Good morning and welcome to Rallybio's Conference Call to discuss RLYB 116 program updates. At this time, all participants are in listen-only mode. This call is being webcast live and is accessible in the investor section of Rallybio's website at Rallybio.com. Please be advised that today's Conference Call is being recorded. I would like to turn the call over to Jonathan Lieber, Chief Financial Officer of Rallybio. Please go ahead. Thank you, Michelle. Good morning, everyone, and thanks for joining us. This morning, we issued a press release announcing program updates for RLYB 116, including data supporting recently completed manufacturing process enhancements, results from a series of biomarker characterization studies, as well as next steps for the RLYB 116 clinical program. As mentioned, the release is available on the investor section of our website at rallybio.com. Before we begin, I'd like to remind everybody that we will be making forward-looking statements on this conference call, and these statements involve certain risks and uncertainties that could cause our actual results to differ materially. Please take a look at the risk factors discussed in our SEC filings for additional detail. These forward-looking statements apply only as of today, December 2nd, 2024. We undertake no duty to update any of the statements after the call, except as required by law. Joining me on today's call are Dr. Stephen Uden, our Co-founder and Chief Executive Officer, and Dr. Stephen Ryder, our Chief Medical Officer. We will begin the call with prepared remarks from Dr. Uden and will then open up the call for questions. I will now turn the call over to Stephen. Thank you, Jonathan. Welcome, everyone, and thanks for joining us on the webcast today. We want to share an update on some emerging data from our RLYB 116 program. We're going to be sharing a lot of detailed data in this presentation. Importantly, the takeaway is that 116 has the potential to be a best-in-class C5 inhibitor, and we're going to show you why. One, we've completed enhancements in the manufacturing process, which we expect will further improve tolerability. And two, since the completion of the phase I study late last year, we've continued to analyze the data to more precisely understand the disconnect between the data from the Phase I study as compared to data we have from preclinical studies. Based on these analyses, we now understand that RLYB 116 achieved greater complement inhibition in the Phase I MAD study than initially suggested. We will share this data with you today. And as a next step, we plan to initiate a confirmatory clinical PKPD study in the second quarter of 2025. In this study, we expect to demonstrate the improved tolerability of 116 and confirm complete and sustained C5 inhibition in line with our preclinical data. Additionally, market research that we've done demonstrates that there is significant patient demand for a once-weekly, small-volume, subcutaneous C5 inhibitor that can be self-administered via an autoinjector, supporting a peak market opportunity for 116 of nearly $6 billion in three indications alone. These three indications are paroxysmal nocturnal hemoglobinuria, or PNH, antiphospholipid syndrome, or APS, and generalized myasthenia gravis, or GMG. As a reminder, 116 is an innovative complement C5 inhibitor created using the Affibody platform. Shown on the right, 116 includes an Affibody, which is an antibody-mimetic protein that has a much smaller molecular weight than a traditional antibody, and this is connected to an albumin-binding domain, which serves to extend the half-life of the Affibody. C5 was selected because it is a proven target for the treatment of a number of complement-mediated diseases. Because 116 is a tiny protein, particularly compared to a traditional antibody, it can be self-administered once weekly as a small-volume subcutaneous injection, uniquely positioning 116 to meet patient demands for a more convenient C5 inhibitor and making this product best in class for patients. In a phase I SAD/MAD study, which we completed late last year, we reported a greater than 99% reduction in free C5 at 24 hours and sustained reductions of 93%. And we will talk more about this today. Recall that Rallybio acquired this program from Sobi. Sobi took a version of this molecule into phase I studies and saw adverse events at the 10-milligram dose. These adverse events were mild pyrexia, nausea, vomiting, and increases in inflammatory biomarkers. Working with Sobi and Affibody, we used our expertise and innovative problem-solving to change the E. coli strain used as the expression system in the manufacturing of RLYB 116 and evolve the manufacturing process, reaching doses above 100 milligrams in the MAD study completed last year. Once we were able to demonstrate that 116 fulfilled our target product profile, there was a significant projected commercial opportunity in just the three selected indications of PNH, APS, and GMG alone. Based on compelling preclinical data suggesting that 116 has the potential to be like Soliris and Ultomiris, but in an autoinjector device similar to those used for the GLP-1s, and given the patient demand for an easy, small-volume, at-home solution, we conducted a single and multiple ascending dose study in healthy participants, which again was completed late last year. The MAD portion of the study was an adaptive single-blind design with a four-week treatment duration and 10-week follow-up period. The study was designed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of 116 and included four cohorts of 12 participants each. The adaptive design allowed us to adjust the dose based on observations from prior cohorts, and we found that we could comfortably administer doses of 100 milligrams once a week. This is the data that we presented late last year from cohort one, the 100-milligram once-a-week dose. This dosing scheme was particularly attractive to us because it used a very simple formulation. This was just a one-milliliter injection given once a week. And what we're showing here is the concentration of various proteins throughout the four weeks of dosing. 116 is the solid yellow line, total C5 is the dotted orange line, and the free C5 is the purple line. Because of the wide range of concentrations, we're showing these data on a log scale. The data show sustained levels of 116 throughout the four weeks, which is one and a half to twofold higher than the level of C5, which should be sufficient to produce complete complement inhibition or greater than 99%. So when we looked at the measured levels of free C5, we expected to see sustained inhibition of greater than 99% over the entire time period. The data here shows that 116 achieves a reduction in measured free C5 of greater than 99% at 24 hours. However, the sustained reductions appeared to be only in the range of 93%. These results did not align with our preclinical data. This is the first point for further evaluation. Additionally, we began to see the emergence of some adverse events, mainly mild to moderate GI disturbances at doses of 150 milligrams. This was reminiscent of adverse events seen at much lower doses of an earlier version of 116 before it was in our hands. As referenced earlier, prior to advancing 116 into this phase I study, a number of modifications had been made to the manufacturing process, and standard release testing indicated an acceptable purity profile. Nonetheless, these observations required further evaluation, and we believed we could successfully address the profile of 116 through further process enhancements. We addressed these two issues concurrently. The manufacturing and process enhancements take time, and we used that time to do additional work to understand the biomarker data so that by the time the manufacturing enhancements were completed, we had a better understanding of how well 116 was knocking down C5. Firstly, the manufacturing process enhancements. We are confident that the process enhancements we put in place will further improve the tolerability of 116, and now I will show you why. This slide illustrates why we believe that host cell protein contaminants were causing the adverse events that we saw at the higher doses of 116. We observed these adverse events within a few hours of administering 116. An illustrative example of the timing of AE onset and initiation of resolution is shown on the right, along with the 116 serum levels. These symptoms appeared well before Cmax occurred, which is around 36 hours, but by 24 hours, these symptoms had largely disappeared. We attributed this to an intrinsic immune response to bacterial proteins. We therefore set about to investigate whether there may have been some previously undetected residual impurities from the E. coli manufacturing process leading to the observed adverse events. Host cell proteins were not observed using the standard ELISA host cell protein release testing. However, we now applied other analytical techniques, including mass spectrometry, which is increasingly being used to monitor host cell proteins in clinical products. This is recently developed, but a straightforward technique. The analysis for the Phase I study drug is shown in gray and demonstrates there were measurable levels of host cell proteins in the bulk drug, identified as HCP 1 through 12 on the X-axis. Please note this is a log scale. While it's not unexpected to see host cell proteins in biologics, they nonetheless can cause toleration challenges. We then produced a development batch using the addition of a custom affinity resin developed by Affibody to further purify the drug substance. And this is shown in purple. Keep in mind that the purple bar you see here is logs lower than the gray bars. And then we produced a GMP batch of the drug using this same new process. And again, you can see we were able to remove virtually all of the remaining residual host cell proteins except for a single E. coli protein labeled as HCP 1, the levels of which are orders of magnitude lower compared to the original batch. We are now very confident that we've effectively eliminated host cell protein impurities. This gives us confidence that we could administer doses higher than 100 milligram and that higher doses of 116 will be well tolerated. While we were working on manufacturing, we used the time to further explore the disconnect between the in vitro complement inhibitory potency of 116 and the free C5 levels as assayed in the Phase I study. Prior to starting the phase I study, we had preclinical data demonstrating that 116 had comparable or superior potency to two commercially available complement inhibitors, Zilucoplan and Ravulizumab. Then we had the Phase I MAD data that showed complement inhibition shy of the levels we were expecting based on the preclinical data. So what is accounting for this discrepancy? Additional characterization of the 116 free C5 assay shows that the assay is meaningfully underestimating the level of complement inhibition due to a specific characteristic of the free C5 assay. We now believe that 116 achieved greater C5 inhibition than previously suggested, and we plan to initiate a confirmatory PD study in the second quarter of next year. Now let's walk through the data itself. This slide shows preclinical data comparing 116 to the approved C5 inhibitor, Zilucoplan. Many of you have seen these data before. What we're showing here is the ability of both 116 and Zilucoplan to inhibit hemolysis, which is an indicator that you're effectively inhibiting C5. So how does this in vitro assay work? If you put foreign red blood cells, typically either sheep or chicken, into human serum, the innate immune system responds. Antibodies bind to these foreign red blood cells, then complement binds to the antibodies and triggers the complement cascade, with C5 activating the membrane attack complex. The membrane attack complex essentially punches a hole in the surface of these foreign red blood cells, causing water to rush in under osmotic pressure, and the cells then hemolyze. When there is no inhibitory drug, there's a lot of hemolysis. Then, as you add increasing doses of a C5 inhibitor, in this case, either 116 or Zilucoplan, there's less and less unbound C5 to be activated, which is preventing the membrane attack complex from hemolyzing the cells. You will eventually reach a point where hemolysis is completely inhibited. In the bottom table, we're showing the IC50, or half-maximal inhibitory concentration. It's a fairly steep dose-response curve, but whether you use the IC50 or any point along this hemolysis concentration curve, you can see that 116, on two separate occasions, matches or even outperforms Zilucoplan. In other words, the ability of 116 to inhibit C5 is similar or even superior to Zilucoplan, which is an approved drug. We then conducted a similar experiment comparing 116 to Ravulizumab, a long-acting version of Soliris that our team had significant familiarity with. So again, we're looking at the ability of increasing doses of either 116 or 112, which is a precursor to 116, or Ravulizumab to inhibit hemolysis of sheep red blood cells put in human serum. You can see that all three drugs do inhibit hemolysis. While it would appear on first glance that Ravulizumab inhibits hemolysis at a lower concentration, it is important to note that the X-axis is appropriately plotted on a molar scale. Ravulizumab is a bivalent C5 inhibitor. So for every molecule of Ravulizumab, you attach two molecules of C5. 116, like Zilucoplan, is univalent. To bind the equivalent amount of C5, you would need twice as many molecules of drug. If you look at the bottom table, the separation between the IC50s is exactly what you'd predict: twofold. It's 0.14 for Ravulizumab versus 0.29 for 116 and for 112. In other words, 116 binds C5 just as effectively as Ravulizumab. You just need more molecules of 116 to bind the same amount of C5. Before I leave this slide, I want to make this point. The key difference is that our molecule is tiny, roughly 120 amino acids, compared to Ravulizumab's approximately 1,300 amino acids. Although the molar concentrations are twofold different, the actual weight or mass of 116 is significantly lower, and hence the ability to pack a lot of anti-C5 activity into a small volume. It's based on these encouraging preclinical data that we advance 116 into phase I study we discussed earlier. In other words, this is a drug that should work as well as Ravulizumab. Again, despite everything we saw preclinically, the 116 free C5 assay suggested we were only getting sustained reductions of 93%, which just didn't add up. Now we know that it is due to the complexity of measuring free C5 in the presence of large concentrations of C5 bound to 116. Let's just spend a minute to discuss how free C5 assays are run. Panel one is a cartoon of a healthy participant who has a normal circulating level of C5, all of which are free since there's no inhibitory drug present. These are the green circles. In panel two, that participant is treated with 116, and the 116 binds to and inhibits the vast majority of C5 molecules in circulation. But remember, this is a protein-to-protein interaction, so drug is constantly attaching and being released from C5. Therefore, there is always a small amount of free C5 present. 116 are the blue chevrons, with bound C5 represented as gray circles, and the free C5 is the green circle at the bottom. Panel three simply shows a blood sample removed from the healthy participant, and then that sample is shipped to the lab where the free C5 assay is going to be conducted. As panel two and three show, the sample shipped directly matches the blood taken. The cartoons are identical. In panel four, we're describing how free C5 is measured. The free C5 assay is an ELISA assay, so it utilizes a capture reagent, which is shown as the orange Y shapes. The capture reagent has to be the same as the drug being tested. So in this case, the capture reagent is 116 bound to a plate. For reference, in any free C5 assay, the capture reagent is typically the same as the drug itself. And the idea is that free C5, shown as the green circle, then attaches itself to the capture reagent, or 116 attaches to the plate of the ELISA assay. One challenge with free C5 assays is that the 116 bound to the plate can start to pull off or bind C5 that just temporarily drops off 116 before it gets rebound. This is now shown at the bottom of panel four, where the C5 that was bound to 116 has dropped off and reattached to the capture reagent 116 molecules. This results in overestimating the amount of free C5 simply because there's competition between the 116 attached to the plate and the 116 circulating in the sample. This challenge is not unique to 116. Our team encountered similar challenges in prior organizations working on C5 inhibitors. Now, historically, the way to get around this issue was to use something called a Gyros assay, which attempts to do a snap measurement at low temperature to measure the amount of free C5 before the drug that is being tested can release bound C5. Based on this prior experience, we believed our 116 assay was overcoming this challenge. However, it has become apparent that 116 has a faster off-rate, so the Gyros technology doesn't completely resolve this problem. While the affinity of 116 for C5 is generally comparable to Ravulizumab, the speed at which this protein-protein interaction drop-off occurs is faster. I would note that the off-rate does not reflect the ability of 116 or another C5 binding agent to inhibit C5. However, it is a characteristic of importance in the context of the free C5 assay. Due to the disconnect between the in vitro C5 inhibition and the assay levels of free C5, we suspected that even with the Gyros technology, we were not able to stop the protein-protein interaction and measure free C5 before C5 that was bound to 116 had dropped off and got attached to the ELISA plate. To prove this, a series of experiments were conducted. The first experiment we did was to compare 116 with Ravulizumab, again using a hemolysis assay. This experiment was performed by taking C5-depleted human serum and spiking in a fixed known concentration of C5, and then adding increasing amounts of 116 or Ravulizumab based on a specific ratio of drug to C5. The drug activity, measured by the number of binding sites, the C5 ratio ranged from zero molecules of drug per C5 up to three molecules of drug per C5. Then hemolysis was measured at each of these ratios. As you'd expect, on the upper left side of the graph, when there is no drug, you're getting virtually 100% hemolysis. When the ratio is about one to one, it's between 60% and 70% hemolysis due to a certain amount of C5 constantly dropping off. But as the amount of drug increases, whether it is Ravulizumab or 116, and the ratio starts to approach twofold, the hemolysis is increasingly inhibited. At around 1.8 to twofold excess of either drug over C5, hemolysis is functionally inhibited. Consistent with prior analyses, this indicates that 116 performs similarly to Ravulizumab at equivalent ratios to C5. We then conducted another experiment to understand the degree of discrepancy between the measured levels of free C5 and the true inhibition of complement. This is a two-part experiment that we ran sequentially. In the first experiment, we took C5-depleted serum, which is normal human serum with all of the normal proteins present, including all of the complement proteins except C5. We then assessed the level of hemolysis as we added known amounts of C5 to this C5-depleted serum. As the amount of C5 increases, the amount of hemolysis increases. At 50 or 60 nanograms per mL, as on the lower left of the graph, there's not enough C5 to cause hemolysis. As you start to approach 500 nanograms per milliliter, exactly as we predicted based on our prior experience, hemolysis starts to occur. And certainly, once you go beyond 500 nanograms per mL, hemolysis is occurring. So the lower asymptote, which is the inflection point at which human serum can start to hemolyze red blood cells, is around 500 nanograms of C5 per milliliter. Next, we assess the levels of measured free C5, at which hemolysis is inhibited, in the presence of increasing amounts of 116 in normal human serum. Based on the experiment we just discussed, we know that the inflection point below which hemolysis is largely inhibited is roughly 500 nanograms of C5 per milliliter. However, when the amount of free C5 is measured using the assay from the 116 program, the lower asymptote for the hemolysis, or the inflection point, appears to be between 3,500 and 5,000 nanograms free C5 per milliliter. But we know, and we've demonstrated in this experiment, that you must be below 500 nanograms of C5 per milliliter before you're inhibiting hemolysis. This confirmed our suspicion that in the time it takes to take the measurement of free C5 in the 116 assay, C5 is dropping off the drug, and we are overestimating the amount of free C5 due to the limitations of the assay, and therefore underestimating the amount of complement inhibition. So when, in fact, there's only probably 500 nanograms per ml of free C5, the assay is measuring a larger apparent amount of 3,500 to 5,000 nanograms per ml of free C5. With this new understanding and looking at the data from cohort one of the phase I MAD study, it appears that the dose of 100 milligrams once a week is achieving sustained complement inhibition greater than 99%, which you can see in the green box capturing the range of 3,500-5,000 nanograms per ml. With the new drug substance and our new understanding that 116 is likely producing greater C5 inhibition than previously indicated, we plan to take 116 into a confirmatory clinical PKPD study to demonstrate the approved tolerability profile and confirm complete and sustained inhibition of terminal complement. We plan to assess dosing of 150 milligrams once weekly and 225 milligrams once weekly. While 100 milligrams once weekly appears to be doing the job, we would like to have a wider margin of inhibition and ensure we can limit breakthrough resulting from potential patient variability. This study will use both hemolysis and free C5 to assess the pharmacodynamics of 116. Now, why do we think this is important? We've previously conducted patient research to better understand the unmet need in patients with PNH and GMG. Consistent with data from our prior experience, the majority of patients with either PNH or GMG who are treated with a complement inhibitor would prefer a weekly subcutaneous autoinjector, like the device used for GLP-1s, above all other potential options. The idea of being able to give yourself a one or two-mL injection once a week at home was selected above any of the other options available, particularly those where you must go to hospital to have the drug administered. Surprisingly, even an oral therapeutic was not preferred over giving yourself this small injection for 10 seconds once a week. Patients suffering from complement-mediated disease have a strong preference for a product presentation that's been made available to patients with so many other conditions. They want a therapeutic that is patient-friendly, subcutaneous, small volume once a week that they can give themselves at home. 116 is uniquely positioned to meet this need. Having confirmed that 116 is both well tolerated and produces complete and sustained complement inhibition, we then plan to move forward with studies targeting patients with PNH and APS. The path for PNH is well known to our team. For APS, there is significant unmet need for patients who are refractory to anticoagulants. Nobody is currently working in this space, and despite years of research, the standard of care remains warfarin. However, based on our discussion with KOLs and a number of case reports, we believe 116 can address significant unmet need for patients with APS who are not adequately responding to standard of care. Additionally, GMG does remain a very attractive option as well. So just to remind you what we've discussed today, our manufacturing process enhancements have been successful and are expected to improve tolerability. Our biomarker characterization work indicates that 116 produced greater C5 inhibition in the phase I study than previously understood. We believe that 116 has the potential to be as potent as Ravulizumab, but in a more convenient, patient-friendly form that is of significant interest to patients, and in achieving our target product profile, there is significant commercial opportunity for 116. Moving forward, we plan to conduct a two-cohort PKPD study in healthy participants to confirm improved tolerability and complete and sustained complement inhibition, with the study on track to start in the second quarter of 2025, with initial data by the year-end 2025. With that, I'll turn it back over to the operator for questions. Thank you, Dr. Uden. At this time, we'll pause for your questions. If you'd like to ask a question, please press star one-one. If your question has been answered and you'd like to remove yourself from the queue, please press star one-one again. Our first question comes from Mitchell Kapoor with H.C. Wainwright. Your line is open. Hey, everyone. Thanks for taking the questions. Firstly, I wanted to ask if you could just elaborate on the confidence level you have for showing what you need to see in the confirmatory PKPD study. And what is that margin of error of what you need to see? What's the margin that's acceptable? Based on the data that we've seen with the hemolytic assays, we are very confident that we're going to see a good result. Sort of the margin of error that we're going to be looking for is no hemolysis, exactly as was seen with other agents that completely inhibit C5. So we will be looking for complete inhibition of hemolysis. And of course, now we better understand the cutoff in the 116 assay levels of free C5 below 3,500-5,000. Does that make sense, Mitchell? Yeah, that makes a lot of sense. And to follow up on that, and kind of if you could just contextualize what you've seen in terms of the severity and type of GI disturbances, and what the level of trade-off is for what's tolerable versus the opportunity to have a subcutaneous C5 inhibitor. Great question. So just to be clear, the sort of the level of the adverse events that we saw at about 150 milligrams were significantly less than what was seen with 10 milligrams with the original version of this Affibody when it wasn't in our hands. It was really just the hint of it. We're pretty confident that removing these residual proteins, bearing in mind how we went from 10 to 150 milligrams, the fact that we're going to remove and saw such good tolerability, we are confident that with this is going to that the doses we're going to study will not be seeing any of these GI-type adverse events. But we need to test that and prove that in the clinic, of course. Yes, that makes a lot of sense. Okay. And then lastly, if you could just talk about the expected differentiation in the 116 profile versus Zilucoplan, and just kind of how you could see the positioning. Obviously, large markets for all, but wondering how Rallybio views the opportunity and kind of the target product profile versus this other agent. Well, this product profile we think applies to all other agents that have either been approved or in development. This will literally be, if this delivers, the equivalent of giving yourself, shall we say, Wegovy once a week. It's a one and a half mil injection given in 10 seconds once a week, something that can be stored almost certainly at room temperature. All of these other agents require either more frequent or typically more frequent injection and of a much larger volume. So this will be just so easy for the patient to give. And they can also be confident. And that's why I think patients with C5-driven diseases often understand their disease. They want to be confident that they are getting that full coverage of C5 inhibition for the duration of between each therapy. Does that make sense? Absolutely. Thank you for taking the questions. Not at all, Mitchell. Thanks for jumping on the call. I forgot to say good morning to you. Apologies. Thank you. Our next question comes from Catherine Okoukoni with Citizens JMP. Your line is open. Hi, this is Catherine calling on behalf of Jonathan Wolleben. I have just got a question about, first, the assumptions for the $6 billion market opportunity in the three respective indications, as well as IP coverage for 116. Yeah, great. Well, thanks for the question. So we have done our internal market research on all of these indications. So let's just bear in mind the PNH, clearly, we're looking for those patients who are looking for that treat themselves at home, the same with the GMG market. So we think that's a pretty conservative estimate of the numbers of patients who could benefit from this therapy. And bear in mind that C5 inhibitors could or should be used in all patients with GMG, or at least tried in all patients with GMG. It tends to be at the moment reserved only for refractory patients, partly due to the complexity of treatment. In terms of APS, there is nothing out there except oral anticoagulants. So again, we would be dealing with our estimate of the market for patients who are not responding to oral anticoagulants and are still having recurrent thromboses and both arterial and venous and the other complications associated with APS. Perfect. Thank you, and then just a question about the IP coverage. Oh, sorry. Yeah. So from memory, I think it goes out to 2034. Thank you. Composition of matter. I'm just being reminded. Composition of matter. So that's without any of the sort of orphan drug or any of those other. Thanks for the reminder, Stephen. And again, Catherine, thanks for jumping on the call. Thank you. Our next question comes from Catherine Novack with Jones Trading. Your line is open. Hi. Morning, guys. Congrats on the data. I just wanted to see if you could tell us what specific threshold for sustained C5 inhibition you would be looking for in the confirmatory PKPD that would lead you to initiate patient studies and that would lead you to believe that you had a viable asset, especially in an indication like PNH. Great. Well, as I say, we would certainly be using both the new cutoff with our existing assay. You have to use the assay with your reagent in it for sort of technical reasons that we could get into. So we would want to see measured levels of free C5 below 3,500 or in that between 5,000 and 3,500, preferably below that. But more importantly, we will be using the hemolysis assay. And that will be the key test. Fundamentally, no hemolysis. Okay. And then if I can ask about the choice of indication specifically about antiphospholipid syndrome, can you help me understand the history of C5 inhibitors in this indication? Maybe why we haven't seen this pursued as a commercial indication by others working in the complement space. Great question. So there are anecdotal and case reports and small theories that have been reported, but in particular with the use of Soliris. In our previous life, our chief medical officer was responsible for a lot of compassionate use in that space. So there's clearly evidence. And then in the sort of things like catastrophic APS, it is used. There's never been any approval for it. I think the fundamental problem why people don't go after it as an indication is that this is a preventative. So the idea that someone is going to have to go to hospital to have an intravenous infusion every sort of two or eight weeks is extremely unattractive. And there are a lot of other indications that companies can go after, which would be better suited to the IV presentation. However, ours is a typical preventative approach. In other words, every Saturday morning, you get up, clean your teeth, take your shot, and you're all done and dusted in 30 seconds. You're not having to go to hospital, etc., etc. So I think it was primarily the difficulty for patients and the low likelihood that it would be taken up. But whenever it's been used in case reports, it's worked. And certainly, as we've spoken to KOLs, very active in this space, they are really looking for a C5 inhibitor and a C5 approach in particular. Okay. That makes sense. And then lastly, can you talk about how initiating this phased confirmatory study would impact your cash runway estimates? We're always carefully shepherding it. We're not. I'll turn to Jonathan, but I think I'm confident in saying that by being careful, we're going to be able to have no impact at all. Jonathan, please. Yeah. No, I think thanks, Stephen. I think, Catherine, the answer is that we don't expect any material impact to the cash runway, so no change to any of our financial guidance. Got it. Thanks, Jonathan. Well, that's it for me. Thanks for taking my questions. Not at all, Catherine. Thanks for jumping on the call. Thank you. Our next question comes from Ritu Baral with TD Cowen. Your line is open. Good morning, everyone. Thanks for taking my question. Wanted to first ask about slide 10 and the residual proteins. It looks like there's a little bit of HCP still left with the new process. Can you give any characterization as to what this protein is and its relative importance in the GI or pyrexia seen in the drug's previous profile? And then I've got some questions about the 150 groups. Thanks. Yeah. Cool. Not at all. So just please bear in mind that this is a log scale. So it's a sort of, what, 100- to 1,000-fold lower concentration of HCP1. We have characterized it. You're correct, Ritu. This is a mass spec assay. However, it is part of ongoing IP work. So we've been advised not to talk in great depth about it. But we're pretty confident that from everything that's known about this particular HCP and the minuscule levels and the fact that this HCP has been seen in other biologics and lower doses sorry, concentrations above this, which seem to be well tolerated, we are as confident as one ever can be that we've done everything we can to remove that. I hope that makes sense, Ritu. Got it. And then as we move through the slides, maybe slide 13, as we look at this hemolytic assay and Zilucoplan on this curve, as you move from the 100 to the 150 dose, what sort of relative impact on inhibition can you expect to see? And do you feel that there need to be any sort of reformulation work? I'm wondering, as you go to the 150 and you want to preserve that same sort of small volume, are you going to increase concentrations? And is there any work that you need to do around that to prevent any injection site reactions? Great question. We were all and it won't surprise you. So I think I mentioned earlier that the formulation that was used in the phase one study and we'll use as we do the confirmatory PKBC study is a real sort of vanilla-flavored formulation, 100 milligrams per mL. It won't surprise you that we are doing, in parallel with work with that, using more sophisticated excipients or what have you to ensure that we can, in fact, get a higher concentration of drug per mL to keep it well within the acceptable level. Though arguably, 1.5 mL for a sub-Q once a week would be fine. As you go up to 225, we may want to start to bring in some of these other process enhancements. In terms of ISRs, we did see ISRs, as you know. They were all of them of a mild nature. I think like with most subQ, we're hoping that removal of HCPs may have an impact on that. It'll be something we'll be looking at thoughtfully as we go into the phase, the confirmatory PKPD study. But they'll probably be there, but we're not, at this stage, it's too early to say how big they are. But please remember, all of the ISRs reported to date were reported as mild. I would add, Stephen, that there were no discontinuations due to ISR. Oh, thanks, Stephen. There was a suggestion of amelioration with continued dosing. Thanks. Just a suggestion of that, but Ritu, this will all be a feature of what we'll be keeping our eyes on with the confirmatory ClinPharm study next year. This is Stephen Ryder. Yeah. Thanks, Stephen, for those two reminders about the sort of amelioration time. Understood. I think my rambling question. First question was just on what you expect on relative efficacy from the 150 versus the 100. We'll probably see further suppression of C5. In terms of the hemolysis assay, we'll probably not expect to see anything very much because we think we're already there. The sort of measured free C5 using our assay, we're expecting we would like to see lower. It's really just to give us more headroom. You're probably aware that patients on tried and tested IV C5 inhibitors such as Celeris or what have you. There are patients who do need that sort of slightly more drug. The complement level goes up due to inflammation or anything like that. We're expecting to see complete inhibition of hemolysis and hopefully levels of drug, of free C5 below the 3,500 mark. Understood, and please don't shoot me. I've got one last question. When we look at the APS population, you mentioned patients that are refractory to warfarin. Do you have a percentage of overall APS patients that are second line that would be addressable here? We do, but I'm not sure if I've got it off the top of my head. I've just got a colleague quickly looking at this who may be able to answer. And just to go back, please be sure the key thing as we push those, we will be focusing very strongly on hemolysis going forward, even though it is a bit more sort of complicated assay, which is why we use the free C5 originally. But we'll get back to you with that number. Our market research has got that, but the appropriate slide isn't to hand, Ritu. Fair enough. Look forward to following up. Thanks. Thank you. Thank you. Our next question comes from Gavin Clark-Gartner with Evercore ISI. Your line is open. Hey, guys. Thanks for taking the question. For the APS indication specifically, what is the smallest and quickest study where you can establish clinical proof of concept? And what does that look like from a trial design, endpoint, and cost perspective? Thank you. Oh, Stephen, shall I ask you to just sort of give your current thinking about that? Sure. Gavin, thank you for the question. And we're really playing off of the experience that we had with a prior firm that we worked at in some neurological diseases. Specifically, I'm thinking of like NMOSD, where you can take patients who are currently being treated by a number of experts who are having recurrent thrombosis despite being on standard of care, which is warfarin, as Stephen mentioned, and administering 116 to them and then assessing them over, say, a year period of time for recurrent thrombosis. And the absence of recurrent thrombosis in this patient population, where patients that are currently being treated have a history, a documented history of these clinics of recurrent thrombosis with some measurable frequency. And that would really give you the confidence then to go into a confirmatory trial. Does that help, Gavin? Gavin? He may have been able to. Yeah, that's very helpful. Thanks, guys. Not at all, Gavin. And just while I've got the floor, Ritu, we managed to find the data that we were looking for. It's 10% of APS patients are estimated to be not well controlled on warfarin today. Thank you. At this time, there are no more questions. I'll turn it over to Dr. Uden for closing remarks. Thank you, everybody, for joining today's webcast. We do look forward to sharing additional updates on the 116 program as it goes forward. And with that, I'd also like to thank my colleagues, Jonathan and Stephen, who joined me on the call. And I'll now hand back to you, Michelle. Thank you for your participation. This does conclude the program, and you may now disconnect. Everyone, have a great day.