Okay, let's go ahead and get started. Thanks everyone for joining. This is the Fireside Chat with Acelyrin. We have the full team from Acelyrin here. Mina, Shep, and Gil, thank you so much for joining us. Appreciate it. Thanks for having us. My name is Vikram Purohit. I'm one of the biotech analysts with the Morgan Stanley research team. I need to read a brief disclosure statement before we get started. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, let's dive right into it. Quite a lot to talk about, Mina, but maybe the best place to start is just by, for those who haven't followed Acelyrin- Yes closely recently, just recapping, some of the recent announcements you made around, taking another look at the pipeline Mm-hmm - and izokibep and lonigutamab, and then we can go into specifics from there. Yeah. You know, maybe I'll start actually earlier this year. Sure. Right? And so, you know, earlier this year, we read out a successful trial in PSA, right? And on the heels of that, we read out very positive POC data in lonigutamab, which is our program in TED. You know, I took this role in May, and at that time we said, "Look, you know, we've got data coming in HS. We've got a phase three trial." You know, we had previously guided to end of year, and we were able to move that into the third quarter. And we said we would take a look at that data, and then we were gonna make some decisions around portfolio prioritization and corporate strategy going forward. And that's what we did in August. So we did... You know, there were some very significant announcements that we made in August. We were very happy with the results and the outcome of that HS trial, which was positive. You know, notwithstanding that, we did say, "Look, while it's positive, and we really continue to believe that izokibep is approvable in HS and in PSA, you know, we're gonna make some choices." You know, those are very large indications, capital-intensive, and they may be better served, and patients may be better served, you know, in those programs by a larger organization with infrastructure and existing resources to move those programs forward. We also really are continuing to be excited by lonigutamab in TED, and that we are going to prioritize that program. In combination with that program prioritization decision, we also then restructured the company in line with those decisions. Pretty significant, but the combination of all of those decisions did allow us to extend our cash runway into mid-2027, right? That allows us to fully fund both phase 3 trials for TED, right? It gives us confidence in our ability to deliver there. Got it. Got it. Based on your commentary then, it's fair to say that the decision to deprioritize izokibep in HS and PSA was not related to your view of the competitiveness of the datasets there? It was more related to your desire to scale the company differently and just find a home for izokibep where it's just better fit within maybe a bigger infrastructure. I think that's right. I mean, you know, I think the reality is, you know, you've got to make some decisions, right? And prioritization, we think, is really important, right, in terms of disciplined execution also, right? For those indications, again, they are larger, and you know, capital-intensive and maybe, you know, TED is right size for us. Also, you know, the data drives that we are very excited by the, the lonigutamab data. Got it. You did decide to keep uveitis in your pipeline. What drove that decision? I would say we haven't made that decision yet. Uveitis— At least for the time being, rather. For the time being. Yeah. Look, you know, that trial was fully enrolled earlier this year, right? Mm-hmm. Fully funded, and we have guided to having data there by the end of the year, so it's coming soon. We'll do the same thing with uveitis that we did with HS and PSA, which is we'll turn over the data card, right, and we'll make a call. Understood. Can you help us understand your view of the uveitis commercial opportunity? What do you think the addressable patient population, excuse me, looks like? If uveitis is successful for izokibep and the drug launches, who would izokibep be competing with? What else is out there? Yeah. Maybe I'll start, and then I'll turn it over to Gil. Sure ... on some of the, the markets. I think, just to frame it up, I would say, you know, uveitis as an opportunity is very different as a standalone versus when we were, you know, really thinking about it in combination with PSA and HS. Even if you just think about pricing, right, around PSA, for example, and what does that imply in, you know, a smaller market like uveitis? Versus is there a potential on a standalone basis for orphan pricing, right? I think there is a sort of shift- Mm-hmm ... right, in the way that we're evaluating that opportunity, because it's been decoupled, right, from those other indications. Yeah. No, that's right. I think that when we look at the uveitis market, Vikram, it's a very high unmet need market. Right now, there's only steroids available, and then adalimumab or Humira is the only biologic approved within uveitis. When we look at the entire population, so we're studying in non-infected, non-anterior uveitis in our study, that's a fairly significant population. It's about 70,000 in the United States, and you can do different sorts of math on treatment and severity, but when you get to the end of it, you have a very significant number of patients, either as second line to Humira or potentially first line when we see the data. As Mina said, with the orphan pricing framework, it could be a very significant commercial opportunity as well. We're looking forward to seeing the data. Got it. And for the data readout, is there anything beyond stat sig on the primary endpoint that you think the data needs to show to look competitive from a real-world setting? Or is stat sig on the primary endpoint, is that sufficient? Is that clinically meaningful itself? Look, I think, you know, like we said, with HS and PSA, we're going to look at everything, right? Sort of the totality, the data. I mean, it is a different setting here because, you know, Humira is the only approved biologic, and we do know that many patients will eventually fail, right? And so, you know, we're gonna look at, at all of that. Got it. Our trial is designed to be very similar, right, to the Humira trial. Got it. Got it. Okay, great. Jumping back to the HS and PSA decision really quickly. You mentioned that it could be a better fit for a larger company. Mm-hmm. Is a BD effort with a target of out licensing, is it kind of for those indications, is that an active effort at Acelyrin right now? Yeah, you know, as Meena said, we really did-- we, we've read out the top-line data with positive in both indications, so there's one, one more trial to go. Mm-hmm. For approval in both indications. We're in the process now. We got the data a couple of weeks ago from HS and kind of looking at all the options for the program. That's the effort that's underway. We're gonna have the uveitis data before the end of the year. That'll help inform the total program approach as well. I would just mention, as Mina said earlier in our cash guidance and our new operational plan to extend cash to 2027, we didn't include any assumptions around partnering proceeds or anything of the like. That would all be upside to- All would be upside. Runway guidance. Exactly. Got it. Okay. Maybe then we should shift over to lonigutamab. Sure. Question one: How has the molecule been designed to be differentiated where the-- versus other kind of IGF-1R agents in the space? Shep, you want to take that? Yeah, I know. We, we're pretty excited. Number one, this is a validated pathway where Tepezza has already shown some promise for patients in a remarkable way. I think there are three key considerations in terms of attributes for differentiation on this molecule for lonigutamab. Number one is potency, and number two is the efficiency in internalization when Loni binds the receptor and internalizes the receptor and any IGF-1 sitting on the surface. And then the second is the unique binding site epitope. I will mention the three and how they proffer opportunities for differentiation in terms of therapeutic impact and benefit risk profile. Starting with potency, it's well characterized that we are seventy-five times more potent than Tepezza and around twenty times more potent than Viridian. In the proof of concept data that we presented, where we had a 40 milligram at week zero, at the time of first evaluation at week three, we already saw robust clinical activity on proptosis, CAS, and patients also improved in diplopia. That speaks to really a low exposure based on the comparison I just mentioned in terms of that potency. If you take a similar, you know, sort of patient on Tepezza, that's 20 mg per kg, and then Viridian, 10 mg per kg. Eighty kilogram patient versus us will receive 1,600 milligrams on Tepezza and 800 milligrams on Viridian. We are very excited that we have a molecule which, at low exposure, we might be able to skirt any overexposure that's associated with safety liabilities. The additional thing of low exposure is that it's low volume. As we look into the future for phase three and when we get to the end of phase three in terms of launch, we hope to have an auto-injector, less than a millimeter home use, and that will be very critical for patients because currently there are no subcutaneous therapies in thyroid eye disease. Moving to the internalization, that's critical in terms of what we are seeing as we have also presented data from our cohort two, that we have a rapid kinetics in resolving the manifestations of the disease. These rapid kinetics could then profile an opportunity for deeper responses at earlier time points that could be durable, and that would really serve patients well in terms of outcomes. The last differentiation is both Viridian and Tepezza are competitive binders on the receptor. When they bind the receptor, we have seen that IGF-1 increases in the systemic circulation to factors between 200-600%. We bind on the periphery of the receptor, so it means if IGF-1 is sitting, we internalize that and degrade. Therefore, when you look at the percentage increase in IGF-1 in the circulation, we are around 50-100%. That has implications around glucose handling, and that could be the reason why you see hyperglycemia with other therapies. We believe we might be fortunate not to have that happening in patients. The last thing around exposure is all the other adverse events that are on label, like significant fatigue, diarrhea, alopecia, menorrhagia, dysarthria, where you recognize the receptor is really present in so many other systems within the body, the gastrointestinal system, and other aspects of maintaining homeostasis. When you overexpose, you end up having patients having more adverse events. We believe our profile might enable us to be successful in having a favorable benefit-risk profile. The last thing I'll say is, our approach is really to serve the unmet need, which is currently there's six dosing in a disease that could be lifelong. It's a chronic autoimmune disease, and there's very clear evidence some patients don't have complete resolution beyond proptosis of CAS and diplopia at the fixed dosing regimen. There is a need for a therapy that's at a minimal optimal exposure, where you can arrive at disease modification with long-term treatment. That's one of the things that we'll be considering, given the characteristic we have of low exposure, low volume, and potential convenience. Understood. That's helpful. I guess with that backdrop in mind, could you kind of walk us through some of the highlights of the data you've presented so far, and how what you're seeing from the clinical data kind of maps to some of the points of the hypothesis for how you believe the agent could be differentiated? Are you seeing that being borne out through the data you're seeing? Yeah. So far, we have presented two datasets. The proof of concept, as I mentioned, we only dosed with 40 milligrams at week zero and week three. We demonstrated rapid improvement in proptosis, and we also showed that, you know, when you look at a CAS below two, 100% of patients maintain that by week six. Off treatment from week six to week twelve, that proptosis response, CAS response, was maintained. There was only one patient out of four who responded in terms of diplopia and maintained that. In the second study, where we dosed with 50 milligrams and 25 milligrams weekly, which is slightly a higher exposure, we saw also a rapid improvement in proptosis improvement, around 67%. That was maintained all the way to, you know, week six. That's the data we have presented to date. We saw a remarkable improvement in CAS and diplopia, around 50%, which is commensurate with the consistency we saw in the first cohort. That is the dataset we have in the public domain. That dataset gives us great excitement in terms of the clinical activity we are seeing that is robust at early time points. Therefore, when we continue to calibrate in our dose range, we hopefully will land at a dose. In the current competitors, there is no dose range that was done with a subQ in thyroid eye disease. We are the first to be doing that, and therefore, we will focus on a minimum effective dose and then calibrate to an optimum steady state without overexposing drug. The steady state will determine how much drug stays in the body, in the system, engaging target, improving or sustaining efficacy. Understood. And then one, one, kind of safety consideration you've spoken about, where you feel like lonigutamab could differentiate, which I know has been a focus for investors, is the hearing benefit... and hearing loss, rather. Kind of educate us first on how big of an issue this currently poses on Tepezza from your perspective and your understanding of the market. For that signal, kind of what are you seeing so far that gives you confidence that that could be a differentiator? Yeah. We are also very fortunate that to date, we have not seen any hearing impairment or sensorineural hearing loss in any of the patients we have studied in the respective cohorts. We measure audiograms at baseline, and we have serial audiograms over the duration of the protocol, and none of those audiograms have shown any change that would be worrisome. We are very excited about that observation. We reported three cases of transient resolving tinnitus, which is a subjective complaint rather than objective change when you look at sensorineural hearing loss on an audiogram. We also believe, as I mentioned, the exposures we are playing at are much lower. There is a hypothesis that when you have a high exposure in a patient who might be predisposed to have maybe IGF-1 receptor deficiency, it's possible that you can then abrogate the blood-brain barrier and then have impact on how cochlear, you know, cells function, and that might result in sensorineural hearing loss. At least what we have seen in patients that have had audiograms in prospective studies in real world with Tepezza is that 10% of patients with normal hearing have succumbed to sensorineural hearing loss. Obviously, if there's mild or moderate, that percentage is higher. We hope in our phase 3 to do audiograms at baseline and measure audiograms sequentially over time, and that dataset will feed knowledge around whether our hypothesis of low exposure will help have lower rates. If anything, we'll then have to depend on that dataset for our understanding of that hypothesis. Got it. Got it. Okay, great. Going to your ongoing study then, you did mention recently that you added a new dose cohort? We did. Could you kind of walk us through the rationale for adding that, that new dose level and, kind of what you believe that could do to the overall development timeline and program? Yeah. Yeah, and so maybe, again, just to go back to what we had discussed previously, right? The original study design had three dosing cohorts, right? And was intended to be sort of a phase one/two, and we had previously guided to a phase 2b start this year. In lieu of that, what we've done is we have added a dosing cohort at 70 mg, right? And what that allows us to do is to complete the dose ranging work in patients inside the phase II trial, right? And so what we said in August is, you know, we will then take sort of the totality of the data that we have, go talk to the FDA as part of an end of phase II meeting later this year, right? That would allow us to finalize the phase III trial design, and we have guided that we intend to start that first phase III trial in the first quarter, right? And that we would report out both on the interaction and the phase III trial design, plus additional data from that phase II, either later this year or early next year. I mean, the big difference is by not doing that IIb, right, which would have been sequential, so you'd run the IIb, and then you run an additional phase III. It does allow us to run two concurrent phase III trials, right? And that is enabled by doing all of this dose-ranging work in patients, right inside the phase II. I think it's important to look at through the totality, right, of the work that we're doing. We're trying different doses and different regimens, right? You know, weekly to Q4, right, and, you know, dosing from 40 to kind of 70, but we're really looking for that optimal exposure that Shep was talking about. For example, if you take the cohort of patients that was dosed with a 50 mg loading and then 25 weekly, it's actually relatively high exposure, right, because of the regimen. We're going to have the totality of that phase II data, really, to inform dose. Got it. Got it. I guess with that data in hand, when you speak with the FDA later this year, what are the key, what are the key questions you have for them, or what are the key discussion topics you think are gonna kinda come up during that meeting? Yeah, I mean, I think we do want to talk to them about sort of dose and phase III trial design. I mean, I think the size of the trial is an important thing to get aligned with the agency around, right? You know, we don't expect them to say, you know, "This is great," or approve, you know, everything. I think getting alignment largely around sort of the size of the trial and around that safety database in particular. Yeah. Having that understanding is going to be important. Got it. Got it. Okay, just shifting the focus back on Loni to commercial considerations. Good amount of competitive development going on in TED, right, from other IGF-1R agents. There's new mechanisms, at least new mechanisms for this space coming, coming to the forefront. Argenx, for example, evaluating their FcRn agent for TED. Where do you think the market, call it five to ten years from now, settles out? Tough question, I know a lot of, lot of data still pending, but, where do you think the market could go if there's multiple branded com-- you know- Yeah ... players out there, and where do you think lonigutamab could fit in that, in that environment? Yeah. You know, good, good question. I think that it is kind of peering into the future, which is always, always a little dangerous. I think with the way we see the, the market developing is, the IGF-1Rs, you know, saying that mechanism is central to thyroid eye disease, we see that staying in the, in the first line for thyroid eye disease. It has the most proptosis impact, CAS impact. In the acute setting, it's been, it, it's delivered a lot of benefits to patients. I think within that market, the move to subQ is gonna be important, and the substantial majority of the scripts, we believe in the future, will be written, i- for subQ. I think that has two impacts, both the transition from IV to subQ, as well as opening the aperture on the patient population that can be addressed with an IGF-1R. Right now, it's primarily prescribed by oculoplastic surgeons in an acute setting. There's definitely room to have an intervention earlier in the patient's journey, before they become a severe TED patient. It's kind of the IGF-1R landscape, and then you mentioned some of the other mechanisms in the space, and I think most of those, or all of them, are more broad-based immune suppressant mechanisms. They seem to have less of a direct impact on the, on the symptoms and, and, you know, sequelae of thyroid eye disease, but, you know, could be important, could be another option for patients more likely to live in the second line. Having said that, we'll see how all the data, you know, shakes out, but that's our current view of the market. We think it's a, it's a big market opportunity. We would, as Shep and Mina described, with lonigutamab, we're seeing very fast onset of action, which we think is, is, is very important, and then delivering it, and, you know, in a, in an auto-injector subQ format, potentially having a therapeutic window that's differentiating around safety and the ability to chronically dose. Got it. Got it. I guess from a freedom-to-operate perspective, given there's a couple of IGF-1 agents in development, one obviously commercialized, do you see any issues there for lonigutamab? And I guess talk a little bit about, at a high level, kind of what sort of IP you have on lonigutamab. Yeah. Yeah. Obviously, we have the composition of matter patents around lonigutamab. As Shep has described it, I think very well, there's some very unique properties of how lonigutamab operates, which bodes well for the underlying IP. We're gonna have significant coverage beyond, you know, approval, and we kind of have a picket fence strategy, as you would expect, with the composition of matter and then other follow-up methods of treatment, methods of manufacture patents. That estate is still building, and that will allow us to build upon biologic exclusivity after we get to market for, you know, I think we'll be a long commer-- long patent life, while we're in the commercial stage. Got it. Got it. Okay, great. Moving quickly also to five one seven, SLRN-517. You mentioned that that asset is also going to be deprioritized. Correct. I guess, what led to that decision? Was it more of a business decision or more of a data-driven decision? Yeah. Look, I think it's just a prioritization exercise around what are we gonna move forward internally. We did publish some of that data. It's in our corporate deck. We did a healthy volunteer study, and the molecule is definitely active, right? You know, I would characterize that very much as a prioritization decision. Got it. Got it. I mean, you did telegraph the openness to more BD or looking at- Yep -other assets going forward. For sure. What would be interesting, and what would be a good time point for the company to start thinking about assets beyond lonigutamab? Yeah. Maybe just a step back. I mean, we do think BD is sort of in the DNA of the company, right? Mm-hmm. It's how we built the portfolio. You know, we all have significant experience there, and so it's something that we're gonna be opportunistic and kinda look at, right? The nice thing about the runway that we have is there is no rush to do anything, right? You know, we think it's really important to focus on setting up our TED program for success, right? That focus is super important, and it's, it's, it's fully funded, right? Which we feel really good about. You know, I think Gil did say that we have left a little bit of room- Mm-hmm -in that cash runway guidance for, for BD. Gil, I don't know if there's anything else. Yeah. No, I think that's, I think that's well said. I think the bar is high, but we continue to process opportunities opportunistically, so that'll be an effort that we continue here. We're very focused on the current, operational plan for the company and maintaining that longer runway that we just set out. Got it. Got it. I know this is a question that is a little bit into the future for the company, but assuming lonigutamab succeeds in its pivotal program, assuming you're ready to go to the market, would you want to prosecute that independently? Do you think that you could right-size the organization to do that, or would you then start looking for maybe a larger partner to help with that commercialization piece? Yeah, I mean, we do like TED because we think we could do it, right? And, you know, again, we've got the trials are funded, right? And so it does give us a lot of flexibility around how we move that program forward. But, you know, just like we said with HS and PSA, we'll do whatever makes sense and is right for the program, and that, you know, we think fundamentally drives value for patients and, you know, and for shareholders. We'll look at that and, you know, it'll... In the same way, it'll be kind of on the back of data and sort of information, and we'll be disciplined in how we make those decisions, for sure. Got it. Got it. Pivoting, I guess, back to the data then that we're gonna be seeing— Mm-hmm I think you said later this year/early next year. Yep. Yeah. Your guidance for investors and analysts on how to best interpret that and how to best, try to gauge how the data is comparing and contrasting to other data sets in the space. You know, it is the only sort of-- it's the only data out there that's in-patient subQ data. Yep. Right? And we think that's important. If you look at the totality of the data set, right, you know, across the four cohorts, it's approximately 30 patients, right? Which is small N, right? So you don't wanna over-rotate on that, but it's meaningful in the context of a TED setting, right? TED trials are not large, and so we think that's meaningful data. We are using it for dose confirmation, right? Mm-hmm. For some of the signals around, you know, early efficacy and, you know, durability, all of those things that Shep was talking about. You know, we think that's a nice, robust data set that we hope provides, you know, comfort, right? In de-risking around the phase III program. Got it. Got it. And do you have aspirations for lonigutamab ex US as well? I mean, we certainly have the right, right? Yeah. I mean, same thing. We're gonna look at all of that going forward and what makes sense. Got it. For sure. Got it. Okay. I guess what would you... I know this is a tough question, but what would you kind of consider, kind of the best-case outcome for the next data update, from a safety perspective, efficacy perspective? Touching on all the considerations, Shep, that you mentioned on hearing benefit, and proptosis response, what do you, what do you think is the ideal outcome here? From the- From the phase II, the next- Yeah ... the next phase II update. Yeah. I think the ideal outcome is to constantly show that rapidity of onset. We are starting now to look at responses at week two. The earliest we did look at before was week three. How do we see the other manifestations also responding according to the different dose levels and dose regimens? I think that, to your point, the overall safety, and then being able to, in that small data set, make sure that there's nothing that we are seeing, given that there are different exposures, there's nothing that's dependent on a certain exposure across where we are playing, which is very low. Understood. Gil, you mentioned that there's the possibility, data-dependent, of course, for lonigutamab to be a first-line, first-line, product option. Do you think that it could be challenging to design a phase 3 study to direct yourself towards that label? I mean, could you design a phase 3 trial where you're only looking at treatment-naive patients? Or do you think just because of the unmet need, you'd have to allow patients to be treatment experienced to come in, and therefore, that could impact your label? Any thoughts around that? Yeah. I think that, we think we're gonna build, design a trial that definitely would get us into the first line. I think that's the, you know, that's the important thing. And then what we're thinking through is, you know, exactly how to incorporate and address both populations. You have both the acute and the less active population. We want to have a strategy to include both of those populations within our registrational trial design. That'll be important to delivering the patient benefit, as we were talking about earlier, beyond the acute setting. Yeah as well, and looking at the benefit for lonigutamab there. So, those will be the considerations. Like Mina was saying, the size and the safety, but also the population design. Got it. Got it. I mean, from the research that you've done in the field, do you feel like, if the efficacy outcomes were maybe slightly lower than what Tepezza has shown, just the fact that it's subQ, that could still be differentiated? Or do you think you need to kind of be equivalent on efficacy and then provide that- Yeah ... that administration benefit to be competitive? Yeah. I mean, I think that there's the, there's the, it's, it's multidimensional, but what we see, as Shep has said with the early data, is we do see very fast onset of action, so we don't, we don't appear to be giving up any efficacy at all on proptosis in CAS responders. I- we're gonna be able to get that same type of efficacy with a lower exposure, which we think could be important and translate into safety benefits and the potential to be able to administer the drug for a longer period of time beyond the fixed-dose regimens, which is the current paradigm for the IGF-1Rs. You know, we think there's opportunity there. Okay. Okay, understood. We don't have that much time left, so maybe I'll ask you one final question to close out. Just kind of recap for us, at this investor event later this year, early next year, in addition to the phase II data update, what else can people expect to learn about the program? We expect to provide more details around the phase 3 program design. Mm-hmm ... right? And an update from the FDA interaction. Got it. Got it. Final catch-all question then: Any other milestones or, even if they're not publicly facing, like public-facing catalysts, any kind of internal development that you would point people to that the company's gonna be thinking through in the next, in the next year that are kind of important to consider when people look at Acelyrin? You know, maybe to go back to the beginning of the discussion, right? I mean, the next data readout is actually not in lonigutamab. It is gonna be- Mm-hmm ... in uveitis, right? I think that will be important, that will be an important milestone for us, right? I think that's sort of the near term for sure. Got it. The typical last question I ask is on cash, but we've talked about cash balance, cash runway. You've said cash runway until? Into mid 2027. Mid '27. Mm-hmm. And that would get you through the pivotal program? Yeah- With lonigutamab ... both phase III trials. Yep. Got it. Okay. Yep. Great. I think with that, we can go ahead and close out. Thank you all for joining. Really appreciate it. Yeah, thank you so much for having us. Thanks, everyone, for coming in. Great. Thanks for having us. Thank you. Thank you. Appreciate it.