All right, we can get started with our next fireside chat. I'm Rosy Liao. I'm a member of the biotech research team at Guggenheim Securities. I'm excited to have X4 Pharmaceuticals with me here today. On stage with me, I have Adam Craig, Executive Chairman. Welcome. Great to have you here.
Thank you, Rosy. Thanks for the invite.
Adam, it's been a little over a year since the new team came into X4. I guess for those less familiar with the story, could you maybe start with a quick overview of the company and perhaps talk about how your prior experience has kind of shaped how you've run the company today?
Yes. Well, thank you. Well, I think the last year has been a period of transformation for X4. The new management team came in August of last year. During that time, we've raised $240 million to finance our work, but we've made a big change to the company. There's been a lot of restructuring. We changed the C-suite. There's been some changes on the board. But the main change is we've become a company that's really 99% focused on the conduct of our phase III pivotal trial in chronic neutropenia, the 4WARD trial. That is the primary focus of the company, and we say to employees, if you don't come in to the office in the morning and think about what can you do for that trial, then you need to rethink, because that is the main value driver of the company.
Great. Can you talk about what you see as the most important changes you've made to the company so far?
Well, I've mentioned the focus on 4WARD. I think the other thing is the financial discipline. The company before we joined was spending a lot of money. Under the leadership of our CFO, David Kirske, who's with me today, we've really become a disciplined company. We're fortunate enough to have a substantial amount of cash in the bank, but we want to use it wisely, and we want to make sure we have enough cash to commercialize the chronic neutropenia opportunity. Through the discipline David's instilled in the company, we're on target to achieve that goal.
Great. You mentioned your focus on chronic neutropenia currently. You're running a phase III trial, 4WARD. You recently had an FDA meeting where you aligned on resizing the trial a little bit. Can you maybe walk us through the design of the trial and the rationale behind the moves there?
Yeah. The trial is a study of primary chronic neutropenia. That's patients who have neutrophil counts less than 1,000, which is moderate and severe disease. These patients, the patients we enroll on trial, are patients who are symptomatic, so they have to have at least two or more infections in the prior year. That's unfortunately the life of someone with chronic neutropenia. They get multiple infections. It could be in the skin, in the ear, in the lungs, wherever. The trial is a double-blinded placebo-controlled trial where our lead agent, mavorixafor, which is a CXCR4 antagonist, is compared to placebo. As many of you know, patients with chronic neutropenia, some of them take G-CSF. On each arm, it's mavorixafor. For the arms, mavorixafor plus or minus G-CSF, placebo plus or minus G-CSF.
The study is 126 patients, one-to-one randomization, and we have two primary endpoints. The first is a reduction in annualized infection rate over a 12-month period, and the second is an increase of the ANC on at least three occasions over a 12-month period of at least 500 cells per microliter. As I said at the beginning, all our patients have moderate or severe neutropenia, so an ANC less than 1,000. You can see an increase of 500 could be a quite significant change and could lead to a reduction in infection rate.
Great. There hasn't been a lot of innovation in the chronic neutropenia space. I think the last dedicated trial was probably run by Amgen back in the '90s.
I guess, could you talk us through kind of how patients are being treated currently?
Yeah. You're absolutely right. Currently, really, the patients are treated in two ways. With G-CSF, which is only approved for severe neutropenics, it's not approved for moderate neutropenics. It's used on our trial, it's about 37% of patients, and that's what we've seen in our market research as well. Around 35% of patients are on G-CSF. It's used in a huge number of ways. There is no standard of care. Some patients take it weekly, some patients take it daily, and there are different doses. There's no standard of care. The patients we're seeing on study are, in effect, G-CSF refractory because they're not responding to it, because they still have low neutrophil counts. So that illustrates you can be on G-CSF for a while, but you don't necessarily respond to it.
The other concern with G-CSF is it's an injection, it causes bone pain, and there's a risk of long-term malignancy. The median age of patients coming on our trial is 34, and our patients are acutely aware that if they take G-CSF, they could be on it for decades. Therefore, many patients don't want to be on it because of the risk of malignant transformation. The other way patients are treated is with antibiotics, long-term antibiotics as prophylaxis. Some patients will take antibiotics if they're going into a social environment, they're going to work, because the risk of infection is higher. But of course, long-term use of antibiotics is a concern from a resistance point of view and obviously some toxicity. That's it. Then there are some patients who will choose not to have either, watch and wait, so-called watch and wait. So, it really is underserved.
What mavorixafor offers, if it does work and reduce infections and increase ANC count, it will be the first orally available agent in this disease area. So when we spoke to potential prescribers about the drug, there was a lot of enthusiasm for the drug, particularly because it's an oral agent, doesn't so far seem to have a lot of toxicity. It seems to be very manageable. So, we're very excited. Personally, I'm really excited about to offer new therapy in this environment, and if it's an oral agent, I think it will get used extensively.
Great. So, you've guided to the phase III trial completing enrollment this quarter. I guess, how close are we to that being completed?
We're happy with the progress we're making and there's no change to our guidance there.
All right.
We expect to complete it by the end of this quarter.
Great. I think the top line is guided for the first quarter of 2028. As you approach full enrollment and we look ahead to the top line data, how are you thinking about the key milestones between now and the readout? And what gives you confidence in the trial's ability to show a clear benefit?
Yes. There's two. The milestones certainly are, first of all, for us to announce completion of enrollment in 4WARD, and there's a lot of people on the street who quite rightly want us to announce that. We do have the 4STEPS trial, which is a trial looking at patients who are already on G-CSF and titrating their dose down once they start mavorixafor. The idea of that trial is for us to be able to provide guidance to treating physicians on how to use the drug when their patients are on G-CSF. The first patient should come in the first quarter of next year, and then a year later, we'll have the 4WARD top line data results, and we'll also have the 4STEPS data results. So, that's how the next 12, 18 months pans out.
We do expect to have the data about 8-10 weeks after the last patient goes in. Assuming the last patient goes in by the end of the year, we are talking about results probably, yeah, the end of the first quarter of 2028.
Great. Let's dive into the details of the trial a little bit. The trial is powered for a one-third reduction in annualized infection rate.
Yes.
I guess, how do you and the physicians you speak to think about what is clinically and commercially meaningful for this population?
Oh, I think that is extremely commercially viable, the powering. Obviously, if we have the bigger the effect, the more commercially attractive it becomes. But as a baseline, a one-third reduction, my personal experience as a pediatric oncologist, and I treated patients with neutropenia on the hematology wards, yeah, I think it would be very, very meaningful, really quite significant. If a patient is getting three infections a year, that is one less infection a year. In 2025, 6,300 patients with primary chronic neutropenia were admitted to hospital with infections, with an average stay of four days. If we can reduce those hospital admissions and the risk of not only just severe infection, but life-threatening infections, then we are going to make a lot of progress. I think the way the study is powered, I think, is a very significant benefit.
Great. You recently had an investor day, and you kind of shared some new metrics on kind of the baseline characteristics of the 4WARD trial, as well as some new data for the commercial opportunity, which I definitely want to get to later. I guess from the blinded baseline data, it suggests that you've rolled in a fairly symptomatic population so far. How representative is it of the patients that you would expect to treat commercially?
Yeah. I think it really depends on the product label. I think that's a really important question you raise. It depends how the label is worded. If the label is worded that we treat symptomatic patients with severe or moderate chronic neutropenia, then the market opportunity, it could go as high as 30,000 patients. If the label is more specific towards the 4WARD trial, where it says we could treat patients who've had at least two prior infections in the last year, then the market opportunity is 15,000. We're working on the assumption that it's going to be an addressable market once we launch. Label dependent, will be somewhere between 15 and 30,000.
Great. I guess, to kind of follow up on that, what would get you to that 30,000? I guess, how would the communication with the FDA need to be?
Well, if you look at the G-CSF label for NEUPOGEN, it talks about symptomatic patients. That's precedent, and the agency typically does follow precedent with labels. If that was the label, then we could potentially go up to that 30,000. If the agency decide to be more specific, then it's the lower number. But obviously, we will propose to the agency as broad a label as possible that we think is supported by precedent and by our data. If we can address the 30,000 market, that would be obviously a good outcome for us and our shareholders.
That's great to hear. You mentioned the 35% of patients who are currently on G-CSF currently, and you mentioned it's not really a super binary choice in terms of whether they get it or not. There's dose reductions, there's a lot of toxicity involved. I guess, how do you see mavorixafor fitting across that range? Maybe, you've mentioned the 4STEPS trial earlier. Can we dive into the details of that a little bit, and what would a good outcome look like for the 4STEPS trial?
Well, I think it would be obviously for patients and physicians to decide. From our perspective, we think mavorixafor has the potential to be the treatment of choice in this setting. We think there will be a significant number of patients who will start on mavorixafor whilst being on G-CSF, and the G-CSF dose will be titrated down. Some patients will come off it, some patients may stay on it. We think that's the same for antibiotics. There may be some patients who want both. I think from a toxicity point of view, and to make a convenience and a compliance point of view, if we can get to the point where patients are treated with an oral agent alone, then I think we could really have something that's quite important for the population.
The market research we've done, we did a long survey, we've held advisory boards with patients, is they want an oral therapy they can take on a regular basis that gives them the protection they need. I think the oral component of this drug is probably key to how it'll be used in the future.
Great. Okay, just on 4STEPS again, I think during your investor day, you mentioned you're planning on enrolling around 25 patients for that trial. I guess, how did you decide on the size of that cohort for
It's a directional study. It wasn't designed with a specific statistical analysis. What we were thinking was, what do our physicians need on day one? What do our reps and MSLs need to be able to communicate on day one? One thing that was obvious, because on the 4WARD trial, the dose of G-CSF, if you start on G-CSF, you're on a fixed dose, there's no opportunity to titrate on the 4WARD trial. In practice, people are probably going to want to do that. We put this trial together so that we can have some data and hopefully a publication out there on day one that when a physician says, how do I use mavorixafor with G-CSF? we can point them towards the publication.
That was the idea for it. It wasn't designed to be a massive study. It was designed to be able to report to physicians on the sort of the day-to-day use of mavorixafor.
Is this data that you're planning to also submit to the FDA to support the label, or is it just going for-
Well, certainly from a safety perspective, that trial, there will be safety data. The label discussion, we haven't had that level of discussion. I think we'll start with the 4WARD trial first, and if that's successful, then maybe we can consider adding it. From a safety perspective, the data obviously always goes into the safety database that the FDA will review.
Great. Sounds good. One step at a time, I guess. Going back to your commercial opportunity, you mentioned the base case of 15,000 patients, upside to 30. Your market research that you presented showed strong prescribing intent among hematologists.
I guess as you think about the launch, what parts of that 15,000 do you expect to reach first, and how do you see the adoption broadening from there?
Yeah. This is an area that I asked. I should give credit, actually. All the data you are talking about is from my colleague, Michael Massello, who is our head of market strategy. I should give him credit for his work. The path of the patient is interesting. Every patient goes through a hematologist in this environment, because if you have a low neutrophil count, at some point you are going to need a bone marrow to exclude other things, MDS, AML, other things. We do know that patients are often, once they are treated by the hematologist, are referred back to primary care. Our marketing and our commercial approach will focus on the hematologist approach, and it is very similar to what we had when we worked at CTI together. About 70% of the hematologists in the community and about 30% are in academia.
That is where we will focus, but we will have some interaction, no doubt, with pediatricians, primary care physicians, and probably immunologists. If we focus on the hematologists, we should pick all the patients up, and then we can have a discussion about whether mavorixafor is suitable for them.
Great. You have talked about this in the past, but perhaps just to reiterate for our audience here, how are you thinking about pricing for a broader indication compared to WHIM?
Yeah. WHIM currently is priced, I think it is about $580,000 a year. That is ultra-rare disease pricing. That would not be sustainable for a population of 15,000 or even 30,000. Based on prior experience, and I am not quoting formal pricing research, David, myself, and my colleague, John Volpone, we think the drug will probably be priced around $250,000-$350,000, but subject to market research. I think there is an opportunity for that level of pricing given it is rare disease in hematology, but it will be subject to pricing research.
Great. You have described a commercial footprint that is similar to that of CTI's, with most patients treated in the community. You just mentioned 70/30 breakdown.
Roughly, yeah.
I guess, how are you thinking about launch preparation? I know you're still a bit away from that, but maybe just talk about the timing and how you're kind of thinking through.
Yeah. First of all, we always think about launch preparation because if anything we learned at CTI is you have to think of the commercial enterprise as early as possible. I've already mentioned, we're talking about the 4STEPS program. We're thinking it's probably going to be, we haven't done a formal assessment yet, it's probably going to be around the 50, 60 reps that we had last time, split between the community and the academic setting. But in the meantime, before that, we're slowly bringing on the marketing team so that we can start commercial research. I mentioned Michael Massello. He's hiring some other individuals to prepare the market, then we will bring in the leadership team in for the commercial opportunity around the time of the data. Then once we've got the data, you bring the commercial team in. But we are thinking about it.
We think about it constantly because everything we do should think about what does the rep need in the field, that's how we're trying to think about it.
Great. Chronic neutropenia, obviously you're focused on that right now. It's a pretty substantial market opportunity. I guess as you're kind of building up the company, how are you thinking about potential expansion opportunities for mavorixafor and also potential other assets that you might bring in?
Yeah, there are other indications. We haven't spoken publicly about them, but we are looking at other indications for mavorixafor. We want to be a rare hematology company, so if there is an asset that fits in with the expertise of the team, which is rare hematology, can be benign or malignant, we'll consider it. We certainly have spent some time looking at assets, but we haven't to date found something that's the fit that we want.
Great. Maybe just to close this out, I guess can you just remind us where you are in your cash balance and how far does that take you toward a launch of mavorixafor in chronic neutropenia?
I was just checking with David what the, because we just put earnings out. The cash is $188 million, and that takes us through commercialization in the chronic neutropenia indication.
Great.
Thank you, David.
Thanks. All right. Well, thank you all for being here today. Thank you, Adam, for coming and speaking with us.
I appreciate it.
All right.
Thanks for the invitation.
Thank you.