All right. Good morning, everyone. Thanks for joining us here, day three of the Leerink Partners Global Healthcare Conference. My name's Thomas Smith. I'm one of the senior biotech analysts here at Leerink, and it's my pleasure to welcome our next company to the stage, X4 Pharmaceuticals, represented today by Executive Chairman Adam Craig. Adam, thanks so much for joining us and looking forward to the discussion. Maybe, Adam, you could just kick us off and level set us. You joined the company last year. You've made a lot of changes. Maybe just talk us through the progress in 2025, what you're looking forward to in 2026, and obviously setting up for a potentially big readout here in 2027. Yeah. Well, thank you, Tom. Thank you for the invitation. It's good to be here. 2025 was a year when we took over as a new management team. X4 is a company based in Boston. It specializes in rare hematology diseases. Our aim is to build the company into being a world leader in rare hematology. Our focus at the moment is our mavorixafor, which has previously been approved for some very ultra-rare indication called WHIM, but we're now focusing on a much bigger indication called chronic neutropenia, and we have a Phase III trial, pivotal Phase III trial called the 4WARD trial, which is really the primary focus of the company. Since taking over, we've reduced costs, we've reduced headcount, and we've focused the company on the execution of the 4WARD trial. The aim is to complete enrollment by the end of third quarter this year, which means, as you alluded to, we'll have a data readout in 2027. That will give us an opportunity to have a second indication for mavorixafor in 2028. Thanks to Leerink and others, we're fully funded to commercialize our launch in 2028. That's excellent. As you alluded to, like, basically recapitalize the company, change strategic direction. Maybe just talk about the blocking and tackling that went into that. You have the approved indication, but we're shifting focus now to chronic neutropenia. Just talk about the rationale. Yeah. The rationale, initially, the first thing to do is we had to have the right management team in. We've made some quite significant management change, management team changes. We removed the C-suite, and we introduced new leadership. The leadership team that I lead is actually the team that worked at CTI BioPharma, which we sold to Sobi in 2023. We're experienced at developing and marketing drugs in chronic in rare hematology diseases. The next thing we had to do is reduce costs. I'm joined today by David Kirske, our CFO. David has been instrumental in reducing the costs, and when you see our earnings release at the end of this month, you'll see that we have significantly reduced costs and we're extending our cash runway every month as we continue to reduce costs. The third part of it is, was to get the execution of the 4WARD trial to a level that we're happy with so we can complete enrollment in a timely fashion. The 4WARD trial was not in a great state when we took it over. What we have done is we focused the team, the whole company, when you come into the building and you have to focus on the 4WARD trial. We ask all our individuals, "What are you doing today for execution of the 4WARD trial?" We've consolidated our CROs. We've moved the away from the commercial activity for WHIM. In fact, we've deprioritized WHIM completely, and now the MSLs are working on helping identify patients to go onto the trial. We've expanded and opened trials in the U.S. We now have around 100 trials open. About 20 of those are in the U.S. We're spending a lot of time in identifying patients in the community that can go to the treatment sites, the clinical trial sites, and be part of the clinical trial. It's rare disease. You have to work hard at finding and identifying the patients, and you've got to help the patients be guided to the clinical trial site. That's our focus. That's what we're focusing on. The restructuring, the finance, and it's really the execution of the 4WARD trial. Yep. Everyone rowing same time, same direction, all towards chronic neutropenia. I wanna spend some time, Adam, talking about the market opportunity, and maybe just kinda level set us on the issue of chronic neutropenia, current standard of care, limitations of standard of care. Yeah. I'll start with the standard of care. Chronic neutropenia affects the population of anyone who's got an ANC of less than 1,500. Hopefully, most people in this room have an ANC of 1,500 or more. If you don't, and it exists on a chronic basis, you have chronic neutropenia. That's about 50,000 Americans currently. Of those, about 15,000 have the population we're targeting, which is patients with severe and moderate chronic neutropenia, an ANC of less than 1,000 who are symptomatic, who have infections. That's the sort of total addressable market per label is the 15,000, and that. When the 4WARD trial is reported, we anticipate that's the market that we'll enter, and we've just done some great research with ClearView Healthcare Partners that we'll talk about later this year that confirms our belief that the population is 15,000. You had a second question. Standard of care. Yeah. The standard of care- So the, the, the CSF, uh- Yeah agents. The standard of care is about 60% of patients are treated symptomatically. They get infections when they get antibiotics when they get infections, but they don't go on to G-CSF, and about 40% of patients do have G-CSF, but not everyone takes it regularly. G-CSF is a wonderful agent. It's cheap, it's readily available, but the problem with it's an injectable, it causes bone pain, patients don't feel well on it, and there is quite a significant risk of long-term malignant transformation to AML or MDS. What I found since I've been out in the field, I was in Tampa yesterday at the children's hospital. When I go out into the field, the physicians are telling me not everyone wants to be on G-CSF. The beauty of mavorixafor, if approved in this indication, is that it's an oral agent, and so far it seems to have a very tolerable side effect profile. If that's the case, the market opportunity for us is not only giving mavorixafor alone, but it's also giving it in combination where G-CSF is currently given. You know, the aim would eventually be to replace G-CSF when it's used by some patients. Among the addressable that you're targeting, you just maybe double-click on that and like, for example, how many patients are currently on G-CSF agents? Our market research, it varies. There are about 30% are on it regularly, and then there's about 20-30% who are on it intermittently because they don't want to be on it regularly. So they'll be on it if they feel like they're developing a skin abscess, or they'll go on it because they're going out to a restaurant or a concert or something. They need that protection. But there are a lot of patients who just don't receive it at all. If you look at the median age of our patients in Phase II is actually in their thirties. If you think about it, if there is a risk of long-term malignant transformation, you really do not wanna be on G-CSF constantly for 40-50 years. That's a concern, particularly in today's, where patients are so well informed. That's a concern about the long-term use of the drug. Of course, it's an injectable and, you know, when I was a pediatric oncologist, the parents I used to work with don't wanna give injections to their children. They'd rather give a tablet or a capsule. Yeah. Are there numbers that we can put to persistency, the discontinuation rates with those agents that would seem to also be just phenomenal candidates for an oral? It's very, very variable. G-CSF has been around, as you know, for several decades. We'll talk about it later in the year. I plan to communicate more to investors about the market opportunity as we consolidate our data. The answer to your question is, it's all over the place. There are patients who take injections every day. There's patients who take it three times a week. There's patients who don't take it unless they feel unwell. It is really, really variable, and it's quite hard to quantify and to say, "This is how it's given." It's a very mature, old field that we're working in. The advantage I believe we have is we have a drug that's active, and it's an oral agent. Yeah. I think that's why we can penetrate that market. Yep. Let's talk about the novel mechanism. Mm. potential to revolutionize that. Just level set us, CXCR4, how exactly is that working to increase the neutrophil levels? It's a really simple mechanism of action. Neutrophils, as they're produced, are held in the bone marrow, and all mavorixafor does is antagonize CXCR4 and allows for that final release of neutrophils into the bone marrow. It's extraordinarily simplistic, and it works. You know, we've got a product label for WHIM that shows that we increase lymphocyte and neutrophil counts, and it's through this very simple release of neutrophils at the final stages of development into the bone marrow. It's nothing more complex than that. Right. You have Phase II data in CN. Yeah. Like maybe hit the highlights of that Phase II data set and what drove the confidence in building out the 4WARD study. You know, I always say it's a small data set. If I'd been doing this work myself, I would've generated a bigger data set. From what we see in the small data set, we see two things. We can see that mavorixafor can be given with G-CSF, and there aren't any apparent toxicity issues. Now, obviously, that will need to be confirmed by the 4WARD trial, but there are no toxicity issues that we've seen so far. The other thing it shows is you can give mavorixafor to patients who are on a very stable dose of G-CSF, and the G-CSF dose can be titrated down and in some patients actually stopped. That's really exciting for us. If we can be a replacement to G-CSF, the market opportunity for this drug is substantial. I know it was a relatively small Phase II study. How much variability did you see in the patient response, either by disease etiology or any other factor? It's hard to comment. That's why I always say when I talk about this data, the sample is small. You know, it's hard to really answer that question because the sample is too small. If we were doing this trial again, I would have done a larger sample size, and then I could have answered that question for you. I can't answer it. It's just too small. That's fair. Even in the small study, though, you saw a reduction in background G-CSF. Significant reduction. Yeah. I think in the overall at six months was 70%, and there were some patients who actually stopped the drug completely and had their ANCs maintained at 1,500 or more with mavorixafor alone, having previously been on G-CSF. It's a good outcome. Great outcome. Talk a little bit about the safety in that study, but also you now have real-world experience. Yes. We have three sort of data sets. We have the clinical trials that were done in chronic neutropenia and on WHIM. We have the post-marketing data set, you know, of reports that come in, and we also have the 4WARD trial, although the 4WARD trial is blinded, so we don't know. I reviewed the data just last month with the team. There were no new signals that we have identified. The DSMB met late last year and just said, "Continue the trial. There were no safety issues." What we know is generally the drug is very well tolerated. There can be some GI toxicity in the first couple of weeks. That typically can be managed with over-the-counter medication like loperamide, and then in most patients, it resolves. This is not an uncommon phenomenon with oral agents, and the more experienced we have become over the years, the better we have become at getting advice. I don't expect that to be an issue commercially. Elaborate a little bit more, if you could, on the 4WARD trial design? Mm. The patients that you're targeting, and then, I know you've made some changes, augmented as well. Like, walk us through kind of the rationale for that. Yes. The 4WARD trial is a double-blind, placebo-controlled trial. 176 patients, 1:1 randomization between mavorixafor versus placebo, and in both arms, there are patients who have G-CSF because that's the real world. There'll be patients who get mavorixafor alone, and there'll be patients who get it with G-CSF. We have two co-primary endpoints. One is a reduction in infections, and the other one is an increase in ANC, and you'd expect those. If one goes one way, you'd expect the other one to go the other way. We're over 96% power for both of those arms. David and I did increase the sample size from 150 to 176 when we joined. That gives us a bit more opportunity to enroll more patients in the U.S. because that hadn't been the focus of the prior management team, and that's important. It also makes sure that the study is extremely well powered. I'm very happy with the trial design. They were the only changes I made. As you know, I'm a physician and former chief medical officer, so this is my area. I thought the team did a really good job in designing the trial, and I look forward to completing enrollment and getting to data. In terms of region of enrollment, I think you made some changes there. Yeah. Increasing number of sites, really trying to drive greater U.S. population. Yeah. Thank you for bringing that up. It's really important that we have U.S. patients, and we develop relationships with U.S. people who've treated, and used the drug in the U.S. and treated patients. The emphasis. When we joined was more on Europe than the U.S.. We've switched that emphasis now. We have approximately 20 sites open in the U.S., some of them which have just opened, and the emphasis is to enroll U.S. patients now and develop relationships and get experience with the drug in the U.S. population. Would love to get your perspective, as someone who came into the company as the trial was kind of midstream, I guess like your level of diligence around the data that was kind of accrued to date, the patients that have been enrolled to date. Mm-hmm. You said you streamlined the CROs. Mm. Right? We've really streamlined a bunch of different processes. Like how comfortable were you? Obviously, you joined the company, right? Well- Quite comfortable around the data that's been collected, but, like, talk about what you've done to, I guess, boost the confidence. Oh, this wasn't a new story for us. David and I actually looked at X4 when we were at CTI three three and a half years ago. This wasn't a new story. There's an element, Tom, of unfinished business here because I really like the drug. Didn't think it had a commercial, there was a good commercial proposition for WHIM. It was great for patients, but not commercially. Always thought chronic neutropenia was an indication. I was very up to speed on the company. I'd followed it since I left CTI. We did do due diligence when we were invited as a management team by investors to join in August. We did do quite intensive due diligence, and we were allowed to look under the hood, which was great. I'll be honest with you, didn't really learn anything we didn't already know, except that we saw the clinical trial was really good. Really good and very well-designed by the team. The clinical development team did an excellent job. Due diligence didn't really surprise us. It was as we thought, and we've seen this with investors. A lot of investors have done work on X4 and were waiting for the right time to participate, and many of them came in in the financing in October of last year. That's great. One other sort of design question. Just on the primary endpoint of the infection rate, because I guess my sense is it can be kinda noisy and perhaps difficult to control for that. Like, how are you ensuring, I guess, like, consistency of you know identification trial site to trial site and consistency of the data collection? Well, I think one of the best things the clinical development team did before we joined was they put an independent panel in place to adjudicate infections. It's not us doing it. It's not the PI do it. There's a very extensive charter that's been written which specifies what is an infection and what isn't an infection. For example, chronic neutropenia patients get a lot of mouth ulceration. That's really common. That's not an infection. We're talking about someone who gets a chest infection. We're talking about someone who gets an abscess in their skin. It's really clearly laid out, and it's adjudicated independently of us. That's really good. The other thing is you've got to have a population where you can show benefit. The agency, the FDA, were really good at pushing the company to make sure the company enrolled patients in whom we can show a difference. The protocol requires that we have at least two infections in the prior 12 months before they come on. What we have in practice is 70% of patients, the latest data shows 70% of patients actually have three or more infections. That's really good. We've got independent adjudication of infections on trial, and we also have a population that demonstrates the need, and then one in which we can demonstrate benefit. That makes sense. One other maybe standardization question. Just, it sounds like we've designed the study to capture like a real-world population, but how are we controlling for the background G-CSF use? Is there any kind of? So- Protocol mandated? Yeah. At the FDA's request, if a patient starts on G-CSF, they have to maintain that dose and regimen for the whole trial. You can't change the G-CSF dose on trial. That variable has been removed. When patients are randomized, there's a one-to-one randomization based on G-CSF as well. We're not gonna get an imbalance of one arm having more G-CSF patients than the other. The only limitation of that is the trial won't produce a lot of data on changes to G-CSF dose unless there's a safety issue where the physicians can change it. We are, I mentioned just last week, a couple of weeks ago at a conference, we are in the process of designing a Phase II study where we're gonna start mavorixafor and then, guide physicians to reduce the G-CSF dose, so we can publish data on G-CSF dose titration. We'll have a 4WARD trial that gives us the big picture, and then there'll be a smaller trial that gives us it gives physicians guidance on how to use the drug in practice. Is that protocol mandated taper, or is it clinician discretion to? No, no. It will be a protocol where we provide guidance, but we're still having quite rigorous debate internally. Once we've done that, the plan is towards the end of this year is to start that trial, so it's available for the MSLs to educate on once the indication is approved. Right. The idea here would be, as you said, like in the hands of MSLs, not necessarily reflected on the label, but No. This would be part of education. It's an obvious question for a treating physician: how do I give this drug in practice? It's very important that we generate the data that provides guidance to physicians on how to give the drug in practice. Yeah. Great. You've alluded to this where you say we're on track for the Q3 enrollment completion. What have you seen since coming in and making some of these changes in terms of enrollment speed and cadence and I guess any change in the patients that are coming in now versus before joining? Slight changes, we have a slightly sicker population. We've noticed that more patients have three or more infections. We've noticed that the median ANC count has dropped a little bit to the low 400s. We have seen an improvement in enrollment, and we'll continue to work on that. The future of this company is dependent on the successful completion of enrollment, and that's the main focus, and we've done a lot of activities that have improved enrollment, and we're gonna continue to do that for the rest of this quarter into the summer, you know. Yeah. Makes sense. Help frame the expectations ahead of the top line readout in the second half of next year. Obviously, like you walked through the powering assumptions. Is it good enough just to kind of like hit stats? Are there other things? Like, what's the difference between a good data set and a great data set? I think we have a high probability success and others do obviously around the clinical trial primary endpoints. I think there are other endpoints that are very useful. I'm particularly interested in fatigue and quality of life. The PIs I talked to, including the person I met in Tampa yesterday, they speak on the Phase II trial of the patients feeling better when they're on mavorixafor, when they get off G-CSF. They feel less fatigued, they feel better. If we can demonstrate not only an improvement in the primary endpoints, but have some secondary endpoint data like improvement in fatigue or quality of life, that will add to our armory when we commercialize the drug, and that would be great. It's really, if we generally improve how patients feel, that would be great outcome for the patients, but also a great outcome for us. That makes sense. Talk about assuming positive data, timing to operationalize this indication. Filing, you already have the approval. Yeah. Shorter review timeline. Yeah. It depends on the review timeline, where the agency takes us. The assumption is that we will most likely launch in the second half of 2028. We have enough money to do that. Once we've got data, we'll start the commercial activities. We've done it before. We'll start bringing in leadership and then eventually MSL leadership and reps, and we expect to launch in the second half of 2028. Wanna come back on the market opportunity and leveraging the data that you're generating here. Like, when we think about subgroups where we could see early adoption, how are you thinking about that? I think the reality is we'll have two groups of patients. We'll have the monotherapy patients, and then we'll have the G-CSF patients. I think the monotherapy patients will probably getting into that market will be easier. I think the G-CSF we will penetrate, but it's gonna take some time. It's a drug, you know. I'll be honest with you, the drug has been around for a long time, so it's gonna take work, and it's gonna take a lot of education because there will be physicians out there who've said, "I've used G-CSF for two decades. Why should I change?" This, you know, this is marketing. This is education. You know, we're anticipating that, and we're gonna work very hard to make sure on day one of launch of this second indication that the MSLs have a data package available to them that allows us to answer questions and make sure that first experience with the drug, 'cause that's the key, the first experience with the drug is positive. That's what we're aiming for. That's what we did at CTI successfully, and we're gonna repeat it here. Yep. What proportion of the patient population is intolerant to G-CSF or complete primary non-response? That would seem to be a very low-hanging fruit. I'm gonna talk about that later in the year in a bit more detail because I'm still collecting. I have some data on that, but I'd like some more additional data. There are definitely three buckets. There's patients that have never been on G-CSF. There's those who are on it intermittently and not at all because they're intolerant to it or don't want to go on it. Then there's the third bucket of patients who are, you know, on it on a regular basis. I'm gonna talk about that more later this year. How should we think about the potential to price in this market? Like, you have the approval currently in WHIM. Yeah. just help kind of level set. Yeah. The current price is $500,000 a year. That's not sustainable for a broader population. As I've said previously, I think there is an opportunity here for premium pricing given how rare this disease is. We need to do pricing work, and we need to do pricing studies, and we need to do it properly. From my experience, I know it's not gonna be $500,000. It's gonna be less than that, but where it ends up will be dependent on what the research shows. That makes sense. Just in terms of, I guess, what's remaining in the company for WHIM and, like, how we're kinda keeping that available for patients, but we're not actively marketing that. Like, just talk about. We had a large marketing force. We had a sales force. That's all been cut back. We would never deny a patient drug. That's the number one rule in the company. The drug is available for patients who have WHIM. We have had some additional patients come on commercially since we deprioritized it, but we're not actively marketing it. When David and I took over, we were spending more money on the commercialization of the drug than we were getting in, and that just didn't make business sense in a company that needed more financial discipline. The drug is available. It continues to go to new patients, but we're not talking about a large number. We are, you know, we do expect to have additional patients every year, but that won't be driven by any active marketing. I think one of the interesting aspects of your clinical regulatory path from here is because you have the approved indication, we've already de-risked many aspects. Yeah. of the drug. I preclinically Chemistry. CMC manufacturing, like, all of those things are essentially off the table. You have a submission in Europe as well that's kinda working its way through. Yeah. I think you've got it to a CHMP opinion. Yeah. in the relative near term. Yeah, maybe just talk about, you know, how important some of that early blocking and tackling is to Well, I think. -to doing. You know, the commonest reason for an NDA to fail is chemistry, number one, and that's the FDA's already reviewed it. We have a well-trodden commercial manufacturing path, so that's not a concern. That does not keep me up at night. In Europe, to talk about Europe, we had a positive CHMP opinion for WHIM a week ago, and the plan, if we get an approval from the European Commission, what we will do is we'll transfer it to our partner in Europe, Norgine, who covers Europe and Australia, New Zealand, and then they will commercialize the drug in Europe. We have a good agreement with them. We get milestone payments, and we also have royalties that go into double digits in the 20s, into the low 20s, so that's a good agreement for us. That MAA will need to be transferred, and we anticipate it'll be transferred around the Q3 of this year. That's great, and yeah, there are very nice economics associated with the- Yeah. the Norgine agreement. Also maybe talk about just getting the drug in the hands of clinicians and, I guess, familiarity with it. I assume because of the price point, we're not seeing a lot of, quote-unquote, "off-label No. -use, but- No, but we're now getting inbound requests for ISTs, because we're open to doing that, and this is part where I was talking about further. We've got to generate a body of data before we launch. If there is an IST we can do that is safe, but expands the use and knowledge of the drug, we will do that, as long as it's safe. The plan is to have all this in place, some clinical trial from us, some IST work, so that by the time we launch, there is that experience that you're referring to. People understand that the drug is available, and they understand how it can be used. When we think about additional news flow or perhaps data generation, like, are there other data sets that we can or sub-analyses we can go back to in the Phase 2 experience and just help us. Like, I'm thinking about a presence at EHA, ASH sort of consistency to raise awareness of the program. There's some, but the dataset from the phase two is small, and it's been pretty well analyzed to date. Now from a prospect of great news flow this year, I don't think there'll be much. The news flow really will be in 2027. Yeah. That makes sense. As you made this comment, it's a drug that's been around for a long time, but how are you thinking about exclusivity assumptions? Just remind us, I guess, on the IP- Yeah. This is an orphan drug. We have a composition of matter patent approach that takes us out to 2038. We are looking at some patents potentially that would take us out to 2041. We're having patent counsel look at those, and we do have exclusivity we'll apply for around the WHIM indication. We're assuming from the time of the second indication it will be 10 years of exclusivity. Regulatory. Maybe a little bit longer. We just have some counsel looking at that, but our internal analysis is for 2038. 2038 with potential to build out maybe an IP. Yes. stayed around. Yes. Yeah. Okay. Perfect. All right. Well, Adam, unfortunately, we're up against time, but thank you for the updates and the insights, and we'll be staying tuned to the X4 story.