Hello, everyone. Good afternoon. Day two, Jefferies Healthcare Conference in New York. My name is Akash Tewari. I cover pharma and biotech companies here for the firm. I have the pleasure of hosting the Acelyrin Management team, the new Acelyrin Management team. I will hand it off to Mina to give maybe some introductory remarks and introduce your colleagues, and then we'll get started with Q&A. Great. All right. Thanks, you guys. Hey, Mina Kim. I am the new CEO at Acelyrin, and I am about four weeks into the new role. But I was actually employee number 45 at the company, so long-tenured. Started there, you know, as the company was building the portfolio, and in particular, came in to help get the ValenzaBio acquisition done, which is where we acquired lonigutamab, which is one of our lead programs, and then we rolled into the IPO. You know, we did announce some management changes, but I would actually describe those as largely internal promotions. We, as a team, have been together for a while, and so we have, you know, continuity and knowledge across the operations and the portfolio. And so there has been a little bit of a title change, I'd say, but very much the same team in place. I'll let Shep and Gil introduce themselves. Hello, I'm Gil Labrucherie, the Chief Financial Officer. I've been with the company about a year, and I'm glad to be here and share more about our company and our vision, and thanks for the invitation to the conference, Akash. Of course. Hi, Shephard Mpofu. I'm the Chief Medical Officer. Started in September last year. Great to be here. Thank you. All right, so let's get started with questions, and it's funny, in this job, I feel like everyone wants takes in, like, 15 minutes. I remember I met with your company, and I met with you, Mina, right after the announcement was made. It was a 15-minute slot, and then I had to spend the rest of the day being like: Oh, what did you think? I don't know, like, it's a little too early to make an assessment on someone. But you know, the things that stood out in that conversation, I think you probably used the word discipline 3 or 4 times, and you're like: We're gonna be very disciplined in terms of shareholder capital. Since we've talked, and you said, "The data will help determine the plan," I don't know what our development plan is here. We've gotten data, it's psoriatic arthritis, which I haven't even really been able to look at this morning. We've also had data in TED with your IGF-1R asset. Mm-hmm. From our last 15-minute conversation to now our 25-minute conversation, what do you think has changed? Yeah. Do you think the data, the signal you've seen with izokibep and psoriatic arthritis and your TED asset is good enough to really move forward and be differentiated versus other pipeline competitors and standard of care? Yeah. So let me, maybe step back and frame it up a little bit, right? In the context of our original conversation, and what we really talked about there was, what are we gonna do, over the next quarter or two? Like, what are the priorities? What is the strategy going forward? And maybe just to frame it up, we're in a really fortunate position where we have two lead programs, izokibep and lonigutamab, that we think are both very promising. We think they're drugs that work. izokibep, in particular, we think is approvable in multiple indications and will be a profitable franchise. That said, it's capital intensive, and this is where I think the discipline, the comments around discipline are especially important. We have also the fortune of having pulled in the guidance around our HS phase III trial, which we originally were planning to read out at the end of the year, but which we are now planning to read out in the third quarter. Hmm. And so we are going to use that data to really drive decision-making and disciplined decision-making around capital allocation and portfolio prioritization going forward. And part of what's driving that is we do have a second asset, lonigutamab, where we read out very early POC data, small numbers, right, at ENDO earlier this spring, but that we thought was very promising and warrants further development. That POC trial is ongoing, and we did read out some incremental data from cohort one at ENDO earlier this week, and we are planning to read out more data from the POC in the third quarter. So obviously, there's a lot in the third quarter that's gonna inform sort of decision-making going forward, but we are very excited about lonigutamab as a program, so looking forward to that readout. Okay, understood. Now, why don't we start off with TED, actually? Yeah. You know, what's interesting... I think, look, there's a lot of companies doing sub-Qs, including, by the way, Horizon will, and Amgen will have an on-body. So I think you're gonna be the most important thing with the sub-Qs, okay, you got out of the infusion centers, and, you know, it opens up opportunities to get reimbursed. I think your approach is interesting 'cause what you're really exploring is, can we dose chronically, and can we avoid the hearing toxicity that we've seen with Tepezza in some of their, you know, trials and also in the real-world setting where I think maybe 5%-10% of patients actually have more durable hearing loss, which I think is more important than any transient ones. I think the pushback I would give you is, when your initial data came out, tinnitus is a form of hearing toxicity, right? Like, other companies have assessed that tinnitus is hearing toxicity, but that does not necessarily mean that leads to more durable, clinically meaningful forms of hearing loss, and I think that's really where all of the discussion needs to be focused on your program. Talk to me about why you feel confident that you can kinda decouple both of those AEs? ... Yeah, and maybe just to push back a little bit on the framing of the question, we actually think that there is potential for differentiation, right? Putting safety aside. Hmm. So you started with sub-Q, and what we have is the first real in patient data in sub-Q. And so I know there was a lot of conversation about sub-Q, and we think that the qualities of Loni are really what have enabled that and what we're excited about, right? So we, you know, Shep can go into some of the details around the data, but what we have seen, even in these early cohorts, is early onset of action, right? Hmm. A durability of that response. So the ENDO data, for example, shows that, you know, we dose patients at week 3, and we see that, you know, that impact lasts through week 12, right? And so given that profile at very low doses, cohort 1 was 40 mg, right? Cohort 2 was a 50 mg loading dose, and then 25 mg weekly. We think that there is a real potential to differentiate in terms of efficacy at much lower doses and to really facilitate a true sub-Q. And again, we are the first to show POC data in patients- Hmm. - in TED, right, in a sub-Q format. So I think there is a lot of differentiation there before you even get to the safety issue, right? And how we think about that is, right now, the hypothesis is that we could win there, but it's hard to prove the negative, and we don't think we're gonna do that in a POC trial, right? We can't declare a victory there, and that's gonna take some time to play out. And Shep can talk about what we've seen so far and how we're gonna measure it going forward. But if the hypothesis holds, and you know, around Loni's attributes, we do think that over time we can differentiate and win on safety as well. Yeah, no, absolutely. Maybe just to add in terms of how our paradigm approach is different and unique, we are focusing on the potency of our molecule, and also we have established an exposure important in terms of epitope availability. Hmm. How much do we suppress? We picked the data quite nicely from our single ascending doses in sub-Q, where we looked at a 20-mg sub-Q, 40, 125 to 50. The 40-mg sub-Q, which we started in our cohort one, gave us the confidence that we have adequate suppression that could last three to four weeks, and the data that was presented matches that. So we are approaching from a minimum effective dose, whereas when we look at other programs, there was no dose ranging done in this study, and therefore we will arrive at a Goldilocks dose with a therapeutic window that has a very good benefit risk that might skirt any other issues in the hypothesis of a high Cmax abrogating the blood-labyrinth barrier, resulting in perturbing the function of IGF-1 for cochlear physiology. The last thing I'll say is, in our cohorts, we do audiograms in patients at baseline and also at any time point where in the first cohort, there were 3 patients that had transient tinnitus. One of the patients had tinnitus on the first dose at week 0 that lasted 24 hours, and then on the second dose at week 3, that lasted 24 hours. All those patients had normal audiograms. Moving forward, we'll be having audiograms at baseline throughout the course of exposure in all of our studies. Up to date, all cohorts have had normal audiograms, and we've not seen any hearing impairment based on sensorineural hearing. Okay, so that's really important, and I wanted to kind of hit on that because, again, I think the question becomes: when are we gonna know enough to go chronic dosing? And that, I think, is gonna be really interesting because, you know, you look at Tepezza, they're looking at 16 dose trials. You are-- you have seen examples of where you just may need to dose longer, and actually, patients get into a proper dosage response. That's really, I think, differentiated. Tell me this: When are we gonna get enough long-term follow-up data when it comes to audiogram safety? Forget tinnitus. I think your point is very well taken. It was transient. But are we going to get enough durability at your go-forward dose? Is that going to occur maybe in the back half of this year? Is that going to occur next year? What is, you know, the follow-up needed for you to really de-risk yourself on audiogram hearing toxicity? Yeah, that's a very important question, and I think, what we are doing currently in our cohorts, we are following patients up to 12 weeks. So we have audiograms at baseline, and then definitely in the middle of the study, and then at 12 weeks. So what we propose moving forward when we move to pivotal studies, we'll do audiograms at baseline and every two months up to a year. Our studies are a year long. Our primary efficacy endpoint is at an earlier time point, but we believe thyroid eye disease is a chronic autoimmune indication where there's dysregulation of the IGF-1 axis- Hmm ... not only in the eye, but systemically. So exposing patients to a therapy at a very good therapeutic window might have benefits not only in the eye but other areas systemically that might have dysregulation. Understood. Now, I think there's a nuance, especially with your drug, because I think when you look at the internalization... and of course, internalization, I've seen different figures, right? I thought, you know, Tepezza, I think initially maybe 15% internalization, maybe the actual internalization rate is higher, but it actually does affect your PD decision as well. Because I think what's interesting is there are signs that maybe dosing higher with a molecule like yours, where you're having a very high rate of the internalization of the IGF-1R receptor, is only conferring more toxicity. It is not actually conferring more efficacy, and it's really tricky to do that PK/PD modeling work from our public disclosures. Talk to me about the dose range that you're picking? Why you think you are kind of balancing internalizing the receptor and getting the clinical efficacy that'll stack up with other therapies in the space, while also maybe avoiding some of the toxicity? Yeah, that's a very important question, but obviously, we still have small data sets. But I think where you're going is important, and I would start by saying, number 1, by being very clear in establishing a minimum effective dose, and we are very fortunate that we have a potent molecule, which at 40 milligrams, demonstrates at 3 weeks, a rapid onset in improvement across all endpoints that are seen with Tepezza at six weeks. With doses, if I was to give an example, a 70-kg patient requires 1,400 milligrams of Tepezza. In our study, it's only 40 milligrams. So we believe that ability to have rapid efficacy with a depth of response, and what we have just shown now is durability after the 3rd week. At 12-week follow-up, patients have still maintained their response, allows us to be prudent to choose a dose that is not too far from where we are starting. And knowing that, when you look at the blood-brain barrier, the blood-labyrinth barrier, sometimes the abrogation of that is due to too much drug that's able to penetrate. So therefore- Mm. If the hypothesis is true, we might have limitations on having that impact in patients, but obviously, we will need to run the audiograms in our pivotal studies to show that this is what we are seeing is a potential safety benefit. Yeah, and just to be clear, right? That POC trial is ongoing. We're in the third cohort. Mm-hmm. So that dose-ranging work and exploration that we're doing, we do think is very important to address this question and does enable both, you know, the subQ format, but that longer- Yeah ... chronic treatment regimen. So I think that is, like, those are all of the issues that we're thinking about, but that is where this POC trial and doing real dosing work in advance, we think is a real advantage for us. And, should we think it's gonna be Q3, or could you actually go maybe monthly is maybe the right approach here? I know there were some questions, even when the initial data came out, that actually, we've got a dose we're not showing data on, which was always fun. But, what happened there? And what, what, what do you think the doses are gonna be that you ultimately select? We are gonna explore monthly, and like I said, we do plan to read out more data from the POC in the third quarter. Third quarter? Mm-hmm. Okay. Now, you know, the funny thing in biotech is sometimes the worst thing is a drug works, but it's just not good enough, right? And then it's really hard for some management teams to be like, "Okay, I've got something that's going to be viable but not differentiated." And I think that's the question I think everyone has on izokibep. Yep. In psoriatic arthritis, let's start with there, 'cause I think the pitch initially was, "Okay, we're gonna show comparable as competitive on some you know, some of these traditional endpoints, but it's enthesitis, where we're really gonna differentiate because we have higher tissue penetration." Initial data came out, maybe high placebo response, but I don't think we necessarily saw that signal, right, where there's a clear differentiation on the enthesitis part. What if, you know, the data came out today, talk to me about the hypothesis of iso in psoriatic arthritis. Do you feel like it is differentiated enough to move in an era where Cosentyx is gonna be going off patent very soon? Yeah, no, thanks for that question. Number one, based on the characteristic unique properties of the molecule, being a small protein therapeutic, 10 times smaller, as you say, than monoclonals like in IL-17s that are currently approved, we believe we have the ability, based on the potency, which is also higher, the ability to penetrate, permeate, and be present in tissues that are difficult to treat in this multifaceted disease. Our data has already shown that in terms of what we will be presenting at EULAR, ACR 50 responses that happened already separating quite nicely by week 4 and being very significant by week 16, PASI 90 and 100 responses that are in the range of where you have an TN F blockade. So we also achieve, to your point, pertaining to enthesitis, in the first 2B study, we saw enthesitis resolution in patients with enthesitis of LE 1 and 2 only, so low burden enthesitis, around 83% improvement. In our current study, despite a high placebo response, when we look at the pre-specified strata for the enthesitis, we see in the low burden, we see three-quarters of patients have resolution, and in the high-burden patients, 50% have resolution. But our placebo adjusted responses show very nicely that- Hmm ... this is the data where you separate placebo in high-burden enthesitis from active drug. We have not seen other people present that data in that way, and we still think there's still an opportunity by improving training in assessing enthesitis in the next phase III studies to showcase this differentiation. Understood. So bottom line, psoriatic arthritis, you have kind of passed that initial threshold. You're gonna be moving forward. Understood. HS, same question. What are you going to see?... That's gonna make you excited enough to push this forward and getting it onto the market? Yeah, and maybe let me step back and put the PsA data into context as well, right? Like I said at the beginning, we are gonna look at this HS data readout and make some decisions around portfolio prioritization and sort of go forward capital allocation, and we are gonna be disciplined about that. Hmm. When we look at iso, we don't look at it, you know, so much indication by indication. This is a classic kind of pipeline in a program type of profile, where we, again, think it's approvable in multiple indications, and it deserves a place in the market, and it's how do you get there, right? Balancing the capital requirements that are required for a program of this size. And so, you know, I think about PsA and HS. We're also reading out uveitis data by the end of the year, and as we think about a potential franchise around iso, what is the best avenue, right, to bring that asset to market in a capital efficient and disciplined way? And so I think the context in looking at them together programmatically is pretty important. And this data, this HS data readout is gonna be key for that future investment. So even- Hmm ... with respect to PsA, we have not made a decision, you know, about the future of that program, and we're not gonna do that in isolation. Understood. So it's gonna be really, do I see enough of proof of concept in both of these indications? Okay. Now, I know these are always gonna be a little more difficult, but I think it's extremely important for your company in particular. You have a lot of cash. Yeah. You know, you think about ROI. Talk to me about in a scenario where I see a signal in HS, and I see a signal in psoriatic arthritis, we are moving forward in terms of getting that on the market, running studies. What is the cost associated with that decision? Yeah, you wanna take that one? Yeah, that's a... Thanks for the question. I think that's something that we're thinking very, very carefully about. As Mina said, we're committed to being very disciplined around the target product profile, and what does it take for the next step to get approval in each of these indications, and from a commercial perspective, what needs to be done to lay the framework for a successful launch? So we're fortunate to have lonigutamab that we're gonna put into late-stage development. We're gonna get more information from the HS study- Right. And that's gonna help us sort of make the capital allocation decisions, and we're gonna stay very disciplined about that, very conscious of our cost of capital as we make that decision, as we go into the third quarter. Understood. Okay, so maybe a little too early to give that definitive data point. I think that's very fair. Mina, if you were to say an investor, they meet you for the first time, and you say, they ask you, "Where should we be spending most of my time on? Should I spend my time understanding izokibep? Should I be spending my time to understand the TED asset?" What would you say to them right now? Where's the best use of an investor's time to figure out the Acelyrin story? Yeah, look, I think, again, two very different profiles. We obviously have put out a lot more information, right, on izokibep, so I think that's all out there, and again, we think that there is value in that program, right? It deserves a place in the market. It's a question of: How do we get there? I think lonigutamab is a place to, spend time, right? We obviously have, put out less data, but again, more to come. But we think that that is, a very promising program. It's the right size for us, smaller trials, more capital efficient, and it's an indication that this team knows super well. So I think that is an area that we are excited about, and, you know, looking forward to talking to folks about that more, in the future. Understood. Okay, so let's say that you have HS data. It's good. It's not great. It doesn't meet your threshold, and then I think you say, looking at izokibep as a program, "You know what? There are better places for us to spend our money." Great. What would that look like for Acelyrin, right? Would that look like partnering with that asset out with other companies, trying to monetize that? Would it look like, you know, maybe, quote, unquote, "starting all over again," or would it look like external M&A? How, in a scenario where izokibep does not move forward, does not meet your ROI thresholds, what are the options available both to you and the board? So I think all the things, right? What I would say is we're open-minded. Like I said, we're gonna be disciplined and look at everything. I don't think there are any foregone conclusions. We will do what we think is best for the programs, for patients, for investors, right, to drive value. Okay. Gil, anything to add on that? No, I think that's well said. So we just wanna find the most efficient path forward, and we're open to every different option, and both Mina and I, and Shep have done a number of different paths to get there. So I think we'll have to see the data and let that drive our decision-making. Yeah, and we are in a really privileged place, right? Because we did- Hmm ... this company is so well-funded and has programs that work. It provides a lot of optionality, right, and time to figure out the right path for all of these assets, and so, I think we are in a really privileged position in that way, and so we'll, you know, look at the data, stare at it, and make, you know, disciplined decisions on the back of that. Understood. Maybe a quick question. You saw, I think lebrikizumab, Lilly started a trial, I think, I think it was systemic sclerosis. It was one of these new indications. It's not hitting me right now. Talk to me... That's where this kind of gets interesting, right? What are some targets with IL-17 that maybe the big guys haven't gone after? What is the next, quote, unquote, "HS" that is a, is a big market we're not seeing? Any ideas about where izokibep could maybe head, what people aren't really talking to you about right now? Well, well, just to throw out, I know we've been talking about HS and PsA. We are reading out a trial in uveitis, and that's an indication that we really like. High unmet need, right? Way less competitive, you know, in some ways, and so that's a nice profile, and we also- Hmm ... have the axSpA, which has been part of, the development timeline. And so that's also one that we don't talk about. So those would be obviously the next two, and then I'm gonna defer to Shep on- Mm-hmm ... some of the more creative thinking. Yeah, I mean, there are quite a number of life cycle management indications. One could go on in IL-17, having worked on secukinumab before, giant cell arteritis, polymyalgia rheumatica, and with the potency we have to penetrate tissue, diseases like lupus nephritis, rotator cuff tendonitis, and even chronic spontaneous urticaria. There is good evidence that IL-17 has a role in there. Interesting. Maybe lastly, we got a minute left. Everyone says there's a lot of mast cell-mediated diseases. Everyone basically stops at urticaria, and that's pretty much it. You have a KIT. I don't know how maybe differentiated it is versus the Celldex or Jasper compound. I think that's TBD, but I was always, you know, curious what Shao-Lee would've taken that indication to. I'll hand the same question to you, Shep. Yeah. Do you see an indication with your KIT inhibitor that you can take this in where maybe other people have not explored, and you would be first in class? That's a very good question. I think at the end of the day, what's important is to focus on an indication where there's great evidence in terms of probability of success, given the well-recognized PD markers in that disease. So that's what we'll be focusing on, and then to your point, then expanding very quickly to any other indications where we see the biology making an impact. Understood. We are out of time. What a great conversation. Thank you so much for this, and really excited to keep the dialogue going. Yeah. Thanks so much.