Thank you. If I could have your attention, please. We are truly thrilled to be here in Montreal today, just incredibly so, and with such a great audience as well. Thank you for coming. It's truly appreciated. I am gonna start with a newsflash, that this whole event is being webcast. If you're gonna ask questions, talk at all, please make sure you've got a mic. We do have an international audience listening in today, so thank you. I was thinking this morning, listening to Christof Geisen give his presentation and seeing our data up there on the slides, when Steve and I had the concept of Rallybio back in about the middle of 2017, you know, this is exactly what we wanted to do. We wanted to bring a team of terrific drug developers together and do something meaningful, something profound in healthcare, and something with the potential that's gonna, you know, transform a condition. You know, I say it often, there's babies born every day with Fetal and Neonatal Alloimmune Thrombocytopenia, and we have the potential to do something about it. It's exactly what Steve and I thought of as we set up the company. Oh, this had been working so well. There you go. I'll do it the old school. Thank you. I am just gonna pause now, though. Our intrepid General Counsel, Michael Greco, asked us to say a few words, and I know he's listening, so I'm gonna say them because he's a pretty good guy. Before we begin, I'd just like to know that we are gonna be making forward-looking statements, including among other statements about the clinical development of RLYB212. These statements involve certain risks and uncertainties that could cause our actual results to differ materially. Please take a look at the risk factors in our SEC filings. These forward-looking statements apply of today, and we undertake no duty to update any of the statements post today. Thank you for that, Mike. Let's move on then to the agenda, and I think you're gonna have a really terrific time here. I'll give a very brief introduction on Rallybio. Certainly, most people in the room know us well, but there are a number of, you know, colleagues on the webcast that I mentioned. Steve will come up and talk about fetal and neonatal alloimmune thrombocytopenia and Rallybio-212. He will come up and speak about that and really set the scene. Absolutely thrilled that Christof Geisen's here again after his terrific presentation earlier today, and he will be presenting the data for the trials that we've been running. We'll pause there and have a Q&A session, so lots of time to get these deep questions that I know you will be keen to ask. We'll move on to Róisín, who leads the program, Róisín Armstrong, and Róisín will talk about next steps in the program. To give you a feel, based on the data that we have, where we're gonna go to. Again, we'll have a Q&A session, lots of time to ask questions about what we want to do next in this program, and then we'll close the proceedings. The background, again, for most of you in the room, you've heard me saying this before. As we set up the company, we truly want to build a sustainable company. We're not in this to bring an asset or two and flip it and sell it. We want to take our programs all the way through to commercialization. We realize we may have to do that with partners, we may do that with some transactions, but in our heart, we want to build this company that's gonna be sustainable. In that, we have a saying that, you know, "Rare disease knows no boundaries," so why should we have those boundaries? Whether it's maternal, fetal health, complement dysregulation, that Steve will touch on a little bit, hematology, metabolic disorders, we're really game for virtually all indication areas. We made a decision not to do oncology. We made a decision not to do infectious diseases. We think that other people can do that. Other than that, if it's a devastating rare disease that we think we can transform the lives of the patients that have that disease, that's fair game for us. At the very heart of this mission, as I alluded to, was bringing this team of just terrific drug developers together and all those people that support the craft of drug development, and we're replete in our company with those folks. I'm going to mention a couple of them in the next slide, who are actually in the room and will be embarrassed, but there you go. Jonathan Lieber's here today, our chief financial officer, runs a great financial outfit in the company. We're in a strong financial position. Our runway goes through to the first quarter of 2025, as we currently stand. We're not finished there. This notion of building a sustainable company is predicated on bringing other assets in that we can develop. We've got a very active business development group under the leadership of Amanda Hayward, tremendously experienced person working in the field of business development, and we're constantly looking for assets to bring in and develop. We set very high hurdles. We've looked at hundreds of assets to bring into the company, and we've probably done, what, Steve? A deal a year. We're very selective in what we bring in, but we want to continue with that philosophy. Last slide I'm gonna show, I mentioned this team of people that have been brought together. A wee bit invidious to mention individuals, but I'm gonna do that anyway. Some of them are in the room. Start off with Róisín Armstrong, that leads the FNAIT program. I've had the privilege, as have both Steves, of working with Róisín at both Pfizer and Alexion. Róisín's last job before coming to Rallybio, she was the global development team leader for two programs in our former company, eculizumab for refractory myasthenia gravis and eculizumab for neuromyelitis optica spectrum disorder. She took both programs from very small phase II proof of concepts, both programs happened to be 14 patients, all the way through to the marketplace. The thought that, you know, we have someone like Róisín running FNAIT is just wondrous. Doug Sheridan, who's also in the audience, Doug is a terrific antibody engineer, that actually doesn't do him service just talking about that part. Doug is also a terrific scientist and laterally, a terrific drug developer now. Doug was the brains behind and the co-inventor of ravulizumab, which you will all know as ULTOMIRIS. Doug took that from a scrap of paper on how to extend the half-life of eculizumab, all the way to now being in the marketplace for paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, and other indications to come. Doug has crafted Rallybio- 212 and has a hand in all of our other scientific programs, including Rallybio- 116, which is our complement piece. Say a little about Rachael. Rachael Alford isn't in the audience today, but Rachael, Steve Uden and I had seen this many times in our career, that one of the difficulties, particularly small companies have, is just making the product. I remember the CEO of one biotech coming, saying to me one time, "How hard can it be to make something?" Well, it turns out it's really hard to make something. Having Rachael in the early days. Lastly, Steve Ryder at the back, our Chief Medical Officer. Steve Uden and I often muse that we have never worked with anybody that has developed so many medicines in their career, Pfizer, Astellas, Alexion, and now Rallybio. With that, I'm delighted to ask Steve to come to the podium and talk about Fetal and Neonatal Alloimmune Thrombocytopenia. Steve? Thanks, Martin. What I'm going to do. Well, I'll just start off by sort of building on the points that Martin made. Just remind everybody that Rallybio is about more than FNAIT. We are a portfolio company, as Martin has said, we've done many deals and still have ambitions to do other deals as we go forward. This is the pipeline as it stands today, as I'm sure you're aware. Two clinical stage programs, FNAIT, probably the most advanced, though over the weekend, many of us have been in touch with Eric, who's running the complement program for us and moving through the multiple ascending dose study. I'll come back to that right at the end of today's discussions, just to remind people about, you know, events coming up this year. We have one true preclinical program, the matriptase-2 antibody for iron metabolism disorders in rare disease, then the two discovery partnerships, small molecules with Exscientia and monoclonals with AbCellera. Today, we're here to talk about the RLYB212 program for the prevention of the preventative treatment, should I say, of Fetal and Neonatal Alloimmune Thrombocytopenia. Quick reminder, although I think everybody in the audience will know this, FNAIT, a rare disease. It's due to a mismatch between antigens on the surface of the mother's platelets and the baby's platelets. In this syndrome, the mothers are one of the small numbers of individuals who have a single amino acid mutation on the antigen, Human Platelet Antigen 1a. It's involved in clotting. This single amino acid difference, the protein functions normally, but it's slightly different shape, so it's antigenic. All the two programs, the two platelets are seen as antigens, sorry, are seen as antigenic. If at any time during the pregnancy or delivery, fetal blood gets into the mother's circulation, she will recognize the baby's platelets as foreign and mount an immune response. These bleeds during pregnancy are actually remarkably common. Now, it goes without saying, if the, if the fetus, even though it's sort of tucked up inside the mother's womb, if it's got no platelets, if it's thrombocytopenic, even the most mild trauma, the bleed will not be controlled, and that can result in intracranial hemorrhage with lifelong neurological disability, miscarriage or stillbirth, loss of the newborn, and then obviously, complications at delivery. These children are born, delivery is something of a traumatic process, and they can be born bleeding into major organs, into the skin, or what have you. Excuse me. Oh, dear. Excuse me, overexcited. RLYB212 is there to prevent FNAIT. Size of the problem, how many mothers would need to be treated to prevent this big problem? Our conservative estimate is that there's at least 22,000 pregnancies out there where the mismatch would occur. The mother is HPA-1a negative. Thanks, sir. The mother is HPA-1a negative. She also has the HLA type HLA-DRB3*01:01. I think we've told you this before. This particular HLA type increases the antigenicity of the HPA-1a antigen, about 30-fold, and of course, the mother is antibody negative. Obviously, we can't prevent something if the mother is already producing the antibodies. This is a conservative number. The epidemiology is well understood in Northern Europeans, where the mutation that causes this is relatively prevalent, and you're gonna hear later on this afternoon from Róisín about some of the work that we're doing to get a better fix on the epidemiology in other ethnic groups such as Hispanic moms, African-American moms. We do know that this mutation is actually incredibly rare, almost unheard of in Eastern Asian mothers, Japanese or Chinese mothers. Interestingly, for a rare disease, the awareness of FNAIT amongst the physicians who would need to prevent it, obstetricians and gynecologists, and maternal-fetal medicine specialists, is remarkably high. Not only are they aware of it, they are also particularly worried that their patients are going to have this syndrome and are very keen to prevent it rather than have to try and treat it, because, of course, once the mother has seroconverted, all future pregnancies will now be at risk of FNAIT. You heard from Martin that we are determined to become a company, a sustainable company. Not only are we really interested in developing RLYB212 and getting it approved, we're already thinking about what would it take for this to become a product that could be available to physicians, available to mothers, to treat and prevent FNAIT. These are the four pillars of our commercial efforts being led by Derek, who's in the audience with us today. The first thing, of course, is that we would need a plan to be able to find these mothers. For any preventative approach, you need some sort of screening to find the at-risk patients. In order to do that, the second thing is you then need to be able to find somebody who can provide the diagnostic on a commercial scale. Now, the good thing, in our favor, and we've discussed this in the past, is all of the diagnostics needed to identify these high-risk mothers already exist. They're used in transfusion medicine, they're used in transplant medicine, we do not have to go out and design and develop a brand-new diagnostic. Part of the effort, you're gonna hear about this from Róisín, is whilst we have an excellent partner for the sort of GCP development program, we also are already looking ahead to say who would be the appropriate partner to provide a commercial diagnostic that could be used across, you know, the at-risk populations in Northern Europe and North America to identify these moms. Clearly, we're gonna talk about this as well, that if things are going to be prevented, doctors have got to be aware of it and in obstetrical medicine, and what's important is getting on the guidelines for the management of a pregnancy. In order to do that, we need health economic data to demonstrate to payers that it's worth screening every mother who becomes pregnant in order to find the moms at risk, treat them, and prevent these terrible outcomes. Of course, we'll need to start to think about, in the future, communicating more about the unmet need. Probably, today is, and has been one of the first steps in that process as we've gone out with some of the data, about which you're gonna hear in a few minutes from Dr. Geisen. These are the four pillars of our commercial and patient access strategy. I touched on this already. The first step will be to start to think about how do we find the at-risk moms. The good thing is that mothers who are pregnant will routinely go to the doctor. Unusually, for a rare disease, these potential patients present themselves to the healthcare system. As I'm sure everybody in the audience knows, that at that very first visit, one of the first things that the obstetrician is going to do is to take blood to screen for factors that could complicate the pregnancy. Is the mother diabetic? Is she hypothyroid, hepatitis B, HIV, et cetera, et cetera. I said already, these are diagnostics already available. They're also based on blood tests. What we will need to do is say, "Look, while you're taking the blood for all of these things here, take an extra mil or two, and we can then test to see whether the mother is HPA-1a negative, and hence, at risk of having a baby with FNAIT." We will need to go on and look at the other risk factors. The first thing will be, is the mother or is she not HPA-1a negative? There's a lot of work going on, and I'm going to talk about that on the next slide, to understand what's needed to get onto the guidelines, so when women present to their obstetrician to say, "I'm pregnant," they will be tested for their HPA-1a status. This is the focus at the moment, being led by Derek, who's with us in the audience. On the left-hand side, you can see the four factors, the four bits of data that the various guideline committees need. In the United States, that's driven by the American College of Obstetricians and Gynecologists. Where I come from, as you can probably tell from my accent, it's the Royal College of Obstetricians and Gynecologists, and so on. Every country has its own professional body, and uniformly, they require these four things. Number one: what is the prevalence of this? You know, how serious is that problem? Number two: do you have a way of preventing it? One of the reasons they do not screen for HPA-1a status at the moment is there's nothing you can do to prevent this happening if the mom has this antigen. All you can do is treat after she's seroconverted. As well as the prevention, you need a validated screening test, where we've discussed this already, the diagnostics already exist. Obviously, we've touched on this, cost effectiveness. These are some of the activities that the FNAIT team are working on, talking to scientific advisors, patient advocacy groups. You're gonna hear more about the natural history study that we're running from Róisín in a moment. Whilst we found a first-class partner for the GCP clinical trial phase of the program, workers already started talking to these big diagnostic manufacturers ready for commercialization. Starting to look at cost benefit, we're talking to payers as well as prescribers. We've already opened those discussions, and starting to think about publications. The data that was presented today will also be in a peer reviewed journal. We're already starting to think about other things that work, that's ongoing at the moment, that we can start to share with the prescriber community and the payer community. This is all the work that's going on to enable this to be a therapeutic that we can get to the patients at need, at risk. If we did that, how big is this opportunity? The four things that really drive any commercial opportunity is shown here. Is there an unmet need? If we can prevent this, are we avoiding cost? You can see some of the costs of a pregnancy that ends with FNAIT, whether it's caring for a child with cerebral palsy, treating future pregnancies with IVIG. Certainly, we can You know, our cost model, our pricing model will be around preventing this huge cost and burden to the healthcare system. You need a readily identifiable population. We've sort of talked about that at length. We know where to find these patients at risk, the good news is, moms already come to the doctor. We will then need to start to think broad and rapid utilization. Everything that we've learned as we speak to physicians involved in the guideline process is, that once something is on the guidelines, obstetricians and maternal-fetal medicine specialists, being very conservative physicians, will adopt things very, very quickly for kind of obvious reasons. Most of their patients are perfectly healthy young moms, they want to keep the world that way. We think this will be a $1 billion opportunity or more, and as you're gonna hear from Róisín at the moment, this is based on just thinking about these Caucasian mothers. We're really going to be trying to understand how many more moms in these other populations will be at risk. I sort of set the scene here in terms of what is FNAIT, why we think this is a therapeutic that we need to get out there and make available to mothers. Now I'm going to switch gears and ask Dr. Geisen to come up and go through the data that he presented at the ISTH symposium. Let me introduce Dr. Geisen. I will have to put my spectacles on. Not only do I choke, but I also need glasses to read. I've been at this far too long. Dr. Geisen, let me introduce Dr. Christof Geisen. He's the head of the Department of Molecular Hemostasis and Immunohaematology at the Institute of Transfusion Medicine and Immunohaematology for the German Red Cross in Frankfurt, and a lead collaborator, without any doubt, for the RLYB212 phase I-B proof of concept, a study about which you're going to hear in a moment. Dr. Geisen graduated from the Medical School of Aachen University in 1991, and since 1993, Dr. Geisen has been practicing in the fields of transfusion medicine, immunology, and hemostasis. I'm delighted that, Dr. Geisen, you're gonna share your presentation again, thank you for that you talked about earlier today. Thank you. Here's the clicker. Thank you very much. Thank you very much. Thank you for the opportunity to share our work again, which I had the honor to present on the ISTH Congress just 3 hours ago. My name, as you pointed out, is Christof Geisen, I will presenting the results from the phase I-B study conducted at the Fraunhofer Institute in Frankfurt. To evaluate the ability of Rallybio RLYB212 to drive the rapid and complete elimination of transfused platelets positive for Human Platelet Antigen 1a, or HPA-1a, from the circulation of HPA-1a negative subjects. These results represent a proof of concept for the potential of RLYB212 to prevent HPA-1a alloimmunization during pregnancy in women at risk of Fetal and Neonatal Alloimmune Thrombocytopenia, or FNAIT. These are disclosures I had to present at the Congress and presentation learning objective. I would like to proceed now to FNAIT. It is, as you pointed out, a rare and potentially devastating disorder that arises when a mother develops alloantibodies against an antigen present on fetal platelets, which previously have entered the maternal circulation by fetal-maternal hemorrhage. These alloantibodies, most commonly directed against HPA-1a, can cross the placenta and destroy fetal platelets, which may result in uncontrolled bleeding in the fetus or newborn. Owing to the similarities in the antigenic mismatch between maternal and fetal cells, FNAIT is often referred to as the platelet counterpart to HDFN. There are three important features that distinguish FNAIT from HDFN. The first is that fetal thrombocytopenia may occur during the first pregnancy. The second is that alloantibodies have been reported as early as week 17 of gestation. The third is that there are no treatments currently available for the prevention of HPA-1a alloimmunization. Over the past 50 years, HDFN has been nearly eliminated through a combination of effective prenatal screening tests for women at risk of alloimmunization, and of course, by the prophylactic administration of highly effective anti-RhD therapeutics. The basic study design of the 212 phase I-B study we're presenting here today is precedented by earlier studies done with anti-RhD therapeutics, as shown here, wherein the therapeutic is evaluated for its ability to drive the rapid and complete elimination of a bolus transfusion of antigen-positive cells. This is designed to mimic a worst-case fetal-maternal hemorrhage. These data, which you can see on the left, published by Maisch et al in 2004, highlight the differences in the elimination kinetics of antigen-positive erythrocytes. In this case, when anti-RhD is given intravenously, the black squares, or intramuscularly, the open diamonds. It is important to note that both routes of administration are highly effective at preventing alloimmunization, even when they are administered up to 72 hours postpartum. The biphasic elimination kinetics of the intramuscular dose we see here, with an initial lag phase followed by a rapid elimination phase, are quite similar to the data I will present in a minute regarding subcutaneous administration of RLYB212. The data on this slide are from a preclinical proof of mechanism study that was published by Xie et al last November in Blood. It closely resembles our RLYB212 proof of concept study design. In this study, antigen-negative mice were given prophylactic doses of 212 in conjunction with an antigenic challenge, consisting of a large bolus transfusion of HPA-1a positive platelets from transgenic mice. In the left panel, you can see the percent of transfused platelets remaining at five hours in the blue bars and at 24 hours in the red bars. What you can see here is that there is an apparent threshold effect of Rallybio 212 concentrations, which can then drive rapid and complete platelet elimination, estimated from this data to be somewhere between 1.2 and 4 units per milliliter in this animal model. On the right, you can see that the same concentrations of 212 that drive rapid elimination of the antigen-positive platelets also suppress alloimmune responses, as shown at weeks two and three. This preclinical proof of mechanism study demonstrates that there is a clear correlation between platelet elimination kinetics and the prevention of alloimmunization with RLYB212. Taken together, we have decades of clinical precedence with anti-RhD therapeutics and compelling preclinical data in hand that suggests that RLYB212 could be an effective prophylactic approach to prevent FNAIT in pregnant mothers at risk of developing HPA-1a alloantibodies. To further support this approach, I now show you results from our proof-of-concept study, investigating 212's ability to eliminate HPA-1a positive platelets when they are transfused to HPA-negative human subjects. On to the study design. This was a phase I-B study conducted in male subjects, aged 18 to 65 years old, with a BMI less than 35, who were HPA-1a negative. Following randomization on day one, two subjects received placebo, nine subjects received a single subcutaneous dose of either 0.09 mg or 0.29 mg of RLYB212 in a single-blinded manner. On day eight, all subjects were transfused with HPA-1a positive platelets. The platelet challenge, selected based on the precedent of trials conducted with anti-RhD therapeutics, corresponds to the approximate number of platelets found in 30 ml of fetal blood. This again, represents the worst case scenario for a fetal maternal hemorrhage. Platelet clearance was assessed between days eight and 15, and safety was followed over a full 12-week period. The primary objective of this study was to assess the ability of Rallybio 212 to accelerate elimination of transfused HPA-1a positive platelets with a predefined criteria of at least a 90% reduction in platelet elimination, half-life versus placebo, to achieve proof of concept. Secondary objectives were to characterize the 212 concentration effect relationship, and of course, to evaluate 212's safety. On to the data. Here we have the platelet elimination data. The left and right panels are from the same data set, just shown on different timescales. On the left, you have the full seven-day post-transfusion, and on the right, we just zoom in on the first 24 hours post-transfusion. The first thing to point out is that the kinetic profile looks remarkably similar to the anti-RhD data I just showed you a few minutes ago, where there is an initial lag phase of up to several hours. This is highlighted by the arrows in the graph on the right, followed by a rapid terminal elimination phase, with mean half-lives for each treatment group noted in the graph on the left. Of note, while both dose groups met the proof of concept criteria of at least 90% reduction in platelet elimination terminal half-life, the elimination kinetics were dose-dependent in both the duration of the initial lag phase as well as the terminal elimination rate. This is consistent with the preclinical data we reviewed earlier, in which platelet elimination, prevention of alloimmunization by 212, were both dose-dependent. Furthermore, if we look at the individual platelet elimination curves now shown on the right, we can appreciate that there's a higher degree of variability in the low-dose group, shown in blue, while the curves of those in the high-dose group, shown in green, have lesser variability between them. This suggests that there's a dynamic concentration effect represented more clearly in the low-dose group. Which brings us to our concentration effect relationship data, where the left panel shows the correlation between the 212 concentration just before transfusion and platelet half-life, and the right panel shows a correlation between 212 concentration and the lag time. You can clearly see that all aspects of platelet elimination kinetics, both half-life and lag time, are concentration dependent, and that the effect appears to be saturated at 212 concentrations above approximately 5 ng per milliliter in this antigen challenge model. Additionally, the inherent variability in the initial absorption kinetics of a single subcutaneous injection of 212, coupled with two different dose levels, provided a wide range of 212 concentrations immediately before transfusion, which then resulted in a very nice, clear picture of the concentration effect relationship. Of course, we are happy to report that 212 was well-tolerated, and there was no reports of drug-related or possibly related adverse events, and there was no severe or serious adverse events observed throughout the study. In conclusion, Rallybio 212 is capable of driving rapid and complete elimination of a large bolus of transfused HPA-1a positive platelets from the circulation of HPA-1a negative human subjects in a concentration-dependent manner. Both doses tested met the pre-specified proof of concept criteria of greater than 90% reduction in platelet elimination half-life. The observed platelet elimination kinetics were consistent with the elimination kinetics of RHD-positive erythrocytes after intramuscular administration of anti-RHD therapeutics. Finally, a single subcutaneous dose of Rallybio 212 was well-tolerated, with no reported drug-related or possibly drug-related adverse events. Collectively, we believe that these data suggest that Rallybio 212 may be an effective prophylactic strategy to prevent FNAIT in pregnant women at risk of HPA-1a alloimmunization. Lastly, I'd like to thank all the study subjects, study coordinators, people from Rallybio and their partners, including medical writers who helped to draft this report. Thank you very much. I think, Steve, you're gonna moderate the QA session, so please come to the stage. Thank you. We're gonna be joined by Doug, who, as Martin told us earlier, led a lot of the science in-house around this, who's gonna join Dr. Geisen. This is an opportunity for anybody in the audience to raise questions or what have you. We do have a microphone that Ami will share with you. This is being recorded, so if you just hang on for a second with your question so that we make sure it's picked up for people listening in. I think Laura's gonna start. Thank you very much. Laura Chico from Wedbush Securities. Dr. Geisen, one question for you, this might be a little bit more theoretical. At the higher dose, what would be the risk of the antibody crossing over in the placenta? Is that a concern or is that more academic? It is, I don't think it's academic. Of course, the higher the dose, there would be possibly a risk of having antibody transfer through the placenta, especially and at the later stage of a pregnancy to the fetus. This dose is still as low that, if you compare the natural model of having antibodies in the circulation, which is a mother who has been sensitized in an earlier pregnancy, this mother has antibodies, and if it is below a certain threshold, maybe thre units per milliliter, it is not harming the fetus. This we know from natural history of observing these pregnancies. This dose, even if it is called a high dose, will result in a concentration which is below that threshold, we do not believe that it would create harm. Thank you. Maybe you would like to add to that. I was gonna say, Doug probably has got... 'Cause I know he was doing a lot of the sort of in-house calculations as well. Doug? Yeah, we've thought about this quite a bit, I can assure you. The short answer is, in the same way that anti-D therapeutics are fully capable of crossing the placenta, we would anticipate that RLYB212 is also capable of that. In precisely the same way, safety is modulated through exposure. You know, the concentrations here, I was just thinking about this earlier today, in the literature references, natural history studies, there is, as Christof mentioned, three international units per mL, was demonstrated as a threshold in a paper by Kelly et al., 2008. The concentrations, even within the high dose here, would actually be below the lower limit of quantitation of that assay, so. Okay, thank you. Maybe one last question for Dr. Geisen. Are there any patients that you would envision this prophylactic strategy not being applicable to? I know there's other anti- antigens that are presented, but within this cohort, any reasons why this wouldn't be a viable strategy? Thank you. No, I would not think there is any reason why a woman, pregnant woman at risk, having this antigenic constellation, being negative for HPA-1a, should not receive the prophylactic. I don't see a reason for not being eligible for this prophylactic treatment. Thanks, Laura. Thanks. Hi, I'm Catherine Novack from JMP Securities. I had one question about just how you're thinking about dosing going forward. Cause we saw that the higher dose really had an effect over a larger range. Are you thinking of kind of keeping that dose or adjusting? I think this might be a question for Doug. I'm sorry. Doug's working on this as we speak. Yeah, sure. Yeah, we are. We are actively working on this. The thing that I would point out with this study, is that, again, both doses met proof of concept criteria. The, the primary, the secondary endpoint here, it really is concentration effect, right? It's not necessarily dose effect. We're in the process now of taking all of the collective human data available, and modeling that out, allometric scaling from this population to a pregnant population. It would be premature right now to comment specifically on the dose, but we do believe that this data clearly demonstrates concentration effect relationship. It puts us well in that. We have a clear understanding, I should say, in the human scenario. The dose selection, in the coming months, we have also, well, prior to the end of the year, completion of the phase I study, repeat dose cohort, which would be critical information for intra-subject variability to incorporate in that model. It's an ongoing process. Thank you. Any other questions in the audience? Martin, I believe you've had some questions, incoming questions, so perhaps you could share those with us. Thank you, Steve. Yeah, we've got quite a few coming in. Some of them are actually more geared towards phase II and beyond. I'm gonna save those for when. Sure, yeah. Róisín's presentation. The ones that are pertinent to now, I'll just run through them all, usually towards you, Dr. Geisen, but with Doug and others around, I'm sure they will chip in. This is a very general one, but, you know, highly important as we move through this program. What are some tools that can take on the pregnancy/neonatal outcome for a potential FNAIT pregnancy that is different relative to traditional pregnancy? Are there critical time points to monitor? Yeah. Yes, of course. I mean, the bleeding in these affected fetuses can occur during pregnancy, there would be the need of monitoring with, Doppler sonography, ultrasound, whatever, to find out if there is any bleeding going on. This is critical and gets even more critical unto the end of the pregnancy. There will be a continuous monitoring needed. I think that continuous piece probably answers the second part of the question. I mean, seems to me that any time point's critical here, and we're, you know, gonna monitor. Doug, anything to add? Just, I mean, as Dr. Geisen mentioned earlier in the talk, we know, unlike HDFN, FNAIT can occur at any time, really during a pregnancy, early second trimester. So, you know, our goal is to identify subjects at risk as early as possible, initiate treatment as early as possible, and maintain that effective therapeutic level throughout the entire course of the pregnancy through postpartum. Absolutely. Changing tack a little, the company spoke about the importance of diagnosis/screening. Dr. Geisen, how do you think about the diagnosis for FNAIT, and what trends are you seeing on the standardization of screen awareness of FNAIT? As earlier has been explained, as there is no preventive measure available, nowadays, it is not routine use to test or to diagnose mothers being HPA-1a negative. In the future, this will be, and is already, a standard technique to test for HPA-1a antigens. There are serological tests available, a DNA-based test available, so I think we will hear a bit later what diagnostic tools are around and could be established. The techniques itself are there, not now in a big scale, in a way to test all mothers, but this will be available without too many complications, as it is available for antigen and blood group testing in red cells or. That will not be a big hurdle to overcome. Very helpful. Thank you. We're gonna get into some data, Steve, and some questions about the data. Right, sir. Actually, a kind of variation on your question, Laura, in some ways, but I'll ask it anyway because someone in the audience has. What was the steady-state serum concentration of two, one, two in international units per ml at both doses? The concentration, specifically at day eight, would be especially helpful. I'll continue on because the questioner continues on. To probe further, can you confirm if the concentration for either dose was above or below either 0.5 international units per ml, something you've noted you're aiming for? Probably Doug would be- Yeah -the best person, 'cause I know you've been going through this. Doug? Yeah. Just one minor correction. There was no steady state. This was a single dose. Yes, absolutely. Right? For this study, obviously, the most relevant time point was immediately prior to transfusion. As I'd already stated, I think, actually, to address your question there, Laura, is using the MAIPA assay that has been reported in the Kelly paper, for which the three international units per mil has been established, we believe that all of these concentrations shown here, they would be below the limit of detection in that assay. We're reporting these as nanograms per mil. I just point out, these are astonishingly low... Yes concentrations. Absolutely. Lower than any antibody I've ever worked with or ever read about in my career in human trials. Yeah. So. No, great stuff. We're well below that threshold. General question here, Steve, one that we've obviously discussed before. I'll ask it anyway. There have been other studies showing that certain species of maternal HPA-1a antibodies may be able to bind to related integrin dimers expressed on the trophoblasts in the placenta or potentially endothelial cells. Wondering if you've done any additional work to characterize that binding or lack thereof for 2 1 2. I know, Doug, this is part of your work- Yeah Which Martin referred to earlier. I'll go ahead and take this. Yes. RLYB 212 does not distinguish between binding to alphaIIb beta3 integrin complex or alphaV beta3 integrin complex. It binds to either of them equally well. With that, while I certainly believe that alphaIIb beta3, which is found in platelets, is the primary immunogen that causes FNAIT, this 212 should also be highly effective at removing any cell fragments deriving from syncytiotrophoblasts or endothelial cells as well. Yeah, those bind well. Very good. Thank you. I'll just continue, Steve? Yes, just carry on. I think I think you've. They're piling in here. That's great, isn't it? Yes. Yes. Must be hundreds of people out there listening in today. It's wonderful. Again, highly specific now. We move from the general to the very specific. More detail on the 1.29 milligram subject, where the platelets seem to rebound. Wondering about neutralizing anti-drug antibodies and immunogenicity. Yeah, that one particular subject, it does appear to rebound. Frankly, it's an assay artifact. The assay used to measure platelets, the flow cytometry assay, with some very skilled collaborators. Frankly, I don't think we could have done this anywhere other than the Fraunhofer Institute, given the amount of almost art required to run that assay. What you see there is it appears to drop down and then comes back up. That's not physiologically relevant, certainly lasting out two weeks. It should be a zero value. It's just noise in the assay. Yeah. So. Thank you. Keep going, Steve? Please do, yeah. Yep. Yeah. Three questions from the one questioner here, and I'll take them in order. They're quite different, quite general. What is the rationale for benchmark of 90% reduction in mean platelet half-life? I think, Doug, I think probably- Sure. Yeah. Again, most of this is precedented based on the anti-D work. It is, I'll be frank, a somewhat arbitrary value, but it is a tremendous reduction in the overall terminal half-life. It demonstrates, you know, significant capacity to eliminate antigen rapidly and completely. Yep. So. I think the graph that Dr. Geisen showed with the, you know, the previous work, the precedented work. Yeah ... really powerful. What is the minimum concentration of platelets for the mother to generate antibody? This is very hard to say, because it is hard to measure. Usually, a fetal-maternal hemorrhage is really very low volume. In more than 95%, it will be less than 2 ml. Yeah. What we here did is really a challenge. 15 ml or let's say, the platelets from 30 ml of blood is really a worst case scenario, and usually, it's much, much smaller. It is not known what is really the minimum dose for an alloimmunization effect. Yes. The next question follows on. What I suggest, Steve, I take this question and hold the phase II question. Oh, definitely. After Yeah, I think we need, yeah, restraint. We just, yeah Róisín presents. Another really excellent question, which is difficult to answer, but I'm asking it and you're answering it, so that's okay. Once the minimum amount of platelet, i.e., sufficient to induce antibody formation, is reached, how fast does it take for the mother to generate antibody? Obviously, probably very low doses may induce sensitization. There might be a relationship, the more the volume of fetal-maternal hemorrhage, the higher risk of immunization will be there. This exact relation is, at least to me, not absolutely known. In some instances, very small amounts will induce an alloantibody reaction. It seems to me, in a very simple way, that if you have 212 on board at the right concentration, then it's gonna remove the foreign platelets, and that's what we're aiming to do. Is that fair, Doug? I think that's right, Martin. I mean, there's a lot of unknowns out there in terms of the timing, the source, the magnitude of antigen challenge required to elicit an alloimmune reaction. Again, in this study, based on the precedent of the approved anti-D therapeutics, what we model here really is a worst case scenario of fetal-maternal hemorrhage. A 30 ml fetal-maternal hemorrhage is practically a catastrophic event, right? Anything larger than that, a larger platelet challenge than that, you've got much more immediate things to worry about than alloimmunization in terms of the health of that child. You know, if we're giving doses here, and you're seeing single digit nanomolar concentrations of RLYB212, capable of fully eliminating those platelets quickly, completely, effectively, we should have more than adequate concentrations to remove any antigen challenge that you'd see during the course of a normal pregnancy. I may be misremembering Dr. Geisen's slide, but I think there was quite a. Going back to the HDFN analogy, wasn't there quite a lag between when they injected the red blood cells before they gave the anti-D? It was a considerable amount of, you know, significant amount of time. Yeah, that's right. Yeah, it's. There was a 24-hour delay. 24 hours, yeah. Excuse me, between the RBC administration and the drug administration. In addition to that, with the intramuscular, you have an additional lag time, while the shape of those curves, and if you look at the slides more carefully, the shape of those curves is qualitatively the same. Yeah. The duration of elimination with the RBA, excuse me, with the red blood cells, is much longer... Yes than it was with the platelets. It's multiple days. again, look at the prescribing information for anti-D therapeutics. They're 98+% effective when administered up to 72 hours postpartum. Mm-hmm After a fetal-maternal hemorrhage. There's a window in there, I guess. Yeah is the way to say it. Thank you for the questions for the webcast. Please keep them coming in. With that, Steve, back to you. Great! Well, I then, thanks very much, Dr. Geisen and Doug, for answering the questions on the study we've just presented. I'm now going to hand over to Róisín Armstrong, who, as Martin said, is the global team leader for this program, leading all efforts on the... Everything from running the clinical program, CMC, aligning the commercial work. Róisín's gonna take us through the next steps in development. Over to you, Róisín. ... Oops, is it? Let me just rearrange the mic. Thank you there, Ami. Okay. Thank you, and stay close to the mic. Okay. Excuse me, while I just get some directions on my appropriate position here at the podium. Okay. Good afternoon, everyone. It's indeed a pleasure to be with you here today, and to be able to speak around RLYB212, which I think here on out, I will succinctly refer to as 212. Its development as a potential prophylactic therapeutic for the prevention of Fetal and Neonatal Alloimmune Thrombocytopenia. Now, thank you, Dr. Geisen, again, for taking us through the presentation. We have just really had a marvelous presentation on the POC study results, and I think it goes without saying, we are very, very pleased with the outcome to our phase I-B proof of concept study. The clear and robust demonstration of the 212 meeting the pre-specified proof of concept criteria in achieving that rapid and complete elimination of HPA-1a positive platelets transfused to HPA-1a negative subjects. The clear characterization of the concentration effect that the study supports for that pharmacodynamic effect. Through the next 25 minutes or so, my focus here with you this afternoon is really going to be next steps in the clinical development program. To be honest, I've been a little bit remiss in not acknowledging upfront as well. Thank you also for being with us here today, for taking time here, those of you in the room in Montreal and those participating via the live webcast. Thank you for taking time from your weekend and this Saturday afternoon to join us as we walk through the 212 development program. Before we come into the next steps of clinical development, what I'd like to do also is take you through the progress of some of our key milestones through 2023. As I speak about those milestones, what I believe you will appreciate also, all of these milestone events are absolutely foundational. They are essential to us moving forward into our first clinical study in the target population, i.e., those women who are at higher risk for the occurrence of HPA-1a alloimmunization in their pregnancy. Let me now move on to those milestones. Obviously, we've essentially, on this slide, at least, we've put a tick mark against the delivery of the phase I-B proof of concept results, as you've heard now today. We also have three other key milestones we're actively working on and progressing, all of which remain in frame for delivery by the end of this year. I'd like to speak a little bit to these in a bit more detail, and again, to contextualize the contribution that each of these deliverables provides to the program and as an enabler to advance into our first clinical study in pregnant women. The first that you see is really around the completion of our comprehensive GLP toxicology program, and essentially, on an essential component of that program is the GLP maternal fetal toxicology. Okay? Now, it is somewhat unusual in drug development, at this early phase of drug development, to be conducting maternal fetal toxicology. Typically, this is an activity which will follow later in development. When you think about our target population, which is, again, as I've mentioned, women who are at risk for alloimmunization in their pregnancy and the occurrence of FNAIT. When you think about how we propose to administer 212, which will be based on our identified dose regimen, will be administered antenatally during the course of pregnancy. It is an absolute essential, it's a prerequisite, frankly, before we start dosing to establish robust safety margins in our maternal fetal toxicology, and we're on track for that. A second milestone I want to touch on is around the completion of the 12-week repeat dose cohort from our phase I, single and multiple dose safety and pharmacokinetic study, which is being conducted in HPA-1a negative healthy subjects. The relevance of this data, Doug did allude to it very briefly, but this, together with all our early clinical data, is going to directly feed into our determination and identification of the target dose regimen of 212 to advance into women in their pregnancy, as we follow them, and characterize the effects of 212. Finally coming to on this slide is before the end of the year, we will initiate regulatory discussions directly in support of a phase II study that we are planning to initiate in the second half of 2024. Again, when we think about the timing of this phase II study, again, I'll recap on the deliverables with the POC results today. We have the completion of our maternal fetal toxicology coming up at the fourth quarter of this year. We have the important repeat dose data from our phase I safety and pharmacokinetic study, which again, is on track for the end of the year. Before getting into the detailed next steps on the clinical development, I do want to share with you, there are going to be two key areas of focus of the development program that we're really going to hone in on through the course of this afternoon. That is the planned phase II study of 212, and our thinking for that study, why we believe is it essential foundation for the program, and our activities towards that. Also, I will be covering in some detail, too, the ongoing non-interventional natural history study presently being conducted. We're showing on this slide a schematic for the clinical development of RLYB212. Very briefly, what you can see going from left to right is our early phase I and 1b clinical studies that we've mentioned now a number of times. Of course, inclusive of the phase Ib POC study that we've been detailing today. Again, our thanks to Dr. Geisen for being here with us. From there, with a determined dose, from our data, we will advance to a phase II dose confirmation study, and our intent is to nail the dose of 212 for subcutaneous antenatal administration through pregnancy before we embark onto the phase III pivotal efficacy and safety study. I'd also draw your attention to the horizontal blue bar on the bottom of the slide, which depicts our ongoing prospective FNAIT Natural History Study, the non-interventional natural history study. An important element to our development program, which has been designed to provide a control dataset for the frequency of HPA-1a alloimmunization in an untreated population, which will represent the control arm for our future phase III single-arm registration study. I'm not quite going to go into the phase II study yet, because I really want to almost take you on the journey for how we're going to now transition from phase I and into phase II, and to really try and impart and share with you the thinking behind this. You know, when you think about it, by the end of this year, we will have a comprehensive body of pharmacokinetic, pharmacodynamic, and safety data from our phase I and I-B clinical studies being performed in HPA-1a negative subjects. In addition, as we've heard through the presentation from Dr. Geisen, with clear characterization also for the concentration-effect relationship of 212, to elicit rapid and complete platelet elimination. We will then take this body of data, and through comprehensive analysis and modeling, taking into consideration also the known and expected, and frankly, the dynamic changes of pregnancy, we will come from that work, we will determine our target dose regimen to advance into the pregnant population. With this dose, we will then embark on a phase II dose confirmation study. This study, also, which will be undertaken in those women who are at higher risk for the occurrence of HPA-1a alloimmunization in their pregnancy. This study will intentionally employ an adaptive design that will afford us the flexibility that, should emergent data suggest, we have the flexibility and ability to modify the dose prior to advancing that confirmed dose into the phase III study. As I mentioned, the phase III study will be a study designed to establish efficacy and safety. I said I would focus through this afternoon, really, spending time around the details of the phase II study and the non-interventional study. A commonality to both of the studies, recognizing that one's interventional, the phase II, and one's non-interventional, the natural history study. A commonality to both studies is, frankly, on a number of fronts. One, I've mentioned, is that these studies, for the natural history study currently, for the phase II planned, will be conducted in women who are at higher risk for the occurrence of HPA-1a alloimmunization. A second point I want to make is we believe these respective studies, yes, while they have discrete objectives, phase II, dose confirmation, natural history study, establish a controlled dataset for future registration study. Collectively, we see these studies as complementary in how they will establish the foundation for a future efficient and streamlined and effective approach to our phase III study. This is gonna be a theme I hope to come back to because it really speaks to the integrated program, and, frankly, getting into the nuts and bolts. First, let me go into the phase II study in a little bit more detail. We thought and continue to think about our design for this study, and I've mentioned a couple of key principles already through the course of the past few moments. As a dose confirmation study. A key component of this study is the application of comprehensive PK monitoring in the study, that will allow us to evaluate the systemic exposure of RLYB212 longitudinally through the course of the pregnancy. Through that intensive PK sampling, really enabling us to understand and characterize, and frankly, confirm the dose and the dose frequency of RLYB212. The intensive PK sampling is a fundamental aspect to the design of this study. I mentioned also that we are developing this phase II study with the capacity to adapt and have the flexibility to adjust the dose, or the dose frequency, of RLYB212 through the course of development. We are using our phase I data from non-pregnant subjects, HPA-1a-negative, healthy, non-pregnant subjects. Yes, we are doing extensive modeling and characterization and an analysis to inform our dose. What we really want to do is, by the time we complete the phase II study, is to come through and advance into phase III with total confidence in the dose that we've studied. To enable this adaptive, this flexible design, we are designing the study with what we call sentinel dosing and with sequenced cohorts. Now, what do we mean by this? The sentinel dosing is where the first woman to be enrolled into the study who will receive RLYB212 at the determined dose frequency, dose intervals through the pregnancy and will be followed through the pregnancy. We will follow that first woman through the pregnancy and take the available data, the complete data, the PK and the safety, and we will look at that, and we will make a determination on whether we want to make any adjustment before we expand enrollment into a subsequent cohort. We anticipate about two cohorts, both of which will each have about three to four women. Again, this intrinsic design is in place to afford us that flexibility to adjust the dose. You know, one of the elements, I think, as we've considered the first study in the pregnant population or the phase II study, is this will constitute the first time administration of 212 to a pregnant woman. When we think about it in that context, it's very much akin almost to first-in-human. Again, I'd emphasize where in fact, we have direct experience in our clinical program with sentinel dosing, with RLYB212 in our first-in-human studies. The first administration of RLYB212 in the clinic was under this, the paradigm of sentinel dosing. We're going to be taking that same approach now in our phase II study. A third design principle really gets to how we will oversee and evaluate safety for the mother and her fetus and her newborn through the course of her pregnancy, and obviously, following up also, including the pregnancy and the neonatal outcomes. Again, in the context of this, in a population who are at higher risk for the occurrence of HPA-1a alloimmunization in their pregnancy, we will, of course, monitor for the potential occurrence of HPA-1a alloimmunization in these women post-pregnancy. Here we have a schematic for the study, and I'll recap on some of the details as I go through it. This has been planned as a confirmatory study to establish the dose in adva.n.ce of phase III. We expect to start this study in the second half of 2024. It will be a single-arm, open label design, in which women who have been identified through screening to be at higher risk for the occurrence of HPA-1a alloimmunization will receive their antenatal administration of 212 through the course of their pregnancy. Commensurate with the objectives of the study being really weighted towards confirming the dose, I've spoken to the PK assessments and also the safety that we will follow in the study. As the schematic shows, post-pregnancy, we will also assess for the occurrence of HPA-1a alloimmunization. Treatment with 212 in the study will be started no later than gestational week 16. As we're running the phase II study, it is our plan to continue and to maintain the pace of the ongoing natural history study so that it continues in pace and in parallel with the conduct and execution of the phase II study. I've moved on to now our schematic for the non-interventional natural history study. I just think, maybe just in terms of the earlier presentations and the discussion of the program today, it's worth spending just a few minutes recapping on the objectives for the natural history study. We've spoken a little bit about the basis of the study that will provide a historical alloimmunization rate to control for a future planned single-arm phase III registration study. We are also committed, as we've touched on, I think it was earlier in Dr. Uden's presentation. We are committed to advancing 212 to all mothers who are at risk for HPA-1a alloimmunization. It behoves us in this study, and it's what we're working to actively progress, is that we are conducting this study in a broad and racially, ethnically diverse population, and establishing the risk for alloimmunization in this population. The study is being performed in the U.S. and at sites in Europe. We will continue with these obviously working towards the objectives for the study. There's also an important element to the natural history study, one which doesn't appear in any protocol, doesn't appear under objectives, doesn't appear under endpoints, and that's the role of our natural history study in establishing the operational precedents, the operational framework, or frankly, as I kinda tend to think about it, almost the backbone to the to the interventional studies that will be coming forth with two-one-two. One thing I omitted to mention on the previous slide, talking about the phase II study, Gets directly to how this natural history study more broadly supports the program, is that to conduct this phase II study, we will take a subset of our sites that are currently active today, screening and identifying women for follow-up in the natural history study, those women who are at high risk for alloimmunization. The sites, a subset of the sites in Europe, that we will then transition them. Through the course of 2023 and into 2024, we will work with these sites as we advance our protocol and readiness for the phase II study to transition these sites, ramping down on their activities for the natural history study and ramping up in their readiness to go forth in the execution of the phase II study. That is a key principle. This kind of works well for us because, you know, when you look at the ethnic literature, as Steve, Dr. Uden, covered in his presentation, it gets to the basis of our commercial estimates. They're conservative because the literature is driven by the data in Caucasian populations, by far and away. When in the conduct of this program, we're already planning for the majority of women to be screened and to enter into the natural history study to come from the U.S. As we transition some sites in Europe out of the natural history study and into the U.S., sorry, into the phase II study, we will expand somewhat the footprint of sites in the U.S. so that we continue to progress in pace with phase II conduct and execution. We continue to progress the natural history study, but importantly, with the mechanisms and pieces in place to really support establishing the risk for HPA-1a alloimmunization in that broad and diverse population. Ultimately, we will come to where we launch from the natural history study, the future phase III study. We really comes back to the backbone, providing the operational framework, first for the phase II study, as we will come to for the phase III study. The study's been ongoing for a little while now, while I'm not today going to get into significant detail on data from the study, there are experiences that we can speak to and share. Where we are today is we're very pleased with the progress of the natural history study. We're very pleased with where we are at the number of women who are screened to date, and we are very pleased with the trajectory we have and the progress that we anticipate against this study. We are also incredibly encouraged by what we see is the willingness of the women to step forward and to who are willing to be screened for the risk of HPA-1a alloimmunization in their pregnancy. Again, keep in mind, this is a non-interventional study. There is no potential therapeutic for these women, and yet we are seeing that they're coming forward and very willing to participate in the study. I've emphasized the importance of establishing the alloimmunization frequency in a broad and diverse population. Looking at the data that we're accruing to date, we can see that the race and ethnicity of the screened population is generally representative of that for the broader U.S. populations and the broader EU population. When we look also at the frequency of the HPA-1a negative gene status, i.e., the gene that confers risk in a pregnancy where you're carrying a HPA-1a positive fetus, the information that we're seeing from the program also is generally consistent with the published literature. I think one important element to highlight around the study is through the application of the screening tests, what we are also seeing is women who have existing HPA-1a alloimmunization. These pregnant women who have existing HPA-1a alloimmunization. These are cases where if screening were in place, if an available prophylactic, effective therapeutic were available, could potentially have prevented these cases from occurring. I think it really speaks to the silent nature of the risk in the pregnancy. Again, in the absence of screening, with no knowledge of the alloimmunization and no knowledge, therefore, of the potential risk for the occurrence of severe thrombocytopenia in the fetus of the newborn. To recap on areas of focus, for the natural history study, we intend to maintain the pace of this natural history study in parallel with the conduct and execution of the phase II study. Really, leveraging the study's ability to provide the operational precedence at our clinical trial sites, that really will set us up, we believe, very strongly for seamless initiation of a future registration trial. By the end of this year, with this pace, we expect to have screened about 7,500 women. I've mentioned that we are going to work with a subset of our EU sites and prepare these sites to ramp down on their activities for the natural history study, thereby allowing them to pivot to readiness for the phase II study, so that we can get going on the phase II study. Again, I've spoken to a number of times how the population of phase II, phase III, and the natural history study, it's all the same population, those women at higher risk of HPA-1a alloimmunization. For the U.S., obviously very important to us, and so what we will do, is we will expand the network of sites in the U.S., certainly to keep us on track with our screening target, and to come in tandem with the completion of the phase II study. Importantly, also, as I've endeavored to emphasize, really, in maintaining our efforts around a broad and diverse population by which to establish HPA-1a frequency. Now I'm going to switch gears a little bit, and other than I think right at the very beginning, I spoke to one of our activities through the second half of this year, will be to engage in regulatory dialogue around the conduct of our phase II study. I haven't really spoken at any degree to our regulatory experience with the development program. I think as you would expect, the development is obviously informed and built on the dialogue, the guidance, and the feedback, and the inputs that we receive from regulators, certainly in the U.S. and in EU. That has been a theme to the program, both in the non-clinical elements and also the clinical elements. For example, the maternal fetal toxicology program, which I've outlined and how it is coming in towards the end of the year, has been very much in consult with the regulators. Not only that, it's fundamentals around the design principles of the clinical development program, including the natural history study, the utility of the data from the natural history study to provide a contemporary control data set for our planned single arm registration study. Indeed, also, I've mentioned a number of times about HPA-1a alloimmunization being followed pre... post-pregnancy, this is as our planned registration endpoint for the program, the frequency of HPA-1a alloimmunization. Indeed, demonstrating the goal of the program, obviously, the effectiveness of 212 to prevent alloimmunization. Through the second half of this year, we will be taking avail and progressing a process in Europe, well, known as scientific advice and protocol assistance around our phase II study. This is in concert with the EMA or the European Medicines Agency. We see this as frankly an important first step to provide us with that early input and dialogue around our phase II study, before we subsequently advance the protocol through the national authorities in the countries that will participate in phase II. Upon when we get to the end of phase II, and we have the dose confirmed for 212, to advance into phase III, and also having established a contemporary controlled data set for HPA-1a alloimmunization frequency in the natural history study. At such time, we will be taking our data, this and much more, to regulators in support of our phase III protocol. Today, I'm not going to detail our exact plans for the phase III study. What I did want to speak to also is what we'd see in the program as the essential requirements for the conduct of a successful registration program. Most of which, on this slide, frankly, I've spoken to today. Obviously, fundamental that we establish proof of concept for RLYB212, we're obviously delighted by the results today, which continue to support our belief in the prophylactic potential of an anti-HPA-1a antibody to prevent fetal and neonatal alloimmune thrombocytopenia. Also, we will have and look to have in place our completed maternal fetal toxicology program, underwritten by robust safety margins before we go into the target population who will receive RLYB212. A third fundamental of a successful registration program is really that we have the therapeutic dose confirmed. We do not want to get into phase III and then start changing our dose. We want that nailed, with this program, as I'm sharing with you today, is designed with the natural history study as the backbone to the interventional studies, as I've outlined, with confirming our dose in the phase II study. With this approach, we believe we will be able to advance into a seamlessly into a very efficient and streamlined phase III study. I've spoken a couple of times now about the role of the natural history study. I've spoken a little bit about when we will engage in the end of phase II regulatory interactions. let me come back to those, the final two bullets on the slide. Another aspect of actually confirming the doses in phase II, is that will enable us to formulate 2 1 2, in the intended commercial device. it's worth sharing with you at this moment, while I won't go into the details of the device, we do intend this as a small volume, patient-friendly device, that will be suitable for self-administration, and we are confident that we will get to that place. As Steve mentioned in his overview of FNAIT, we are working with Versiti Labs today, an excellent labs who are directly supporting the conduct of the clinical program through today. In fact, Versiti, in itself, is a leading referral center for suspected FNAIT cases. As we look and turn our attention towards the phase III study, we will be identifying and working with what we see as a world-class diagnostic partner, and working with that partner on the FNAIT screening tests, their application in our phase III registration program, and ultimately, in the commercialization of 212. I'll use this slide to briefly recap before passing back to Dr. Uden, who will take us through a few catalysts that are still to come from Rallybio through 2023. To recap for the next steps on the clinical development of 212. What I have outlined is now on the body of data that we have, our plan to advance into a phase II dose confirmation study for 212. We see this as an important, a key step to nailing the dose before we advance into a streamlined phase III study. We will conduct this study. In parallel, we will continue and maintain the pace of the natural history study so that it runs in pace with the phase II study. I have attempted to outline, and if I failed, that's my limitation, but how the natural history study will form the backbone for our future interventional studies. By this, I spoke about how we will take sites currently participating in Europe, who will directly support the phase II. At such time, as we've completed our end of phase II regulatory interactions and dialogue, we will be converting sites, down-ramping or ramping down, their contributions, obviously, to a natural history study, and ramping up for their capacity and readiness to directly support the phase III study. One final note before closing. I mentioned also how we are encouraged by what we're seeing as the enthusiasm for women in our natural history study to come forward and to be screened for the risk of HPA-1a alloimmunization occurring in their pregnancy. Based on our experiences from the natural history study, and based on our discussions with the physicians and the investigators and working with their sites, we believe this also bodes well for our ability to move forward and efficiently conduct our interventional studies. I know we'll come back to Q&A, and I look forward to that part of the dialogue with you. At this point, I'm going to hand back to Dr. Uden and the catalysts. Thank you. Thanks, thanks, Róisín. I'll try and do this without choking to death again. Just to focus in, these are some of the catalysts, or these are the catalysts we're expecting this year. Róisín has already sort of spoken at, in quite depth about what we're expecting from the FNAIT program with RLYB212. The phase I multiple dose data are on track to be reported out. The focus there, of course, is safety and PK, translating everything that we heard from Dr. Geisen's presentation today into doses that we would start out in the phase II study, and of course, completion of the maternal fetal toxicology program. As Róisín reminded us, normally of sort of a byline, critical for this program, and again, will all feed into the dose selection. We shouldn't forget that the partner also has a complement inhibitor, the Affibody, RLYB116. As I spoke to you earlier, myself and Steve Ryder, the CMO, have been in contact with Eric over the weekend, who's working hard on the multiple ascending dose data, and we're expecting those data to be reported in 4Q this year. Everything remains on track for that. At the same time, we will be unveiling the indications that we'll be going after with the Affibody-based program. A huge, huge effort, simply reflecting the scale of complement biology and what's emerging there. That sort of sets things up for the Q&A, and I'm going to ask Jon Lieber, our CFO, to join us. He will moderate. I will join Steve Ryder, the CMO, Doug, and of course, Róisín. We will field any questions that may come either from the audience or I'm sure people are mailing in. Martin's giving me the thumbs up. Róisín, please. First question, go ahead, Laura. Thank you very much. Róisín, I'm wondering if you could talk a little bit more about the sampling activities that you're planning in the phase II study, just the frequency, kind of what is your base case assumption in terms of how frequently you'll be monitoring the patients? Yeah. No, thank you for the question, Laura. To be quite frank, we're really in the throes of developing the protocol right now. I think the key point that I would highlight is, we will do the PK sampling that will be done, will obviously be designed and sufficiently rich to enable us to confirm the dose and dose frequency. Obviously, in being operationally, in the conduct with the site. We would expect it very much less PK sampling in a future phase III study. The details we're currently working through at the present time. Okay. Then I wanted to clarify one point on the phase II study. It looked like in the deck, there will be no U.S. sites at all. Could you speak a little bit more about kind of the rationale and the geographic selection? Yeah, no, thank you. Thank you for that question. There's probably a couple of dimensions to this thinking. First of all, I should confirm, you're right. We are not planning to have U.S. sites in the phase II study. Really, there's a couple of key lines of thinking behind this. One is, which is what I touched on, is really ensuring the racial and ethnic diversity of our natural history study. Which I believe will be a differentiator from natural history studies that have been conducted to date in the field of FNAIT. That's consistent with our intent to advance to one, two as a therapeutic for all women at risk. We're already planning to have more patients screened in the US compared to Europe. There's also in Europe, it affords us the opportunity to take our experienced seasoned sites. As I mentioned, they're actively participating today in the natural history study, and frankly, a number of them have participated in prior natural history studies. To work with this selective group of sites to really advance the phase II. We want, and it beholds us to maintain the pace of the natural history study, and that's why we will expand the number of sites, since we'll lose a few as they transition in Europe to the phase II. We will then expand by somewhat, the number of sites in the U.S., and really use this footprint to continue to drive the natural history study, in pace with the execution of the phase II study. Does that address your question? Thank you very much. Hi, this is Catherine Novack again from JMP Securities. I kind of had a question about the phase II study. This may be a little bit too early, like you said. One question I had was just about dosing. Are you particularly looking at frequency or just the actual volume of dosing and also follow-up for the 1st cohort? Sure. When we talk about the dose confirmation, could it be the dose, could it be the dose frequency? These certainly will be under the purview of our consideration. Again, I think it goes back to, yes, we do have a rich body of clinical data, unequivocally from our early clinical studies, and we're very pleased with the data. Of course, the POC data is a, is a, is an important contributor, and the knowledge it confers as well around the concentration-effect relationship. Nonetheless, we are first time advancing two on two into, frankly, a new population, and that is women who are pregnant and for which there are known and anticipated physiological changes that would occur through the pregnancy. We do believe it beholds us to take this phase II study and ensure that let's advance the dose in one woman to begin with, we'll look at the data, and then we'll expand the enrollment, we'll open up a cohort. If we see a need to modify the dose, be it in amount or in frequency, to really ensure that we have got and are maintaining our target therapeutic concentration, we have the flexibility to do that in the phase II study. Just a question, just about, like, for the follow-up for that first cohort, the length of follow-up for the first cohort before deciding kind of? Oh, I'm sorry. Yes, the first cohort where we have three to four women. I'm sorry there. We will follow those women also through their pregnancy and take that data, evaluate it. Should any dose adjustment be required, yes, no, modify, not, and then progress into what we think could be a second cohort. Thank you. Looks like we' got some questions coming in from the webcast. We've got tons, actually, Jon. What I've tried to do in the background here is definitely club them into categories. Some of them have already addressed, actually, Róisín, brilliantly, but I'm going to ask them because they've come through here, and I'll just take them, kind of in order. Question about phase II, beyond the primary endpoint, of pharmacokinetics in pregnant moms, what are some of the other things that we'll be looking for as secondary endpoints? Thank you. We will obviously, as mentioned, be covering pharmacokinetics, sampling in the mother, and obviously the safety. We heard earlier, Dr. Geisen, speak to some of the monitoring through pregnancy that can occur through ultrasound, which will obviously be factored into our design. We'll be following the outcomes from the pregnancy and indeed the outcomes and follow-up of the newborn. I mentioned also about the importance of HPA-1a alloimmunization in these women who are at higher risk, determining whether it has occurred or not. Okay, thank you, Róisín. A quick one for you, Doug. Jon, you just send it straight to him because it says, "Follow up for Doug." What is the lower limit of quantitation in the MAIPA assay? Yeah. My understanding, from speaking actually with the authors of that study, is the LLOQ is somewhere between 1 and maybe as low as 0.8, U per mil. Yeah. Thank you. Very clear. Again, you've touched on this, Róisín, but I'll ask them as they come in. When would you be in a position to select doses to take into phase II? You've covered that in. Yeah. Directly. Yeah. Really, that will come at the end of 2023. Again, keeping in mind, we are on track to complete our 12-week repeat dosing cohort, and that data from that cohort will feed in directly, along with our other data, into the determination of the dose. Thank you. Questions that I know you've answered during the presentation, so I won't go there. Jon, based on your assumptions of phase II, when do you think we would see top-line data? Sorry, is this for me? Yes. Yeah, I mean. Sure. Go ahead. Yeah. I mean, this is work that we're working on at the moment, Martin. I think, you know, we need to speak to the investigators who are gonna be involved in this. At this point, it's probably a little bit early. Now that, you know, we've really sort of honed in on the design and then, you know, the efficiency of having a phase II, and then stripping away a lot of the sort of detailed PK work as we go into phase III. That's something we're actively working on. If you could just bear with us as we start to sort of work those timelines up, it would be inappropriate to make commitments at this point, I feel. Would you agree with that, Róisín? I would agree. Thank you. Thank you, Steve. Good, good. into the natural history study, not surprising at all. And again, you've touched on this, Róisín, but what is the expected rate of alloimmunization in the natural history study, and thus also in the phase II proof-of-concept study in pregnant women? So a little follow on there, and I'll give it now so that you can take it as a combined. Is there a risk that if the observed alloimmunization rate in the natural history study is significantly below expectations, that regulators could potentially require a placebo-controlled study? Okay. Thank you for that one. Again, the natural history study will be following the course of the alloimmunization. I think what I would maybe take a step back and is really to speak to our thinking around the design of the natural history study. In thinking about that, you know, we've anticipated that we could screen up to about 30,000 women to identify a population that would participate and under follow-up in the natural history study for the occurrence of alloimmunization. There is a point where you do need a representative data set on the frequency of alloimmunization against which to demonstrate if RLYB212 is effective, that it indeed prevents alloimmunization. I think at this point in time, I would prefer to really focus on. We've built in our sampling size based on assumptions around the HPA-1a negative gene frequency, and I spoke a little bit about that in the presentation. This is obviously an enriched population, which I think Steve spoke to, in that they are also positive for the HLA-DRB3, which confers the antigenicity, increased antigenicity. Frankly, I also spoke to those through screening. We're identifying today existing cases. Yeah -of alloimmunization. I think we have confidence, we do have confidence in the conduct, for the natural history study, and this, how this will control a future arm registration trial. I'll just take a moment and ask if Dr. Ryder has anything he would like to add. You, you've covered the points, Róisín. I mean, we've already confirmed, you know, HPA-1a alloimmunization is real. You know, newsflash, right? Yes, it's real. Confirming all the literature that's been in existence, and not our work, but the work of Professor Geisen and his Prophylix colleagues and others in Tromsø have confirmed that in women that are HLA-DRB3*01:01 positive, have that HLA genotype, which nicely matches the epitope of HPA-1a, right? With the leucine present there. They have an increased risk, and what is the absolute rate? It's somewhere in the ballpark of 15%-30%, if you go into the literature, something like that, of those mothers will... Yes ... alloimmunize. That's the rate that's been recorded. Yes In the literature. We're looking to confirm something in that neighborhood. Yes. To be more precise would be incorrect right now. Yes. No, I completely agree. It speaks again, as we often discuss, the power of natural history studies in rare disease. It's just so fundamental to those areas where there's just not enough, you know, knowledge. We're moving tack here a little, 'cause there's questions on the numbers in the natural history study, and you covered those admirably, Róisín. For phase III, though pending phase II data, based on the rarity of the condition, how many patients do you think you would need to enroll in the single arm study or to be required by regulators? Frequently asked question. ... Thank you. Have I got this on? Yeah, I have got it on. Oops, dizzy. Lesson number 1: never fiddle with the mic. Yep. Okay. So, how do we anticipate the size of the phase III study? You know, I think there's a couple of key points to answer that. Sorry, the future phase III study. The natural history study, in of itself, will inform our size for establishing efficacy, okay? I emphasize that component. How it will inform the number of women we will follow to establish the efficacy of 212 for the prevention of HPA-1a alloimmunization. As in any development program, not least, when you're developing a novel agent for a new indication, safety is obviously a key component. Really, it'll be... Fundamentally, it'll be a dialogue with the regulators. We will have a proposed size for the study, the number that we ultimately arrive at for the execution will be a blend, really, the number required to follow for safety, the number required to establish efficacy, and that will really be part of our end of phase II discussions. Yeah. I think I'm right in thinking... Steve, you go. I think you're gonna say the same thing. No, you go, please. Oh, no. I think if you, if you just look, and we've talked about this again frequently. If you just look at the numbers in terms for efficacy, it's kinda quite small because they're such an enriched population. Steve, I think you're gonna say similar. That's exactly where I was going. I mean, What you can say is that, look, we're looking for a categorical endpoint. It's binary. You're either alloimmunized or you don't. It's not a quantitative endpoint. It's not mean change in joint count or, you know, mean change in blood pressure or something like that. It's a categorical change, and we're also looking for a transformative effect. We're not frankly interested in a 20% reduction in alloimmunization. We want an RHD-like effect. Yeah. a RhoGAM-like effect. That's 90% plus? Yeah. Right? Where you expect 10 and see zero, well, things get pretty interesting, if that's the case. If you have the empiric basis for saying that the 10 should be present, we're gonna have every element of a sound, empiric basis. What do I mean? I mean a contemporary control, directly relevant, exactly the same patient population, exactly the same endpoint, temporal proximity, geographical stability, the exact same sites, every element. If you expect 10 and see 0, it's pretty exciting. Yeah. Absolutely. I feel I'm stealing your thunder here, Jon, as a kind of pseudo moderator, but I know this one's for Steve Uden, Steve Uden. Phase II study will be running through 2026. Are we expecting data along the way or not until 2026? We'll be constantly monitoring the data as it emerges and, you know, updating as things go along. Back to our earlier point, you know, we're still, we're not going to make any firm commitments, we will certainly be using any opportunity we can when we think we've got data that are going to be helpful and informative, being ready to share those data. Does that answer the question, Martin? It answers it really well. I mean, we have been very transparent. Yes. As a company to date, we will continue to be very transparent. Yes -as things come through. That was the last question of the combined variety, so I'm now gonna pass back to you, Jon. Okay, thank you. Any other questions from anybody else in the room? Perfect. With that, thank you, everybody, for coming, who came to Montreal to see the presentation. Dr. Geisen, thank you very much for all of your help. A special thanks to Ami and Alana for pulling this all together in their work. Thanks to those who listened in on the webcast as well. I think hopefully we were able to convey to you our excitement around the program, our excitement around the proof of concept data, giving you the direction of the future program for two, one, two, the milestones coming for through the end of this year, and also the excitement we have around one, six, which also has a number of milestones coming before we get to the end of this year. Thank you, guys, very much. We appreciate your time.