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Good morning, everyone, for today's our first session, we have Spiro Therapeutics. And on the stage with me is Esther Rajavili, the CEO of Spiro. Thanks for coming, Esther. Thank you for having us. Absolutely. We have about 15 minutes or so, let's just jump right into it. you can start with like an introduction, you know, overview of Spiro today. You know, you've made some changes, right? Repositioned the company around SP-001, the immunology story. Just walk us through what happened and how did you go about this and what are your next 12 months going to look like? Sure, thank you. Before I answer that question, I'll just refer you to our forward-looking statements, which you can find in our corporate deck. But really, I mean, Spiro today, you know... We are a development stage company and we've always been a development stage company. Our lead asset, as you say, is SP001, which is an anti-CD40 ligand-targeting antibody. It's a third-gen antibody, and we can get into why that's relevant. And we're planning a Phase II trial in immunoglobulin G4-related disease, planning to initiate that trial in the second quarter of 2027. And so, you know, having approved, gotten the first, our first drug approved and now licensed to GSK for commercialization, and also, you know, we've also fundraised about $105 million in a non-dilutive, non-recourse, partial monetization of those commercial milestones, we feel we're in a very good position to bring this new asset in and continue developing. Perfect. Perfect. So why lead with IgG4RD, right? Because you have Sjogren's data. How did you pick IgG 4RD? Sjogen's is a bigger market size than IgG 5RD. So walk us through that rationale. Sure. So we find IgG5RD to be a very compelling development opportunity. It is an indication that's fairly early in its lifecycle. And we think that the unmet need and the potential for a differentiated mechanism would be highly relevant to this treatment paradigm. And because, as you know, this indication, the first drug was approved just last year, and there are the other agents, a couple of other agents that are in development, all focus on B-cells, and we're moving upstream of that, targeting the CD40 ligand, and we think that potentially has the ability to cover aspects of the disease that are not appropriately being addressed by B-cell targeting agents. Sjogren's is also highly attractive to us. Obviously, there is no approved therapy, especially in the West, for that indication. Our partner, InnoVent, is guided to initiating a Phase II trial in Sjögren's by early 27. So the evidence for 001 and Sjøgren's will continue to evolve as we make progress in IgG4RD. Perfect. You mentioned Innovent. So, you know, you got the asset from InnoVent. What did your diligence focus on? What was convincing before you, like, you know, got on board? Sure. So being a clinical stage company, you know, we are sort of search parameters were focused on validated targets or targets that at least have partial validation in the clinic. And we were looking for molecules that had the potential to differentiate relative to other agents that are in development. And then the third aspect was really looking at being able to differentiate with that target in evolving markets across different therapeutic areas. And we were able to hit all of those with the CD40 ligand antibody that we had licensed. As is typical in any BD process, we checked all the boxes. So we looked at non-clinical and clinical data, IP, the regulatory interactions that InnoVent had had, CMC quality. So very typical of a process like this. Okay, perfect. The first-gen CD40 antibodies had problems with thrombosis, mainly driven by FC binding to FC gamma R2A on platelets. How is your silencing going to address that, and how confident are you? What evidence did you see that that would be addressed? Yeah, so the history of the target was something that we spent a lot of time thinking about. The first-gen molecules, the first- gen antibodies had an active FC region, which led to the thrombotic events that we saw in the first trials that were ran, I believe, in lupus. So, SP001 has a fully silent FC region, and the molecule, the antibody has been tested in two healthy volunteer trials in phase one, as well as a phase 1B Sjogren's trial, and in approximately 100-plus human subjects that have been tested, we haven't seen any evidence of thrombotic events. Obviously, safety is something that we will continue to monitor very closely and will will be a focus for our trials going forward. OK, perfect. And then CD40L is upstream of both T and B cells, right? And the goal is to address fibrosis and not just flares. So what evidence supports that? How are you going to measure that in the clinic? Yeah, so the phase two that we're planning to run in IgG4RD will generate the evidence based on some of the data points that we are planning to collect in that trial. So really the onus is on us to provide the evidence on the role of T cells in IgG4RD. There are some publications that discuss it, but for this particular antibody, our phase two would be very relevant. So there is evidence that T cells play a role in the pathophysiology of IgG 4RD, and CD40 ligand sits upstream, and it's an upstream mediator of both the innate and the adaptive immune responses. And we think both aspects of those immune responses play a role in the steady state of 4-IgG, 4-Rd patients. So our objective is to gather data points in the phase two trial that would really help us characterize the benefits of targeting CD40 ligand for this population. And that could include impact on fibrosis. Wonderful. Okay, so let's talk a little bit about the actual data itself. So maybe start with the mouse model. So your one make per kick suppress anti-KLH response more than for Xylomab, right? How's that preclinical potency gonna translate to human dosing? What studies have you done to like check for translation? And then maybe you can put the phase one B data into context as well, like is the cross trial comparison like relevant, small end sizes, that sort of thing on SDI and the placebo adjusted changes, et cetera? Yeah, so I wouldn't really look for translation directly from the mouse model dosing into human clinical trials. What that, the in vivo mouse model data really demonstrates the antibodies biological activity and we'd have to, you know, and we have to rely on sort of the full database of human trials and the data that an event has generated to really think through dosing for IgG4RD. With regards to the phase 1B Sjogren's trial that was done, and I think you're referring to one of the slides in our deck that does a cross-trial comparison, I would view that data set as contextualizing versus really sort of making a head-to-head comparison with those trials. Obviously, these were different trials run in different patient demographics across different geographies. But what really excited us was, even though the Phase 1B was a very small trial with three doses across three cohorts with eight active and two placebo patients, so a very smaller data set, and even within a small treatment duration of four months versus six months with the other agents, we saw evidence of activity across all the doses. And that supports continued investment in that antibody. Yeah, so not much weight on the cross-trial comparison, but what does that tell us about dose response, how are we picking doses, et cetera? Yeah, the data set that we have includes two phase one healthy volunteer trials where both PKPD were assessed and then the phase 1B Sjogren's. So we would have to look at the entire totality of the data, look at PK, PD, as well as the safety and tolerability data across all those trials to really determine a dose to move forward. And the phase two trial that we are planning to initiate will have two doses for IgG4RD, and those data will also continue to inform us about the appropriate dose in a registrational trial. Okay, perfect. And put the safety data in context, right, especially the upper respiratory infections. Is this something you're watching for, and what should the FDA say before you start, like, dosing in the IgG4RD? Sure. So as with any immunomodulatory agent, monitoring for risk of infections and tolerability and safety is going to be fundamental in our phase two trial will include the appropriate metrics to continue to inform us on the tolerability and the safety profile of the drug. We, I think your second part of the question was what would the FDA need to see? Correct. You know, we believe the data package that we have from InnoVent positions us well to initiate those conversations with the FDA, and the Phase II trial design that we're contemplating is reflective of the other two Phase II trials that were conducted in this indication. Perfect. In the last five minutes or so, let's talk a little bit about differentiation and competition with what's out there, and then wrap it up with the catalysts and cash runway. So we have a Plisna, you have Obilexamab, and Rilzabrutinib all potentially could enter. So where do you fit in the treatment paradigm? Is it going to be after the B-cell therapy fails or more in terms of long-term maintenance? Frame that for us. Yeah, so it's a little early for us to really, you know, hone in on where in the treatment paradigm this asset would fit. What we're trying to do is really contribute to the understanding of this disease. As I said before, it's very early in its life cycle, and there's still a lot of, you know, a lot information gathering that is happening. So our objective is to really differentiate with a new mechanism that focuses on the T cells, B cells, and the antigen-presenting cells, all of which play a role in the pathophysiology of IgG4RD. Some of the other agents you mentioned focus primarily on B-cell targeting, and that, you know, from the data that has been generated to date, support, you know, really kind of compelling, provide compelling evidence on flare control, but we do think that IgG4RD has other, you other features, especially continuing tissue damage and fibrosis and prevention or preservation of organ damage. All of those things are important aspects of managing a patient that we think a differentiated mechanism could potentially address better than just controlling flares. Got it. But on flares specifically, are you trying to beat, for example, the 56% reduction that Obaliximab showed and about, I think, 87 or so that Oplezna showed? Is that the goal? So the B-cell targeting agents have done a fantastic job with managing flares, either controlling them. And our objective with the CD40 ligand as a target is to address broader aspects of the disease that are not appropriately addressed with just controlling flares. And some of the data that we're going to gather in our phase two trial should provide evidence to support that. Okay, perfect. And then in terms of the IV and the self-injection, subcutaneous, oral, how much of a hurdle do you think it is that you don't necessarily have subcutaneus because it's an IV drug, correct? Yeah, the drug is currently formulated to be a once-monthly IV dosing. You know, IgG4RD is a serious chronic condition, and paramount is safety and tolerability and the efficacy signals. So we are planning to initiate our phase two with the IV dosing to establish proof of concept. And while there are advantages with coverage, you know, with an IV therapy, We do think patient convenience is important and could potentially explore other delivery modalities as well. Okay, awesome. In the last two minutes or so, maybe just walk us through your next catalyst that we should watch out for and what the cash position is and the runway would support. Sure. So when we announced the in-licensing in July, concurrent with that, we also announced $105 million non-dilutive, non-recourse financing through a partial monetization of the royalties from our commercial partner, GSK, for the first drug that was approved, Dutepsi. That positions us to deliver data on the phase two for IgG4RD. Our runway is into the second half of 29, so we do have a comfortable cushion for that readout. And our next catalyst is really the launch of this phase two trial, which we've guided to in the second quarter of 27. Okay, awesome. I think we have time for that much, so I'll leave it at that. Great. Thank you so much. Thanks for having us.