Hi, everyone. My name is Liisa Bayko, one of the biotech analysts covering small- and mid-cap, here at Evercore ISI. We're gonna be hosting Regulus right now for a fireside chat, so thanks for joining us. We've got Preston and Jay here, and we're going to be sort of digging into Regulus'. I've mentioned Regulus to a couple of people, and they're like: Regulus is still around? But I think you've kind of come to, like, sort of there's, like, a new Regulus, I want to say. So let's dig into that. Tell us about the new Regulus. Sure. Well, thanks for having us. Of course. I'll jump in. I've been around at Regulus for eight years, and I would describe it as a new Regulus in the sense of where our focus is. And our focus is on our program targeting ADPKD. We're fortunate that we've evolved the technology base that we were born with from our founding from Ionis and Alnylam, to preferentially be able to deliver oligos to the kidney. And as you know, ADPKD is the disease of the kidney, genetic disease of the kidney, and that's where we're spending our time and our main focus. We're in a clinical study right now. I know we'll get into it later. Okay, so just let's dig into a little bit about Regulus' core capabilities, platform, and then we'll dig into your indication. Absolutely. I'll ask Preston to chime in, too, about it. But, yeah, our core capability are designing oligonucleotides. We have the intellectual property from both Ionis and Alnylam to design oligos directed at microRNA. And as I mentioned, we've since evolved that serendipitously through what's called a length walk or discovering that a certain motif turns out can preferentially distribute to the kidney. Delivery is always a challenge with all the nucleotides. You know, we can use GalNAc if we had a disease of the liver that we were interested in or deliver naked oligos to the CNS via IT administration, which others have demonstrated. You know, the PK and PD is clear there, as evidenced by other therapeutics that have advanced, and so we leverage that same technology for haploinsufficient diseases where microRNA play a role. So you've kind of honed in on nephrology Yes. and CNS. Correct. Why those two things? Yeah, we found, You know, there was a broad literature around the role of microRNA associations in lots of diseases, and when I first joined, we were sort of a mile wide and an inch deep in lots of different therapeutic areas. What we've found is that the understanding of the role of microRNA, which are fairly complex, they're by design pleiotropic mechanistically, but they're non-coding RNA that regulate message. And we've zeroed in on haploinsufficient diseases where microRNA are dysregulated, where targeting them with a steric blocker can effectively de-repress gene expression and be able to almost a gain of function, create more protein, where you have a haploinsufficiency and insufficient amount of you know, the downstream proteins that are encoded by those genes. In our case, with ADPKD, miR-17 is upregulated in the disease, and our objective there is to bind miR-17, thereby de-repressing PKD1 and PKD2 genes, leading to increased polycystin one and two, which are deficient in the disease. So let's dig into ADPKD. First of all, tell us a little bit more about the sort of disease itself, the etiology, who gets it, you know, what is it? Sure. Preston, you want to take that? Sure. So, hi. It's an autosomal dominant disease. It's. So while it's rare, it's one of the most common monogenic diseases, human diseases, so the incidence is about one in 500-1,000. And what happens is you have a knockout of the PKD gene, one of the alleles, and over time, that causes a transformation of renal tubular epithelial cells to proliferate abnormally and then change into cystic epithelial cells, and then cysts develop and start to grow. And they grow throughout life. The disease is often not recognized until late because there's not, you know, genetic testing at birth for this. What happens is the growth of those cysts not only destroys the renal tubular epithelial architecture and function, but as those cysts enlarge, they fill with fluid, presses the rest of the normal, healthy renal tissue, glomeruli, et cetera, and kill that as well. And so you find that, with PKD1, there's two PKD genes, so there's a PKD1 mutation, PKD2 mutation. About 85% of it is PKD1. That's the more severe form, and the median time to dialysis is by age 55. And so it's a very significant illness in terms of- or disease, in terms of, you know, its clinical consequence. As it turns out, as a hyperproliferative disorder, miR-17 really sits kind of at the nexus of all of those proliferative pathways that are being activated. It's a really nice story in terms of the ability to selectively block miR-17 with our short oligo. Well, it seems like it's a pretty common disease, so what's the total like, prevalence then? Yeah. So, it is, again, one of the most common genetic disorders. The prevalence is currently diagnosed at about 160,000 patients, but- In the U.S. but again, we think it's probably three to four -fold that over- Okay you know, over time because there's a lot of unrecognized disease. So it's- Why is that? Again, it's not, it's not, you know, standard genetic testing- Okay at birth, and so it's not kind of discovered until later. And so often you'll, you know, someone who does get diagnosed with ADPKD, they'll, you know, suddenly realize: Oh, you know, my grandfather also passed, and I was told he passed from from late-stage kidney disease, and then my uncle had a problem as well. And so there's just a lot of that disease that previously hasn't been diagnosed. Yeah, there hasn't been a therapy approved until the middle of 2018, in the U.S., a molecule called tolvaptan. And so when you don't have an approved therapeutic, you know, you're not seeing as much screening and awareness. We expect that to grow over time, and there's been studies done, epidemiologic studies, within healthcare datasets. Geisinger did one, which, you know, confirmed that frequency of approximately one in a thousand, which would suggest that it's probably closer to half a million in the U.S. alone. So tell us more about tolvaptan, and that's obviously gonna be kind of like one of the other benchmarks out there for the field, and how is it doing commercially? Who's using it? What are the limitations? Where would you fit in relative to that? Yeah, so they were approved in the middle of 2018, and it's doing about, I think $1.3 billion in 2023. It's fourth full year on the market. The pricing would suggest they're about 6%-7% penetration- Of the price? - of the addressable. It's about 200,000 a year. Okay. So at that price point, you know, that would suggest about 6,000-7,000 that are on therapy. Which, you know, with the 160,000 diagnosed, of which about two-thirds are what are called Mayo Classification 1c, d, or e, and those are the most likely to progress to dialysis is about 100,000, roughly. And so that's about 6% penetration. The main issues with the molecule are: it comes with a black box warning for drug-induced liver injury. It's been observed in the post-marketing setting, and they had issues with the first phase III program they conducted in the U.S. And so consequently, they have a REMS where you need a clean liver function test to get your prescription filled every month. The bigger issue with the molecule is the tolerability, and Preston can go into the mechanism. It targets vasopressin. The consequence, though, is that you have polyuria because of the way that the drug works, and it's dose BID. And so when you talk to patients who've tried the drug, you know, you see this churn of maybe they try it for a couple of months, and they just can't handle that tolerability profile. Yeah, It's a tremendous amount of thirst and urination frequently, day and night, and so it's just a challenging drug to take. Okay. So, you know, we think the market, first of all, it's a, it's a well-informed patient population from an advocacy perspective. Information travels, you know, across the patient population. There's clearly an unmet need. This is a, you know, has a significant, you know, morbidity with the onset of dialysis and/or end-stage renal disease. And clearly, the only therapy that's approved... Because all the other standard stuff you would do: blood pressure control, antiproteinuric, you know, effects, those are all good things to do, but they have much less impact on this, on PKD, than other types of chronic kidney disease. And so there's really only one therapy that's directed at it, and it's a very difficult drug to take. So I think the bar is pretty low for us, you know, being able to have a, you know, a nice competitive edge. Yeah, and the good news is that we've demonstrated preclinically that we can be used in combination with the molecule, and we wouldn't expect any untoward, you know, safety issues, you know, by combining the two. And so, you know, what we would envision in our pivotal phase II program is to be to include those that are on stable background tolvaptan, who can tolerate the drug, to get some evidence of being able to use alone or in combination, and be able to to add more benefit on top of what they've demonstrated. Tell us a little bit more about the role of miR-17. You've kind of touched upon it earlier in the disease specifically. Yeah, so, a lot of this work was kind of initially done by Dr. Vishal Patel at UT Southwestern. He noted, as he was doing kind of transcriptomics, et cetera, in PKD modeling, that there was a very clear, strong upregulation of miR-17. It turns out that the PKD gene mutation itself kicks off a series of transcription factor signal pathways that ultimately increase expression of the oncogene c-MYC. And so combo makes sense because the disease is a hyperproliferative disorder, and in fact, miR-17 has been looked at in the oncology setting, you know, previously. And so, this upregulation of c-MYC results in the kidney, predominantly in an upregulation of miR-17, and miR-17 controls a variety of proliferation pathways. One of which actually turns out to be back around on the PKD gene product itself, which is polycystin, and it can suppress the production of polycystin. Polycystin basically exists to help control the proliferation, the location, and the function of renal tubular epithelial cells. And so when you don't have polycystin around, you see abnormal proliferation, you see this transformation of the cells into cystic epithelial cells, et cetera. Polycystin isn't the only proliferation pathway that miR-17 regulates, but it is one that we can measure and we follow. So that's our key pharmacodynamic measure of polycystin. But it's very clear you can actually produce the PKD gene mutation in a mouse. At the same time, you can delete the miR-17 family cluster from the gene, and you don't have the disease, or you don't have the disease nearly as much. And so it's very clear that a lot of the proliferative action of the PKD gene mutation is essentially traveling through miR-17. And so our ability to block that is, w e think is a significant stopgap in terms of the pathogenesis of the disease. What are you looking for in terms of a clinical endpoint here in this disease? Like, how was tolvaptan approved? What is the output? Yeah, so there are two primary endpoints that the FDA looks at. First and foremost, what they want to see is clinical benefit, which is eGFR, right? Okay. So that's a renal function study over time. You just wanna kind of delay the progression, halt it- You want to delay the progression. Okay. Right. You don't have to turn it around- Where do people present? What level of eGFR decline do they have? Where are they when they- Generally around kind of the mid-40s. Okay, so pretty- It's pretty low. Yeah. Advanced already. Yeah, because it's not- Okay ... it's not recognized early, typically. I see. Okay. I see. Okay. The FDA wants to see eGFR for full approval, but unfortunately, for companies in development today, there's an accelerated approval pathway to get there more quickly. Now, you're still gonna need to do the eGFR study, but the way you can get approved is by showing a reduction in the progression of overall kidney size, called total kidney volume, or TKV. Okay. Okay. And so generally speaking, you can start to detect, based on, you know, the normal growth in kidney size in a placebo-treated group, you can generally start to really see changes in several hundred subjects over about 12 months period. And so we're estimating about 300 patients for treated for a year can really enable us to, you know, distinguish the effect. So that's on TKV, and now it's very clear that the FDA accepts that for accelerated approval. Then you need to keep going- What kind of change in volume matters? Well, so tolvaptan showed a 50% reduction- 50%? Wow! 50%? Wow! Okay. in the progression. So it still progressed- Okay but it progressed less, 50% slower than placebo over a 12-month period of time. Okay. that ultimately resulted in about a 30-ish% reduction in the progression of GFR- Okay in a longer two-year base study. So, meaning, the size of the kidney, it didn't shrink, or? You slow the growth of the kidney. You slow the growth- You slow the growth. Oh, I see. Okay. Yeah. You slow the growth of the kidney- Okay. You slow the reduction in GFR over time. Yeah. That- Like, the baseline demographics of our first cohort of the phase 1b that we read out earlier this year, those kidneys were nearly 10 times the size of a normal kidney. Wow! Yeah, there's a picture in our corporate deck. So- Shows these. They're, like, the size of, like, a rugby football. Unbelievable. Huh. So just to backtrack, if there was genetic testing, would you treat these patients earlier? Earlier, absolutely. Or you just wouldn't- Earlier, yeah watch and wait till there was some disease, or what would you? It's a cystic proliferative disorder. I don't know why you wouldn't start that early. Okay. Interesting. Is that something you'll push for if you- I think it's—I mean, again, it's when—once you have actual therapies on- Yeah the market, they can, they can work- Right then you really focus on diagnosis. Absolutely. Okay. So you've got some data coming up. Can you tell us about kind of, what is your program look like? When will we have data? What do you hope to see? Yeah, sure. Let me, I'll touch just a little bit in terms of our expectations, and we've got it, too. So, the second cohort of our ongoing multiple-ascending dose study in patients with ADPKD was fully enrolled, and we have guided that we'll have data in the Q1. This is three months of treatment and then one month of follow-up, so about four months plus some data analysis between cohorts. Our third cohort is enrolling now. We're enrolling well. We would anticipate data sometime in the middle of next year. And that third and final cohort is at 3 mg per kg. So we've shown the 1 milligram per kilogram data, where we saw, saw the increases in polycystin that we wanted to see. And then, the 2 mg per kg, is, as I said, we'll have in the Q1, and then the 3 mg per kg mid-next year. We are planning to have one additional cohort in this study, sometime in the H2 of next year, would read out, showing a fixed dose, would work suitably relative to what you'd expect with a weight-based dosing, so that we're positioned for, a fixed dose in, in phase II. Because that would be, as Preston mentioned, you know, with accelerated approval, you wanna have your commercial presentation incorporated into your phase II study. What's the presentation of the drug, then? Right now, it's vialed. Okay. So it's a 1 ml, and we formulated 150 mg per ml. So depending on your weight, you know, it's around- Are you gonna try to get- 1-2 mls this into an auto-injector or something along those lines? Yeah. Yeah, we'll start with a prefilled syringe, and auto-injector is certainly a possibility. Okay. Yeah. And then, so after this. Frequency of dosing is? Every other week. Okay, every other week. And so after this current phase Ib study in patients, that's to, you know, to find the right dose, then we go into our phase II study, but as it turns out, that's actually our pivotal study- Okay because of accelerated approval. Right. So that will be about a 300-patient study, treatment for a year, and on the basis of that- Will you get some infor- we would submit for approval. Will you get some information from this upcoming kind of work you're doing on dose finding, about kind of how to power the phase II/III study, and? We're generally using kind of what we've seen from other therapies, predominantly tolvaptan, in terms of programs. Okay. There have been some other programs, but when you use that as the basis, that's kind of where we get the patients from. Okay. But how do you know how much impact your drug will have on top? I mean, you can get information about- We know, we know mechanistically and from non-clinical models- Okay that this mechanism is quite powerful. It looks better and not better than tolvaptan, but also additive to tolvaptan. And so we believe we're taking a relatively conservative assumption by kind of using model- Those models translate well, you think? Yeah, we think so. Yeah, they're genetic models of the disease the microRNA is conserved across mammalian species. So, you know, we see about a 50% increase in polycystin correlates with significant anti-cyst activity in preclinical models. Okay. Okay, and what, like, any kind of, tolerability, safety issues you're looking out for? Like, what have you seen in animals when you push the dose? What's kind of on your mind from a safety perspective? Yeah, we've completed our mouse chronic tox, which was the most sensitive species, and saw nothing. So the top dose of 300 mg per kg, which is a, you know, a tenfold margin to the NOAEL, where the therapeutic dose would be, mouse to mouse, we've seen nothing. So, you alluded to it earlier, but, you know, this next-generation molecule has benefited from incorporating small molecule drug discovery techniques in lead optimization, which is something we hadn't done historically, and now it's de rigueur for everything we do in research. Treat these single-stranded oligos like they're small molecules. And, so, it was designed purposefully, and haven't seen anything, both in vitro as well as in vivo. So just, as we wrap up, give us kind of your vision for the company now. You've got this program. Looks like it's got some traction. Yeah. Where do you go from here? Well, my vision is that we've got an asset that we can take through a phase II study, and recently adding Preston, a trained nephrologist, ran all the nephrology programs at a little company that we both used to work at called Amgen. He's run much more complex studies, and a 300-patient, you know, multinational study is well within our capability set. And in this indication, in nephrology, as you well know, with the companies you cover, it's readily commercializable for a small company. So we don't see anything keeping us from being able to pursue this opportunity. I think, you know, we got to obviously drive value in the program. But there's been a lot of interest, too, from both investors and pharma, and I think if we continue to execute and see promising results in the study, then our dream of building this company out and being able to commercialize and develop and get this drug approved for patients would make a big difference. Excellent. Well, thank you so much. Thank you. Thanks.