X4 Pharmaceuticals, Inc. Aktie

All right. So welcome to this fireside chat with X4 Pharmaceuticals. I'm Michael Schmidt, Senior Biotech Analyst with Guggenheim. And it's my great pleasure to welcome Adam Craig, Executive Chair of X4 Pharmaceuticals. Adam, thanks for joining us today.

Thank you, Michael. Thanks for having us.

So maybe just starting off with a high-level question. So you and the management team have been in place now for about 6 months or so at X4 Therapeutics. Maybe just remind us of your broader vision for the company and what you're trying to accomplish.

What we're trying to accomplish is being a leading company in the development of new therapies for patients with rare blood disorders. What we're focused on at the moment is the development of our compound mavorixafor for chronic neutropenia for patients who have low white counts and are very exposed to infections.

Over the last 6 months, we spent a lot of time focusing the team on that goal. We've reduced costs. We've reduced headcount, and we've really become a company that's focused on completing our Phase III trial successfully so that we can bring that new indication to patients.

Okay. Yes. Maybe then a few questions about mavorixafor. So this therapy targets CXCR4, which has been shown to have bone marrow mobilizing effects. And so yes, maybe remind us what is the value proposition of mavorixafor relative to other CXCR4 inhibitors or antagonists that -- and also G-CSF, which is used in this category.

Yes. With regard to other CXCR4 compounds, Plerixafor is an IV compound that has demonstrated limited benefit in WHIM, which has our first indication. We don't really have a main competitor in the CXCR4 space in the commercial environment and on our clinical trial, obviously, G-CSF is used extensively in these patients. About 40% of all patients with chronic neutropenia have G-CSF therapy. But it's a therapy that has limitations. It's subcutaneous, whereas mavorixafor is an oral therapy. It causes bone pain.

There's a risk of long-term transformation to leukemia with long-term use. And I know from my personal experience as a pediatric oncologist, a lot of patients do not like having G-CSF. And that's why our market research shows only about 40% of overall of all patients take G-CSF and it's not constant.

Many patients will take it intermittently, particularly if they need to go out into socialize or they're going to a restaurant, they'll take it to give themselves some protection against infections when they're outside their homes.

Okay. And so mavorixafor is already FDA approved actually for a very rare condition called WHIM syndrome. You've discussed in the past that the company is sort of not actively promoting the therapy there. But yes, maybe talk a bit about the data. And to what degree does it validate the therapy? And to what degree does it read through perhaps to the chronic neutropenia opportunity?

Yes. So just to sort of finish that off, WHIM is an ultra-rare indication. And when we took over the company in August of last year, we were -- the company was spending more than it was bringing in revenue. So we've deprioritized the commercialization of WHIM.

We will always provide the drug to patients and it is available to patients that require it, but we're not actively commercializing it. But as you say, the WHIM data is very helpful with regards to understanding chronic neutropenia.

WHIM is a form of severe neutropenia that is patients with ANCs less than 500. They also have hypogammaglobulinemia, and they're very prone to infections. So the WHIM data shows that the -- with treatment of mavorixafor, the ANC can improve and infections can improve in a small sample size, as you'd expect for an ultra-rare indication.

So it's very validating for me for the main hypothesis in the broader chronic neutropenia population that mavorixafor will have a benefit.

Yes. And I know you've -- again, it's not promoted, but there are some sales in WHIM in the U.S. and there are European, I think, approval decisions coming up at some point, too. Do you see upside to the near-term commercial opportunity in WHIM for mavorixafor?

I think the more physicians know about mavorixafor, the more they understand the clinical trial and potential commercialization in a broader indication, yes, there will be benefit from WHIM. At this point, for the WHIM indication, at this point, though, it's just not feasible for us to spend more money on commercialing something than we are getting for revenue coming in. It's just not good business sense.

But as I say, we have picked up a number of patients since we stopped commercializing. So we're still in new patients, but the numbers are very, very small.

Makes sense. Okay. And so you're obviously evaluating the therapy in chronic neutropenia, as you mentioned, in a Phase III study, the 4WARD study. Just maybe remind us of the size of the opportunity in this indication?

We estimate -- we've done some -- we've done a number of market research studies. The most recent was from ClearView Partners in Boston, and we worked with them. And they identified that there are about 15,000 patients with symptomatic severe or moderate chronic neutropenia. And that is patients with ANCs less than 1,000 or less than 500.

The estimate is to start with some of those are on G-CSF and some of them are not. The estimate from ClearView Partners is our base case is about -- we will treat about 1/3 of those patients, about 5,000 patients. Initially, we will penetrate the market, they think more successfully as a monotherapy. And over time, as we develop relationships and share data, we'll have more and more patients who have mavorixafor with G-CSF.

So we're working on a base case of 5,000 out of 15,000 patients. And of course, there are opportunities beyond that if we generate more data.

And maybe talk a bit more about the sort of the major or the main unmet medical need in this patient population. Is it patients that don't respond well to G-CSF? Is it patients that are on it but not happy with tolerability? Or is it other subset of patients?

There are certainly patients who have been on G-CSF for a long time. If you look at their history, they're on higher and higher doses. I was in London last week at Great Ormond Street Hospital, where the -- one of the physicians was describing patients having super doses of G-CSF because over time, they're just not responding. That's true. There are patients who just don't want to be on G-CSF because it causes bone pain because it's uncomfortable because there's a risk of long-term malignancy.

And the life of these patients, the patients we're treating are patients who have infections. On our clinical trial, 70% of patients entering the clinical trial have 3 or more infections a year. And we're not talking about infections like mouth ulcerations. We're talking about infections that require attendance at the emergency room, may require hospital admission, may require antibiotics.

So it's -- the unmet medical need is really quite significant. If we can improve on the infection rate by increasing the ANC of these patients, we will change their quality of life.

Yes. And then yes, perhaps talk about the Phase I and Phase II data that you have already generated with mavorixafor in chronic neutropenia. And to what degree does that -- did that inform the design of the Phase III study?

It was very informative. It's a small data set. I think it's important to make that clear. But the Phase II -- Phase I, Phase II data in chronic neutropenia for me shows two things. The first thing it shows is that mavorixafor can be given to patients with low ANCs and the ANC count can increase above 1,000, above 1,500, where there will be some protection from infection.

The other part of the data set was using the drug in combination with G-CSF and in that population, we showed that the drug can be used safely in combination with G-CSF. Obviously, that will be confirmed by the Phase III. And we also demonstrated that you can lower the dose of G-CSF, but still maintain a decent ANC.

So a small data set. If I had run the trial, probably have done a bigger trial, but it really does prove to me that the principle of using mavorixafor alone and using it in G-CSF is -- the data is good, and it supports the conduct of the 4WARD trial.

Okay. And I mean, Plerixafor, which is a simple mechanism drug is used to mobilize stem cells as well. And so I guess my question is how selective is mavorixafor towards increasing neutrophil counts specifically? And is it -- is there a risk of other cells are being more out of the bone marrow?

Not that I'm aware of. We continue to monitor -- I look at the safety data once a month, both from the market and on the clinical trial blinded data. I've not seen any new signals. I haven't seen any long-term signals, but it's always possible. Plerixafor is IV and our market research shows it's used in about 2% to 3% of the chronic neutropenia market. It's not really a main competitor, first of all, because there's not substantial data in the area. And the other thing is given IV as opposed to G-CSF, which is subcu or our drug, which is oral.

Yes. Makes sense. And then yes, maybe just walk us through the design of the 4WARD Phase III study. So remind us again of the eligibility criteria and what the powering assumptions are.

So it's a trial that includes all groups of chronic neutropenia. It's 176 patients randomized 1:1 between two treatment arms. So it's mavorixafor versus placebo. And on each arm, patients can receive G-CSF. So it's mavorixafor placebo plus or minus G-CSF on each arm.

And we're -- to be eligible for that trial, you need 2 infections a year in the past year. And what we're measuring is a change in the -- an increase in the ANC as one primary endpoint and the co-primary is a reduction in infection. And we do think they will go together. If you increase the ANC, you should reduce infection rate.

So 176 patients split between the 2 arms, and our aim is to complete enrollment by the end of the third quarter of this year. We did inherit when we came in August, a trial that wasn't functioning properly. We've worked very hard to increase the enrollment weight, which we're doing and very hard to find patients and identify them and get them on trial. Operationally, that has been -- the operational conduct of the trial has been our focus.

How are those patients managed today? What types of decisions? Are they hematologists? Or is it more in primary care?

No, they may be identified. This is the difference between WHIM. If you look at where WHIM patients are, they're all over the place, dermatologists, hematologists, immunologists. Chronic neutropenia patients tend to be -- eventually end up with hematologists, very similar prescriber base to what we had when we were running CTI with VONJO in MF.

About 80% of the patients will be within community practice, and they tend to be hematologists. When a patient has a low count identified, they're typically referred to a hematologist for a bone marrow examination, and they'll be managed in that setting. Most of the patients are managed in that setting.

And on the -- in the FORWARD study, you said roughly 40% to 50% of patients will be presumably on G-CSF.

About 40% we're seeing.

Do you allow for down titration of G-CSF?

No, we don't. And that's when we joined, that was the one limitation of the trial that we studied. I'm glad you brought it up. So in consultation with the FDA, it was decided that the G-CSF dose will be fixed. The problem with that is it means we wouldn't have data in the marketplace to say how G-CSF could be used with mavorixafor. So what we're in the process of discussing and working with the clinical development team is looking at a -- doing a small Phase II study where we can titrate the dose of G-CSF against mavorixafor whilst maintaining ANC.

And my objective is by the time we get the approval of -- for mavorixafor in chronic neutropenia, which should be in 2028, we will have a publication in place that will provide some treatment guidelines on how to use G-CSF with mavorixafor. The full trial is well designed, but that's the one bit of data we will not get from the trial. So we need to run a smaller study.

But in forward, so the patients that are on stable G-CSF, they still have to have low ANC count?

Yes. We have patients from all different doses of G-CSF from high to mega doses, super, super doses as some people call them. There are patients who've been in G-CSF for a short period of time, and there's patients who've been on it for a year, particularly the congenital neutropenia patients, some of them have been on it since childhood, and they have very, very high doses of G-CSF, but they're still they still have severe and moderate neutropenia.

Do you expect differences in patients' ability to increase ANC dependent on whether they're on G-CSF, obviously not responding or naive?

Yes. I've spoken to the team about that at the time. The answer is no. We're really dealing with a refractory population for the G-CSF. If you are on G-CSF and you're still getting 2 infections a year, you're not -- it's not being controlled. It's not working.

In fact, I think I've already said 70% of patients coming on trial have 3 or more infections. So we are examining -- we are exploring here a population that is symptomatic and is quite sick despite the use of G-CSF.

Okay. And then the other thing my understanding is Plerixafor or CXCR4 antagonist, they were really fast, right? I mean I think you can mobilize these cells within days or a day. And so how much is known about the long-term effect of that ANC increase? How stable are these increase over time?

We have data. It is maturing. Obviously, the initial data set here is generating the ultra-rare indication of WHIM. But we have patients 3, 4 years out now who are doing very well on mavorixafor, but it's important for us to continue being following up patients. And the 4WARD trial does have a long-term follow-up component to it. So if we get approval for many years, we need to continue.

The answer to your question is I haven't seen anything yet, but it's important that we conduct ourselves properly and have pharmacovigilance looking for any long-term effect nothing at the moment, but we continue to look.

Yes. From a -- and then this is a 1-year study, right, 52 weeks. From a safety tolerability angle, anything you're watching specifically? I think the drug has been very well tolerated, but any concern.

Well, first of all, the independent data monitoring committee met last quarter and didn't make any changes to the study. So that's gone well. I review the blinded data with the clinical team. I did it last week, every quarter -- sorry, every month.

I've not seen any changes in the safety signal. It is blinded, so I'm seeing both treatment arms. But no, nothing new. We know there is some GI toxicity that needs to be treated symptomatically. But to date, there's nothing new to report.

Okay. And then I know you alluded to some changes that you're implementing to the study conduct. Just maybe elaborate a little bit more on what are some of the things that you've done to really ensure the study has the highest possible chance of success.

Yes. The main thing is this is rare disease. So you have to find the patients. So we have -- we moved the MSLs away from commercializing the drug to patient recruitment. And together with the Clin Ops team, our CRO, our job is to identify patients and get them referred to the treatment center.

So if there's a site in L.A., there will be one hospital in L.A. that's conducting the trial, but there are other hospitals that have these patients. So we're using AI to look at databases. We're spending a lot of time in the field. I'm in Europe again next week, Mainland Europe, working with some PIs, developing relationships.

It's really about identifying patients, getting them into screening and then seeing if they can go on the clinical trial but it requires a lot of groundwork, a lot of field work, and that's the change that we've tried to bring to the company. We've made it about relationships, and we've made it about getting into the field and talking to physicians and identifying patients. That's the focus, and it's working.

It sounds like you're tracking towards 3Q enrollment complete.

Yes, we are. I'm not going to give an update today because we're still seeing the benefit of our changes. But towards the end of the year, I'll provide an update to the Street.

Okay. And then -- so presumably, then data would be available one year later, right?

Yes.

And I know it's a little bit early still, but how do you think about pricing and access in the market, especially relative to biosimilar G-CSF, which played really well.

Yes. Well, I think the benefit here is reduced infection, which, as you know, within the American health care system, admission to hospital for infection is very expensive. I think there is an opportunity for premium pricing here. We've not done formal pricing research, but based on my experience, I think there is an opportunity to have premium pricing in a rare disease. I don't think the pricing of the drug will be sustained where it is, which is in the $500,000 range. I think it will be lower than that. But I do think given the benefits and given how rare the disease is, we could have very healthy pricing here.

Okay. Are there any other potential competitive programs in the industry that are in development for this?

Not that we're aware of, if there are, I'd love to know from anyone in the audience, but we're not aware of any competitors at the moment.

Okay. And do you see any other potential label or opportunities beyond chronic neutropenia that could be interesting for...

Yes. Yes. We've had a lot of interest. There are other forms of secondary neutropenias. There are other indications where we could potentially expand the use of the drug. Most patients with chronic neutropenia actually have mild neutropenia counts of 1,000 and above. So I think there's opportunity to do that. At the moment, though, we're focused on getting the beachhead with the chronic neutropenia, severe and moderate indication and then we can expand.

And the team have many ideas as to many of my Board and how we should do that, but it's not the focus at the moment.

Got you. And I mean, when I think about GCS, it's obviously approved in a range of indications. Are there any other things that are obvious opportunities for mavorixafor that are related to G-CSF?

Yes, there are. But that will come out in time. We'll talk about them. Yes, there are -- it's funny when you join a new company, people bombard you with new ideas. And what we've got to do is keep the team focused on achieving the primary goal and then we can work on the other ideas.

And then any -- as we look ahead, so ahead of the 4WARD Phase III data, presumably towards the end of 2027, any other milestones or events investors should be watching out for?

Well, we do later this year, I think we need to present to the Street what we think the market opportunity is. A lot of investors have been asking for that. So we are looking at having some presentation where we can present our work.

I've already mentioned that we think there's room for G-CSF titration study. So these -- and then obviously an enrollment update. So I think this is the news flow for this year. I'm still working on the first one, making sure we've got a very clear and accurate presentation of the market opportunity.

We've had investor meetings, thanks to you this morning. And it's a common question. Can you present the market opportunity and can we see some of your data, and we'll do that.

Are there any analog markets or some precedent that come to mind comparing this to...

Not off the top of my head. Did you have anything in mind?

I didn't. I'm thinking just from a patient number perspective, obviously.

No, I think there's -- because there's not a lot of work going on with other companies on this. And I think it's up to X4 to present to the Street what we've done. And so people can understand and make their own assessment. And that's something we need to do this year.

Great. Well, thank you, Craig. That's all ahead. So thank you for the Q&A session and really appreciate you being here today.

It's always a pleasure. Thank you, Michael. Thanks.