study. With that, I will turn the call back over to Jay for closing comments. Thanks, Preston. So to summarize, here's what we hope you all took away from today's call. We had a very productive and collegial meeting with FDA aligning on the key aspects of our pivotal program, including the suitability of our CMC and nonclinical packages, and importantly, the opportunity for accelerated approval based on kidney volume. The interim data from the nearly complete fourth and final cohort confirm our understanding of dose, kidney exposure, and target engagement as measured by the polycystin biomarker response profile. Now, for a third time, we also see early evidence of an impact on the growth rate of the kidney. When combining a third and fourth cohort, which have similar exposure profiles, and projecting forward to a year on therapy, we see a high probability of potential success to see meaningfully slowing of kidney growth rates. With these important milestones, we are on track to start this pivotal study in the third quarter of this year. Before we wrap up and turn to your questions, I want to bring this discussion back to the reason we're here. With a dearth of late-stage therapies in development, I've had the opportunity to connect with a number of patients dealing with ADPKD. To bring this into perspective, I've heard personal stories of patients who didn't know why their older relatives may have passed away from undiagnosed kidney disease, only to find out in their 40s or 50s of their own disease state and prognosis, often due to flank pain and abdominal fullness due to their enlarged kidneys. One recent conversation included the realization of its impact to family members and the challenges of trying to utilize the one approved therapy. Managing through with tolvaptan, even though on the mid-dose and skipping the evening dose because of the tolerability challenges, is unsettling. This individual says he religiously drinks two gallons of water per day with his 16-ounce bottles laid out each morning. The thirst sets in within 20 minutes of finishing one of those 16-ounce bottles. Unfortunately for him, his eGFR has dropped precipitously over the last six months, and he's understandably curious about what research is happening in the field. Another individual who participated in our ongoing study shared that their abdominal pain subsided after the fourth dose and experienced pain symptom relief for several months after cessation of dosing, only to have it come back after the trial was complete. And finally, a third story of a person who described a devastating impact a disease has had on multiple family members with a plea to potentially be able to participate in future studies of farabursen. It's these kinds of stories that inspire the team at Regulus to continue our efforts to bring a new therapeutic option to patients with ADPKD. On behalf of the entire team at Regulus, we want to extend our gratitude to the over 100 patients and volunteers who have participated in our trials to date, as well as the numerous physicians and administrators helping us conduct these important studies. And with that, we're ready to take your questions. Thank you. We will now begin the question and answer session. As a reminder, to ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw it, please press star then two. At this time, we will pause momentarily to assemble our roster. Today's first question comes from Joseph Schwartz with Leerink Partners. Please proceed. Great. Thank you. Congrats on the progress. Looking forward to the phase III, how long do you expect enrollment of the 336 patients to take, and how much of a lift will site activation be given the htTKV measurements which will need to be taken? And then I have a follow-up. Thanks. Yeah. Overall, based on the work that we've done to date, as well as just looking at programs over the course of time, over the recent number of years, we're estimating kind of a base case of around 18 months. It may go more quickly than that. I will say that essentially with each of the cohorts in this study, we've increased the speed of enrollment, and I'm very confident with our team in terms of global execution. How much training is involved, and how many sites are currently able to do the htTKV measurements according to the standards you'll want to? Yeah. In terms of, yeah. So we're estimating around 100 sites. Again, it'll be a global focus, and in terms of the training, it's an MRI of the abdomen that captures the kidney. We also capture the liver as well, and then we use central reading for total kidney volume, as well as cystic architecture measures, etc., and so from a training perspective, kind of the details are in just getting a clean MRI, and that is par for the course for MRI centers that are connected with sites, and then it's in the reading of the total kidney volume that is very actually computer automated, including AI technology. Right now, for this study, we use the Mayo Clinic. Dr. Tim Kline is at the forefront of total kidney volume analyses, including cystic architecture measures, and their group will be involved in an oversight role as well in the phase III program, so we're very confident with our ability to execute and get high-quality data. Okay. Great. Thanks for that color. And then I would imagine that a late-stage program targeting an indication as large as ADPKD might be of interest to large biopharma companies. Are you thinking about partnering farabursen at any point? And if so, what kind of a deal would you seek to do? Yeah, Joe. Yeah, you're spot on. Obviously, there's been a growing interest that you see in terms of business development activity in the rare renal space. And given the dearth of late-stage opportunities in ADPKD, coupled with the size of the opportunity, we've had many inbound calls wanting to discuss our interests. I would say that we're always evaluating opportunities for business development to advance the program and minimize dilution. But what we're not interested in doing is simply licensing out the program. This is a study that our team can conduct and certainly run in the U.S., but for instance, outside of the U.S. is an area that we certainly would be keen to potentially explore. Great. Thanks for the color. The next question is from Whitney Ijem with Canaccord Genuity. Please proceed. Hey, guys. Congrats on the updates. Great to see consistency in this fourth cohort as well. Can you confirm how many patients in cohort four saw TKV shrinkage? And I guess as the number of those patients grow, I know it's still small numbers across the study, but any additional learnings or thinking about what might kind of characterize some of those super responders? Yeah. Whitney, we saw roughly half of the subjects in cohort four have kidney size reductions and roughly half growth, with one that looks like an outlier, larger growth, which is why you see that spread. I mean, I think as you combine, as we've alluded to, when you combine cohorts three and four, which have overlapping drug exposure, it tightens up. And you saw that on the slide deck right around zero. And I just want to reemphasize what our bar here is and all of our powering assumptions that we are looking to slow the rate of growth, and that would be a huge addition to the armamentarium here. These data suggesting halting of growth are well above our expectations. Yeah. Just to add on to that a bit, again, in terms of where we set the bar for our powering, it's that 50% reduction in the growth rate. What we're observing, particularly when you combine cohorts three and four, because they're essentially taking the active dose that we're going to be using or the level of active dose we're going to be using in the phase III program, it's just under zero in terms of change. And we really are excited by the conditional probability analysis results that we showed in terms of what that may mean for change out to one year. But that also brings up the other point that the data we're showing are based on very short treatment duration, just three months. And so I'm personally very excited to see what can happen over the course of a year. And again, in phase III, we'll be testing MRI for kidney volume at baseline six months and 12 months. And finally, just in terms of sampling and making sure that we're on track from a powering perspective, we have that sample size re-estimation procedure during the course of the study. So at the six-month time point, when about half the subjects have those data, the independent DMC looks at it and makes a conditional probability assessment to be sure we're on track. Got it. And now that 50% having reached week 26, is that just a sample size re-estimation? It's not an interim or anything like that? No, it's not an interim that you would take an alpha penalty hit on because we're not looking at the data. It's the independent DMC, and they just give guidance as to whether you're on track or, for example, if you needed more patients to enroll to have an appropriate level of conditional probability power, so to speak, then that would occur as well. So you will get relative information from that interim or from that probability assessment by the DMC, but we don't take a look at the specific data. Got it. Got it. Okay. And last one from me that hopefully will be quick because Preston, I think you did a good job covering this during the prepared remarks. But just on eGFR, fully understand the thinking as to why you'd need to see or you need to study longer and larger numbers to see any benefit. Just can you kind of just maybe reiterate as we look at the eGFR rate of change chart on slide 21, is there anything that could be taken away from this on the other side from a safety perspective or concerns in that regard? Definitely from a safety perspective, we're not seeing anything that's problematic at all. And again, I think this goes very much along with what we've seen in terms of the mechanism of action of the drug. So unlike some of the other drugs that have been tried or, in fact, are approved in ADPKD, this mechanism doesn't involve early hemodynamic changes or any early and rapid fluid volume shifts. And so this is, I mean, the way I think about it is kind of a slow and steady mechanism. And we're just not seeing anything that would be problematic from an acute perspective. In addition, just it's nice to have the checkbox on our chronic tox completed, no accumulation in the kidney, no adverse findings in the kidney, very high doses with large safety margins. So we're very confident with where we sit from a safety perspective. And we rely on the known correlation between changes in total kidney volume relating to changes in eGFR. One year of kidney volume tends to correlate with about a 0.7 correlation coefficient for changes in eGFR out to two years. And that's, in fact, why because it takes so long because of the variability, it takes so long to get to eGFR. It's one of the reasons the FDA has now accepted total kidney volume as that appropriate surrogate endpoint for accelerated approval. Perfect. Thank you. The next question comes from Andreas Argyrides with Oppenheimer. Please proceed. Hey, and thanks for taking our questions. And congrats also on your visit to be supported from the FDA. So congrats. A lot of good questions were asked here. So maybe just following up from a couple of those as well. Just on the sample size re-estimation, do you have in place or does the IDMC have some idea as to how many patients, I guess, could be added? Just kind of thinking about potential planning and capital considerations for additional patients that might be needed. And then on baseline characteristics of the patients, can we assume that they're going to be similar to what we've seen already for those that are being enrolled? I know you gave an eGFR of 25-90, but are there any other characteristics that need to be considered here? And then maybe one more follow-up. Yeah, sure. Just on the sample size re-estimation, so we're putting together, finalizing the protocol, then we'll finalize the statistical analysis plan, independent DMC charters. All of that takes a bit of time. But that will be embedded within the charter in terms of how the DMC should look at it and kind of what the parameters are under which the company would want to have the study proceed forward. I will say that, again, based on what we're seeing, if anything, we are overpowered because we powered the study on the assumption of a 50% treatment effect. And right now, again, if you just look at cohorts three and four together, and still these are small numbers, but the point estimate for that is essentially hovering at a bit larger than 100% in terms of treatment effect over just three months. We'll see where we go with that. But we just put that in as kind of a safety valve procedure to make sure that we've got the right numbers. And then in terms of baseline characteristics, for the most part, very much in line with what we've enrolled in this phase I-B trial, our enrollment criteria for eGFR. The key factor is ADPKD diagnosis with Mayo Class 1C, 1D, and 1E. So that's moderate to severe disease. And that essentially sets the population that you see in the slide when we showed all of the demographics. Having an inclusion criteria for this study, it's 30 -9 0 in terms of eGFR. We'll lower that a bit, 25 - 90. And then the only other factor is that we will allow some of the younger patients with Class 1E disease, so very large kidneys, they can actually have higher GFRs up to 120, even 140, and still have a lot of disease progression, a lot of increase in the kidney, relatively speaking, and rapid decline in GFR. And so we want to have the opportunity to include them as well. That's the only kind of major difference that I see. If anything, that might mean a bit more overall rapid decline in GFR over time, which, again, we think is probably beneficial in terms of determining difference between treatment groups over the long haul. Okay. Great. Yeah. Thanks for all the thorough color here. I'll actually jump back in the Q&A if there are some more questions. Thanks, guys. Great. Thanks. The next question comes from Yi Chen with H.C. Wainwright. Please proceed. Thank you for taking my questions. My first question is, as you mentioned, tolvaptan slows down kidney volume growth by 50%, which is coupled with slowing the eGFR decline by about 33% on an annual basis. So if farabursen is confirmed to not just slow down kidney volume growth, but actually reduce total kidney volume in patients, do you think the drug has the potential to actually help patients maintain their eGFR instead of slowing down eGFR decline? We'll have to see. That's, again, not our target product profile. What we've looked at is having an efficacy that is tolvaptan-like or better. And most importantly, having a safety and tolerability profile that is better because that's actually the rate limiters Jay mentioned in his opening comments that really limit the patient population that is ever able to actually take and stay on tolvaptan, those tolerability issues related to the vasopressin receptor action of the drug, intense polyuria, intense unquenchable thirst, etc. And so we would be very pleased with tolvaptan-like efficacy in terms of impact on total kidney volume and eGFR, slowing the eGFR rate of decline. Really, the name of the game here is doing everything you can to delay the time to end-stage renal disease for these patients. Hitting ESRD with dialysis or transplantation is just fraught with huge levels of morbidity and mortality. It's an incredible life-changing event. Anything we do to forestall that, we think, is very important. Slowing the rate of decline in eGFR is what we're looking to do. If we could stabilize it, I mean, that would be fantastic. I don't want to make any predictions at this point, please, because, again, it's very, very challenging to make any predictions on eGFR on the basis of short-term data and a small number of patients in terms of projecting out. Interesting, we really haven't seen anything that has, if this can be replicated and shown in a large number of patients over a year, for example, completely halting kidney volume growth. We don't know that we can do that, but the early evidence is encouraging. What that can do in terms of eGFR, I don't think anyone knows. We'll have to see. But it's very interesting. Got it. Thank you. And my next question is, what is your estimate earliest time point at which you can observe a drug benefit on kidney function, the eGFR? And does this benefit achieve its peak level at two years? It's a good question in terms of the time course and what impacts look like year to year. And there's not a lot known because there haven't been that many therapies tested in very large and very long-term studies. We don't have all the answers related to that. Personally, I believe that it takes over one year to really see how the trends in eGFR differences between treatment groups are setting. And you clearly need to have a lot of patients. And one of the important factors for how many patients you need is actually how many times you collect eGFR because what you're doing is you're looking essentially at a slope over time. You're looking at that trajectory over time. And that's a slope within each individual patient. So you can go out two years, but if you only check eGFR, say, three times over two years, that's not going to give you enough of an estimate for that individual patient. And then you will need thousands of patients in order to have appropriate clarity in terms of differences between treatment groups, which is why we're collecting it pretty frequently. Every other month or every eight weeks in the study over two years enables that 336 number that I mentioned to have very sufficient power for detecting a delta in eGFR over two years. So, long answer to the question, I think somewhere over one year. I think by two years, for sure, we anticipate seeing that benefit. And then over time, maybe we can have longer-term evaluation just to see how patients are continuing to do. Got it. And my last question is, you mentioned that tolvaptan has limited market penetration of 7%. So if your target drug profile is achieved in a pivotal trial, what's your estimated peak market penetration rate for farabursen? Yeah. That was on the slide, the initial physician reaction to a product profile that has tolvaptan-like efficacy, but safe and well-tolerated, meaning no black box for drug-induced liver injury or no polyuria. Physicians stated over 80% intent to utilize, which you adjust for overstatement when you do market research studies. So that's the other column of 46% utilization. And we've done a sort of full revenue buildup model. And it's in the multiple billions of dollars potential opportunity in terms of peak penetration. Thank you very much. The next question comes from Catherine Novack with JonesTrading. Please proceed. Hi. Good morning, everyone. Congrats on the data. I'm just curious, is there an opportunity to look at some longer-term data from cohort four, given that 12 weeks might not be enough to see real TKV effect, for example, an open-label extension so we can see longer-term data while you're enrolling the pivotal study? Yeah. It's a good question. Unfortunately, the answer is no because up until recently, we hadn't completed that chronic tox, so I mentioned in my comments, we've completed the chronic tox program. The rate limiter was completing that second species, non-human primate, and until we have that done and completely blessed with final reports, etc., we're unable to extend dosing beyond the three months that we've been doing, and so with all patients now off drug for a while, it's going to, and then you have to spool up another protocol and all of that. It would be too much time between to make that be a meaningful extension in terms of that, and so we're just going to move forward into the pivotal phase, phase III, and we're very excited with what we've seen in terms of the impact to total kidney volume. And again, very pleased with the results of our chronic tox program. So we have very large safety margins, etc. Got it. And then it looks encouraging that you've gotten alignment from the FDA. Curious if you have any comments on the European regulatory path. Is the population size there similar? And what's the sense that you can use htTKV there for conditional approval, for example? Yeah. It's a great question. We do intend to go interact early this year with European regulatory authorities, EMA, for scientific advice and have these full discussions and there haven't been that many programs that have gone through the process so it's not like there's a lot of history to look back on when tolvaptan was going through. Tolvaptan did get approved in Europe on the basis of kidney volume. They also had a lot of GFR data at the time so we'll have to see where that goes also have to make an assessment of conditional probability versus going to the end for full approval with GFR. Just from a reimbursement perspective, we know that the overall reimbursement picture is different in Europe than in the U.S. and so we'll make all those assessments once we actually have formal interactions with the EMA. We're planning to do that. We really wanted to get to FDA as quickly as possible because having this aligned view, as I described today, allows us to finalize a protocol. That allows us to work with our CRO and other vendors to really start the planning to get moving forward. As we go interact with other global regulatory authorities, if there's tweaks we need to make, additional cuts or other things we need to do in terms of the protocol, we can build that in as amendments prior to actually initiating the study, but kind of the key here was getting to the FDA to finalize a protocol so we can move forward with our planning, and we're looking forward to initiating the phase III program. We said mid-year from Q3 for that phase III program. Yeah, and as far as the opportunity in Europe, it is a quite large opportunity. We did conduct the market research study in both the U.S. and Europe with both physicians and payers, and they reacted very favorably, again, to the profile we presented, which would be efficacy on par with the one marketed drug, but something that was safe and well-tolerated. You actually have more subjects on a percentage of population that have been identified in Europe just given national health systems and the approval of tolvaptan much earlier than it was approved in the U.S., so it represents a significant piece of the overall opportunity here. Got it. That's helpful. Appreciate you taking my questions. Thanks. And again, if you do have a question, please press star, then one. The next question comes from Yanan Zhu with Wells Fargo Securities. Please proceed. Great. Thanks for taking our questions. I was wondering if you have looked at the correlation between PC1, PC2 change, and the total kidney volume change in this 300 mg fixed-dose cohort. Also, whether you have looked into any correlation between the patient's body weight in this fixed-dose cohort and the total kidney volume change. Thanks. I have a follow-up as well. Thanks. Yeah. In terms of polycystin, we're going to wait until we have the completed cohort to really take a look at that to get the largest sample. In general, that correlation has been not extremely tight just due to the small sample size overall. So we're not anticipating seeing a lot there. But again, what we're looking to do is block as much miR-17 as possible. And that does seem to be tracking with the ability to induce reductions in kidney cyst volume. Not shown here, but we do track kidney cyst volume as a cystic architecture measure. And as we showed before with some of the previous cohorts, that's a very tight correlation. The changes in kidney volume that you see are being derived from reductions in cyst volume. And so that's encouraging. And in terms of body weight, no clear correlations with body weight in terms of the effects that you're seeing on total kidney volume. Again, TKV is actually height adjusted. So there is some adjustment in terms of body size with total kidney volume generally as a kind of denominator factor, but nothing specific to see. Got it. And for the final analysis of this 300 mg fixed-dose cohort, what might be the timing for that? And what's the expectation on total kidney volume change that could. And what might be what do you consider would be a positive result at the final analysis? Thanks. Yeah, so the remaining 12 patients will have those efficacy results in terms of polycystin biomarker, total kidney volume, etc., in the March-April timeframe. Essentially, we just want to repeat what we've been seeing. I think what's nice about having an additional 12 patients is it just helps again. These are small sample sizes, but any addition to the patient population helps tighten up the standard errors. That will enable us to do a little bit more exploration in terms of those conditional probability assessments I mentioned. What I would anticipate is that if we see basically something similar to what we've seen already, we'll actually have a higher level of conditional probability of seeing a true result of, for example, 90% or even 100% treatment effect out to 12 months as we get more patients into that calculation. Great. Thanks for the update and for taking our questions. Thank you. This concludes our question-and-answer session. I would now like to turn the conference back over to Jay Hagan for any closing remarks. Thanks very much for your time and attention this morning. We look forward to providing updates as the program progresses. Thank you. The conference is now concluded. Thank you for attending today's presentation. And you may now disconnect.