Cantor Conference on day one. Very excited to be hosting X4 Pharmaceuticals. We have Adam Mostafa, the CFO. I describe X4 as one of our undercover gems that everyone needs to pay attention to. It's a lot of great stuff under the radar, should be valued a lot higher. So thanks for being here today.
Yeah, of course. Thank you for having us, Kristen. We appreciate the opportunity.
Yeah, so it's been a great year for you. You're celebrating your ten-year anniversary very recently.
Yeah
... and what better way to do it than getting your first drug approval for XOLREMDI in WHIM syndrome? How are spirits and momentum going at the company in light of this, these days?
Yeah, spirits are very high. It's been a big year at X4, started with our approval of XOLREMDI in April. People are really excited as well about the potential global impact of the drug. We're heading towards our MAA filing in early 2025, and we're exploring ex-U.S. partnerships as well to help globalize the drug, and of course, chronic neutropenia is really exciting for people. We shared some recent phase II data that was very encouraging. It was on top of phase I data we had previously shared, showing the drug's efficacy, so people are really excited about the potential, and we're now commercial obviously with an ongoing launch, and impacting patients every day, so it's great. It's been a great 10 years.
We, we've come a long way, but, there's still a lot more work to do to help a lot more patients. So-
Okay, great, so you got past the challenging part of going through the trials-
Yeah
... proving efficacy and getting it approved. Now, the big task ahead is identifying patients with WHIM syndrome.
Right.
Could you walk us through some of the initiatives, even some of the stuff you're doing ahead of approval, really to kind of help-
Yeah
... see who's available out there, and how is this leading to more diagnoses?
Yeah, so maybe just a little bit about WHIM. So-
Please
... WHIM is a rare ... We estimate about 1,000 or so US diagnosed patients, primary immune deficiency, and it's caused by gain-of-function CXCR4 mutation. That causes white blood cells to get stuck in the bone marrow. Now, XOLREMDI is an oral CXCR4 antagonist, that's our drug, which was shown in our phase III trial to increase neutrophil counts in the peripheral bloodstream, and that led to a significant reduction in infection rate, severity, and duration. Now, WHIM is a heterogeneous disease, so it presents in a bunch of different ways. In fact, less than a quarter of the patients present with each one of those letters in the acronym. And so infections is really the hallmark. These folks get serious recurrent infections. They have chronic neutropenia. But this heterogeneity I mentioned makes diagnosis a challenge.
And the other issue is there hasn't been a reason to diagnose in the past. There's been no treatment that addresses the underlying cause of the disease, that is, until now with XOLREMDI. So we fashioned our commercial strategy to address these challenges. So we're focused on physician education, engagement, disease awareness, patient access. We have a national sales team of sales reps. These are all folks who have a lot of experience in rare disease that have been deployed across the country. We have medical affairs professionals, patient advocacy professionals, and they're all focused on raising visibility and awareness around WHIM. So they're using things like online campaigns, targeted education venues, and we have a genetic testing program as well. We're focused on key hematologists and immunologists, where we're helping them find patients in their practices.
and we also launched a patient hub. It's called X4Connect, and this helps patients to navigate the what can be complicated insurance process, obtain pre-authorizations, reimbursement, and that's all going very well. So it's early days, but anecdotally and otherwise, things are going really well with the launch.
So in the clinic, all of your endpoints correlated very nicely here with the blood cell counts, but then also looking at how this corresponds to reduced infections, a lesser degree of the severity infections, able to work more, et cetera. But in a commercial setting, how are physicians going to determine whether or not this drug is working for their patients?
Yeah. So I think you said it. It comes very much down to infections.
Yeah.
So in our phase III trial, we had patients come in with over four infections per year and seven weeks of infection duration per year. On XOLREMDI, that dropped down by 60% in infection rate and down from seven weeks to two weeks. So as you can imagine, going from seven weeks to two weeks per year has a drastically positive impact on people's lives. So I think for physicians, they'll look for that same infection benefit on people's lives and potentially some longer term health outcomes that we might see. So we expect the same thing we saw in the trial to be reflected in the commercial realm, and then would give support for physicians to prescribe the drug.
Okay, thanks. And obviously, WHIM syndrome's a meaningful indication, but I think bigger picture-
Mm-hmm
... these data really set the stage to tell you more about the mechanism and validating it, which could-
Yeah
... you know, potentially be applicable for others, so the ability to increase the neutrophil counts and reduce the burden of infections. So obviously, the next big task for you-
Yeah
... is chronic neutropenia. So how similar and dissimilar are these two indications, and should we be making essentially read through from one to the other?
Yeah. Yeah. So, given the mechanism of the drug, looking at it in places with CXCR4 genetic variations made a lot of sense, like WHIM. We did see previously. We studied the drug in healthy folks and in oncology patients, elevation of white blood cell counts, even without necessarily these genetic variations. So that gave us some encouragement early on to look beyond WHIM, and the first of these is chronic neutropenia. It's also an immunodeficiency. We've already tested the drug in a phase I and phase II. We reported data in June showing significant neutrophil count elevation and extending that out durably, through six months. If we continue to see that through 12 months, as we showed in the WHIM trial, high correlation between that ANC elevation and infection benefit.
They're also similar from a call point perspective, so the commercial investment we discussed also applies to the same hematologists and immunologists who are treating chronic neutropenia. But this is a much larger indication. We estimate about 50,000 patients diagnosed in the U.S., of which about 15,000 would represent the initial target market or high unmet need. A lot of clinical and commercial synergies between WHIM and pass-through to CN in what we're seeing so far.
Okay, thanks. And moving on to chronic neutropenia. Sometimes when it's been literally decades since a therapy's come to market, you question, is that because people are satisfied with current standard of care? No, no reason for that, but I think we've figured out that that's absolutely not the case-
Yeah
... with chronic neutropenia. So why is it that patients are desperately seeking new therapies, and what are some of the main limitations that mavorixafor might be able to address?
Yeah, so immunodeficiencies in general have been under-innovated. There hasn't been a lot in the area. G-CSF was approved decades ago as a growth factor. It's more so used, and you might be familiar with chemo-induced neutropenia.
Sure.
So this is a place where chemo can deplete or compromise bone marrow, and then these folks are more susceptible to infection risk. Now, in that acute short-term setting, it's used to sort of bridge patients through their chemo. The issue with G is it does come with significant side effects, particularly in a chronic setting. So you're talking about severe bone pain, nausea, fatigue, flu-like symptoms, and long-term malignancy risk. So physicians in a chronic setting now, we're talking about chronic neutropenia, are hesitant to give the drug regularly. In addition, even when they do give the drug, they typically dose it under label, so they don't give quite enough, and then it can have efficacy concerns.
Patients, we hear from our commercial team all the time, are crying out for something else, and something that doesn't have all these side effects that they've gotta deal with for the rest of their lives, potentially. So it's an injectable, tough-to-take drug that isn't suited for chronic treatment. Now, our drug is a safe, oral, once a day, that we think is very well-suited for chronic treatment, and would solve a lot of these challenges and be something that could be the go-to for physicians and patients in a chronic setting. So that's what we're aiming to do with our trial. We have the phase III up and running now. We're ramping up enrollment, and you know, we're targeting next year to complete that.
Okay.
Yeah.
So I know that there are classifications, right, in terms of neutrophil counts related to the indications of severity. But do you have a general sense of how to correlate specific neutrophil counts to infections? And do these levels of severity that are out there? Is that the same as what physicians look for in a real-life setting?
Yeah. So in terms of ANCs, you can think of it as every sort of 500 increment puts you in a lower infection category. So patients that are below 500, considered severely neutropenic. 500-1,000 is moderate. 1,000-1,500 is mild, and above 1,500 is normal. So physicians will look at it that way as well in terms of these incremental increases to reduce infection risk. In our WHIM phase III trial, patients came in quite severely neutropenic, an average of about 250. We increased them by over 500, and we saw that very beneficial impact on infection reduction. We showed the same thing in our CN phase II data just recently in June.
If you look at the severe subset, we got them to that eight hundred to a thousand range. That's where physicians typically like to see their more severe patients, WHIM and severe chronic neutropenia. And then in the G-CSF, we'll talk a little bit about CN, hopefully. .
But in that area, we were able to increase between MAV and G-CSF. The elevated ANC was 1,000 in month one and beyond that in further months. So that means room to potentially titrate down G-CSF. This is data we'll have in November to give you more clarity on that. So these are some of the metrics that relate between ANC, infection risk, and what we've already seen in WHIM that we hope to see in CN.
Okay. Well, the good news is-
Yeah
... we have seen some good data-
Yeah
... in CN as well-
Yeah
... to further emphasize that. So maybe we could talk about some of those key findings. Some of this data was recently presented.
Yeah.
We have more to come. We could talk about that in a minute. But are there a few different ways that we can consider these data a win? I mean, in terms of raising neutrophil counts, reducing G, addressing some of these tougher-to-treat patients. How are you thinking about that?
Yeah. Yeah, so this, so the phase II trial is a six-month trial, and there's really three groups, if you will, patients. There's those on mavorixafor monotherapy, so just MAV; MAV plus stable G, so not adjusted; and then mavorixafor plus G that is titrated down in later months. So far, we've reported on the first two groups in June. Those patients were all out to three months, and about half of them were out to six months. And in terms of different cuts, so if you look at both those groups combined, if you go out to six months, 100% of them had achieved at least a 500 increase, so that 500 category change, I mentioned. If you look at the monotherapy group, we got them to 1,500 or above for the later months, so we normalized them.
If you look at the stable G plus MAV group, we got that increase to 1,000 in terms of cells per microliter in one month, and then even more so in later months. So very drastic increases. And then if you look at the severe, as I mentioned, we got them to the 800 to 1,000 range, where physicians like their severe patients to be. So you can cut it a lot of different ways, and you find yourself with a win. You find yourself with a de-risked phase III trial, which we're currently underway on. The drug was also well-tolerated and safe, which is important for a chronic treatment. So we're very encouraged by the data we've seen, as it relates to the upcoming trial and our potential success there as well.
Okay, and you've guided to the Street we might get some more data in November.
Yeah.
Can you give us a sense of what level of data we might see in that update?
Yeah. So we'll have those first two groups I mentioned, the mavorixafor monotherapy and MAV plus stable G, folks, out to six months. And then we'll have new data on the mavorixafor plus titrated-down G, where we'll do our best to share where ANC levels were over time relative to how much G was decreased over time. So a little tricky and exploratory trial. Patients are on variable frequency and/or dose of G. But keeping in mind that even a 25% reduction in G dose and/or frequency is meaningful to patients and for physicians. So that's what we'll share, and it'll be the final phase II dataset... that should help give confidence, hopefully, in the phase III.
Okay, which has already started.
Yeah.
So wanted to talk about that in a little bit more detail. How do the ANC assessments that take place through 12 months work?
Yeah. The ANC response is defined as follows. It's a response over 1,500 cells per microliter, except if you come in below 500, then it's a twofold increase.
Okay
... double. Now, keep in mind, in the phase III, the primary endpoint is a two-component endpoint, ANC response and infection rate. So the ANC is a good correlative measure. So we're sharing that in the phase II. We saw what happened when we increased ANC in the WHIM trial to infections, and the infection is what we'll measure over a longer term, hence the 12 months of treatment. So it'll be similar in terms of the actual measurements. It'll be measured over several hours as folks come in at different time points over the two weeks, similar to the WHIM trial, in terms of the measurement itself. But again, if we continue to see what we've seen already at six months and extend that out to 11 months, we would expect to see infection benefit, as well.
I would say the trial is in many ways similar to the WHIM trial and informed by that. So...
Okay, thank you. And then how do you think about the potential for mavorixafor to be effective across the different subgroups of chronic neutropenia?
Yeah. So in the phase III trial, we're studying it in autoimmune, congenital, and idiopathic CN patients. And we expect the drug to be, you know, safe and efficacious in all those groups. We don't have reason to believe it would be different.
Sure
... among those, so.
Okay.
Yeah.
This is a very sizable market opportunity.
Yeah
... for you. Can you walk us through what numbers you think are reasonable in the U.S., maybe where an initial launch might take place, and if things go really well, if there's opportunity to expand?
Yeah. So, as mentioned, we estimate about 50,000 patients diagnosed-
Sure
... with CN in the U.S.. Now, in terms of the initial target market is accessible by our phase III trial, we think that's about 15,000. And this is a mix of patients who either are not on G-CSF, so maybe they're congenital, they can't tolerate it, or physicians use it very acutely in a short-term basis to kind of bridge them through some issue. And then you have patients who are on G, but on lower dose, and would love to come off of G, and that's a lot of the feedback we've been getting. So that 15,000 represents target market. We don't have any reason to believe it would be much different outside the United States. Most of our work is an estimate of about the same, around 15,000 in Europe.
We are, as mentioned, exploring ex-U.S. partnerships to potentially help us commercialize outside the United States in both WHIM and CN. We will have EU sites and patients in the phase III trials. That'll be part of the regulatory package.
Yeah
... the global trial, so very sizable opportunity, significantly in excess of WHIM, but in WHIM, in many ways, sort of sets the playing field on which we can launch into CN. It's the same, as I mentioned, same call points, immunologists, hematologists, and who are being trained and learning on the drug as we go before we launch into this much bigger place.
I know you're looking for global partners, but do we have a general sense of what the market size is, ex-U.S.?
Yeah. I mean, so the work we've done, we're estimating a similar 15,000 or so-
Okay
... in Europe-
Sure
... in sort of the EU5, similar to the U.S. in terms of that. So, very meaningful still, particularly for rare disease.
So there's just so many shots on goal here. I think, you know, you proved yourself, you got your drug approved. CN, the data looked quite strong in this last update. We have more data to come. So what do you think investors just don't get or resonate? Because, again, these are very good opportunities, and you have some de-risking data.
Yeah. I mean, I think we're very well positioned. We have an approved drug now that's out generating sales. We're looking forward towards an MAA filing early next year to globalize the impact of the drug. As I mentioned, we may be able to to secure some non-dilutive capital via partnership to help do that. We have a lot of potential in chronic neutropenia. We've already shared very encouraging phase I, phase II data in what is a much bigger market. We're looking forward to November, so just around the corner.
We'll share the final CN phase II data set. We're ramping up enrollment in the global phase III trial in CN. We just sold our PRV in record time for $105 million, added that to the balance sheet, so we have runway out to late next year, that's excluding sales, and over that time, we'll have multiple valuable milestones, so for us, we see this as an extremely compelling opportunity, particularly at our valuation.
Yeah. Well, thank you so much-
Yeah
... Adam, really appreciate your time and your support for coming.
Yeah. Thank you, Kristen.
Thank you.
I appreciate the opportunity. Thank you.