Great. Welcome everyone to the next session here at the Healthcare Conference. Excited to be joined by X4 Pharmaceuticals. We have Executive Chairman Adam Craig, and interesting time for you guys. Maybe I was thinking we can kind of just start. Obviously, a lot has kind of gone on in terms of you guys coming in, kind of transforming the company. Maybe just kind of like set the stage of everything that's happened over maybe like the last year or so, and kind of what got you guys excited to join, and kind of what's the path forward from here?
Well, first of all, thank you for inviting us. We're pleased to be here. As David, CFO, who's with me today, David Kirske, and I have known about this company for three or four years ago. We looked at the company when we were at CTI BioPharma because we always thought mavorixafor was a good agent, an active agent, and an agent in which it could be developed successfully in chronic neutropenia. About a year ago, the opportunity came along with a new investment that was made to work with some new investors and come into the company. In July of last year, and then in August, there was a refinancing and we joined as a new management team. We haven't been disappointed. Mavorixafor is what we thought it was.
Yeah.
Once you get inside, you see the data. We have spent the last year really sort of making the company more efficient, reducing costs. We've reduced headcount. We've changed the management team. We've brought in some people outside with certain expertise. All that has led to us focusing on the enrollment of our pivotal phase III trial, the 4WARD trial. Which is, as I've said repeatedly, is the main focus of the company that employees need to think every day, what are they doing towards that trial. With that, we are looking forward to completing enrollment by the end of this year. Then that would lead us to having topline data for the phase III in chronic neutropenia in the first quarter of 2028.
Awesome. On the trial, earlier this fall, you guys lowered the end slightly for the trial. Maybe just kind of talk about the decision to do that.
The trial when we joined, it was grossly overpowered. The 176 patients, the powering of each of the primary endpoints was greater than 96%. We became confident that we were enrolling the correct patients. The characteristics of the patients were correct, and that the patients were sick. This is something the FDA said to us, "You've got to enroll sick patients in whom you can show a difference. When we saw that happening, we took another look at the sample size, and we saw that we could retain 89% powering for the infection endpoint and 93% powering for the ANC endpoint, if we took the sample down to size to 126. It really was for two reasons. One is it obviously makes good, it's prudent, it's good business sense not to over-enroll a trial. It's a double-blind, placebo-controlled trial, and I don't want to enroll more patients than we actually need
Yeah
to test the hypothesis. We've been very comfortable with the change. As I say, we're heading towards closing enrollment by the end of this year.
Yep. Yep, makes sense. You also announced kind of around that, bringing in a new CRO, and it sounds like the enrollment kinetics have like really kind of flipped with this new
Yeah, there were quite significant operational challenges that I've spoken about quite a lot.
Yeah.
We've been very fortunate to now partner with Parexel who have been great. We now have the best enrollment dynamics that we had, particularly the number of patients in screening who then convert and then will randomize to the trial. The last couple of months has been very good for us, and Parexel being a great partner.
Yep. Great. Definitely want to talk about commercial, but maybe to start on the trial itself, you kind of laid out, still very well powered at this sample size. Maybe just kind of talk about the assumptions around effect sizes and kind of your comfort in terms of what led to those decisions.
Yeah. So we, the team, and obviously this is before I joined, but when I joined, I sat down with the statisticians and the clinical team. We really tested that they had made the correct assumptions, and I wanted to see conservative assumptions. I remember I sat in a room for four hours with them thinking that I would find something. I couldn't. I couldn't. They had actually made very, very good assumptions, and the protocol itself the biometric teams are very strong. So top line, what we are looking for is approximately a one-third reduction in infection rate, and then we expect at least a one-third of patients to have an increase of their ANC of 500 cells per microliter on at least three occasions over the 12-month period of the trial.
That's a conservative estimate. If you look at the WHIM data, the WHIM data is a bit more than that, and then we've got phase II data. So what I wanted to see with the team is that we make a conservative estimate, and that's what we have.
Yep. Yep. Makes sense. At your investor day recently, one of the more interesting things that you shared were some of the blinded baseline characteristics. Especially around the rate of infections that these patients have had. Maybe kind of just expand on that a little bit and as it relates to that event rate dynamic.
Yeah.
Again, how that
Well, the first thing to say is we wouldn't have made the change in sample size unless the blinded characteristics were where we wanted to be.
Yeah.
They were in keeping with the overall assumption of the trial. Just very briefly, we have a median age of 36. We have 68% of the patients have got three or more infections, which is more than is required to go on study. You need two or more in the prior 12 months. And about 37% of patients have G-CSF. That really is tracking where we have modeled it.
Yeah
Which is really, really important. And again, gives me more confidence that any change to the sample size was okay because there wasn't any outlying data there that could cause a problem.
Yep. Yep. Makes sense. You mentioned WHIM, that sort of the prior WHIM studies, effects are very conservative relative to those data. You obviously had a phase II before you were there, phase II in chronic neutropenia. It wasn't necessarily as enriched in terms of an infection benefit, but have we seen ANC data in sort of these moderate to severe patients who are on G-CSF and those that are not on G-CSF?
Yes, we have, but the sample is very small. I've always been very transparent about this. Had David and I done this trial ourselves two or three years ago, we'd have enrolled over 100 patients here. It is what it is. That phase II data set is very useful. It shows that in patients with low ANCs, that mavorixafor can increase the ANCs to normal level. That's number one.
Yeah.
Number two, it shows with patients with higher ANCs who are on G-CSF, that the G-CSF dose can be titrated down.
Yeah.
I think it's 70% overall, and in some patients actually stopped completely. A small data set, but directionally, it really does reinforce the hypothesis that mavorixafor works in CN.
Yeah. Makes sense. With WHIM, on both ANCs and in infections, we didn't see any really placebo response in that study, right? Is there any reason to think that would be different in chronic neutropenia?
No, there isn't. I've been asked this question before. I can't think of a reason why there would be a placebo. There will obviously be infections, but there won't be any ANC change. The assumption for the infections was it's going to be a minimum of two or more if that's what they have in the prior 12 months. But from an ANC, there shouldn't really be any effect there.
Yeah. Makes sense. Then, kind of along the same lines, it seems like the biology here is just very linear across chronic neutropenia, WHIM, ANCs look very similar. Any reason to think the sort of ANC to infection sort of dynamic would be different in chronic neutropenia than it was in WHIM in terms of
Well, WHIM is a different biology, but we've taken a conservative cut from WHIM, and that's one of the reasons why.
Yeah.
I think there's no reason to think there won't be an effect. Will it be as great as WHIM? Possibly not.
Yeah.
Possibly not. We'll see. We don't really know. But we are confident that we're going to see an effect across all the different forms of chronic neutropenia.
Yeah.
One of the things one of the medical monitors was telling me a couple of months ago is, even though we classify these patients in buckets, many of them have features of the different kind of disease. I suspect chronic neutropenia is like most diseases, a spectrum of disease that we don't fully understand at the moment, but we do expect to have a response across that spectrum.
Yep. Okay. Yeah, that was going to be my one other question, which has come up a couple times with people, just the etiologies of chronic neutropenia are maybe a little bit more varied than with WHIM, but like you said, you're confident in kind of consistency across the different-
Yeah, that was one of the questions. Well, obviously it will be tested in a randomized phase III, but that was one of my questions a year and a half ago when we were doing due diligence, was there confidence there would be activity? And the medical team that we have is confident there'll be activity across all the different kinds.
Yeah. Makes sense. Then maybe just one other question here around infections that has come up a few times. Just in terms of how events or kind of infection events are being defined and adjudicated, i s there anything sort of specific there you can say or any color you can provide?
Yes, it's laid out quite extensively is the answer.
Yeah.
We have a blinded independent committee that has a hematologist on it, infectious disease doctor, internist, and they have criteria. Each system is outlined in a very long charter, and they have criteria for whenever there is an infection, it gets flagged. They see it in a blinded fashion. It goes to them, they can request more information, and they will then adjudicate. But I haven't sort of gone into a lot of details to what those criteria was, except to say that every system is outlined and what to expect. I can say, for example, mouth ulceration is very common in small ulcers, are very common in chronic neutropenia. That doesn't count.
Yeah.
It's got to be a proper infection. So far, the blinded data, as John Volpone said during the call, the blinded data is tracking the way we expect it to track.
Yeah.
But we will see what it shows when we unblind.
Yep. Makes sense. So yeah, I mean, anything else to keep in mind as it relates to the trial itself, in terms of efficacy and then maybe safety too, just like anything to keep in mind from a-
Safety, so I do see safety data-
Yeah
about once every couple of months, and we haven't seen any new safety signals.
Yeah.
That's quite reassuring because over time we're getting patients with longer and longer exposure. That's a good sign. We're hoping at the end of this that we have an efficacious oral agent with reasonable toxicity. Any investigator that's used the drug does report GI tox.
Yeah.
That can be treated symptomatically, and it appears to resolve after a couple of weeks. That's good, and we can manage that, but we haven't seen anything new to date.
Yeah. Makes sense. And maybe as it relates to WHIM in the real world, has any safety been an issue at all in sort of the real world with WHIM patients?
Not that I'm aware of, no.
No. Okay. Great. Well, maybe just kind of moving, thinking about beyond the trial to regulatory, what do you think sort of a label's kind of going to look like here? Is it going to be just broad treat for moderate to severe chronic neutropenia, or is it going to be more specific than that?
I think the base case of a model is what the label for Neupogen
Yeah
which talks about chronic neutropenia and talks about decreasing infections and severity, and I think duration of infection. So it's sort of symptomatic patients, chronic neutropenia, and the effect on the infections. That's what I'd expect our label to be.
Yeah.
The label is really very important. During our investor day, we were talking about there's a market opportunity of anywhere from 15,000- 30,000 patients. If the label is non-specific with regard to it just says symptomatic patients, then we have an opportunity to go to a larger market opportunity. If the agency goes to more of the, which says at least two prior infections then our market opportunity is 15,000. I think the latter is unlikely. The agency doesn't tend to label in that way.
Yeah
as specifically as that. So, that's one reason why at the investor day we were talking about the potential upside here is double the number of patients we were thinking of previously.
Yeah. No, that makes sense. And maybe just on that point, as it relates to the commercial opportunity, I mean, you kind of acknowledged it or mentioned it. I think like a skeptical investor looks at the historical kind of enrollment kinetics here, kind of before you guys came in and was like, "Oh, if there's so many patients, why is it taking so long?" You've obviously kind of, as you discussed, changed things, and you're seeing that materially change. But anything else to say to a skeptical investor who kind of points to enrollment kinetics
Yeah
as it relates to commercial opportunity?
There's two components to this. One is the operational issues that we have now solved.
Yeah.
The other one is, this is a registration trial that's a confirmatory trial for the accelerated approval of WHIM. It has a lot of the additional items that are required for the FDA for full approval.
Yeah.
The trial is quite onerous for patients. There's a lot of blood draws, there's a lot of clinic visits, there's a lot of tests. In my experience, having been in clinical trials for a long time, this is quite a tough trial.
Yeah.
I am not surprised that some patients don't want to make that yearly commitment.
Yeah.
We can't change that because that was the requirement of the FDA. What we can change is the operational efficiency.
Yeah
We've done that. But overall, the enrollment is, in my view, is not a function of the market opportunity.
Yeah.
It's a function of the protocol, and it's a function of the operational challenges that we inherited. But it in no way should reflect the real world.
Yeah. Makes sense. I think that's what we hear from docs pretty consistently as well. Maybe just getting to the commercial opportunity, 15,000, even sort of like maybe the most conservative scenario as it relates to the potential label. I think at the investor day, you laid out some additional kind of like market research work, claims work, kind of supporting those figures. Maybe just kind of like help us understand what gives you confidence in kind of that avenue.
Yeah, I should give credit to my colleague who's in front of me, Michael Massello, for doing this work. Initially, when we joined the company, we had IQVIA claims data for 2023 to 2025 that suggested the 15,000. But Michael encouraged us to go to the Komodo database as well. It's believed to be more robust, and we came up with the same number. We've done other research. Not only have we looked at claims data, we've done physician surveys, we've talked to patients, we've held advisory boards. What we presented at the investor day was the sort of composite of all that.
Yeah.
We're very, very confident that 15 There are 95,000 patients with primary chronic neutropenia, 30,000 of those are symptomatic, "I have infection," and 15,000 of those have two or more infections.
Yeah.
But there was one data point that I wasn't aware of until Michael did the research. In 2025, 6,300 patients were admitted to hospital with this condition, with a median stay of four days. So you can see the impact this disease is having on patients' lives.
Yeah.
It's not just being in that 15,000, it's having a risk within that 15,000 of a severe life-threatening infection and possible hospital admission.
Yeah. That's a really interesting number to kind of like ground in. And, I guess, as it relates to kind of the treatment dynamics today, how do you think about sort of like what patient segments are most eligible, and where maybe the greatest unmet need is in terms of how docs think about incorporating mavorixafor into their treatment paradigm?
Well, I think, as you go into the market, the obvious patients that will come to physicians' minds will be the severely neutropenic patients.
Yeah.
During our investor day, we had Dr. Julia Warren from CHOP talking about the risk of a patient who's got a fever and a low ANC and how important it is to treat those patients quickly.
Yeah.
Those patients can have life-threatening and potentially fatal events. So I think they're the patients who are going to come to physicians' minds immediately. Any patient with an ANC less than 1,000 is at risk.
Yeah.
What's so sad about this disease is it limits their lives. We presented data on the adults can't work, don't get promotions at work, don't have normal careers. Children have interruptions to their schooling.
Yeah.
There's so much more benefit this drug could provide if we reduce the number of infections than just stopping severe infections. We could actually change the lives of these patients. For a company like, small company for us, that's very exciting.
Yeah. No, definitely. As it relates to pricing, obviously it's way too early to be super specific, but how are you thinking about pricing?
Yeah. My comments I always make are based on my personal experience. I think we're at $585,000 a year for WHIM.
Yeah.
That would be completely unsustainable in the larger market. I think based on prior experience, without any formal market research-
Yeah
we'll probably price this around $250,000-$350,000. I think that's where it will end up. It's a rare hematology condition where there's value on it above G-CSF and other agents.
Yeah.
I think that's where we will end up. Obviously, $585,000 would be too much.
Yeah. I guess in that context, are you thinking about 30,000 being kind of like the right TAM here versus 15,000? Does that even matter as it relates to kind of pricing this?
I think for a company of our size, 15,000 patients with that kind of pricing would be substantial.
Yeah.
If we had 30,000 patients, it would be double that.
Yeah.
So I do think as a company where we are, there is a huge opportunity for us to be a lot bigger and grow.
Yeah. Makes sense. And then as it relates to kind of like the current treatment paradigm today and the different use cases for where mavorixafor could fit in, you announced you are going to be running this G-CSF tapering study. So maybe just help kind of like frame up what that study is and what you are hoping to see.
Yeah. The study was conceived because in the 4WARD trial, the phase III, excuse me, in the 4WARD trial, the G-CSF dose is fixed. The FDA wanted us to do that, so G-CSF dose didn't become a variable in the analysis, and I understand that. What that leaves us with is very limited data on how the dose of G-CSF can be titrated once patients are on mavorixafor. The 4STEPS trial is about a 25-patient trial where patients are on mavorixafor and G-CSF. Then the four steps are 25% reduction, 50%, 75%, and then removing G-CSF, reduction in G-CSF to see if we can get patients off. The idea of that is by the time we then go to the market with chronic neutropenia, we'll have a manuscript out there so our field force can provide guidance to physicians on how to administer the drug.
Yeah.
It's very much part of our philosophy is what does the rep need on the first day?
Yeah.
That's what we try and think ahead. Everything we are doing, we are thinking, "What do they need?" It was clear they would need some form of manuscript to guide use of mavorixafor when it is given with G-CSF.
Yeah. Okay. Is that something that eventually would make its way onto the label, or it just needs to be kind of published out there for docs to provide reference?
I do not think it. Well, probably will not. It would be a small single-arm study.
Yeah.
Probably will not make, but the publication is what is important here.
Yeah.
The field force needs to be able to talk about peer-reviewed data.
Yeah.
That was the idea of that trial.
Yeah. Makes sense. I think you have some prior data showing, like a little bit of like tapering data.
Yeah. We do.
Maybe just kind of like talk about what that kind of showed.
Yeah. So we I think it was about nine patients on the phase III, and the majority of them got off G-CSF. What we were looking for was could they maintain an ANC above 1,500
Yeah
if normal ANC, if the G-CSF was removed, and we showed that. But we need to do it now on a larger scale.
Yeah.
And a little bit more methodically. That's why it's called 4STEPS, because we've got these four steps, reductions in dose of G-CSF.
Yeah. That just kind of, at each step, you're just like making sure essentially the ANCs stay consistent.
Yeah. There's criteria. It's on our corporate website if anyone wants to look on our corporate deck. There are criteria that will be followed at each of the stages.
Yeah. Makes sense.
That data should be available Q1 2028, which gives us enough time, assuming we're launching at the end of 2028, early 2029. That gives us enough time to have a peer-reviewed manuscript out there.
Yeah. Makes sense. So yeah, I guess like anything else as it relates to the commercial opportunities, specifically highlight for chronic neutropenia?
Nope. I am looking at Michael. He is saying no. So no, thank you. I appreciate the opportunity. It is nice to be able to talk about the commercial opportunity.
Yeah
Because that is why we had the Investor Day. We wanted investors and your fellow analysts to understand how excited we were. So I really appreciate the time to talk about it.
Yeah. No, of course. And yeah, I mean, I think that is one thing that definitely, when you talk to docs, there is a clear unmet need. So I think it makes total sense. And yeah, I guess as it relates to cash runway, what does that look like and
Yeah. We have enough cash to go into 2029. We have enough cash to commercialize.
Yeah.
We were fortunate last year to raise $240 million in a PIPE and then a following offering. With David's guidance, we are very prudent with cash. We do not overspend. From a cash point of view, we are very comfortable.
Great. Awesome. Unless there is anything else, we ran through all of our questions. I appreciate, Adam, you taking the time to join us.
Thank you, James. I appreciate it.