Hello, everyone. I'm Max Skor. I'm a biotech analyst with Morgan Stanley. Before we get started, for important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. And now moving on, I would like to thank Paula Ragan, CEO of X4 Pharmaceuticals, for joining me. I guess if we would like to start off, if you'd like to start off with any opening remarks, then we can dive into the Q&A. Yeah, no. Well, thanks so much for hosting us. This is a great conference. It's nice to kick off the fall with the energy here in the city. And, you know, just X4's had a really big year to start with, so just very quickly kind of summarizing the last few months and then zooming out big picture. But we've had a drug, our first drug approval, Xolremdi, in a rare form of immunodeficiency, great positive phase II data for our next broader immunodeficiency indication, and then we sold our PRV in record time. But what that really enables us to do as a company is to achieve our vision. Our vision is to create a lasting product that can impact as many patients with immunodeficiencies as possible. This group of patients lived every day like we lived with COVID for those first, you know, few years. They have a high risk of severe recurrent infections and sometimes life-threatening or life-ending in certain cases. And it's been a group of patients that have been predominantly ignored, or it's a very complex set of diseases. So we are really excited to be a company committed to this space and to bring possibly the first oral treatment in certain cases, certainly with WHIM syndrome and with our broader indication in CN. So we're in a great place, being now a fully integrated pharma company, launching our first product, and hopefully on our way to serving even more patients as possible. Great. Thank you. So just to kind of level set, mavorixafor, the generic name for Xolremdi, could we just talk about the mechanism of action? Specifically, how does CXCR4 antagonism impact the bone marrow, leading to increased circulation of neutrophils and lymphocytes? Yeah, so it's great. So all of us hopefully have white blood cells circulating in our bloodstream to help us fight infection. That's the army that is needed to address bacterial, viral, or the whole spectrum of foreign pathogens, and white blood cells are made in the bone marrow. All of these cells have some form of CXCR4 expressed on them as they journey through their evolution into fully functioning immune cells in the bloodstream. And probably the most impactful component of their journey is their maturation and then migration ability. Imagine if you had a well-trained army that was locked up. You know, it's not really going to really do the job. So mavorixafor enables the migration of white blood cells from the bone marrow into the circulation so that they're then released and can perform their immune surveillance job. In immunocompromised patients, this migration component of capability is significantly impacted, so mavorixafor overcomes that, helps these cells migrate from the bone marrow and become the effective immune cells and disease-fighting army that is needed for health and safety. Great. So, pivoting to the recent approval of Xolremdi for WHIM syndrome in April 2024, congratulations. We could start high level, talking about brief overview of WHIM syndrome, severity, incidence, prevalence, et cetera. Yeah, so WHIM syndrome is a severe combined form of an immunodeficiency. So all of the, the white blood cells that I described earlier, they're all suppressed and locked in the bone marrow, predominantly because of an oversignaling in a cascade called CXCL12/CXCR4. So mavorixafor intervenes that step and helps these cells move forward. So it's a rare form of immunodeficiency that is congenital. These patients are born with this problem. To date, we've really focused our efforts in the U.S., so today we feel comfortable saying there's about a thousand patients with WHIM syndrome in the U.S. And the approval of Xolremdi is the first drug ever specifically approved to target the origins of their disease. We're so excited about the, the partnership that we had with the FDA or the, the collaboration to get this drug approved in this rare population. The label itself describes how meaningful the drug is in terms of our reduction in infection rate, which was 60%, as well as a component of severity. And so we're really grateful to the entire community that helped get this drug first approved as the only targeted treatment for WHIM syndrome. Targeted treatment, and expanding on that, you're actually addressing the underlying cause of disease, and that's included in the label. How could you expand a bit on how that's differentiated? Yeah. So specifically with WHIM syndrome, these patients are defined by having an oversignaling of a chemokine receptor called CXCR4, and what that does is it kind of holds these white blood cells in check. They're almost imprisoned in your bone marrow in an extreme case, and by antagonizing, we have an oral, once-daily CXCR4 antagonist. That's the mechanism of action of mavorixafor. And what that does is it actually blocks that brake, and it allows the cells to proceed and enable white blood cells to circulate. And then, more importantly, clinically, it's certainly cell counts are meaningful to predict the patient's risk, but at the end of the day, we saw in our phase III study a reduction in rate, severity, and duration of infections quite meaningfully. So this drug is really hopeful to transform these patients' lives from sort of a risk-... on situation where they're living very much like the COVID lives we all experienced, to hopefully a much more normalized life, 'cause their immune system are now capable of responding to infections. Great. And diving a bit deeper into the patient profile, I imagine internally you have estimates on the penetration rate of the 1,000 patients, U.S. patients, but can you talk a bit about is there a spectrum of severity? What percentage do you think will be, really, first comers to this, medication? Yeah. So we've done a lot of market research, so the thousand, in our view, is really representing that moderate to severe end of the spectrum. There certainly are likely. All rare diseases have the full spectrum of mild, moderate, and severe, but I think what we've shown with our phase III study and what we believe as representative of the overall market, is who are still getting those repeated severe infections. Our phase III showed that these patients were getting four to five infections in a year, and they had about seven weeks of illness per year. Thankfully, with the Xolremdi treatment in the phase III, we saw a reduction to about one and a half infections per year, and only two weeks in total of illness or infections a year. So I think we are incredibly pleased with that data set, and that is going to help drive, of course, the utility of it across the patients who still need it, which are the ones that are getting these recurrent infections. Mm-hmm. Okay, now pivoting to the launch, can you talk a bit about the price, copay, payer coverage, what kind of sales force you're putting together? Yeah. So we shared that. So we're launched in the U.S.. We have about two dozen people in the field, including our sales force, as well as our medical science liaisons and patient advocacy individuals, and that covers the full country. So it's actually a very specialized, very experienced group of people that we've been able to thankfully attract to join X4. They have rare disease experience. So it's really about driving education, awareness, and then helping support with the physician and the patient. We have a hub, a payer. I'm sorry, a hub system where patients and physicians can utilize the start forms to really get patients on quick start therapy and then help them navigate the payer coverage in the meantime as well. Are these patients, is there a pretty good understanding of where the patients are going to seek treatment, what the care is like, geography breakdown? Yeah. So we've been in the field for a couple of years, obviously, pre-commercial with education and awareness. So we do have kind of our tiers. We have physicians that we know that are managing WHIM patients today, and then we broaden those tiers out as we've done market research and begin to develop tiers of relationships and tiers of awareness. So we certainly feel very comfortable, again, with that thousand number, and then how quickly we penetrate that is really a cascade of working through these different layers of relationships and also education and awareness around the recent approval of Xolremdi. And as you had said previously, this is the first approval for WHIM syndrome. But how are these patients currently being addressed? What's the competitive landscape look like? I know IVIG, G-CSF, and then, of course, plerixafor, but that's. I don't think that's used specifically for WHIM syndrome. Yeah. Similar mechanism. Yes. Yes. So the standard of care is heterogeneous, like the disease, and they're basically trying to address the different splices of the disease as really, versus the underpinnings or the single root cause. So yes, these patients, if they have low immunoglobulin levels, they can be prescribed intravenous or sub-Q immunoglobulins. In our own phase III, we still saw a benefit on top of that. So there is still unmet need, even despite IG, and at times they are given G-CSF. In particular, in WHIM patients, the bone marrow pain associated with G-CSF administration is exceedingly high, so it's used in a very limited ways and more sort of in more rescue situations. So I would say these patients have a heterogeneous and piecemeal standard of care. We certainly expect that a once daily oral treatment that has the benefit and, safety profile that mavorixafor will have will really become the underpinnings of their care long term. Okay, that's helpful. Last question on WHIM is whether you're on track to submit your European MAA by early 2025. Is everything on track there? Yes, absolutely. We are pleased. I mean, we started this journey with our European regulators, many years ago, where we sought scientific advice, so that we made sure our phase III was lined up with their expectations. And then, of course, now with the study completed, we've gone back to them with basically, like it's like a pre-NDA meeting equivalent with the MAA, and we are nicely on track, clear on what the expectations are. We'll be delivering that filing early twenty twenty-five. How does the prevalence look in Europe? Very similar. There's no... Sometimes with these rare genetic diseases, you'll find pockets that are more founder effect related, so they'll be enriched populations. But interestingly, with WHIM syndrome, it's been a pretty consistent prevalence across the world that we found directly. Certain regions in the world do kind of have sort of higher propensity of rare diseases in general, but no founder effect per se, in terms of the genetics. Okay, that's helpful. I guess the last question, but this is also pivoting to chronic neutropenia, which is a much larger indication. You also have studies underway there. How did the results in WHIM syndrome inform your approach to testing mavorixafor for chronic neutropenia? Yeah, no, that is a great connection 'cause. So WHIM syndrome is a form of congenital neutropenia. It's very specific and defined, which was a great way to start our clinical development strategy. It's kind of a higher and enriched population to help for success. But that's where we really can crosswalk very nicely. What we have seen with mavorixafor in WHIM is an increase of neutrophil counts to about 800-1,000 cells per microliter, and this really consistent benefit in infection burden. So rate, severity, and duration were nicely reduced with mavorixafor in our phase III. Neutrophils then crosswalk into chronic neutropenia. These patients similarly have low neutrophil counts, and they need to boost those to fight infections. So as we've generated data in WHIM syndrome, connecting that, it's called ANC, absolute neutrophil count, to reduce the infection burden, we can now crosswalk or begin to crosswalk what we're seeing in chronic neutropenia because similarly, our ANCs are nicely boosted over time in CN. So we can hopefully draw that conclusion and gives us huge conviction to move forward as quickly as possible with our CN phase III. Okay, can we talk about the target patient profile, severity of these patients, prevalence, anything there for chronic neutropenia? Yeah. So chronic neutropenia is an easier disease to study 'cause it's a larger population, and therefore, there's more information in our healthcare records and actually more diagnostic codes to truly identify these patients. So today in the United States, there are about 50,000 patients with diagnosed chronic neutropenia, ICD-10 codes, so it's a much easier group to track over time. From that first sort of market research that we've done, we've recognized that about a third of those patients, 15,000, are truly high unmet need. They're either refractory or unable to take G-CSF, which is the only approved treatment, or they're just sometimes contraindicated because of their etiologies of their CN. So that patient population, the 15,000, is how we've now targeted our phase II trial design. It is focusing on high unmet need, refractory patients to G-CSF. They have recurrent severe infections and low neutrophil counts. So we believe if we are as successful with our CN phase III as we were in WHIM, we're really going to continue to unlock the benefit of this drug for even a much larger patient population. Okay, before jumping into the data you've presented so far, could we just talk about how G-CSF is currently used, and as you talked about the unmet need there? Yeah. So G-CSF is the only approved drug to chronically treat severe chronic neutropenia, or SCN is the label. The drug on the positive, of course, do help with infection benefit. When you increase neutrophil counts, it's very nicely correlated with a decrease in infections, and maybe this audience might be more familiar with, like, chemotherapy-induced neutropenia, right? You give someone chemo, unfortunately, it wipes out their bone marrow, and they have very high risk of infections. G-CSF is used to treat those patients acutely to kind of bridge them through their chemo. So again, it's a nicely validating approach to neutrophil counts up, infections down. Now we are moving to a completely different population. These people are not on chemo, they're just their own primary disease, that their bone marrow is suppressed, and they can't produce enough neutrophils. So these patients are also given G-CSF to try to help restore their neutrophil counts, and on the positive side, it does. However, G-CSF has very significant long-term risks in terms of increased malignant transformation to the bone marrow, so some physicians are very hesitant to give it chronically over time. And then, if you think about these poor patients, they are experiencing the bone pain that you experience with G-CSF, but it's for the rest of their life. It's not a bridge until they get through chemo. It is, you know, daily to weekly, depending upon their frequency of injections, and it's a tough drug to take. It was not really designed to be a chronic prophylactic treatment. We believe with mavorixafor, if an oral, safe, once-daily can help also reduce that infection burden. It will again kind of create the right drug for these patients to be sustainable for their lifelong journey. Okay, great. Recently, you presented follow-up phase II data, if I'm correct. Maybe initially, we can talk about the phase II trial design, enrollment criteria, the severity of this patient population, and then just data to date. Yeah. So the phase II study. I mean, again, I X4 is really always trying to do the most sort of groundbreaking approach. No one has studied chronic neutropenia in 30 years, since G-CSF. So our phase II was really to kind of level set. Let's take this population, understudied, misunderstood, and just begin the journey of what happens when you give mavorixafor, same doses in WHIM, to these patients, regardless of how they walk in the door. So some were neutropenic without G-CSF, some were neutropenic still on G-CSF, and some were normal on G-CSF but interested in seeing if they could ever reduce it. So those were kind of the three tracks that we explored with our phase II. It was an all-comers exploratory trial. So in June, we actually got to share information on two of those three questions. So can the drug impact neutrophils as a monotherapy? Patients came in neutropenic. They actually should have been on G-CSF, but they were not. They're either refractory or their risk is too high. Nicely, they took mavorixafor oral once daily, and we see this nice sustained curve of neutrophil counts increasing, very similar to what we saw with WHIM phase III. So again, it gives us confidence this drug has the possibility of helping their infections. The second category was patients who are on stable G-CSF. Can we give the drug safely in combination with G, and can you see an effect, or is there some ceiling with two drugs? The beauty of that second panel that we saw is, of course, we can give it safely. That was a very positive outcome. And then, number two, there isn't a ceiling effect. When you add mav to G-CSF, you actually see an increase of almost an additional three thousand cells per microliter on average. That's a really big jump. That's double what we really need to be normal, so it was a really nice, resounding combination effect, and then that led us to, "Hey, this looks like you can actually reduce G-CSF." You could pull away some of that drug that is the harder of the two to take, frankly, and that leads us to the third question, which we have yet to present data on. That will come in November. When you combine the drugs and they achieve the right neutrophil counts, can you start to back off of G-CSF so it becomes more tolerable and less risky to the patient, so those are the last set of data that'll come in November. We did have a couple patients anecdotally that we presented about a year ago, and the answer looks pretty good, but of course, we need a fulsome data set. We'll have eight patients' worth of data coming in November. Eight patients. Okay, and could you kind of set expectations going into the November readout? What are the key efficacy or clinically relevant endpoints that you're looking at? I know ANC, change in ANC. Is there a threshold you're hoping to hit there? Yeah. So the most important thing is always the doctor and the patient, what is relevant to them. So in this universe of treating chronic neutropenia today, physicians will target about eight hundred to a thousand in these patients to get... They want to see ANCs of about eight hundred to a thousand on an absolute scale to feel like they've reduced their risks enough. And enough means, you know, G-CSF is a tough drug to take, so they're always trying to kind of titrate that balance. So the phase II study, we said, "Use mavorixafor and G-CSF as you would in your normal clinical practice." So clinicians were targeting eight hundred to a thousand as their metric of when they can adjust dose. So what we can expect in November is, what does that look like? Can we achieve that clinical target of 800 to 1,000 with mavorixafor alone? Can we, can we do it in combination with G or some reduced proportion of G? So that'll be helpful for sort of the overall spectrum of opportunity to potentially either completely back patients off or back them off meaningfully so that they have much less G. Or I still think some patients will always need G. In the spectrum of human immunodeficiency, there's always going to be those tough to treat ones. We don't want to exclude those, but we'll start to see what that full picture look like. So the patients who are on G going into the study, where you'll see eight patients worth of data in November- Yes. What was their baseline neutrophil counts, approximately? Yeah. So it is variable. So some are neutropenic, meaning below fifteen hundred, but some of them are also up in the normal range, which is above fifteen hundred. So what the win is for these eight patients is, can they stay around eight hundred to a thousand, with mavorixafor, but with some or a lot less G or no G? So that's really the metric for success is: can you get them into their clinical target zone, that is in current standard of care today, with either just mav or mav plus much less G? Or you know, we'll see what that balance between mav plus G is. The physicians, it's up to them in regards to how they'd like to taper down the G? Yes. The challenge with G, I mean, we'd love to create some formula that is sort of an automatic, but G-CSF is a very tough drug to administer. The same patients, or two different patients with the same weight could have dramatically different reactions to G-CSF, so it is very individualized, which makes it hard to manage patients. Like, literally, we have some patients that have to, they come in for their G-CSF treatment alone. It takes them many months to find the right dose. So this six-month trial on eight patients will help us begin to sort of, I would say, create guardrails around what we think is possible, but at the end of the day, hopefully, when the drug is used commercially, it'll be always in the patients', in the physician's hands to determine how that happens. I imagine you've spoken to many KOLs. Do you think there's a disconnect between investor expectations or how investors are digesting these data and what KOLs and physicians are thinking? Absolutely. So I mean, I think, you know... What I think is hardest for investors is lack of benchmark, really. I mean, we are in a brand-new therapeutic area, just immunodeficiencies in general, and then chronic neutropenias, there hasn't been anything for thirty years, so it's very difficult for today's investor to know what good looks like. Our KOLs who treat patients and our clinicians who treat patients every week and month know what good looks like. They know they want to see that eight hundred to a thousand target, and they believe that when they see that, that's going to translate into infection benefit. And we've proven that in WHIM syndrome, right? That same target and same expectations were proven out with mav and WHIM and our ultimate approval of Xolremdi. So I think the investor community just needs more time to really connect those dots, right? We have an approval with Xolremdi. That profile for approval is already looking good enough with mavorixafor and CN, certainly from the clinicians' perspective, because they're helping us enroll the phase III. And certainly, you'll hear that directly from the KOLs as you know, we bring them on some of our investor calls. They're very excited about a safe, oral, once-daily, fixed-dose drug, simple to administer, and hopefully something that can support these patients throughout their life. Okay, I think that's a good pivot now. We can now talk about the phase III trial, how the phase II kind of informed the phase III design moving forward as either monotherapy. Basically, thought process behind the pivotal phase III trial. Yeah. So the phase III trial, you know, starting with the product and working backwards, we want to deliver something that is clinically meaningful for patients. Today in the U.S., that's that 15,000 number that I mentioned. These are the folks with recurrent infections, with or without G-CSF. They just, the standard of care is not delivering what they need, and they are getting repeat chronic infections and severe ones. And over time, it actually, you lose function, so you lose lung function, you lose hearing function, so we know what long-term implications of those repeated infections are. So our phase III study design is to target those severe patients. To join the study, you must have had at least two infections in the year prior. That's the definition of recurrence. And then you must be neutropenic. You must show an abnormally low neutrophil count, which puts you at risk. So those are the inclusion criteria. Now, those inclusion criteria can be on top of whatever standard of care you have. About two-thirds of the patients we'll enroll in the study will not have anything on board. Those are the refractory or intolerant or just not able to be administered G-CSF. Some of those will still have some G-CSF on board. They're able to tolerate at least the right dose but still not achieve a full clinical response. So that's the study design, because we think that design will ultimately target the high unmet need patients, regardless of standard of care, who still need more and are still at high risk. So there's not a dedicated monotherapy arm? No, so there is. Yeah. It's a randomized, placebo-controlled, double-blinded study, very high bar, one year to complete the study on treatment, and about two-thirds of the patients will be on monotherapy balanced across both arms. I'm sorry, about ninety patients out of the hundred and fifty will be on monotherapy mavorixafor alone or placebo. And then about the remaining sixty will be on whatever background G-CSF, as long as they meet the inclusion criteria and also balanced across each arm. Okay, great. And how is enrollment going? Good. If you can talk about that at all. Absolutely. I mean, I'm sure folks familiar with our industry, a phase III trial is always the highest operational lift for any company. It's all about numbers. So just to benchmark, our WHIM phase III had about 30 patients and about 18 sites. Now we're going for a fivefold multiple of that, fivefold operational kind of challenge. But we've been there, done that before, so I would say we have direct learnings from the WHIM phase III that apply to our operational success in CN. And thankfully, there's not another global pandemic going on right now, which was certainly a lot of headwinds for immunocompromised patients during, you know, 2020 to 2022. So we are in a very good position, and we know the sites, we know the countries, and we know the regulators. That site activation curve is coming first, and then that patient enrollment curve is following very nicely. We fully expect to enroll the study by midyear next year. There's no interim readout? When will the final data set come? Yeah, no interim readout. I can assure you, as a small-cap biotech, we would love something as fast, as soon as possible, but we won't sacrifice the integrity of a trial. So it will be a full readout, approximately a year after enrollment, so mid-2026, with data second half of twenty twenty, phase III data second half of twenty-six is where we're looking at. Okay, great. And then on your second quarter earnings call, you reported $170 million in cash, cash equivalents, which is expected to provide a runway into late 2025. Could you just walk me through a bit of your thoughts on capital allocation? You have the launch going on, the phase III, finishing up the phase II. Any thoughts around financials? Yeah. So we recognize the kind of the continued drumbeat of the company in terms of milestones or the additional data in CN at the end of this year, MAA approval early next, or sorry, submission and approval kind of early next year to later next year, and then CN phase III data second half of 2026. You mentioned cash through, you know, the end of, or at end of 2025, so we do have capital needs. There's lots of ways that we're exploring to solve for that. So we have shared that we're looking for an ex-U.S. partnership. Certainly with the ingredients of an FDA approval, great CN phase II data, and an MAA submission on the horizon, that certainly are the right ingredients for a successful recipe for an ex-U.S. partnership, assuming we get the right terms. As certainly our cash runway doesn't include revenue from Xolremdi, so there's always extensions beyond that, and other non-dilutive ways certainly will be around, you know, sort of royalty deals, et cetera. So we do think we have a few levers to continue to pull on as we try to continue to capitalize the company. And certainly, equity is always on the table for companies at the right time. Of course, right now, we don't think the value proposition is right at this point for an equity component, but we have lots of options and are looking forward to our execution in the next few quarters. So in regards to Xolremdi guidance, revenue expectations, consensus, any thoughts on that, basically? Yeah, no, I think the analysts have done a nice job kind of appreciating that these. You know, in 2024, it's really like building the infrastructure to enable that funnel, and then 2025 is really where the revenue starts to pick up and have more of a material impact on our burn. Beyond that, again, 2026 and beyond, there's always a lot of wild cards as you get further out, but we feel reasonably represented. But at the end of the day, our job is about execution and delivering, and we certainly look forward to doing that. Great. In the last few minutes, is there anything else I missed? Anything you think investors should be focusing on, to get a better understanding of the X4 story? Yeah, I mean, I think we have a simple story, and I think I will. You know, we've had the pleasure of talking to a lot of great investors here today. We have a simple story. We have an oral once-daily treatment, and this really neglected patient population that has shown, at least in WHIM syndrome, to correlate neutrophils up and infections down. And we have a much larger population coming imminently behind that, of which we've already shown neutrophils up. So I think we're in a really exciting moment in this company's history. We have an approved drug, we're launching, and we have something following fast on the heels, and we're here to stay. So we look forward to more opportunities to share in the future, and you can fact-check me a year from now. I guess last question, IP protection, how does that look, going out? Absolutely, so I've come from Genzyme on the deal side, so IP has always been a big focus of ours, so we have an issued U.S. patent through 2023, 2038. It's called a fingerprint patent on mavorixafor. This is the same type of IP that Biogen used on Tecfidera, so the composition claims have been allowed, but now we have composition claims on the full drug substance. My COO is here, and she knows exactly how important that is and how robust our processes are to support that. It's U.S. granted, I think it's also ex-U.S. granted, and of course, we continue to build the multiple ring fences around IP, so a number of issued methods of treatment as well. Great. Thank you very much. Thank you. I really appreciate it. Appreciate the time. Thank you, everyone. Thank you. Thanks.