All right. We're going to go ahead and get started. I am Stephen Willey, one of the senior biotech analysts here at Stifel. Glad to have you with us here for the next session. The CEO of X4 Pharmaceuticals, Paula Ragan. Thanks for coming, Paula. I know we've done this a bunch of different times. Any opening comments you want to make before we jump into Q&A?
Yeah, no, absolutely. We are excited. I'll just take a seat here. And so, I mean, 2025 has been a transformative year for X4, just showing, I think, what the company's capabilities are and what we can do to impact patients. We got the approval of mavorixafor in April, now branded XOLREMDI, hitting our launch metrics the first half of this year in terms of outreach, driving education of physicians and awareness. And importantly, we're even thinking already about that next stage of growth in terms of leveraging our FDA approval in countries that accept it. We're on track to file that MAA early 2025, and potential partnerships could even further expand on that. So WHIM and mavorixafor is off and running. And then, of course, we're already thinking about our next indication with our CN Phase 3 trial.
We just gave a very robust update both on data to de-risk that Phase 3 and huge leaps forward in progressing on the CN Phase 3 trial execution. So I'm hoping people hear that story of we know what we need to do. We're operating on all cylinders and looking forward to diving in more detail with you in the Q&A.
All right. We are going to dive into all of those things.
Nice.
You just reported the first full quarter of XOLREMDI sales last week?
Yes.
I know that there was a little bit of a, I don't know, visceral reaction to the number that you guys threw out there. I know you as a management team have been fairly tempered in your characterization of what patient onboarding would look like at the outset. So I don't know if you just want to kind of expand upon what you think perhaps caused that disconnect, and does this at all change the way that you think about messaging launch progress as you go forward?
Yeah. So I don't think it changes anything in terms of our messaging because it's been fairly consistent. Of course, we need to do that more often and maybe louder, but we've always described WHIM as an ultra-orphan market. We knew from the beginning that there were only a handful of patients from the Phase 3 and that there wasn't really any bolus of patients waiting to come on study or off of study onto drug. So all of our patients did convert from the trial from the OLE. We've been investing in kind of identifying those patient and physician pairs out there in the community and helping drive that reconnection, education, and awareness. Because what we do know, certainly from our early days. But demand is increasing, education and awareness is increasing, and then screening is certainly on the uptick as a result of all these efforts.
So we are excited about where we are. Certainly 2025 and beyond is really where the revenue story will be. But we're really excited about our label, what the commercial teams have been able to do to date, and the fact that we have a disease-modifying drug out there.
Okay. I know you indicated that you have already reached 100% of, I think, the more than 3,000 HCPs that you were targeting at the beginning of the launch. So what needs to now happen to make sure that those physicians that you've reached out to remain engaged? And what are you now doing to further drive disease awareness and patient screening efforts?
Yeah. So I think, again, it's always about getting that broad umbrella kind of reconnected, which they're active and reconnected. And now the question is how to keep that engagement live. I mean, what we have done is we've measured ourselves, right? What we did was we pre-launched, we measured how many physicians are aware of WHIM syndrome. We've seen a huge uptick to already over 75% of that same target audience now being aware of the disease. And if they have a WHIM patient, they would prescribe XOLREMDI. So we feel like all the pieces are there. What we now need to do is continue to support what I would say peer-to-peer interaction.
So we've been working on some physician peer, sorry, webinars to help educate the broader physician communities from those that are experienced with XOLREMDI and WHIM patients to just help them convert their intrigue and interest into action and bring their patients in for treatment.
Okay. Bless you. So I know that you've talked about some of the pre-launch efforts. I know that you had some legacy patient identification efforts that were ongoing prior to the launch. I think you were looking at claims analyses and you were providing genetic testing for a little while as well. So how would you characterize, I guess, the ROI on those early patient identification efforts? And have you been able to mobilize any of those previously identified patients kind of into the treatment queue?
The answer is yes, right off the bat. So absolutely, we have had some good success with identifying patients and physicians ready and waiting for the approval of our drug, and those are converting into demand. Importantly, though, we just want to remind everybody there really is no reason for WHIM patients to be actively managed by their specialists, right? They are managed a bit more broadly on their day-to-day, but they do on periodic routine go back into their specialist office. So that's what we're waiting for, this flywheel to start moving. We know these patients and physicians. For anybody in the commercial world, post-COVID environment of getting that foot in the door for a sales force is not easy.
We've been starting to build that trend, kind of get back in those offices, and we certainly believe that those known WHIM patient-physician pairs are going to be beginning to convert even more readily in 2025 and beyond.
Okay, so what does that cycle time look like then, right? If I'm a WHIM patient, how often am I going to see my specialist or a specialist?
So it depends on what you're being treated with. So there's the IG patients. Again, a lot of there's IG clinics that they actually don't need to go back in to see their specialist. So I do think there's a little bit of catch here around how to mobilize the patients that are kind of in stable situations to get into their physicians earlier. That's actually where we have an excellent program with our nurse educator. We have consented patients that are able to be outreached directly from X4, and she continues to build that patient population. So we have all the pieces in place. Again, it's only been four months as of our last reporting. So I think that we have all the building blocks to make sure that the existing patients that we know are starting to reconnect with their physicians for potential treatment.
And then, of course, we're always building the education and awareness to help build that physician pool looking for WHIM patients and, of course, connecting the patients that we do know to physicians who are aware.
Okay. I'm guessing this is probably too early to answer, but are you seeing patients who you've screened, identified as having WHIM, but have not yet chosen to initiate therapy? And I guess, is there any rationale for that?
So again, very early days, but no, we've not seen any of those examples. But I also want to caveat not 100% of all patients are ever going to receive or want to receive treatment. There's certainly going to be some fraction of that, but so far, so good.
Then how would you characterize the progress that you have made on the reimbursement front? Has there been any pushback whatsoever?
I mean, what we're experiencing is typical for ultra-rare disease at the value points that we're projecting. There are prior auths. We're cycling through those in your typical kind of cycle time, which on average is about 90 days, but we're tightening that up the more experience we get. The payer systems today, the key payer systems we've been reimbursed at are now covering about 150 million lives with their policies. So that'll help to kind of tighten up the cycle time as the drug launch progresses.
Can you speak to what some of those prior auths are in terms of what is being required of prior treatment history, or?
Yeah. I mean, it's really just making sure that the physician is diagnosing WHIM. And in some cases, they're trying to confirm that it's consistent with the label, 12 and above, diagnosis of WHIM syndrome. Some payer systems are holding to some genetic testing. Not always, obviously, there was a smaller genetic variant population study in the Phase 3, but all those elements between diagnosis, either genetic or otherwise, sometimes myelokathexis is accepted. We're not really seeing anything unusual here so far.
Okay. So I guess this kind of 90-day reimbursement process, I know you're trying to shorten it, right? But I'm guessing it also gives you perhaps a little bit of an advantage to the extent that it provides you with some visibility into the number of patients that are kind of getting queued up for treatment. And so I guess, is there anything that you can say about what that current paperwork queue could imply about new patient starts in the fourth quarter or going into the first quarter of next year?
Yeah. So I mean, we just want to keep reminding everybody. Early days. Like, 2025 is really the year I think we want to focus on kind of the revenue growth. We've been trying to get these patients back in to see their physicians. And again, the start forms are a leading indicator, so we'll be able to provide some more insights into 2025. But we really are playing the long game here. There is no approved treatment for WHIM patients. They are very poorly managed, and you can appreciate they've been kind of just hovering on whatever existence that they can. Now there's a reason to get in to see their physicians. There's a reason for physicians to invite their patients back in. It's just going to take some time. The good news is no competition.
This is a lifelong treatment that we expect to continue to grow over time over the many years that we hope to help these patients.
Okay. I know you had a number of patients participating in the open label extension for the 4WHIM trial, the registrational trial. And it was, what, a 27-patient study, right? So I'm guessing when I say number, it's in the context of that. But have those patients been converted onto commercial therapy or some portion of those patients?
Yes, so everyone on the OLE was converted to commercial treatment. Reimbursement is still in the process, right, so we have quick start for patients. Some of them had clinical trial material that, of course, they could continue to utilize. But now all of them are on commercial, and of course, that'll pull through into revenue as the quarters go on.
Okay. I know you have different price points for the drug depending upon what the patient weight is, and again, this may seem like a nuanced question, but it could make a difference perhaps from a modeling perspective, right? There's a decent price point difference, so do you know what the breakdown of patients might look like in terms of those who are, I think, below that 50-kilogram threshold and get that lower dose versus those that are north of 50?
Yeah. So I mean, in the WHIM Phase 3 trial, it was about 90-10, 90% being above 50 kilograms, 10% being low. We're not really seeing anything different to date. Again, early days, but we don't think that's going to be a big swing in any direction.
All right. You mentioned the MAA submission early next year. I think you have talked about evaluating strategic options with respect to ex-US plans. I guess, is there anything that you can say about the level of strategic interest that's out there and how you might be ideally hoping to structure a partnership?
Yeah. So I mean, certainly you can appreciate with an approved drug and especially with our positive Phase 2 data in CN, there's lots of interest in our product profile and the potential patients that we'll serve. Now the question will be, can we create the right deal structures that are beneficial for both a party and for X4? We'll try to clue you in certainly when we have more specifics. But I think we're in a really strong position to be able to determine what makes sense for X4. And we have an asset that is a very strong profile. You can appreciate an oral once daily benefiting with infections and a niche population with a much larger one coming on fast behind it is a good recipe for potential success here.
Yeah. And so I would imagine, like you mentioned, right, any deal would certainly have to contemplate potential success in CN.
Yeah. I mean, I think, yes, for any deal that makes strategic sense to X4 and its shareholders, that would be the bite that would have to be taken off. Now there are other ways to do it. If we want to retain that value ourselves and go the distribution model, we can also have that as an alternate solution. So it'll really be very dependent on what type of partner, what capabilities they have, and of course, the overall value proposition.
Would you like a partner to be able to offset some of your Phase 3 development costs in CN?
Yeah. So again, I think it depends. Every partner has their own flavor of how they like to do deals. Obviously, we're not going to do some live negotiations here, but let's just say it needs to be meaningful both near, mid, and long term to X4 and our shareholders. So hopefully we'll see what happens in that direction.
I was going to jump into a mock negotiation next.
Okay. All right. Let's go.
I guess we'll avoid that.
All right.
All right. So you also gave us some incremental data from the Phase 2 CN trial last week. I think that data continues to look pretty interesting. I know the data you showed us back in June kind of really served to de-risk the Phase 3, right, to the extent that those were patients who were either on monotherapy or stable G-CSF. But this data update seemed to kind of really inform how this drug could be used in the real world. And so what are the key takeaways that you highlight from the incremental data that you provided? And then how do those takeaways, in your opinion, potentially inform how this drug is used in the commercial setting?
Yeah, absolutely. So let's just talk about the highest unmet need and the number of patients in that category in the U.S. alone. So there are about 15,000 patients today with diagnosed chronic neutropenia who are refractory to treatment or breaking through treatment, right? That is a large number inclusive of standard of care. Their needs are not being met. So when we think about what we just showed with the Phase 2 data, we showed our drug is effective in monotherapy. We were robustly getting neutrophil counts on average to normal ANC levels. Even when we drilled down into those most severe patients, we were correcting their neutrophil counts equivalent to what physicians target with G-CSF. So the drug is clearly active in this patient population that has already been proven that ANC and infection rate benefit correlate. It's a highly validated approach that we're taking.
So we feel incredibly solid with our monotherapy data, right? You have to show that what the drug can do as a standalone. Now when we talk about the G-CSF-treated population from this Phase 2, one it's relevant to the Phase 3 trial because we will allow folks with stable background G-CSF so long as they're part of this breakthrough or high unmet need group. That broad label will really help us get this full market potential. And then finally, you mentioned the real-world evidence. At the end of the day, nobody wants to be using G-CSF. It's painful acutely. It causes muscle cramping. And on long-term, physicians are worried about malignant transformation. It is a growth factor, right? It is impacting your bone marrow every day. So coming up with a safe oral once daily treatment is going to be transformative for this patient population.
We likely project it'll be backbone standard of care. Again, assuming our Phase 3 is successful, most folks will start on an oral once daily and then top off to G. For new patients, for people on G, they have to figure out how to titrate and find the right balance. And the Phase 2 data just showed about a 70% reduction on average by six months. So all those ingredients are quite meaningful as we think about the long-term commercial success of the drug.
That background G in the Phase 2 trial was titrated on the basis of the subjectivity of the investigator.
Exactly. Very real world. They play around with G on their patients today. It actually takes them many months to kind of find a steady-state dose. So the fact that after two months of combo therapy, they're already willing to give it up is a great indicator of how ready people are to give up their G so long as neutrophil counts are being maintained where they need to be, which is what we've just shown.
And the disclosure last week also included some data from this sub-study that looked at neutrophil functionality. I think at one point there was a little bit of a narrative or some concern around the functionality of the neutrophils that were being mobilized. We know that there's pools of neutrophils that exist in reservoirs in the lung, et cetera, et cetera. But what do you think that data kind of showed specifically? And do you think that this whole neutrophil functionality question has been kind of put to rest?
I definitely think it's been put to rest. I mean, what we do know is these patients have low counts, right? That's the definition of their disease. Both with G-CSF and with Mav, has anybody ever actually looked at the true functionality? Are these neutrophils less mature, less able to attack and kill bacteria? So we have upped the level of evidence to support that mav orixafor is not only mobilizing and increasing counts, but those cells are perfectly capable of attacking and destroying via ROS bacteria. So we really have kind of gone the final mile to show that how the potential of this drug can quickly translate into infection benefit, which is what everybody wants to see.
Was that prior data that was put out there kind of postulating around neutrophil functionality? Was that put out by Sanofi?
You mean when you say, but I'm not sure what. Sorry, Steve, when you say postulating.
I think there was a question around functionality that came out of, I think it was the plerixafor.
Oh, interesting. So neutrophils are hard to study. There was a Phase 1b study that explored plerixafor, but it was a really short-term study. I can't remember the endpoint data exactly, but what you really want to see is the long-term kind of sustainable profile of neutrophils and bone marrow. And since we've looked, I mean, we looked at day one and month six and neutrophil functionality, both from phagocytosis engulfing the bacteria to ROS, which is injecting and kind of breaking up the bacteria, look robustly functional over the entire time these patients are being dosed.
Okay, so you're enrolling the Phase 3 CN trial now. Can you maybe just talk about some of the key design elements of that trial, why you think those elements are or why you think those elements improve your chances of success and then also improve your chances of getting the broadest potential label?
Yeah. So the trial, if we kind of first benchmark to WHIM, right? So we were very successful with our WHIM Phase 3, 30 patients, one-year study, infection rate benefit reduction in 60%. So we know the drug correlates, neutrophil counts go up. We see this nice reduction in infection rates in the WHIM population. It's even in our label. How are we now interpreting the Phase 2 data to ensure that the Phase 3 can be successful? So number one, monotherapy. We know the drug is robustly increasing neutrophil counts in a population that needs it. The Phase 3 trial is actually broken up into sort of two parts. There's a monotherapy initial portion of the study. So 90 out of the 150 patients will be monotherapy treated. And then the additional 60 will be in combination with G-CSF.
The way we've structured the success possibilities of the trial is we're first assessing the monotherapy. That is our first question we will answer. Is infection rate being improved in monotherapy? Is ANC going up in monotherapy? Then the next question we'll answer is, is the entire population also benefiting? So we will look at the 150 patients as the next hierarchical question. Are we improving infection rates? Are we increasing neutrophil counts? So we have this kind of multi-layer WHIM sort of stepping stone where we're going for the lowest hanging fruit that's correlative with WHIM very nicely. And then that 150 patients will really unlock the full market potential of the drug, even for patients on concurrent G-CSF.
Okay, so the primary endpoint here will be the annualized infection rate in those initial 90 monotherapy patients.
Correct.
If positive, you trigger the statistical hierarchy and go to the entire population.
That's the ITT. Correct. Yep. Yep.
And I know this trial is also enrolling different subtypes of chronic neutropenia. Is there some threshold representation of each subtype that you're trying to strike from a balance perspective in the study?
Yeah. Thankfully, we're not requiring too much. I mean, there's so many stratifications you can do. Again, what we've seen in our own Phase 2 studies, it's relatively representative of what the existing overall market is, where it's just about 70%-80% are idiopathic or also called autoimmune. And then the other 20-30 are congenitals. So I would expect our Phase 3 study to represent that. Maybe a slight shift more in the congenitals just because they're typically sicker. But again, as long as it's stratified, balanced one-to-one, we're not too worried about that overall profile. And certainly, the study can absorb a pretty wide range of profiles.
Okay. So what is your level of confidence, I guess, in the annualized infection rate assumption that you're making in the control?
Yeah. So the study is being designed to, on average, look for about a 40% reduction in infection rates across the ITT. Sort of more of it will come from the monotherapy and less of it is demanded from the G-CSF therapy, which is intentional, right? We know you can actually, I mean, if we reflect WHIM, you can even go higher. So we feel really good about the way we have distributed the risk in terms of going for high unmet need, including the G-CSF, but not requiring so much from them from a positive infection benefit, and then creating this hierarchical statistical analysis. So hopefully that addressed your questions, Steve.
Yeah. And I would imagine a patient's or each patient's individual infection rate risk is probably driven by whatever that baseline ANC is, right? So is there a way for you, how have you kind of standardized that baseline ANC to make sure that these patients are kind of tracking to that same infection rate risk over time?
Yeah. So what I would say is we have robustly powered the study. I mean, you cannot control for every variable, right? So what we can say is that, first of all, randomization one-to-one is huge, especially in these smaller studies. You'll see in other trials, oh, is it two-to-one? Because it does help motivate the patients when they have a two-to-one chance of getting on treatment. We have very purposely always designed our studies one-to-one because that's exactly how you mitigate variability. And then in terms of ANC levels, most of us are not concerned about hitting the ANC responder analysis. It's really going to be about this infection rate.
Correct.
And the way we've addressed that is actually requiring everybody to demonstrate before they enter the study that they have had at least two infections in the year prior that are medically confirmed. It's not just recall. They have it in their charts and the physicians are affirming that. In the 4WHIM, we did not even require that. So again, we had a more permissive 4WHIM with a highly successful infection rate benefit because we believe certainly the drug is working. Now that we created this additional scrutiny to the patients, we expect this to be an incredibly robustly designed study.
Okay. So I know there's a lot of folks who are interested in the pace of enrollment into the Phase 3. I know you provided some guidance here on the call last week with respect to the number of countries that you're now authorized in, the number of sites that you have activated. Should we think about continued enrollment progress updates kind of following that same game plan? Or should we also think about being able to hear about you reaching certain enrollment milestones? So i.e., for instance, you complete 50% patient enrollment. Is that something that you provide to the investment community?
Yeah. So I mean, maybe just first what we have provided, what we're instilling is hopeful confidence, right? You need countries, you need sites, and then you need patients. So on the country side, we're almost at target. On the site side, we're almost 40-plus% of the way through it right now. And then, of course, the patient screening will continue to climb. And we still have six, seven months before we're even supposed to hit our numbers. So we're really excited about already the baseline kind of operations that are ongoing. And now when we think about the first half of 2025, we will, of course, be giving any relevant update that continues to demonstrate confidence in this trial. We expect to be able to communicate how and when.
Not going to preview just yet, but I can assure you that it is top of mind for all of us at the company to demonstrate that we're continuing to operate and perform well. We recognize this is important to our investors and to the patients.
Okay. In terms of the prescriber base for chronic neutropenia, can you talk to the additional infrastructure that you would need to build out with a CN label in hand on top of the WIM access that you already have?
So this is the beauty of what WHIM additionally provides in addition to helping patients and revenue. It is almost building the existing infrastructure, the exact infrastructure and relationships that are needed to be rapidly launching in CN. We shared already that about there's almost 70% overlap in the physicians that hold on to CN patients. These are the hematologists and hold on to WHIM patients. So they're going to have a couple of years of being familiar with the drug, being familiar with us when they're treating their WHIM patients. And of course, we hope to walk in that door with that expanded label infection data benefit. That in itself will really help us launch robustly in the U.S. and CN for sure.
Okay. And you talked a little bit about how you think about the market opportunity in the U.S., i.e., 15,000 patients. How does that look outside of the United States? I know there's, I think, less G-CSF use outside the United States. And so does that mean that there's a larger pool of patients who could be candidates for mavorixafor monotherapy? Are those patients harder to find because you can't track them as a function of G-CSF use?
I would say, so we'll talk about Europe specifically. I would say the CN patients are a bit easier to find just because of their tertiary care systems. We've done some market research. This is consistent with what our understanding is, and then in terms of the number of patients, we're actually finding, again, possibly more congenitals just because I think their healthcare system is a little bit more enabling, right? They create these kind of screening hierarchies. Some countries do it as part of their standard of care, so I think it'll be similar, possibly slight shift in terms of the number of congenitals versus idiopathics, but overall a very robust market, similar to the numbers that we've already talked about on a population adjusted basis.
Okay. Are there any other questions? Yes?
Yeah. Paula, congrats on the success so far. Just a quick question. Can you shed a little light on what the payer mix looks like for XOLREMDI and the WHIM indication?
Yeah. We haven't given details, but I would say.
The question was just on payer mix for the people who are listening.
Oh, sorry. Steve, thanks. Yeah. So payer mix in the U.S., predominant number is commercial payers. Actually, most of our patient population is younger. Even at the Phase 3, average age was 33. So these are working individuals. So Medicare, not a very big proportion. Medicaid some because we have 12 and above, but we're not seeing anything atypical there in terms of the overall mix being predominantly commercial.