Good morning, and welcome to day one of the 23rd Annual Needham Healthcare Conference. We are excited to have X4 Pharmaceuticals CEO, Paula Ragan, here with us today for a presentation. At the end of the presentation, we will leave roughly 5 minutes to answer any questions. As a reminder, please click the chat button or chat icon at the top of your screen, and that will prompt you to be able to submit any questions. With that, I'll pass it over to you, Paula.
Thank you, Ryan, and good morning, everyone, and thanks to the Needham team for helping us and selecting us help to kick their 4-day conference off this morning. Just to share, we will be offering forward-looking statements throughout this presentation. If you'd like to better understand X4's risk profile, we welcome you to come and see the most recent filings in the SEC back in March. X4 Pharmaceuticals is at an incredibly exciting moment in its history. We are at the cusp of an FDA approval, which is our target PDUFA date of April 30th. But what does this mean for the patients and the community that we serve? Really, we're focusing on a group of patients with rare forms of immunodeficiency.
This group of individuals have had no innovation for 30 years, and we're bringing our expertise in a particular and well-validated area of biology called CXCR4 biology. Not only are we focusing on the biology, but we have a pipeline of indications with our lead asset, mavorixafor, that we hope to unfold and deliver the true value of the product to the many patients that could possibly benefit. Our cash runway takes us out into 2025, which covers this next wave of key milestones for us, which I mentioned, our PDUFA date in just 22 days. We have another round of data coming in our phase two study in chronic neutropenia, and we have a host of regulatory and commercial milestones ahead of us.
So a wonderful moment for X4 in our history and our sort of coming out party as a commercial company. So chronic neutropenia, what is the problem that we are trying to solve? There's about 50,000 people in the United States alone that walk around in existence with very low neutrophil counts, and neutrophils are needed to fight infections. They are your first line of defense. Within these 50,000, there's about 15,000 with very high unmet need, even given the one current standard of care. These 15,000 have recurrent infections despite being treated, or sometimes they're not able to tolerate a very difficult treatment to absorb on a daily basis. The current single standard of care is an injectable drug called G-CSF. It's very challenging to take because it has dose-limiting toxicities.
Either the patients feel worse with the higher doses and the longer they take it, flu-like symptoms and bone pain, or physicians are always hesitant to give a maximum tolerated dose throughout their lives because there—in some cases, there's been incidences of malignant transformation in the bone marrow, given its propensity as a growth factor. So what does this patient community need? They need more. One treatment is not enough. They need a safe, oral, chronic, once daily that can hopefully also improve their infection risk, similar to the, to that of you and I. That's the problem we're trying to solve. So a bit more about how... what it means to live with low neutrophil counts. As I mentioned, neutrophils are that first line of defense of infections, and there's a gradation of severity. So severe, mild, and moderate patients have all abnormally low neutrophil counts.
Threshold for normal is 1,500, the most severe is 500, and every increment up from that, that you go closer to normal, you have lower infection risks. So these patients have different ranges of severity and risks, but ultimately, they have life-threatening infections. They can wind up with hospitalizations and long-term complications, and even loss of function of their various organ systems. So again, something is needed beyond just a single injectable and challenging drug to take. This is where we've already started to show some optimism for mavorixafor as a potential to help these patients. First of all, mavorixafor has been shown to be a well-tolerated drug on a chronic basis in a number of indications. But most excitingly, we've had a positive phase 3 study in a type or a subset of patients called WHIM syndrome, who also present with chronic neutropenia.
These patients had neutrophil counts of as low as 200. We improved their neutrophil counts to mild to moderate ranges, around 1,000, and saw a 60% reduction in infections, and we also saw a duration and severity of infections decrease as well. We've also shown positive data in our phase 1/2 studies in chronic neutropenia, helping improve neutrophil counts in 100% of the patients in the phase 1B after a single dose. And then, we had 3 patients that demonstrated durability of effect, and we look forward to having a more robust data update in the first half of this year. So in totality, mavorixafor is well-positioned to help these 50,000 patients, first starting with a subset called WHIM syndrome and broadening out to the larger population as we continue to advance this drug in additional studies.
Just as a reminder, what is the mechanism? How does the drug work? Well, really, it's a drug that is enabling the white blood cells that are produced in the bone marrow to mobilize and move into the bloodstream and perform immunosurveillance. Many of these immunocompromised patients have low counts. They can produce the cells, but for various reasons, they're locked in the bone marrow. Mavorixafor helps unlock their potential and unlock their capabilities to perform immune surveillance. With respect to WHIM syndrome, we've already shown its favorable regulatory designations, specifically with the FDA. We have breakthrough therapy designation based on our phase 2 data and the compelling evidence at that time. We received fast track designation and rare pediatric disease designation, which allows us and enables us to have a, hopefully a PRV, or receive a PRV voucher upon approval.
We also have orphan drug status in the U.S. and Europe, and we have patent protection of the drug through 2038. So again, a very well-positioned company to now transition from R&D to R&D and commercialization. Just a quick overview of our pipeline. As we mentioned, mavorixafor is the lead asset. We have a preclinical follow-on called X4P-003. But most importantly, we're ready for hopefully our FDA approval pending April 30. With that, we're prepared to launch the drug in the U.S. ourselves. Of course, we're continuing to push hard to advance our phase 2 data and initiate a phase 3 trial in chronic neutropenia the first half of this year. So let me just now reorient and tell you a little bit more in detail about this first patient population that we're well-poised to help.
WHIM syndrome is a disease that people are born with, and what happens is their immune system is functioning poorly because of over-signaling of the CXCR4 pathway, and mavorixafor nicely antagonizes or blunts that effect. Interestingly, WHIM syndrome, which is characterized by the letters of the name W-H-I-M, is a syndrome. It means it's a spectrum and ranges of disease presentations. Some patients have warts, some patients have a low levels of immunoglobulin, which is a protein in your blood that helps fight infections. Most of these patients, almost all of them, present with severe infections, and then many of them have an overcrowding of the bone marrow, which on a pathologic diagnosis is called myelokathexis. But interestingly, only one in four patients all present with the full range of the diseases, which then speaks to how hard it is to diagnose.
So today, we've done a tremendous amount of work understanding the true population of WHIM syndrome in the United States through market research, through direct field work, and we're very comfortable to say that we believe there's at least 1,000 people in the US with that WHIM syndrome diagnosis and profile, and we certainly hope to be able to help them, should mavorixafor be approved. We're excited to share that we've had a successful, pivotal, global phase 3 trial in WHIM syndrome. It was an incredibly rigorous study completed during COVID, so you can appreciate the challenges for these patients and the challenges of running a global study assessing infections in a very immunocompromised world. But importantly, we were incredibly successful.
Our top-line data showed our primary endpoint, time above threshold, which was agreed to by both major regulatory bodies, was a hit, the primary endpoint statistically significantly, and we measured a host of secondary assessments as well. So we're well poised to hopefully get approval very shortly with our lead indication in WHIM syndrome in subjects or patients 12 and above. But let me dive a little bit more down into the details of the results and the impact of this drug on hopefully our first patient population. So as I mentioned, again, we hit our primary endpoint, time above threshold, which was a clinically relevant shift in the hours a day that your neutrophils are in more normalized ranges above 500.
We also demonstrated the drug improved all counts, not only neutrophils, but as well as white blood cells, lymphocytes, and monocytes. It was well-tolerated, and importantly, we saw reductions in infection rates, severity, and duration. In these next few slides, we'll walk through the specific data. So our primary endpoint, we showed that time above threshold had a fivefold increase versus placebo, with a P value of 0.0001, tremendously significant. And nicely, it correlates to that elevation in neutrophil counts. You can see on the right-hand slide, the blue line represents neutrophil counts, and we're shifting these patients from counts as low as 200, very confidently up to even ranges between 600 and normalized, which is 1,500. So a nice boost in their overall counts that float around in their blood cells. But most importantly, this isn't a disease of just blood counts.
It's not just about how many neutrophils you have in your bloodstream, but how do you feel? How are you able to resist infections as they continue to attempt to assault the immune system? So the great news with mavorixafor in this randomized, placebo-controlled, and double-blinded study was that in our secondary endpoints, we saw a reduced annualized infection rate, a 60% reduction with a p of less than 0.01. We saw about a 70% decrease in the severity of infection rates as measured by CTCAE criteria, so that's the NIH's standard. And finally, we saw a huge shift in the duration of days with infection throughout the year, when patients on average were 6-7 weeks a year, almost 49 days, and we reduced that number down to about 14 days with the application of mavorixafor.
So profound results consistent with the disease-modifying benefit of a drug that's targeting the root cause of WHIM syndrome. As I mentioned, our PDUFA date is coming up very quickly, so just 22 days away, and we are well prepared as a company to launch mavorixafor to treat WHIM syndrome in the United States. We've built a commercial team. We've certainly been learning more about the patients and the communities through our field force and medical science and medical affairs liaisons. We continue to try to prepare for the market in terms of working with the various payer systems to enable broad patient access. And of course, what we're doing is evolving the company.
We're really going from an R&D to an R&D commercialization and all cross-functional needs that we need to deliver on, from understanding what the patient needs are directly, to building the supply chain to enable patients to access their medication.... So it's an exciting moment for the company. So let's go beyond WHIM syndrome. We're certainly ready and well-prepared for that, but more importantly, we wanna continue to help as many patients as we think this drug is able to do. And so now we're going after the larger patient community, those with chronic neutropenia, and chronic neutropenia is consisting of idiopathic, cyclic, and congenital patients.
There's three subsets to that, but ideally, what all these patients want is a treatment that reduces their infections, gives them an oral option to an injectable drug, have a good safety profile, and just give them a choice beyond something that's hard to take. So these are our different physicians that we work with, as well as the surveys that we've had with our patients and caregivers, and we do believe that mavorixafor can hit this target product profile. We're listening to them, and we're able to approach what they need, where they need it with mavorixafor. So currently, we are studying the spectrum of chronic neutropenias. The interesting subset of unmet need falls in three categories. So some patients are not able to or refuse to take a chronic G-CSF.
It's very difficult to take on a daily basis, and some patients just are unable to accept it. So they need an alternate monotherapy. They need anything, something that can help them improve their infection risk. The middle category are patients who are on G-CSF, so they're certainly gaining some benefit from it, but their neutrophil counts are still not normalized, and they still are at risk of infections. In addition, while they're taking G-CSF, they unfortunately get all the side effects that come with taking that drug. Finally, there's a third category of patients who are well-treated, and their neutrophil counts are normalized, except they're ready for something different. They are interested in something oral, chronic, with a clean profile that doesn't introduce the toxicities that they experience when they're accepting G-CSF daily dosing.
So here are the three categories, and we're studying patients in all three of those in our phase 1b. So in the phase 1b, we were successful to show that we could increase neutrophil counts across those three patient populations quite robustly, and that was after a single dose. We're currently assessing the chronic durability of the positive impacts we saw on the phase 1b, again, in these three different subject subsets of the population, so the monotherapy patients, the undertreated on G-CSF, and those with G-CSF, but need something to potentially switch to from an oral once daily. So what we've shown in our first three patients, and they were anecdotal, was really in the later two buckets. These initial three patients were on chronic G-CSF. With the administration of mavorixafor, all of them had robust elevations in neutrophil counts.
These were multiples of shifted 500 cells per microliter. So if you can remember, we just need to shift them up by 500 to show clinical benefit. We saw shifted cells up by many thousands in these first three patients. It also gave us quite encouraging signals to be able to take patients off G-CSF. Some patients went and started at around 1,000 and jumped up to 10,000. Literally, they had an excess number of neutrophils floating around in their blood that could then be modulated by pulling off the toxic drug or the toxicities related to G-CSF. Finally, what we still have yet to study and what we will show later this year is what is the drug's impact as a monotherapy.
So again, there's a decent number of patients who are unable or unwilling to take G-CSF, and we're looking forward to showing the durable benefit of what we've seen in the phase 1b in this final population that yet needs to be studied. So overall, what have we learned so far in chronic neutropenia? We certainly believe that the bone marrow is intact in these patients. That's a fundamental question. Are there enough cells to even mobilize and move into the bloodstream? The phase 1b showed a resounding yes. These patients have a functioning bone marrow. They just need the ability to unlock those further and move them into the bloodstream. We've shown that in patients on G-CSF, there's a synergistic effect with mavorixafor. We've saw profound responses with the combination of therapy, enabling patients to start to titrate down G-CSF.
Finally, the open question is: What does mavorixafor do alone as a monotherapy? So we're looking forward to this next wave of data coming through the first half of this year. But most importantly, all of these data continue to build robust evidence, where we're moving forward with our phase 3 in chronic neutropenia as quickly as possible to really finally develop that robust level of evidence, which we hope to mirror what we've seen in the phase 3 of WHIM syndrome. So that segues nicely now into how are we studying for chronic neutropenia in the phase 3? We've completed FDA interactions, so this phase 3 trial design has incorporated all of their input and we believe would certainly support approval in chronic neutropenia. Very similar to WHIM syndrome, it's a phase 3 study, which is randomized, placebo-controlled, and double-blinded.
It's split 50/50 or a 1:1 randomization between the two arms, and we have two components that we're measuring for the primary endpoint. The first component is infection rate. As you may recall, in WHIM syndrome, we saw a 60% reduction in infections in WHIM. We're targeting about 40% reductions in the chronic neutropenia trial, and finally, we also want to look at neutrophil responders. Similar to WHIM, counting kind of a neutrophil count metric, we're trying to assess how many patients actually respond and either normalize or double their baseline count. So it's about 150 patients. It's powered over 90% off of those two components of the primary endpoint, and of course, we will continue to assess the multitude of other clinical symptoms, like infection severity, duration, quality of life, IV antibiotic use, et cetera, to really understand the impact of the drug.
So one more point about the primary endpoint in this study, it's around annualized infection rates, which I had mentioned was quite meaningfully demonstrated in our WHIM phase 3. But on the primary endpoint around biomarkers, the responder analysis is actually broken into two components. Because some of these patients are so severe, we were tracking along the same lines of how G-CSF approached it in terms of uniqueness of the more severe population. So in terms of the responder analysis, if you enter the study with neutrophil counts below 500, you need to at least double to be a responder. If you enter the trial with neutrophil counts between 500 and 1,500, the responder analysis requires a normalization of ANCs.
So that helps us to create the right response criteria across both the severe and the mild to moderate patients. So now let's just zoom back out and think about where we are as a company, and how mavorixafor could possibly go beyond WHIM and CN to additional diseases with immuno- with cell count immunodeficiencies. So first of all, we have certainly seen in our WHIM phase 3 that the drug favorably impacts patients with WHIM syndrome versus placebo. The FDA has accepted our NDA filing and given us an April 30th PDUFA date, and both the FDA and the company are on track to meet that date, supporting our first U.S. launch in WHIM syndrome imminently. The second series of value propositions for the company is this larger 15,000 patients initially with our phase 3 study.
As we've seen already in just our handful of patients in the phase 1b and the early data in the phase 2, the drug durably and meaningfully increases neutrophil counts. We have the final wave of data coming certainly the first half of this year to unlock that one last question around mavorixafor monotherapy, but it certainly sets us up to kind of put the gas pedal down and accelerate towards enrolling- initiating and fully enrolling our phase 3 in chronic neutropenia. But as we've learned about the drug's effect, we really are beginning to try to unlock where else could we go? There's certainly other cellular immunodeficiencies. There's almost 250,000 people in the United States with varying degrees of immunodeficiencies, and subsets of those also have the potential to benefit from increased neutrophil counts or increased lymphocytes or monocytes.
So we're still looking forward to exploring those opportunities, and we'll share more of the WHIM phase 3 data as it unfolds. So we have an exciting next wave of time ahead for us. Certainly, in the next just couple of months, the company will be truly transformed from an R&D to an R&D and commercialization company. As I mentioned, our PDUFA date is in a mere 3+ weeks at this point. We expect to launch that drug ourselves. We've built our commercial field force, and we have the infrastructure ready to go. We also are looking forward to providing that additional snapshot of chronic neutropenia data in the next few months, first half of this year, once again, to really help people appreciate the impact of mavorixafor alone in patients with this rare form of immunodeficiency.
Finally, initiating that phase 3 trial and possibly building the company even beyond that, because the applications of CXCR4 antagonist are certainly more significant than just WHIM and CN alone. And so with that, I appreciate your time and attention, and I'm very happy to open up the floor for any questions.
Thank you, Paula, and, as a reminder to everyone, please click the chat icon at the top of this presentation screen if you would like to submit any questions. The first one we have here, you know, as you're kind of shifting, from just an R&D company to R&D plus commercialization, you know, what kind of field force is required to do that within the US?
Yeah, so we will share more when we, hopefully announce our positive PDUFA. Right now, we're estimating across both the sales and the medical affairs and patient affairs teams, about 24 people should cover the country, both at the clinical sites, as well as to support the patient groups that we aim to serve.
Thank you. And then another one: What type of physicians typically diagnose WHIM, and what type of physicians typically diagnose WHIM?
Yeah, so WHIM syndrome patients are typically diagnosed and managed by either immunologists or non-malignant hematologists. The neutrophil counts is kind of what catches everybody's attention, and then depending on where they... what type of symptoms they need, the immunology group sometimes will manage them if they're taking immunoglobulins, that IVIg treatment, or if they're treated by acutely with G-CSF, then they're managed by the non-malignant Hemes. But both of them are playing a major role in diagnosis.
Thank you. And then how are your conversations going with payers, given the expected high price point in an ultra-rare indication like this?
Yeah, so I mean, payers are often, they're always looking for the value of the drug, and certainly, starting from mechanism, they can appreciate we are modifying the root cause of the disease. But the best data set is always to walk in and say, "Here's the clinical impact. This is what it's meaning clinically for these patients." So the fact that our phase 3 trial design showed a 60% reduction in infection rates, that very meaningful reduction in severity and duration of illness, it's a very strong data set to engage in the payers to get them to appreciate that we're really potentially creating a game-changing offering for these patients, and they recognize the value proposition of that.
Certainly, a lot of these ultra-orphan pricing paradigms have varying degrees of value proposition, but we certainly are very committed to standing behind what we've shown so far in our Phase 3.
Thank you. And then the next one, although, it's still a little ways away, do you think you will need to find a partner in chronic neutropenia due to the size of the indication?
It's a great question. So I would expect it, certainly in the U.S., that's the beauty of launching in WHIM syndrome first. WHIM syndrome, the clinical communities that treat WHIM syndrome are very synergistic with the clinical communities that are treating chronic neutropenia. So our initial sales force, these next few years in WHIM, will really begin to develop those relationships and understand not only WHIM, but possibly patients that we could enroll in the phase 3. So in the U.S. alone, we certainly think both WHIM and chronic neutropenia, we can serve ourselves. Ex-U.S. is always a different challenge. Just globally, different regions and different payer systems require different, different levels of infrastructure. So at this point, we're still open to and exploring different ways of commercializing WHIM ex-U.S.
CN ex-US certainly could be something we could do as well, again, depending on where we're at as a company.
Thank you. It looks like there are no other questions at this time. So Paula, I guess, you know, I appreciate you taking the time today to do this presentation, and thank you for answering all the questions we had come in. With that, you know, hope everyone has a great day and enjoys the rest of the Needham Healthcare Conference. Thank you, Paula.
Thank you, Ryan. Thanks, everyone.