...for joining us on our next fireside discussion. I'm happy to have up here, some members of the, Viridian management team. To my right is the CEO, Steve Mahoney, and to my far right is Shan Wu, from Viridian. Obviously, pretty exciting times, because, obviously a lot going on in Thyroid Eye Disease. But also, you're gonna come upon some phase III data, coming up. So maybe I would just, offer, you the opportunity, Steve, to talk a little bit about your lead, program, 001 in phase III. Mm-hmm. Tell us about your confidence in the potential positive phase III results that are supposed to be coming, I think, in September. That's right. Top- Presumably, that should be an important value-driving positive catalyst for the stock, and it feels like the market is skeptical. I don't know. We can talk about that. Okay. But why should they not be skeptical, and why should you have positive results? 'Cause there seems to be a lot of nervousness about the results. Yeah, great. Thanks, Mike. So yes, we have our phase III top line readout for our IV program for what we refer to as VRDN-001. That top line readout will occur in September, which we recently guided to in our earnings release in early May. We have a lot of confidence in that outcome on the basis of two primary drivers. IGF-1R is a clinically and commercially validated target as shown by Tepezza. We antagonize the same target, which is obviously that's a good place for us to be. And then secondly, we had very robust responses in our phase II setting, where we showed on a cross-trial comparison basis, which is what comes with all the caveats of cross-trial, but we looked as good, if not better, across the relevant endpoints of proptosis, which is bulging of the eyes, CAS score or clinical activity score, which is your pain, roughly mostly your pain score that associated with the disease, and then finally, diplopia, which is double vision. And as you can imagine, with bulging, and pain, and redness, and double vision, the quality of life for patients with these types of symptoms, which are ordinarily the moderate to severe portion of the patient population, that has a debilitating effect on quality of life. And so what's really important is the ability to address those symptoms for these patients. And again, as I said, IGF-1R is clinically validated and commercially validated as a target. So we have a lot of confidence going into that data set coming up in September. And we have a differentiated profile, importantly. We have a less of a burden on these patients. Our The current IGF-1R, Tepezza, has a 20 mg per kg dose, dosed 8x, 8 infusions every three weeks, and has a 60-90-minute infusion time, as compared to us, where we have a 10 mg per kg versus their 20, five infusions versus their eight, and our 30-minute infusion time. All that adds up to about a third of the less drug, a third of the amount of drug that they put in. We think, to answer your question, our success profile looks like we could have a similar profile to Tepezza, both on efficacy and safety. Because if we do, and all evidence suggests that we should, once we have that, what the dynamics in this market is that this is a symptoms-driven market, meaning that people, regardless of when they got diagnosed, whether they got diagnosed yesterday or they got diagnosed five years ago, they come and they present to the physician and say, "I have these symptoms. How can you address these symptoms?" In that situation, with our IV versus the other IV, we think we're gonna win every day if we have that similar profile on safety and efficacy, and that's our expectation. What is the bar for positive results when you put them out in September? Obviously, a statistical significant result on the primary endpoint. Now, the primary endpoint is proptosis response. Mm-hmm. Then we also have to look at the magnitude of the average reduction, and then also safety and efficacy, primarily hearing loss. So, does one suspect that, in general, the proptosis response number will basically be identical to Tepezza, or are there any reasons it could be lower or higher? And I think from memory serving me right, the proptosis response is around 50%-75% placebo-adjusted for Tepezza. And it's a wide range because they had two different studies. One was actually 50, I think one was actually 75. Mm-hmm. So that does give you a band. But in the first result, is that the expectation is that you're gonna fall somewhere between 50-75, and are there design issues or anything I should consider, to set the stage before we get to the results? Yeah, we haven't guided on exact numbers, but we—like I said, we do expect to have a similar profile because of the same target and from the evidence that we've already seen. In fact, our 10 mg per kg dose that we're studying in phase III, when we looked at it in phase II, we had an 83% proptosis response rate after just two infusions. So that was really encouraging. That's what got everyone excited about the approach that we were taking. So we do expect to fall in line with a similar efficacy profile there. Right. Yeah, sorry. Yeah, yeah. So, cross-trial comparison, small numbers, normal caveats apply. Yes. That in general, you have had higher proptosis response and at an earlier time point. I want to say higher, I know you'd say 83 versus 70, 57.5, but a very competitive, if not numerically higher result, cross-trial comparison. My point was at an early time point. Correct, and small numbers. Yeah. But and small numbers in the phase II, but again, very encouraging, and on the footsteps of or in the footsteps of a validated target. So our expectations are in line with that. Now, I would also suspect that the proptosis reduction will also generally fall in the same range, which is around a 2-mm placebo-adjusted decline on average for the patients. Is that also something you would subscribe to? Sure. Shan, do you want to take that? Proptosis reduction, the amount of proptosis reduction, not just the response rate. Yeah, we saw really robust, going back to the phase II study, we saw really robust reduction in proptosis change as well. Yeah. And that is a secondary endpoint in both THRIVE and THRIVE-2. So it's a reasonable assumption that across all of these relevant disease endpoints, proptosis response, mean change in proptosis, Clinical Activity Score, both the resolution as well as the change, the decrease in that CAS score, and diplopia resolution, a successful profile is to be similar to Tepezza on efficacy. While not setting that expectation that it would, because the expectation is that it should be similar, but the early data is numerically better and/or at earlier time points. One would suspect that the base case is similar, but there's some off chance it could be actually better. Sure. Because it is a more potent antibody, right? So just to be clear, I know this is not the expectation, but by developing a program, you're not necessarily developing and investing in a program to be a me too. So you would suspect that the properties of the antibody, just to be clear, are potency, et cetera, and a full, full blocker? Yeah, we are- Full blocker. full antagonist Yeah. Tepezza is a partial antagonist. So why, why couldn't you be better? There, there's certainly that potential, and, and again, the phase II data was encouraging with respect to that. And then I would also add that, you know, it, because, we think we can be similar to Tepezza on its, on its AE profile on the safety side, you know, just as a reminder, the safety profile of Tepezza is very good. It's benign in terms of the ability to manage, you mentioned hearing, the ability to manage the AE profile, and the benefit risk profile that Tepezza presents for patients is great, and we think we can match that. But again, on the IV side, when we match our IV versus theirs, we feel really good about that patient choice, given the burden, the IV burden. That's on the IV side, and then we can talk about Sub-Q as opening up a whole other segment of the market. Before, yeah, before I get to the Sub-Q, because in part, to be fair, people are going to make read-throughs to the Horizon's initial success of the IV because, the Sub-Q is a YTE-enhanced version- Mm-hmm. - of that initial drug. So we wanna work on the first generation first and then see significant opportunity. Well, my gosh, you're probably gonna work. YTE's a longer-acting version. Yeah. Now, going back to just to clarify these details, because it is important, on the proptosis response, one of the things that people are worried about in any design is that you are using less drug. It's five infusions versus eight. Therefore, at least in cancer, more drug is better, longer treatment is better, and people would say, "My gosh, you're only doing five infusions versus a placebo," but the results that people are at least looking at the label for Tepezza is eight infusions versus a placebo. So while there is a label that requires more infusions, technically speaking, if you follow the label, you might get a better response. That wouldn't be ability to dose 8x because you're using a five-infusion regimen. Is if I had to look at the curve, are the proptosis responses of 2 point... Is it 2.2? 2 mm 2 mm. 2 mm change. Does that basically all happen by the third or fourth infusion, such that if you're worried about more than five infusions, that should not be a concern? Because the responses are gonna happen, they're gonna happen in the first few infusions. Giving the seventh and eighth is not relevant. Right, and we would argue- At least on the response rate. Right. The ultimate numerical decline of 2 points on average, more infusions is gonna get some more people deeper. But can you comment on those two things? Yeah, but I would argue—I would point out that if you look at the phase III data from Tepezza, the placebo-adjusted response on proptosis, the incremental benefit past 5 doses is minimal at best. For the response rate. For the response rate. Yeah. That's what we saw in order and that, that is the opportunity that we identified, that clearly, without a dose-ranging study conducted prior to that phase III, there's opportunity for us to come and have that same outcome, but with less drug. Yeah. This is not a case where more drug is better. But yeah, they designed a study, we're going for eight, and they felt that that was sufficient drug because they want to win.... Right. It when the design said it works, you wouldn't wanna shortchange yourself. And by using the learnings of that with a more potent antibody, you would subscribe that nearly all the benefit certainly is all happening by five, certainly in the responder rate. That's exactly right. Okay. Yeah. So I'm gonna have to go look at the number of people responding by time point. I actually don't know if they have that with Tepezza, but I think yours, again, on small numbers, very high response rate by two- 2 and 2 infusions. Yeah, 2. So why are we worried about infusion six, seven, and eight? That's exactly right. We think that the doses of six, seven, and eight for Tepezza are essentially not adding any benefit, and therefore- Like, you do see some incremental average decline, but the response rate, you know, is all by, by- But even that- Yeah ... you need to squint at. Okay. Yeah. Number two is the safety. So before we worry about having at least a similar effect, we certainly wouldn't want a drug that has more concerns on safety. Tepezza has a 10% versus 0% rate of hearing loss. However, in your study, in the early studies, although small numbers, it was approximately 10%, even with a few infusions, small numbers. Can you talk to the confidence, whether because you have ongoing blinded data, but why should we feel that giving a more potent blocker, which is perceived to be an on-target effect of the hearing loss, why would giving a more potent blocker lead to same or lower rates of hearing loss? Well, again, we do have a third of the amount of drug that we deliver compared to theirs, so it's a lot less drug. But do you believe that the- But, but- ... like the drug is going elsewhere? Like, to the, to... I believe, just to be clear, and you can help me out here. Oh, in terms of the distribution? That, the distribution. The hearing loss is related to, I believe, hitting IGF-1R near the hair follicles- Mm-hmm ... and other vasculature there, yeah? Mm-hmm. You know, as opposed to the periphery. Mm-hmm. So you infuse the drug, the more drug that you're giving, the more chance that that's getting into other tissues, including in the ear. Right. So, that I would agree on that. That's a hard one to understand. Some people just think it's a Cmax issue, so it has to do with an infusion amount, although you would, again, say less drug. So it'd have to compare the amount of drug on a PK, milligrams per deciliter, whatever it is. Can you walk me through some math or explanation just about why a more potent drug... Because you would also say it's more potent- Mm-hmm ... therefore, the affinity to get to that hair follicle is also high, even though it's less drug. It's not just the amount of drug, it's avidity to the target. Yeah. But, yeah. I mean, again, I think I just point to our phase II results, where we saw the treatment effect size that you need for moderate to severe patients, and on the AE profile, it was quite clean in terms of... You referenced the hearing. There was a case of tinnitus in the active study that resolved on its own without intervention. Mm. And then in the chronic study, there was, like, an ear plugging or a discomfort, but that was in the placebo arm. Right. There were zero cases of hearing adverse effects- Mm ... or hearing loss? I think zero cases of the adverse hearing adverse effects. Right, and there's a difference- Let alone zero hearing loss. Right. Yeah, hearing loss, we have not seen. Because another company that had reported some sub-Q data maybe two months ago reported no hearing loss, but they did have some hearing impairment. Correct. Right. They- Which are two different things. ... they distinguished between here, yeah. Yeah. They distinguished between hearing impairment and tinnitus, which I don't know if I agree with. Right. I would say that most people just don't want to see hearing loss. Yeah, that's exactly right. Yeah. And it This has a 10 versus 0. That is exactly right. We're not really, we don't see a lot of hearing loss in our trials. How many patients were in the chronic study or in the, in the acute? How many patients- In our phase II? Yeah, in your phase II study. Uh, twenty... It was six patients per arm in the chronic. Three arms. Yeah, uh- 18 treated patients. Twelve treated. 12 treated patients. Okay, so if it was 10%, it's either gonna be zero, one, or two. That was chronic. Yeah, for the chronic. Then on the acute study? It was, 21. 21, and there were two cases divided by two. Yep. Okay. So overall, this. I'll just add that, we believe it's related to treatment. Mike, you had mentioned that, but for the most part, these events are mild- Mm ... and almost all resolve on their own, and that's the experience with Tepezza. That's the experience that we've had in our phase II studies. And now, having been on the market for four years, physicians have had insufficient experience with Tepezza, and what they tell us is they feel really comfortable managing this AE. And it goes back to the urgency to treat for these- Mm-hmm ... moderate to severe patients, where they have such debilitating symptoms that, the patients as well as the physicians want to be able to give them an IGF-1R because of the remarkable efficacy. Totally. And just to wrap that up, and then we'll move to the Sub-Q, which of course is extremely important, and you are proceeding to a phase III. On the phase III IV, you certainly, as a company, are aware of ongoing safety side effects. You do get updates on the ongoing study, certainly from a side effect, SAE, hearing loss component. Is that fair? ... Yeah, I mean, we- Blinded, but you do get updates. We certainly have a team, but no, I haven't seen the blinded data. But we do have a DSMB, as you would expect. They're monitoring the data at all times- Right ... for safety, and they obviously have the option of being able to tell us, "Hey, you should stop this study." We have not had any of that conversation. Okay. That has not happened. But you do not see blinded data, is what you're saying? That's right. Okay. On the Sub-Q, you recently announced that you're proceeding to start the phase III, right? Yeah. Our guidance was that we have had our meeting with the FDA. Yeah, yeah ... and that we are, our plan is to start a pivotal program. We have not provided details on what that pivotal program consists of yet. So what would be the next steps, and is it reasonable to believe that the Sub-Q would be something similar to the design of the IV? And is that also five injections, or how would that work? So we put our PK/PD data out in December- Mm-hmm ... for our Sub-Q program, and we were really happy to see the results there because we saw an extended half-life of 40-50 days on the PK basis, and on the PD basis, we saw IGF-1 levels, which is an important PD marker for this, for this target. We saw fourfold increases in IGF-1 levels, so indicative of target engagement. So that was all very good. And what that told us was, it gave us options to explore different exposure levels that we saw in the IV program- Yep ... that those exposure levels that correlated to clinical response, we can match those in the Sub-Q in terms of matching the exposures. So for instance, it gives us options to explore a Q8 weekly, so every other month dosing regimen, where that matches or ties back to the 3 mg per kg IV- Yeah ... exposure that correlated to very good response in our phase two studies. And that, again, is an option available to us. We also looked at exposures that correlated to 10 mg per kg- Yep ... on Cmin and AUC, that matched to a- Month ... four, yeah. Yeah. A Q4 weekly or monthly dosing regimen. Yeah. So think about that- We have a Q2. Yeah. Yeah. And you have a Q2. Oh, there's gonna be a Q2. There's a Q2 weekly. So what we said is, in December, is those gives us those options. What we have not disclosed is exactly the trial design yet, but that is coming, relatively soon. All right. So again, if you look back at the IV data, 3 mg is similar to 10 mg. We agree with that? IV. Yes. Yes. The 3 mg had a good clinical response, as did the 10 mg, exactly. It's generally- As did the- ... in the vicinity. Yes. And, I think that if you did the PK/PD exposure, that would align. Is that fair? Like, so, sure, more drug is better, but, 3 mg is already sufficiently covering the target- That's right ... an increase in IGF-1, such that, sure, while more drug is better, from a pharmacodynamic perspective, you're getting the same effects with 3 mg. And you saw that with that data. But to be conservative, you're doing the 10 mg, which is good. Well, so just to be clear- And the IV ... we have not actually talked about exactly what the trial design. No, the IV. Yeah, and the 10 mg for is the IV dose. Correct. And then how we- It's good that you're using the high dose- Absolutely ... from a risk perspective. Right. But in the Sub-Q, you are going to choose between a every two week and every four week and an every eight week. Exactly. Now, would you say you'd like to use two different arms, or you're gonna pick two of the three? Yeah. Our guidance has been that we intend to use at least one active arm. So that means more than one possibly. I need to think about which one's the best of those three. Yeah, I mean, but I think, like, I think that's what the opportunity- It's like one goes for home run- Yeah ... and then one goes for a more conservative approach. Yeah. But I think that's exactly what the opportunity is, right? With Tepezza was not dose ranging. Would you need to run two studies? Yeah, so we have guided that we will run two well-controlled studies- Okay ... and have a safety database. This is a new molecular entity, although it has the same binding domain- Yes ... and CDRs as 001, the IV antibody, the only difference is the YTE half-life extension. If you did two studies, couldn't you pick two of the three for one and two of the three for the other, so you've covered your bases? I'm not sure I understand the question. So if there's three different arms, two weeks, four weeks, eight weeks- Mm-hmm ... you're gonna pick at least one of those- I think two. ... per arm per study. Correct. Yes. Therefore, you can cover your bases because two of the three could be one study, two of the three could be other. Those would overlap. You're covering the lowest effective dose while still going for a home run, and both studies use two mgs in the every four weeks, excuse me, the middle one for both of those. Is that a fair assumption? Yeah, that's a fair assumption. Okay. We haven't come out and given the specifics on that, but yeah, that, I think, that's the right principle. Okay. And then when would we get a next update on that presentation? It's coming soon. Okay. And the reason I talk about that is because, obviously, again, the key is that the PK/PD overlaps with the Sub-Q as to the IV, and so therefore, that should de-risk that program. Right. And again, this is for the first time in IGF-1R, this is the opportunity to actually explore the therapeutic index that has not been done before. So that's a really exciting place for us to be. And the patient convenience, you can imagine, every eight-week dosing would be a great place to land for patients, given the convenience. One final question, it's an economics question, but it addresses some of the investor debates. Can you talk about the economic incentive or disincentive dynamic of using Sub-Qs versus IVs for ocular specialists and other endocrinologists that are administering these drugs, who do currently for Amgen's Tepezza, and they'll be here tomorrow, currently, there is economic payments for that infusion, such that going to Sub-Q is a disincentive? Yeah, so that's a market dynamic that's also in our favor. Okay. In addition to the fact that this is a new start market, meaning that you present with symptoms, you get treated. It doesn't matter when you've been diagnosed. That new start dynamic is very critical to what we think is gonna be success. So, to your question, ophthalmologists and oculoplastic surgeons do not have their own infusion centers. There is no financial incentive for them to keep- Oh ... patients in-house. They are more than willing to refer patients out. Because when they- There's no sticky financial incentive. When you're just prescribing Tepezza, nearly every time the infusion's obviously not at his practice, it is somewhere else. It's outsourced ... an infusion center outsourced, there is no economic tie back to that. Right. Interesting. That's another positive market dynamic. Interesting. That is different than Rheums MS- Oncology ... multiple sclerosis, oncology centers. Yep. Interesting. Different, different dynamic. Okay. It's a good setup for us. Okay, very good. Well, thank you very much for the discussion. We look forward to continued execution and the data- Great ... somewhere later this summer. Great. Thank you, guys. Thank you. Thank you very much, Mike.