Great morning, everybody. Thanks for joining us for day three. I'm Matthew Harrison with investment banking here at Morgan Stanley. Pleased to have X4 with us for the first fireside today. Just quickly before we get started, I have to read a disclosure statement. Please note that all important disclosures can be found at morganstanley.com/research/disclosures. So, Paula and Adam, thanks for being here. Appreciate it. I thought maybe why don't we just start out a little bit with, obviously, you're developing an asset for a variety of neutropenic conditions. Maybe you could just talk a little bit about, you know, where the drug came from, what's the mechanism, and sort of, you know, how you've decided on the indications you're going after.
Yeah. Thank you, Matthew. Thanks so, so much for having us here at the conference. You know, we're really excited about X4, the company's focus on really doing something quite innovative for patients with immunodeficiencies, specifically neutropenia, as you mentioned. Unfortunately, today, everything's injectable that... and there's very little to treat these patients, so our oral once-daily mavorixafor really differentiates itself, both obviously on sort of the safety profile and its convenience of delivery, but its mechanism, as you mentioned, is quite unique. It's something they take once a day, and it actually mobilizes neutrophils or moves white blood cells out of the bone marrow, and it allows them to circulate more. So for patients who have low white blood cell counts, this is really revolutionary.
Normally, they're either taking an injectable drug called G-CSF, some of them get injectable immunoglobulins, which are all quite challenging and life-altering to change. So it became a very obvious choice for us, first focusing in a niche indication called WHIM syndrome 'cause there's a very tight mechanism correlation with the disease and our drug, and then the broader population, chronic neutropenia, of which there's about 15,000, as our first addressable market, is just waiting for something that's oral versus their injectables.
Okay, perfect. Just for people who aren't familiar, so how does CXCR4 wo rk in terms of the mechanism? You know, I think people when they hear novel small molecule mobilizes cells maybe they think, are there safety risks that they should be worried about? So just talk about the mechanism there.
Yeah, that's a great question. So CXCR4 is a receptor held on a variety of white blood cells, and it's typically part of the normal developmental stage of a bone white blood cells being produced by your stem cells and then evolving along the way. So the good news is we know a lot about safety 'cause there's actually one approved CXCR4 antagonist that's injectable only. It's been on the market in, you know, thousands of patients now, so we certainly have a window into safety from that molecule, and then our oral once daily is almost a descendant of that molecule, reused for chronic, hopefully lifelong treatment to help patients. To date, we've really just seen it do exactly what the mechanism is known to do physiologically, which is really help advance the maturation of white blood cells and move them into the bloodstream.
Okay.
Super. You indicated your first indication is WHIM. Obviously, rare disease, maybe people don't know so much about WHIM. So maybe just tell us a little bit about what is WHIM, and what's that market size?
Yeah, so WHIM Syndrome, it's a rare disease of the immune system. It's caused by sort of over-signaling of CXCR4 receptor, either directly through mutations or sometimes through alternate pathways, and that's where our drug plays extremely well. Our drug actually antagonizes or blocks that over-signaling. The disease itself, I always try to anchor people, it's a little bit like the "Bubble Boy" syndrome, not quite as severe 'cause those folks really need to be almost isolated from an immunocompromised state. But our patients walk around with lifelong high risk of very serious infections. They get repeated infections, and then they lose function. They lose of lung function, hearing function, they get acute cellulitis. So imagine living like COVID days, except every day of your life. So it's a very tough road for them to go down.
There is no treatment specifically for WHIM syndrome, and we're really excited about our data that we just showed. Our Phase III data was tremendously positive, and we're really giving some hope to these patients. Talk about how many patients there are, we believe there's about 1,000 at least confirmed in the U.S. today, so again, niche market. But it's just such a great correlation between the mechanism of the drug and the cause of the disease that I feel... That's our industry, is, like, great opportunities we can actually get at the root cause.
Great. Yeah, and so you talked about Phase III data, so maybe just remind people what the data was, you know, what kind of regulatory endpoints you needed to meet here because I'm sure there's some uniqueness given the size of the population.
Yeah. No, thanks. So we had great partnership with the FDA for many years. In fact, they granted us breakthrough therapy status based on our phase II data. That really is reserved for diseases of high need with basically essentially little or no treatment. So we were you know, pleased and privileged to be granted that, and as a result, we had lots of close dialogue with them. So our Phase III was very tightly aligned with their requirements and guidance. It was a randomized, placebo-controlled, double-blinded trial, so very robust. Our primary endpoint was something called time above threshold for neutrophil count.
It's really a measurement of how many hours a day are they back into sort of less risky ranges, and we hit that out of the park with a, you know, p-value < 0.001 in terms of statistical significance. And then the secondary endpoints were around other metrics, most importantly around clinical benefit, and that's, in May of this year, we showed that our drug meaningfully and statistically improved a number of those metrics, including reduction in frequency, severity, and duration of infections. It really. I think even the investigators were blown away with what we showed.
... So in terms of next steps there, I know you recently filed in the U.S. so how should people think about the timeline and the path to market in the U.S.?
Yeah, the clock is on. So we filed our NDA towards the end of August. So it's about a 60 days review cycle, so end of October, early November. And then from there, that's when they accept the NDA. Once it's accepted, and assuming they give us Priority Review, which we would expect in this context, it's about a six months to approval PDUFA target action date. So we're planning kind of a mid-Q2 launch next year for mavorixafor for WHIM syndrome in the U.S.
In terms of commercialization, you plan to commercialize this yourself. What sort of preparations are you doing, and-
Yes, we are. So our Chief Commercial Officer is very busy at this moment, so he's building out the infrastructure to support launch. We certainly... And actually, in Q4 of this year, we'll prepare a launch- ready sales, update for the market so they know what we're doing. But really, it's always about supporting education awareness and patient diagnosis right now, and then building kind of that readied sales force, obviously, for when there's approval to re-engage with some of the physicians and patients and patient groups that we've been building these relationships over the years with to let them know that the drug is available, if appropriate.
Did you run a natural history study, or are there any things you've done to sort of prepare the market or sort of build a bolus of patients, you know, at launch that you might consider to be appropriate targets?
Yeah. So that, I would say we've been developing kind of our network, so I would say, of known patients and physicians, so I would say there's some groundswell there. Since the drug has, you know, demonstrated the Phase III data, I actually think that's where the ramp is gonna nicely take off. You're always trying to balance that expectation with patients, and not, sort of go out too hard in terms of, of over-hoping or over-hyping the drug. But now with the Phase III results out and our PDUFA date in sight, I think we have a very nice kind of increased cadence of drum beating to develop those relationships and hopefully hit launch off on a strong note.
Okay. Okay, good. Outside the U.S. maybe just remind us what the plans are for WHIM outside the U.S.
Yes. So we are still considering how to work outside the U.S. So I'd say there's almost, like, three buckets that we're considering. For sure we'll be finding some regional partners where we just won't go. There are some countries, even Genzyme, that was part of my background. We use regional folks who really do know rare disease in some of these, I would say, more diverse areas of the world. And then, Europe is kind of the one that we're still playing with, where do we retain some of our own infrastructure build over the timeframe in preparation for our next indication? But we will be seeking some support, either regional partners or strategic partners, and disclose a little bit more detail as we head into to next year.
From a regulatory standpoint, are you waiting to sort of decide on that before you file in Europe, or what's the filing plan, and how much regulatory dialogue have you had in Europe?
Yeah. So no, we are going to be filing for MAA approval about a year net from now with our current filing package. And the goal there is to just be ready, whether we wanna do it ourselves or if we bring in other collaborative partners, the regulatory path. I mean, we know the drug so well, it's a rare disease, and we did have prior dialogue through Scientific Advice with the European regulators. So I do feel like we're in the best position to ensure that the filing continues to be prosecuted. Of course, if someone wants to help us in that partnership process, we'll be open to that as well.
Okay. Okay, great. So you obviously highlighted the larger indication is chronic neutropenia. Maybe just describe for people. I think they hear that and they say, "Well, what does that patient population look like? How do you define the chronic neutropenic population?" So maybe just talk a little bit about those patients, what sort of underlying conditions they have that makes up that population.
Yeah, it is. It's not a very well understood, known or treated population, because I think the world often thinks of chemotherapy-induced or secondary neutropenias. They have some other disease or other drug on board that causes your neutrophils to get compromised. In fact, in a lot of the oncology presentations, I'm sure part of that safety profile, unfortunately, is neutropenia. Those are not the patients that we're treating, actually. There are patients who either are born with or develop, and they think it's for autoimmune disease causes, but not 100% sure it's idiopathic, is that they develop chronic, lifelong neutropenia. They walk around with neutrophil counts very low and therefore are at very high risk of infections. So very similar to our WHIM patients in terms of that infection risk profile, that severity, and then again, no treatments or ag...
With chronic neutropenia, there's one treatment, and it's an injectable either once or twice daily.
Okay.
So we think that with an oral once daily, that can really stabilize chronically and provide that better safety profile. We think we can really offer something very innovative to these patients.
And just from a mechanism standpoint, because you said these patients are idiopathic, like-
Yeah
... do you think their underlying disease is sort of independent of mechanism or, you know, how should people think about the biology of the disease of those patients?
It's a great question. So I would, I would look at patients in terms of where they are almost in their own life cycle. So neutrophils have an eight-hour half-life. I don't... that was something I have learned along the way, so, I mean, it's a very short half-life. So if your bone marrow is deficient and can't produce neutrophils, unfortunately, you, you will likely die within your first few years of your life. So the patients that we're treating have an intact bone marrow, enough to get by, but have a very hard life. So we believe that as long as there's an intact bone marrow, there's a reserve of neutrophils that just need to be moved from the bone marrow into the bloodstream to help fight infections, and that's actually how, you know, G-CSF acts along those lines. It does help boost production, but it's a-...
Pretty big mobilizer as well. So G-CSF is a nice validation biologically of what we're doing. It does have some safety risks for patients long-term, and it's obviously quite painful to take on a daily basis. So I think from a biological mechanism, existing drugs help validate what, what we're doing. Our drug, we believe, is really going to, for some patients, be possibly monotherapy if they have enough reserve. Maybe G-CSF might be added on top to some.
Okay. Okay, great. So I guess then, building on that, you know, you have a couple pieces of evidence, right, to support, you know, what you're doing in the chronic neutropenic population. Obviously, you know, data in WHIM, they're not exactly the same. You have some phase I data, and you recently released some phase II data. So maybe talk to everybody about, you know, what you see as the body of evidence that sort of supports.
Yeah
... what you're doing in this population.
Yep. So I think the interesting point that you highlighted was the diversity of cause. So what... In our Phase Ib study, we kind of had all comers, like, will the drug mobilize? Will it increase neutrophil counts? And even some of our investigators were guiding us to this population and not that. So what we did was we just studied it. We had a diverse population of neutropenic patients in phase Ib, and we looked to see if mavorixafor would increase neutrophil counts, and if so, by how much? How much is an important metric? So for every human being, if you shift your neutrophil counts up by 500 cells per microliter, like starting from zero, you decrease your risk till you get to normal, and there's about four different ranges.
In all of our patients, 100% of them, a single dose shifted neutrophil counts by at least 1,000 per microliter and some we were getting 3,000, 4,000, 5,000, 10,000 per microliter. So it was a profound response that I think even blew away our investigators' views, and it did that in everybody. So we're extremely pleased with the broad utility of the drug after a single dose in that Phase Ib. Now, in the Phase II, which we've just disclosed a little bit of data on, now it's, can that be repeated on a daily basis in a safe way? So we learned in our first three patients, again, that we're getting profound responses. In fact, they overshot the normal range, and we had to titrate off G-CSF. The physicians decided to do that to get them back to within range.
So it's a really exciting situation for our patients. They see a world for those that are on G-CSF of coming either dramatically reducing that G-CSF dose or possibly coming off of it.
Okay. Okay. And maybe we just spend a couple moments on the handful of patients that you've disclosed already. So I guess the first question is, I think you said we're gonna get more data maybe at ASH this year, so maybe just describe for people what to expect in terms of additional follow-up from those patients.
Yeah, so we've been getting this question a lot. So that we disclosed three patients, so of course, we'll have those patients on with additional data. And then, as we mentioned, actually, in August, we did have some recruitment sort of delays, but it's kicked back up now that the summer's passed. Some of our student or patient populations are younger and like to have summer off. So we will have our three patients, of course, that were on study, and then beyond that, we're waiting to see how recruitment goes.
Okay, but, I mean, is there an expectation that we'll see more patients, or it's still a little bit TBD?
I would say we just wanna- we don't wanna overpromise-
Sure
... and underdeliver, so we'll just get there when we get there.
Okay.
Again, it's the recruitment's picking up nicely, and whether it'll be December or shortly thereafter, but I feel really good about where we're headed right now. It's always... Trial recruitment is the bane of many companies' existence-
Yeah
... so it's just hard. So, we'll look forward to sharing more of that data when we have it.
Okay, perfect. So then, I guess the second question is how to think about durability, 'cause obviously that's an important component for these patients. I think I can't remember exactly how much follow-up, but you had different amounts of follow-up for each-
Yeah
... of those patients you disclosed. So, you know, from your point of view, how much durability do you think you need to feel good about, you know, the long-term prospects? And then secondarily, what do you think the regulators want to see in terms of durability?
Yeah, so, I mean, I'll take those two. So our WHIM data, which is actually very nicely reflective of how to think about chronic neutropenia, you can see durability after one to three months of dosing, 'cause that's almost the bone marrow gets into a new steady state. And then in our Phase III study, where we had robust measurements, what you saw after three months was the same as what you saw at 12 months. So I think what you see in that one to three months window is very indicative of what you see long term, especially with neutrophils, 'cause if you think about they last eight- hour half-life out when you're at one to three months.
So we feel really good about that window to assess durability, and then the data that we just presented had three patients with at least three months of data, and it was looking great. I mean, I am so impressed with mavorixafor's profile in terms of you can see almost immediately when the drug is responsive within a day or two, and then in that ensuing month, it actually creates a new... we call it the new low-tide mark. Neutrophils can go out and back into the bone marrow, but after many cycles, we actually create sort of a new lower threshold of neutrophil count, and that's really what's helping patients, so we're happy to see that.
Okay. And then I think one other area that probably caused some debate among investors around the data was obviously when you titrated off G-CSF, neutrophil levels came back down a little bit, and so I think people were trying to figure out where do they stabilize-
Yeah
... so, you know, just how do you think about that, and you know, what's your level of confidence that you know, you are able to stabilize people above an appropriate level?
Yeah, absolutely. So, I mean, I think we have always said that some patients may be able to go on monotherapy, and some patients may need to still have some frequency of G-CSF. But I'm amazed. So these patients are all... Even with G-CSF, the patient that we showed with G-CSF was neutropenic. So with standard of care, they were still at high risk of infections, and we more than increased that neutrophil count by an order of magnitude with mavorixafor. So of course, when you start to pull off G, you do expect the neutrophil counts to go down. So we do have to wait for that patient to get out to longer-term studies, but I expect, like, minimally, the last data we had was this patient was on about one-eighth their baseline dose of G-CSF plus daily mavorixafor.
That alone is a huge and positive shift to that patient. That's where they wind up staying at. If they could get to zero and do that in a steady state way, that'll be also extremely meaningful. So in either regard, the data that we're seeing is we keep referring to this as a significant reduction or withdrawal of G-CSF. Anything in that realm is going to be something that'll be better for patients, ideally zero, but if it's one or two injections a week, I still think will be quite meaningful.
Okay. Okay, great. Regulatory. So obviously you've got some pretty interesting data. How do you get it approved in CN? You know, what does a pivotal program look like?
Yeah, so we disclosed even already that it's gonna be very similar to WHIM. So the good news is we've been there, done that quite successfully in WHIM. A lot of them are the same investigators across the world, so we've been developing good relationships. So from a regulatory perspective, it's a randomized, placebo-controlled, double-blinded trial that the agency has agreed to, so it's not head-to-head against G-CSF. Actually, it's on top of what our standard of care they are at. Just because G-CSF is so variably used, some patients can't use it, some patients won't use it, and some physicians really almost use the minimum effective dose. So regardless of what they're on at baseline, they'll be randomized. We'll add mavorixafor and placebo in a balanced way, and then the primary endpoint is a co-primary endpoint.
Thus far, we've mentioned that it's going to be minimally some sort of neutrophil metric, plus something clinical benefit oriented. We're still hammering out that last final bucket with the agency, but it'll likely be something that we were successful in the Phase III WHIM trial on, something related to infection, severity, duration, and we'll have that final answer by the end of this year.
Okay, and in terms of the neutrophil endpoint, I mean, is that like a certain amount of time above a certain amount, or how should people just think about what that will look like?
Yeah. So again, we're waiting for this final round of interactions with the agency, but for example, with the G-CSF label, they did a responder analysis. So did you either achieve normalized levels, or for some patients, they had something called a partial response 'cause they were extremely low. So that's the type of-
Okay.
I think it'll be some form of responder analysis, but we still have to hammer that out.
Got it. Got it. All right, super helpful. So maybe you could talk a little bit about the market, right? You mentioned, I think, 15,000 patients. You know, how much work have you done on that figure? You know, what's the range of that figure, and you know, how do you think about getting ready for commercialization?
Yeah. So we, we originally tried to learn what's the total scope of the market. We originally came up with about 50,000 patients across the three different subtypes of chronic neutropenia, and we had... Everyone was sort of, is that, do all of them need therapy, or today, are they all on therapy? So of course, with all rare diseases, there's a, a bell curve of unmet need. So what I would say the 15,000 represents is that true highest unmet need that our trial is actually being designed to treat. So these patients are still neutropenic. They've been treated with some form of G-CSF or not, but regardless, they're neutropenic. They're still getting infections at least two a year, and then that's the target population that we want to address, right? We want to be giving, you know, treatments to those who need it.
So we feel really good about the way we're designing the study. It's crosswalking into that initial addressable market, and actually, it's 12 and above. That 15,000 is also aligned with the requirements of our trial, which is ages 12 and above. So yes, we can go, hopefully, in the future, into younger patients. You know, it's a hard line with at least two infections a year, but if you had one serious one, that certainly might merit therapy, as we've heard from our patients. So we think there's a larger market beyond that. How we step into that from a clinical trial perspective is still to be determined.
Okay. Okay, and then commercialization, again, it sounds like, you know, WHIM obviously gives you a foothold in the U.S., and so you presumably you'd expand that, to launch in chronic neutropenia. Is that, is that the current plan?
Absolutely. We the WHIM patients are sort of split between the immunology and non-malignant hematology specialists, so we'll be developing relationships with, but all of those, healthcare providers, and it really does create a nice way, even today, to speak about our trial in neutropenia, and then hopefully, as we launch in the U.S. in neutropenia, it'll be a lot of synergies of what we've already built with WHIM.
And then as you think, you know, you obviously discussed the potential for licensing or partnering outside the U.S. I mean, is that a package where you'd look at WHIM and chronic neutropenia together, or are they separate? Or, you know, just how do you think about commercialization outside?
It's a great question. So right now, I think we're focusing primarily on WHIM. Chronic neutropenia has a lot of value to it, so I think the partnerships that we're currently looking at, and again, it's dependent on the partner, but I would say we're so excited about chronic neutropenia. We don't wanna lead with giving up too much value to begin with. So WHIM, I think there's certainly nice ways of leveraging other, rare disease distributors or specialty groups across the world. CN, we're still thinking about.
Okay. Okay, super. We got a handful of minutes left, so maybe just talk about other areas you might think, you know, potential label expansion.
Yeah. So we're still even learning today about the impact of the drugs through the Phase III. The one amazing thing about running a placebo-controlled trial is you can really understand what your drug is specifically doing. So certainly, the nice correlation between neutrophils and infection rates was robustly demonstrated in our Phase III, and now we're trying to pick apart that next layer. We also had a huge impact on other cell types, B cells, T cells, so there are some immunodeficiencies that may translate into benefiting from that type of response as well. So we're looking across the immunodeficiency space. Then, of course, there are a number of secondary neutropenias. People have asked us about. Actually, investigators have asked us to explore their drug, but so it's to be determined.
We'll see on how deep and broad we can go, you know, given this mechanism is quite applicable in many places.
Okay, super. And then, Adam, maybe can you just talk about financial position? Obviously, biotech companies need money all the time, so, you know, how are you financed right now, and where does that take you in terms of run rate?
Yeah, sure. So as of June 30, we announced about $165 million of cash, and that includes $22.5 million that we just took down recently from our debt refinancing. So that takes us into 2025. That debt financing as well gives us some additional capital over time, so some optionality around that timeline. That period excludes the potential proceeds from our Priority Review Voucher, so we anticipate receiving that H1 of next year, aligned with potential approval in WHIM, and we would look to monetize that. Those are typically in the $100 million to $110 million range or so, so in our case, would extend our runway further by about a year.
Okay.
So strong balance sheet, well-positioned to hit a lot of the milestones that Paula mentioned without the need to raise, and with some optionality around the debt I mentioned.
Okay, great. Well, Paula, Adam, thanks for being here. I appreciate the time.
Thank you. Thanks.
Thank you very much.
Appreciate it.
Appreciate it.
Yeah.