Good afternoon, and thanks for joining us to have a conversation with Paula Ragan, CEO of X4 Pharmaceuticals. X4 is a commercial stage company now. They are having developed drugs for underserved rare immunodeficiency diseases. FDA recently approved the company's mavorixafor. It It is a first-in-class, once-daily oral inhibitor of CXCR4 for the treatment of WHIM syndrome, a rare inherited primary immunodeficiency disease caused by genetic mutations in the CXCR4 receptor gene. The drug is also being evaluated in early-stage clinical studies as a treatment for chronic neutropenia, a major indication with a larger market potential than WHIM syndrome. So to learn more about mavorixafor, let's get started with Paula. Paula, thank you for joining us, and appreciate you accepting our invitation to talk to our audience today. So, briefly, could you help us, you know, set the stage of what we should be thinking about in terms of mavorixafor, its mechanism of action, and also why you think this drug has a wide potential across different indications? Thanks, RK. So thanks for the invitation here. So, you know, X4, as you highlighted, is in an amazing place in its history, just going commercial. But most importantly, we're at a special place because we're really impacting a high area of unmet need in a large patient population. So we're focused on patients with immunodeficiencies, and that field has been largely neglected over the last several years, with only one or two injectable treatments. The way that we're going about addressing that larger population is through a rare immunodeficiency called WHIM syndrome, which did just gain approval for XOLREMDI for the treatment of patients with WHIM in the U.S., and now we're broadening that out to chronic neutropenia and potentially other types of immunodeficiencies. So it's a special moment for the company. The drug's mechanism is broadly applicable, and we've certainly seen with the recent FDA approval that it has strong efficacy as well, right in the sweet spot to help these immunodeficiency patients with reducing their infection burden long term. So yeah, as we said, X4 is launching XOLREMDI for WHIM, but you're also initiating a phase III study for chronic neutropenia. So let's spend a few minutes on chronic neutropenia and what you're doing there. So how large of a market is this? And also, can you discuss the ongoing phase II study where you have highlighted some initial data? Yeah. So similar to WHIM, chronic neutropenia patients have low cell counts. WHIM has low cell counts across the board, and chronic neutropenia has in particularly, very low neutrophil counts. So it's a nice crosswalk, seeing WHIM, you know, being beneficial in our first patient population. Now with CN, we think there'll be a nice translation of increase in neutrophil counts and reduced, infection burden in CN patients. In the United States today, there's about 50,000 people diagnosed with primary neutropenia. So it means you're born with these diseases, or they're acquired over some period of time, but there's no reason, like, a lot of people think about chemotherapy-induced neutropenia or HIV-induced neutropenia. This is a separate disease. These are really, like, the primary and sole cause of their disease is the fundamental chronic neutropenia at play. So again, it's a nice reflection of what we've seen in WHIM in terms of their unmet need. They only have one treatment available to them. It's an injectable drug. It's very challenging, and literally, their challenges are dose-related. So anything that they can tolerate is helpful, and oftentimes they're trying to tolerate the minimum effective dose. This is why we're so excited about mavorixafor in this population, because it's been proven to be a safe oral once daily for WHIM syndrome. And again, the patient populations are so similar in their unmet need. We're hoping to see a nice translation of what we've seen so far into this potential 50,000-patient group. Perfect. So, there is a next set of data that's coming out ... from this phase II study, and, that, that's supposed to be released, in the first half, which is probably in the next couple of months. So what is, what is the set of data that, you know, you're expecting to release, and how significant is that going to be in terms of the next stages in the development? Yeah, so maybe we can walk through what's been shared to date. So about a little over a year and a half ago, we shared the phase Ib data, and it was resoundingly positive. Every patient responded to the drug after a single dose. So you give a chronic neutropenia patient a dose of mavorixafor, and they all increase their neutrophil counts by 500 cells per microliter. And really, what we've been trying to learn is, what is the durability of that? So we've been studying these patients now. We've released that we have over 20+ patients enrolled, who've completed enrollment, and I think the most exciting data set, or it's going to be the clearest data set, of course, is patients on mavorixafor alone. Again, if we harken back to WHIM syndrome, we had seven patients in our phase II study. Everyone could see how successful the drug was, looking at that point in seven patients with six months+ of data. So we certainly hope that the monotherapy data generated in the CN population will have like, similar clarity in terms of its potential in these patient groups. I would say the one added challenge and benefit, 'cause obviously it's a much broader market, and there's one approved treatment therapy, is what do we do about the standard of care being G-CSF? The way we've addressed this in our phase III trial is we're letting everybody come into the trial, with or without standard of care, but they must have infections, and they must have low neutrophil counts. It's kind of the undertreated world, is how we think mavorixafor is well-positioned for success going forward. Okay. So you also, you know, telegraphed that the pivotal Phase III is being planned for initiation in the first half of 2024. So do you have a certain design in mind for this late-stage study? And what data should we be focusing on from the complete Phase II data that's coming out, when we start thinking about success in the next Phase III? Yep. So the phase III study design is very similar to WHIM. It's a randomized, placebo-controlled, double-blind study. It's a one-year assessment, and the good point that we're at in conversations with the agency is that we have a clarity on the combined primary endpoint. So if we go back to the phase II data, what will we show? The phase II data, actually, we are studying a similar population, you know, either with mavorixafor and... Sorry, either without G-CSF and neutropenic or with G-CSF and neutropenic. So that data will crosswalk really nicely, and will show the bridge between the phase II data that we've had, and then hopefully the potential success that will kinda fold into the for the phase III. We feel good about that, because, number one, we're able to look at these patients' neutrophil counts over six months. The trial's a year. Certainly in WHIM, whatever we see in the first six months, we see in the second half. There's not much variation. And then finally, there's a very nice correlation, as we've seen in our prior successes, where increased neutrophil counts decrease infection risk. So we really think that this phase II data set will be very directionally supportive, and frankly, we're already, you know, as I've mentioned, or you've highlighted, we're already moving forward with the phase III as quickly as possible. We all know increased neutrophil counts decrease infection risks, and we've seen our drug in every other patient population perform well. This next final wave of data will certainly, I think, be clarifying in terms of the monotherapy potential and on where we're going. On the regulatory and commercial pathway for this indication, do you plan to do a separate study for EU, or the same study could be used both for filing both in the U.S. and in EU? Yeah, so we probably will take a similar approach to where we had it with WHIM syndrome, where we did get some advice from regulatory agencies. We don't have that yet for CNs, to be clear, but I think for the most part, agencies have been very supportive of looking for either additional or new treatments for these types of immunodeficiencies, given how limited the treatment paradigm is, and frankly, how severe these patients can be. Hmm, okay. And then, just on this program itself, what is the market really missing in this program, and what is your confidence for potential success of mavorixafor as a treatment for chronic neutropenia? Yeah, I mean, I'm extremely confident. I wouldn't be pushing the team as hard as I am to get the phase III started. I think, getting that, obviously the ultimate success in chronic neutropenia will unlock massive value for patients, and then everything follows from that. In terms of what we know today, in every patient that we have shared, our drug increases neutrophil counts meaningfully, and by meaningfully, it's at least 500 cell tick up or more. That is the line of clinically meaningful. Like, that is the universe of these patients truly are living in the world of a few hundred to low thousands. So if you, on a scale of 0 to 1,500, 500 increments matters tremendously to reducing their risk of either severity, duration, or frequency of infections. So we are in a great place. The phase Ib data, even if you just looked at that in the same buckets of patients that we're looking at in the longer-term study, it was very consistent. It's a nice elevation, and even our KOLs were thrilled to think about, Gosh, could I have an oral, once-daily treatment for my patients? 'Cause they're all very interested in minimizing their exposure to G-CSF. Okay. So now moving to the, to the commercial indication that we have, which is WHIM syndrome, what is, what is the commercial potential itself, for, for XOLREMDI? Because the debate has always been around, you know, how large is the market, and how can we make sure that the, you know, that the entire market, is accessible for to this drug? Yeah, I mean, maybe it's. It's always difficult to predict the future, but maybe I can review a case from the past. So as you know, RK, my experience was at Genzyme for many years, and many of our board and some of our founders come from Genzyme. So Genzyme's second drug, which was a drug to treat, Fabry's disease- Mm-hmm ... was, I would say, a very similar analogy to us. Like, they already had seen success with Cerezyme, ultra-rare, became very large, and even they were doubtful about Fabrazyme. In our, in their 10-Ks and 10-Qs that they were disclosing, they were predicting maybe 500, 700 patients total for Fabry disease. I mean, these were the experts. These were the people who broke open the world of rare disease, and they underestimated the market by an order of magnitude. Mm-hmm. Because the drug worked, the patients were complex to find, but, you know, if you build it, they will come, and we all know the Fabry story at this point in time- Yeah ... in terms of being massively successful. So WHIM syndrome is hard to diagnose. We look exactly like a WHIM patient. There is nothing physically evident from them other than their neutrophil counts and lymphocyte counts.... that would designate they are even compromised in any way. So it's gonna take some time to open the eyes of the physicians, but we're already- it was a wonderful timing for us to gain approval two days before CIS- Sure ... which is the Clinical Immunology Society. It was in Minnesota, Minneapolis. We had people approaching our booth going, like, Oh, wow, there's something oral and new in the immunology space, which in and of itself is a nice, you know- Mm-hmm ... door-opening comment. And then as they learned about WHIM syndrome, they're like, Oh, I might have some of these patients. So we're already hearing, like, it... You know, if the mind knows, the eye sees. That's one of the kind of catchphrases we use in rare disease, but the mind doesn't know yet. Mm ... because there's been no motivation to do so. Previous to XOLREMDI, there was nothing a physician would ever do differently if a patient had WHIM syndrome or CVID or chronic neutropenia. So now we've given them a reason to look and also a reason to believe that they can help them, given our label. We have infection rate, benefit in the label. We are in an excellent position commercially. So talking about the experience from the CIS conference, so when the doctors come to know about XOLREMDI and WHIM syndrome for the first time, I know you've been working with trying to get a diagnostic in place as well. So how is that really helping some of these doctors go back to their patients and kind of ensure if or if not the patient has WHIM syndrome? Yeah. So the great part of our label, as you may recall, RK, is the indication is for the clinical diagnosis of WHIM syndrome. And interestingly, WHIM is a spectrum of a spectrum of symptomology. So it's the warts, hypogammaglobulinemia, infections, and myelokathexis. Only about 25% of confirmed, genetically confirmed WHIM patients present with all of them. So number one, I think we've really shown the clinicians, Listen, you don't need to have warts to have WHIM. That was a comment that we heard a lot at CIS. Like, Oh, I thought you had to have everything. No, like, actually only about half to two-thirds of them actually have it. So I think the mind is now open. I think they're now looking just most broadly, Who do I have that's neutropenic and lymphopenic? And then from there, that will help them look for any of the additional symptoms. Do they have low IgE levels? Do they have a genetic test? Do they have... There's also a bone marrow aspirate assessment called myelokathexis that they can look for. So I think it's just really going to spark the idea that maybe one of my patients could benefit from this drug. Let me go examine them a little bit more closely. Okay. And then, do you feel like when you speak with these physicians, and as you talked about the Fabry disease, there will be a, you know, the mushrooming of the patient population, you know, not only here, but also in the rest of the world? Yeah. So I think... It's funny, I would probably say because of our healthcare system, the U.S. might even be harder-... than a lot of these other healthcare systems, where they just naturally have primary, secondary, tertiary care centers- Yeah ... and they funnel in the sicker patients. So I think if we can crack the nut in the U.S., I actually think the rest of the world will follow actually slightly easier. I mean, rare is always a challenge. So I think we're excited already to be learning and having the test case in the U.S., really understanding the patient journey and the presentations. We're obviously working with global physicians through the phase III study and the ongoing OLE. So I think that sets us up very nicely for commercial success across the world. Now, how we engage that directly, you know, we've been very clear we're looking for ex-U.S. partnerships, depending on the type of structure, 'cause we certainly wanna make sure we get the U.S. correct. Yeah. I mean, we really have to focus on, on the bird in the hand and on helping our patients that we can immediately benefit. So talking about that, you know, can you talk a little bit about your commercial team as it stands now and the plans you have as you you know initiate the launch and get the launch going? Yeah. Absolutely. So we mentioned that we have about 24 folks that are dedicated to field work. Most of them are the... I would say they're the, on the sales side of things, so we call them rare disease specialists. And then, you know, about the other, a little bit less than a third of it, are the medical science liaisons. Mm-hmm ... and also the patient affairs group. The important thing to recognize is the medical science liaisons are helpful two ways. Number one, they can help respond to questions, help educate about WHIM. But interestingly, and this is where CN is an excellent leverage point for us across many components of the business, physicians will raise the question of chronic neutropenia. The MSLs are allowed to speak to it and talk about our Phase III trial. So as physicians learn about the drug itself and learn the different ways their patients can contribute, we're there and ready to educate them about our ongoing Phase III study, and hopefully, that will help with even recruitment in the U.S.. It's a great synergy across the investment that we've made commercially, both obviously to get WHIM up and moving and ready for CN, hopefully when it's commercial, but it also helps our ongoing enrollment in the phase III. So, you're saying it's the same call point for the commercial team when they approach a- Correct ... physician who is treating a WHIM patient? Correct. Correct. Some of the things that we've learned, interestingly, is that even in the immunology setting, there is overlap with CN. You know, neutropenia are kind of more aligned with the hematologists, just given their comfort with G-CSF. But as we learn more in the field, we're recognizing there is this, like, nice continuum for the immunodeficient patients across both these call points. Mm-hmm. Okay. And then beyond these two indications, is there any other indication that you can think of that mavorixafor can be a treatment for? Yes, certainly. So there are a number of other chronic lymphopenias, which of course, we would be uniquely positioned to address, as well as other types of immunodeficiencies. So at this point, I think how we're trying to think about mavorixafor, again, is it's pretty big, heavy lift to get a drug launched and a phase III launched, all at the same time. But as we begin to learn more, even from input from the clinical world, possibly doing investigator-sponsored trials, there's lots of opportunity to think about where mavorixafor can go. But I think it'll be later in the year or early next year where we can say, "Here's how we can take it to the next level with additional indications." Yep. So anything, any anecdotal information that you can provide us from the commercial teams that have been doing this for the last, what, two weeks now or three weeks? Well, maybe the anecdote is, last week we had our launch meeting where they were trained on the final label. The thing that I would share is we have an incredibly experienced team. We have 250 years of boots on the ground experience finding patients, so that was phenomenal. And then number two, we had a patient come and speak to the team. Okay. So they are so motivated to be able to share that, moment in time of like, this, this is a person that you can help, and these types of people that you can help. And then their experience in knowing how to engage physicians and generate that awareness, I think we could not be at a better place. Fantastic. So you recently monetized the priority voucher that you have had. So, with the funds that you're gonna receive from that, you know, what are the plans for that? And, you know, would you be bringing any additional assets from outside? Hmm. Yeah. So that capital gets us into late 2025. In terms of additional assets, I mean, X4 was founded by in-licensing these molecules from Genzyme, so I certainly know a number of us understand what good looks like, and also always trying to find that diamond in the rough. So we're always opportunistic, always looking, but we do always wanna be managing that balance of our maintaining our runway, making sure we do what we say and say what we mean, and then be opportunistic as assets might fit with the company. Fantastic. So I think in the, in the last minute or so that we have... So what's the runway that you could get from this, from the total funds, plus the monetization of the priority voucher? And what are the next catalysts that we should be looking out for? Yeah. So we're excited because I think this year we'll have—I mean, even in June of this year, we presented the CN Phase II data. Beyond that, we'll be filing the marketing authorization application for WHIM, towards the end of this year, early next year. And we have shared that we are looking for types of strategic, ex-U.S. strategic partnerships. And certainly, you know, depending on the type of deal, if it's available for us, that might be an interesting component of the company's growth as well. Then, of course, as we see success in ex-U.S. approvals, we will be building out our commercial, commercial elements across the world as well, so. Perfect. Good luck with the launch, and talk to you soon. Thank you, RK. Thanks for the opportunity. Thanks, everybody.