Good morning, and welcome to the X4 Pharmaceuticals webinar to review and discuss the interim results from the company's ongoing Phase 2 trial of mavorixafor in chronic neutropenia. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentations. If interested in asking a question via the live webcast, you may submit questions through the Q&A text box below the webcast player. For our analysts on the call, please raise your hand to indicate you would like to join the live queue. It is now my pleasure to introduce our host for the event, Dr. Paula Ragan, Founder, President, and Chief Executive Officer of X4 Pharmaceuticals.
Thank you, and thanks to all of you for joining us today. Before we begin, I'd like to remind everyone that on today's call, we will be making forward-looking statements regarding our interim results, regulatory, clinical, product development, and commercialization plans. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in our most recent Form 10-K and Form 10-Q, both on file with the SEC. Here we outline our program. During our presentation today, I will be joined by our Chief Medical Officer, Dr. Christophe Arbet-Engels, and throughout the presentation, we will be also joined by two physician experts, Dr. Jean Donadieu and Dr. Peter Newburger.
These two experts will share their insights into the challenges of treating patients with chronic neutropenia, as well as their reactions to the interim results from our ongoing Phase 2 trial of mavorixafor in CN. During our program today, I will provide a quick background on chronic neutropenia, detailing mavorixafor's validated mechanism of action and why we're so excited about its potential to meet the specific needs of the chronic neutropenia community. Christophe will then present the interim results from our ongoing Phase 2 CN trial and provide an update on our Phase 3 CN trial. We'll then summarize and open up the event for your questions when we will be joined by Dr. Newburger, as well as the rest of the X4 executive team.
As you know, X4 is at an exciting stage with growing momentum and a clear strategy to leverage our clinical and commercial capabilities to deliver for those living with certain rare diseases of the immune system. With the recent FDA approval of XOLREMDI, the first targeted therapy ever available to increase the number of circulating mature neutrophils and lymphocytes in patients with WHIM syndrome, a rare immunodeficiency, we are now a fully integrated biopharmaceutical company with proven operational success. This morning, we are pleased to share that we now have our first patients dosed with commercial product. While the launch is in its early stages, it continues to ramp up nicely.
We have a strong balance sheet with the recent sale of our pediatric Priority Review Voucher for $105 million, which we sold in record time and which has enabled us to extend our runway into late 2025. All of this provides a strong foundation for advancing the next value driver for X4, which is mavorixafor, as a potentially transformative treatment for chronic neutropenia. Let's jump right in to the good news. Our interim Phase 2 results strongly support the potential of mavorixafor for the treatment of those with CN. In a few minutes, we'll share data demonstrating that mavorixafor durably increased absolute neutrophil counts, or ANC, to clinically relevant levels in all participants evaluated in this interim analysis, whether as a monotherapy or in combination with G-CSF, the current standard of care.
We will also show that mavorixafor, as a monotherapy, increased ANC in the most severely chronic neutropenic patients, a population that is most similar to the population studied in our successful Phase 3 WHIM syndrome clinical trial. Finally, we will share safety results that indicate mavorixafor continues to be generally well-tolerated, both as a monotherapy and in combination with G-CSF, as of the interim analysis cut-off date. All of these results support the design and rapid advancement of our global pivotal registration trial in chronic neutropenia. In fact, today we are proud to announce that we have officially initiated our Phase 3 clinical trial of mavorixafor in CN and are now screening participants across a number of sites around the world.
With these interim Phase 2 data and the initiation of a pivotal clinical trial, we are now poised to potentially transform the treatment landscape for tens of thousands of patients with chronic neutropenia in the U.S. and other regions around the world. To better understand why additional therapeutic options are needed, first, let's quickly dig into the challenges faced by those living with CN. In the U.S. alone, there are approximately 50,000 patients with diagnoses that carry diagnostic codes aligning with idiopathic, cyclic, or congenital chronic neutropenia. This is a sizable and well-defined population that is frequently underserved by the available treatment options. When we take a deeper dive into the severity of this population, we see that more than 15,000 continue to experience recurrent infections, despite the availability of G-CSF and despite some of these patients being on chronic prophylactic treatment.
While G-CSF has been shown to increase neutrophils to address infection risk, it comes with the discomfort of injections and adverse events, including bone pain and others. With chronic administration, G-CSF has also been associated with myelodysplasia and leukemia in certain patient populations... Although G-CSF is an available treatment option, to more effectively address the long-term complications from frequent and severe infections of CN, in those experiencing inadequate relief of their disease symptoms or unable to tolerate G-CSF, there is a clear need for an effective alternative therapy, ideally oral, that is well-tolerated to support sustained and chronic administration. In developing mavorixafor for the treatment of chronic neutropenia, our goal is to ultimately reduce the risk of serious and/or recurrent infections. Fortunately, measuring absolute neutrophil counts, or ANC, enables us to reliably assess that risk, which is particularly important for the most severe CN patients.
Normal neutrophil counts tend to be above 1,500 cells per microliter, and when neutrophils are maintained above that level, a person's infection risk is similar to that of the greater population. But as you can see here, the lower the neutrophil count, the higher the infection risk. Neutrophil counts between 0 and 500 cells per microliter correspond to the most significant infection risk, and as neutrophil counts increase by increments of about 500, infection risk steps down from the highest to moderate to lower infection risk. For those with chronic neutropenia, infections can be severe, resulting in hospitalizations and life-threatening complications when ANC remains below 500 cells per microliter. Our clinical experts now share more color and their perspectives on the importance of increasing neutrophil counts and how this can meaningfully benefit the patients they treat.
Hello, I'm Peter Newburger. I'm a pediatric hematologist-oncologist. I work at the University of Massachusetts Chan Medical School and at Boston Children's Hospital. I have been taking care of patients with neutropenia and other neutrophil disorders for more than 45 years. My laboratory is also devoted to the study of neutrophil disorders and neutropenia, as is my clinical research through the Severe Chronic Neutropenia International Registry. The current standard of care, and in fact, only available drug for chronic neutropenia is G-CSF. Almost all patients with severe congenital neutropenia require G-CSF therapy. When I treat with G-CSF, there is a very clear correlation between the absolute neutrophil count and the resolution of symptoms such as mouth sores and gingivitis. It is harder to judge the occurrence of infection because people get viral infections which are independent of absolute neutrophil count.
But certainly, study data indicate that maintaining an absolute neutrophil count above the 500-800 level correlates with a very significant decrease in the occurrence of pneumonia, cellulitis, sepsis, and other severe infections. There is also a correlation with quality of life. Patients who have chronic neutropenia with absolute neutrophil counts below 500 end up having to go to emergency rooms, generally in the middle of the night, because that's when fevers occur, get IVs, get IV antibiotics, and this is a major disruptor of sleep, school, work, and a major impacter of quality of life. When I speak to patients and families, either in the clinic or at the Neutropenia Network family meetings, the holy grail that they all seek is to have a simple oral drug that they can take once or twice a day and be free of injections forever.
They would also like to have a drug that does not have bone pain as a side effect.
Good morning. My name is Jean Donadieu, and I am from Paris. I am a pediatrician, a hematologist, and I am also a statistician. My practice is now oriented for immune deficiency and specifically chronic neutropenia. I coordinate the French Reference Center for Chronic Neutropenia, and I coordinate since 30 years ago the French Registry for Chronic Neutropenia. So about the unmet needs of patients with chronic neutropenia, I think we can say that we have to spare some injection of G-CSF. We have to find something more compatible with a normal quality of life.
I think, well, at the first time when we have no other treatment, we are fighting and we can say for the patient, "You have to receive this G-CSF every day to protect you." But we know that, it's very difficult for patients for years, sometimes after this G-CSF treatment, to accept this treatment. And so, a very clear medical needs is to have a more acceptable therapy.
... to prevent the infection. And it is also related, because the G-CSF on the long term is not really accepted, patients have tried to take down the treatment, and they are maybe sometimes under treatment, undertreated. And so, that's a consequence of this, well, poor quality of life related to the injection. So it is a medical need to improve the infection rate of the patient by a less aggressive or less, well, I can say, painful treatment.
Now, let's focus for a few minutes on mavorixafor's profile and why we believe it could match up well with the hopes and expectations of the CN physician and patient communities. As you've seen from our previously published data, mavorixafor's mechanism of action is well validated. It is an orally active CXCR4 antagonist, demonstrated to mobilize white blood cells, including neutrophils, from the bone marrow into the peripheral circulation. Neutrophils, among other white blood cells, are the necessary first lines of defense to enable the body to fight infections and also develop memory, improving our ability to fight infections in the future. Our previous Phase 1b study in CN patients showed consistent elevations of neutrophil counts of at least 500 cells per microliter after a single dose of mavorixafor, either as a monotherapy or in combination with G-CSF.
Based on these results, we launched a Phase 2 study assessing the durability of these results with chronic mavorixafor dosing. Importantly, as we mentioned, mavorixafor has been approved for use in patients 12 years of age and older with WHIM syndrome, a rare primary immunodeficiency, with patients typically experiencing severe chronic neutropenia as a component of their disease. Let's take a quick look at these data from the successful Phase 3 trial in WHIM as background for the interim Phase 2 CN data. Here, we highlight results from our randomized, placebo-controlled, double-blinded study of mavorixafor in WHIM patients. These are just some of the data that supported the recent approval of mavorixafor by the FDA for the WHIM indication, but they're relevant to our discussions of the potential of mavorixafor in CN.
The trial met its primary endpoint, which evaluated neutrophil counts and hours per day above a targeted threshold of 500 cells per microliter. The bar chart details the absolute neutrophil counts over the 52-week trial. As you can see at baseline, both the treatment and placebo groups started with severe neutropenia, with their average ANCs around approximately 200 cells per microliter. The light blue bars, which represent the mavorixafor-treated group, show an average increase in ANC of about 600 cells per microliter across the 1-year trial. The placebo arm, represented by the red bars, essentially shows no change over the 52-week trial. Now, we'll see how this increase in ANC translated into clinical benefits in this WHIM population. Here we see the primary clinical impact of the 52 weeks of treatment with mavorixafor in our Phase 3 WHIM syndrome trial.
You'll note there was a consistent and favorable clinical impact, with a reduction in infection rate, duration, and severity as a result of the increased neutrophil counts. Specifically, we saw an approximately 60% reduction in annualized infection rate on average. Participants experienced about five fewer weeks with infections over the year of the trial, and fewer mavorixafor-treated patients experienced serious infections throughout the trial relative to participants on placebo. These data resonate strongly with clinicians who are interested in impacting all aspects of infections experienced by their patients. We'll ask you to keep this clinical benefit in mind, noting that this impact was achieved through a mean ANC elevation of about 600 cells per microliter. I'll now turn the presentation over to our Chief Medical Officer, Dr. Christophe Arbet-Engels, to present the interim Phase 2 results. Christophe?
Thanks so much, Paula. We had three main objectives in this interim analysis of our Phase 2 study in CN, with the overall goal to help us understand the potential of mavorixafor to elevate ANC and improve infection rates in our Phase 3 clinical trial in chronic neutropenia, which we have just initiated. First, we wanted to assess the ability of mavorixafor to durably increase absolute neutrophil counts by at least 500 cells per microliter, either as a monotherapy or in combination with stable G-CSF. Second, our aim was to assess the benefit of mavorixafor monotherapy in the treatment of participants with severe chronic neutropenia or those entering the study with baseline ANC below 500 cells per microliter. This patient population is viewed by academic experts and healthcare providers to be tougher to treat.
In fact, we often hear that physicians typically target an ANC of about 800-1,000 cells per microliter for their severely neutropenic patients. In addition, we see the severe CN subgroup as the most apples-to-apples comparison with the population studied in our WHIM Phase 3 trial. Finally, the third objective of the study was to assess the safety and tolerability of mavorixafor, both as monotherapy and in combination with G-CSF. Our study design is a six-month trial. It is an open-label study where we allowed patients with or without background therapy for CN into the study. Mavorixafor was dosed orally once daily on top of background therapy, G-CSF, or as monotherapy at the same dose levels used in our WHIM Phase 3 clinical trial, which supported our recent FDA approval.
At baseline, prior to administration of a dose of mavorixafor and at assessment points of 1 month, 3 months, and 6 months into the study, we drew blood samples up to 7 times over an 8-hour period to examine the daily mean ANC across that day of dosing. We also examined the peak and trough values to determine increases in ANC over the 8-hour assessment window. Recruitment in our Phase 2 study completed earlier this year, and a handful of participants remain in study, finishing out their 6-month assessments. We enrolled a total of 23 participants across three subgroups, which include 10 participants on mavorixafor monotherapy, 5 participants on mavorixafor plus stable dose G-CSF, and 8 participants on mavorixafor plus G-CSF, with allowance for dose adjustment to their G-CSF. We expect to share data from this last group, those with dose adjustment, towards the end of this year.
Our interim analysis and today's presentation includes the two groups that mirror the participant population of the Phase 3 CN trial, the mavorixafor monotherapy group, and the mavorixafor plus stable G-CSF group. We are continuing to collect and analyze the data on the third group, and we do expect to be able to present additional data from all three groups sometime later this year. As you can see in the highlighted table, 10 participants entered the study without G-CSF treatment and were started on mavorixafor as a monotherapy. As of the cut-off date of May fourteenth, four participants had completed the six months of the study, four participants remain on treatment in the ongoing study, and two participants discontinued, one just after the month one assessment and the other just after the month three assessment. The mavorixafor plus stable-dose G-CSF group comprised five participants at the start of study.
3 patients have completed the study as of the cut-off date. 1 patient remains ongoing, and 1 patient discontinued before the month 1 assessment. The three participant discontinuations were a result of the GI effect early in the study. Given that the symptoms tend to resolve after a few months of dosing, we increased education and awareness about the GI tolerability with physicians, and this improved patient adherence once implemented. No other participant has discontinued the study since. In the study, the overall disposition resulted in about two-thirds of the patients diagnosed with idiopathic, also known as autoimmune chronic neutropenia, and about one-third diagnosed with a genetic background to their neutropenia, referred to as congenital CN, which also includes cyclic CN. So now let's go to the interim results.
On this slide, we show the percentage of participants who achieved an increase in ANC greater than 500 cells per microliter at each time points of the efficacy assessment: month one, month three, and month six. This includes both monotherapy and those on stable G-CSF in combination with mavorixafor. By the first month, 79% of the participants achieved a target increase in ANC greater than 500 cells per microliter. By month three, the percentage was 92%, and by month six, all evaluable participants had achieved the target ANC increase of at least 500 cells per microliter. This demonstrate a consistent, sustainable, and we believe, clinically meaningful increase in ANC with mavorixafor therapy.
In particular, of the 6 participants who completed the study, 100% achieved target ANC at month 3, and 100% maintained target at month 6, showing a consistent, durable response for each individual participant. Similar responses are emerging in those who remain ongoing in the study, with 5 of 6 subjects achieving target ANC increases by month 3. We are very pleased to see this initial data set because it is consistent with the ANC increase we had initially seen in the Phase 1b study... but now with durability out to 6 months. On this slide, we present results from the mavorixafor monotherapy group on its own. On the y-axis, we enumerate the absolute neutrophil count measured in the blood, specifically the mean of the average ANC measurements across the 8-hour efficacy assessment period.
The red, orange, and yellow section highlighted on the y-axis correspond to the infection risk in these patients, with red being severe, orange being moderate, and yellow being mild infection risk, as we presented earlier with the ANC infection risk dial visual. As you can see at baseline, the 10 participants had an ANC count of about 700 cells per microliter. At month 3, and then durably continuing through month 6, the mean absolute neutrophil count reached the lower limit of normal. As we mentioned, the study is ongoing, so the month 6 time point is represented by a smaller N of 3 participants reaching completion in this monotherapy subgroup. We are thrilled to see an early and consistent increase in ANCs, with participants who have reached month 6 showing on average a mean ANC of 1,500 cells per microliter.
In addition, we also wanted to understand what was happening at peak or the maximum, and trough or pre-dose ANC during the assessment days. So let's continue with the presentation of that analysis. Here we show the means of the peak ANC values alongside the means of the trough values throughout the trial in the monotherapy group. Importantly, we noted that peak ANCs began exceeding the lower limit of normal by the first month and were sustained throughout the six months of the study. And interestingly, we observed that the trough levels also rose meaningfully throughout the six-month study, with an increase in ANC of approximately 500 by month three. Together, these data provide further confidence that mavorixafor, with its oral once daily dosing, is raising counts meaningfully for these patients and providing ANC coverage between daily doses, potentially translating into a corresponding reduction in infection risk.
Now, let's examine a subset of monotherapy patients that can help us correlate what we're seeing in chronic neutropenia with what we have already seen in our now published data from the WHIM Phase 3 trial. Here we present participants who entered the study with severe chronic neutropenia. All five participants had ANCs below 500 cells per microliter, with their mean ANC being about 350 cells per microliter. This is a group that would be considered at higher risk of severe infections based on this ANC profile. After one month of dosing, the mean increase in ANC achieved the target levels of greater than 500 cells per microliter, and by months three and six, mean ANC levels sustained increases to about 1,000 cells per microliter.
These observed ANC increases in participants with severe CN are similar to those demonstrated in the WHIM Phase 3 study, which, as we've mentioned, resulted in a profound reduction in infection rate, severity, and duration. We certainly hope to be able to confirm such finding in the CN population as we advance our ongoing CN Phase 3 trial. We will now shift to the second major subgroup that we examined in this interim analysis of the Phase 2 study. Five participants were enrolled with background G-CSF therapy for their CN and maintained a stable dose of G-CSF for the duration of the study. As participants entered the study at varying levels of G-CSF dosing and with various levels of baseline ANC, we examined the impact of mavorixafor by normalizing changes in ANCs to each participant's individual baseline ANC values.
This approach allows us to clearly see the added effect that mavorixafor is having in combination with G-CSF. The y-axis here shows the mean change from baseline in ANC, with the target being an increase of at least 500 cells per microliter. The x-axis shows the mean change from baseline at months one, three, and six. As you can see, at month one, there was already a clinically meaningful increase in ANC of more than 1,000 cells per microliter for participants with mavorixafor added to a stable dose of G-CSF. By month three and six, this increase exceeded 3,000 cells per microliter. We strongly believe that these large increases in ANC support the potential of mavorixafor to enable a decrease in G-CSF dosing regimen in some patients currently on G-CSF. We also believe that if these results are replicated in further clinical studies......
These data would resonate well with the patients and physician communities, allowing them to consider a potential future where less use or less frequent dosing of G-CSF may be required. We were also very pleased to see that the safety profile of mavorixafor in our interim analysis of the CN Phase 2 study has been very consistent with what has already been demonstrated with mavorixafor in prior studies. This is based on all 23 participants enrolled in the study through the data cutoff of May fourteenth. No new safety issues have emerged with mavorixafor dosed as a monotherapy, or importantly, when dosed in combination with G-CSF. There were no deaths and no drug-related serious adverse events. Consistent with what we have seen in the WHIM Phase 3 trial, the most frequent adverse events were GI-related, nausea, and diarrhea.
While this is consistent with the safety profile of mavorixafor, we note here that the 3 participant discontinuation were a result of the GI effect early in the study. And as we mentioned earlier, since these symptoms tend to resolve after a few months of dosing, we increased education and awareness about GI tolerability, and participant adherence improved in the study. In summary, we are very excited by this positive interim Phase 2 results. As we achieved all 3 of the objective of the interim analysis, which included demonstrating that mavorixafor durably increased mean ANC over the clinically meaningful targets of 500 cells per microliter in participants on monotherapy, and notably increased mean ANC above the lower limit of normal at month 3 and 6. Importantly, when examining those with severe chronic neutropenia, remember that these are participants with baseline ANC below 500 cells per microliter.
We saw results approaching the 800-1,000 cells per microliter value targeted by physicians for this tougher to treat population. This is consistent with the results from our 52-week study of mavorixafor in WHIM syndrome, in which all study participants were severely neutropenic at baseline. We also saw significant increase in mean ANC versus baseline in those on combination therapy with mavorixafor and a stable dose of G-CSF, suggesting the opportunity for mavorixafor to reduce or replace G-CSF in some patients. Equally important, mavorixafor remain generally well tolerated with and without G-CSF throughout the study as of the cut-off date. In totality, you can appreciate why we are excited to move rapidly forward to execute on our global Phase 3 registration trial. Let's hear now from our clinical experts on their impressions of this interim data analysis.
Here you have presented, Christophe, 15 patients, and you show that in 15 patients, most of the patients have a good response, and it is, I can... Well, essentially, I can say that it is a, a good, good expectation, good preliminary results. Good. Well, it seems that, we are on the good way to demonstrate that, mavorixafor may also, chronically, increase neutrophil in this group of patients, which is a, a very, very good, good, good news. Phase 2 study offers a rationale of a Phase 3 study, and so it means that you are probably the good way to demonstrate that mavorixafor will, change the, at least the, the daily life of such patient. But, so it's, it's important to see this, new step, in this development of this drug.
Having seen the interim results of the Phase 2 study of mavorixafor in chronic neutropenia, I am very impressed by the universal response of these patients to achieve absolute neutrophil counts above 500 and to maintain them over 3-6 months. I never say always or at 100%, so I'm sure eventually there will be exceptions, but this response rate is extremely impressive. The response rate also answers the very important question, not addressed by the Phase 1b study, of whether the response to mavorixafor will be sustained. I was impressed that the response to mavorixafor was not only maintained over 3-6 months, but the response rates and levels actually increased over that time period. Very importantly, there were no drug-related severe adverse events recorded in the trial so far, either for chronic neutropenia or WHIM.
I think that the safety profile compares very favorably with that of G-CSF. Of course, the proof of the pudding will be the results of the Phase 3 study. I am encouraged by the Phase 2 results to think that the Phase 3 will be successful in meeting its primary endpoints because of the excellent and sustained responses we've seen so far in the Phase 2. When I meet with patients and families, the almost universal wish is to have an oral drug available for neutropenia. Of course, they hope that G-CSF can be discontinued, but they also would like to have the opportunity to decrease frequency or dosage. I think that the availability of an oral drug will be welcomed and applauded by patients and families, and I believe it will also be accordingly welcomed by physicians.
As I think you can appreciate, Dr. Newburger and Donadieu have provided some great insights and share our enthusiasm for studying this drug further in the global Phase 3 trial. With that, we'll provide some updates on the trial design and status. As Paula mentioned at the outset, we are thrilled to be sharing today that our global Phase 3 trial, named the FORWARD trial, is now initiated. We have multiple sites activated and have patients already identified and in active screening. As we've guided before, we continue to project that enrollment of the study will be completed in about 12 months, and we will provide enrollment updates in 2025. The FORWARD trial design is similar to our Phase 3 for WHIM trial. It is a randomized, double-blind, placebo-controlled trial with a 1-to-1 randomization ratio. The treatment duration is 52 weeks.
Key inclusion criteria are as follows: eligible patients must be diagnosed with congenital, autoimmune, or idiopathic neutropenia, and they must have both an ANC count that is below 1,500 and an infection history of at least 2 serious and/or recurrent infections in the prior 12 months. The primary endpoint is a two-component endpoint that includes both annualized infection rates and positive ANC response. Secondary endpoint will range across a number of metrics, including infection severity and duration, antibiotic use, fatigue, quality of life measurements, and safety, among others. Importantly, we thought it would be helpful to put the data from the interim analysis of the Phase 2 CN study into context using the two-component endpoint of the Phase 3 trial in CN. Again, the primary endpoint of the Phase 3 trial comprises an ANC response evaluation as well as an assessment of annualized infection rate.
Let's first look at how the interim Phase 2 results inform our thinking around possible success of the Phase 3 positive ANC response endpoint. As you can see here, 10 participants evaluated in the Phase 2 study met the Phase 3 inclusion criteria of ANC less than 1,500 cells per microliter. In the Phase 3 trial, participants will be analyzed in two subgroups according to their baseline ANC counts. One group with a baseline lower than 500 cells per microliter, and the other group with baseline ANC from 500 to less than 1,500 cells per microliter. When we apply the Phase 3 criteria to these Phase 2 participants, we observed that 80% of the participants in each of the two groups met the expected positive ANC response criteria of the Phase 3 ANC endpoint.
These results in the Phase 3 context will exceed 90% currently proposed for ANC response in the trial, with a sample size of 150 participants. For context, and as you can see on the right, in the FORWARD trial, we observed that increases in ANC greater than 500 cells per microliter correlated to clinical infection rate benefit. In terms of the initial market opportunity, we believe that mavorixafor could offer a substantial benefit to CN population that have the highest unmet needs, a base case population of around 15,000 patients in the U.S. alone. These are patients with recurrent infection, despite the existing standard of care, G-CSF. About half of these patients are taking prophylactic G-CSF and yet are still also experiencing infection. The other half experience frequent infections, but are on no prophylactic treatment to help reduce the severity of their disease.
Clearly, an alternative options to help these patients is needed, and we envision a world where oral once-daily mavorixafor is used as the primary chronic treatment for a large number of CN patients. Additionally, for those with tougher to treat CN, we see mavorixafor being used in combination with a lower dose of G-CSF as a way to achieve target neutrophil counts, while also helping to minimizing the overall exposure to the side effect of G-CSF. Given these interim Phase 2 results-
... We're hopeful that the Phase 3 study may establish that mavorixafor represents a significant opportunity as a potential oral, generally well-tolerated, once daily treatment for this group of CN patients in the United States, and to the even larger number of patients in the regions across the world. I'll now turn it back to Paula to conclude our event. Paula?
Thanks so much, Christophe, for that deep dive into our compelling data, the design and promise of our Phase 3 trial in CN, and the role that mavorixafor could play as a novel oral once daily treatment option for people with chronic neutropenia. In summary, we are thrilled to think about a future where mavorixafor could potentially address the needs of the chronic neutropenia community. This patient group has only one approved treatment, one that is injectable and that has dose-related, dose-limiting, and challenging side effects and risks. Treatment success is very well defined in the chronic neutropenia population, with increases in ANC of 500 or more, having been shown to be clinically relevant.
With the interim Phase 2 data we presented today, it's now been shown that mavorixafor has the ability to increase ANC by more than 500 cells per microliter in both WHIM and CN populations with once daily oral dosing. Naturally, we hope to repeat the success of reducing infection burden seen in our WHIM Phase 3 trial as we rapidly progress our Phase 3 CN trial, which has been specifically designed to align with the more than 15,000 patients already identified in the U.S. with recurrent infections and remaining high unmet need despite available treatments. We would like to note as well that a potential U.S. approval for mavorixafor in CN could offer us the opportunity to leverage our existing sales and medical field force now executing on the WHIM launch.
At the time of a potential approval in CN, we believe we will have generated knowledge and skills that will be readily transferable to engaging with the CN physician community and the broader CN population, supporting a rapid and robust launch in CN. So in conclusion, we hope you can appreciate that X4 as a company, is well positioned to deliver on the promise of mavorixafor. In just the last 2 months, the company has transformed itself. We have gained U.S. approval of XOLREMDI in WHIM syndrome and have successfully launched our commercial efforts to support access across the country. It was quite a meaningful milestone to know that our first patients are now on commercial therapy. Today you heard about the exciting Phase 2 interim results for the study of mavorixafor in chronic neutropenia, supporting our now initiated Phase 3 trial, which we can't wait to complete.
We also expect to present a fuller data set from the Phase 2 trial, including data on participants on adjusted G-CSF dosing later this year. We continue to believe that there are even more geographies and pipeline opportunities ahead of us to support longer-term growth of X4. We won't be stopping with our patient populations of today as there are even more people in need to help and serve. Thanks for your attention today. We'll now open the program for our live question-and-answer session.
Thanks, Paula. We'll now be opening up the event for your questions. At this time, we're joined live by the X4 senior management team, as well as Dr. Newburger, who you heard from during the program. As a reminder to our analysts on the call, please raise your hand to join the queue, and if you are joining us on the webcast and would like to submit a question, you may do so using the Q&A text box below the webcast player. We'll now take our first question from Kristen Kluska at Cantor Fitzgerald.
Hi, good morning, everybody. Congrats on these data, and congrats that the launch is also going well in the background. So the first question I had for you, I think you made this important point that mavorixafor could reduce or replace, and I think there's been a lot of questions about what success would look like for reducing. So maybe for the management team and for Dr. Newburger, can you help us understand what degree of reducing G-CSF truly is meaningful from these patients, both from the burdensome of injections, but maybe more importantly, on reducing that bone pain and why this is so critical? Thank you.
Thank you, Kristen. Nice to see you this morning, and I appreciate that excellent question. We're always very focused on the patient voice and the physician perspective. So, Dr. Newburger, it would be wonderful to hear what you think the patients would find as clinically meaningful in terms of any reduction in dose or frequency of G-CSF.
Thank you. I think there are several aspects to that question. One is the issue of frequency. Patients certainly welcome the opportunity to have fewer injections, so alternate day or every third day is very meaningful, especially for the children. The other, probably more important issue, is that bone pain is definitely dose-related, and we see that we often have to decrease the dose in order to reduce bone pain, and that reduction leads to an inadequate response in terms of absolute neutrophil count, ANC. So the most important, from a patient point of view, is the reduction or hopefully elimination of G-CSF because of bone pain.... Another patient concern is the risk of development of myelodysplasia or leukemia. This is particularly relevant to those with congenital neutropenia, because they have an inherent predisposition to MDS and AML.
The data from this registry, the Severe Chronic Neutropenia International Registry, and other registries, indicate that those on the highest doses of G-CSF have as much as a 40% risk of MDS/AML over 12-15 years, whereas the risk for those on the lower doses is down to about 10%. This may be a function of the inherent biology of the disease, but it is very likely due to the driving effect of G-CSF. So I think patients would welcome an opportunity to reduce dosage in the belief, which I must admit is not experimentally proven, that it would reduce the risk of MDS/AML.
Thank you for that. Very helpful. And then for severe chronic neutropenia, what % of that initial 15,000 patients you've laid out, do you believe, present with these dangerous levels at baseline? And anything in particular about their CN profiles that lead to such low neutrophil counts?
Thanks, Kristen. So I'll take that question. The 15,000 patients that we've examined through EMR research are all representative of the severe clinical end of that spectrum. So in terms of some of the underpinnings of that severity, we've not really delved too deeply, but the importance is really the clinical presentation. All of those 15,000 patients are experiencing severe and/or recurrent infections, despite the availability of standard of care. So they're experiencing all the challenges that you've heard, Dr. Newburger highlight, but really not getting the clinical benefit and relief that they need, given the severity of their disease.
If I may add, I think that many physicians are hesitant to use G-CSF because of the published risk of MDS/AML, so there is a very serious problem of undertreatment due to either experienced or perceived side effects of G-CSF.
Thank you. If I may squeeze in one last question, just on the three discontinuations. You noted that from your WHIM trial experience, that these effects of diarrhea and nausea really alleviate over time as they become more comfortable with the treatment. Can you remind us when you typically see some of these side effects go away, and how this has been articulated in the conversations and education you've done with the patients, which has, you know, seemed to fix the problem for now? Thanks again.
Thanks, Kristen. Christophe, can you add to that?
Sure. Thanks, Kristen, for the question. So yes, we, we see these three discontinuation. These are mild and moderate, and they tend to resolve. They occur very early in the treatment, and they resolve fairly rapidly within just a few weeks of treatments. What we've done as education is mostly inform those the sites, the investigators, and the patients, and with limited treatment for those symptoms or no treatment at all, the patients continue to adhere to the study. And so that's what we've seen in our Phase 3 WHIM, and we're gonna implement similar education for the Phase 3 study, and that is ongoing right now.
Thank you for the questions, Kristen. The next question comes from Edward Tenthoff at Piper Sandler.
Hey, good morning, everyone. Let's see. I'll take myself off video. Oh, no, it doesn't... Yeah. Hi, how are you? Thanks so much for taking the time today, and I had a question for Dr. Newburger. With the current data set in hand in neutropenia, how do you envision deploying mavorixafor? Specifically, do you think you would probably wean patients from G-CSF, or would you discontinue outright? How do you envision sort of initially using this? And, I guess for the company, you know, I appreciate there's a small end, but are we seeing characteristics that may differentiate either biomarkers, early response, or neutrophil levels, that may indicate who would respond versus not responding? Thank you.
Thanks, Ted. I think, Dr. Newburger, you'll hear the broader communities are very interested in learning who might be benefiting from a monotherapy versus some combination of G-CSF, and for those combo patients, how would you approach that, should mavorixafor be approved in CN? So we'd love to hear your insights.
Thank you. It depends and will depend on the underlying pathophysiology. I would certainly, excuse me, approach a tapering schedule rather than cold turkey discontinuation of G-CSF. The patients who have chronic idiopathic or autoimmune neutropenia would have the greatest potential for discontinuing G-CSF entirely, because they already have a bone marrow reserve pool of mature neutrophils. I would expect that many, perhaps not all, but many, would be able to wean off G-CSF entirely. For those with congenital neutropenia, it would depend on the underlying genetic defect. For the most common form, seen in about 40%-50% of patients with congenital neutropenia, with defects in the ELANE gene, there is a maturation arrest of the promyelocyte and myelocyte stage of development, so at least some G-CSF would be necessary to promote maturation to the stage of mature neutrophil.
Those patients, I think, would most likely require some ongoing G-CSF, and I would expect it would be at a lower dose. For those with congenital neutropenia that allows full maturation, as in WHIM syndrome, I would expect that we would be able to radically decrease the dose and probably discontinue G-CSF. This would have to be on an individualized basis, so a weaning approach would be the best one.
That's incredibly helpful. If I may ask a quick follow-up question. For new patients who are chronic or idiopathic, and not congenital, could you envision even starting straight out on mavorixafor and foregoing G-CSF? Thank you again, Doctor.
That would absolutely be my approach. Based on the Phase 1b and Phase 2 data, the response is detectable within the first day, and certainly within the first few weeks to months, so that one would see very quickly whether it would be possible to continue with monotherapy with mavorixafor. I would bring in G-CSF only in those I would expect to be few patients who had an inadequate initial response.
Thank you for the questions, Ed. The next question comes from Leah Cann at Brookline Capital Markets.
Thank you. My question has been answered.
Okay, we'll move over to the next analyst, R.K. from H.C. Wainwright.
Thank you. Thanks for this presentation, and congratulations on the data. Certainly very, very interesting and encouraging. Looking at the monotherapy data that you presented, and looking at the dynamics of the ANC increases over month one to month six, I'm just trying to understand, you know, I'm just going by absolute values, and maybe that's not the right way to do it, but just to understand, when it gets to month six, there's a decline in the increase on the ANC. Is this a factor of who the patients are within that three patients, that group of three patients, or is there something else that we should be thinking about in terms of, you know, absolute value decline?
Thanks so much, R.K. Christophe, can you take that?
Sure. So, thanks, R.K., for the questions. The value that we see first represents a smaller sample size, and you're correct to assume that the type of patients that is in these three patients at six months are more severe for two of them, and that's what is driving this. When we look at the individual data, these all the three patients continue to actually increase between month three and month six, and are very consistent with the overall picture that we see with for ANC over the six-months period.
Thank you. A quick question for Dr. Newburger. The split between the different types of patients that are currently in the trial, is that typical to what you see in your practice in terms of who the types of patients are that come into your clinic?
No, I think the trial probably purposely included more patients with congenital neutropenia, whereas in practice, the very, very large majority of patients have idiopathic autoimmune neutropenia.
Mm.
This is true both in pediatric and, in particular, even more so in the adult population.
Fantastic. Thank you. Thanks for taking my questions.
Thank you for the questions. The next question comes from Kalpit Patel at B. Riley.
Yeah. Hey, good morning. Thanks for taking the questions. Maybe two for the company. Have you guys analyzed the infection before and after rates? I know this is open label. We have limited follow-up so far, but are there any early indicators that the infection rates are trending lower in the patients who have at least six months of follow-up?
...Thanks for the insightful question, Kalpit. This study was really designed to assess durability of A N C, which is a reflection of the overall trajectory on infection rates. However, we're not having a placebo control to the study, nor do we know this entry infection rates going forward. So what we're most excited about is the consistent increase in A N C across all time points and all patients. That should be quite indicative of the infection benefit. However, it was only for safety purposes in the Phase 2 that we were measuring this, and that information will be part of the end-of-the-year information.
Okay, fair enough. And will we get additional data for the patients that are still on therapy later in the year for both the monotherapy and the combination therapy arms, but we don't have six-month data for?
Yes, the full study data set will be released towards the end of the year across all of those three subgroups.
Okay. Okay. One last question, maybe this one's for the CMO. Doctor, what do you think about the Phase 3 trial design and its potential applicability for the real world? One of the pushbacks that we get or we have gotten is that the study's requiring a stable dose of G-CSF if a patient is on background G-CSF. You know, and that sort of eliminates how we should view any potential real-world applicability of G-CSF reductions.
Yeah, Dr. Newburger, I think people are interested in your perspectives, and I also think Christophe can add to the color of that, given the challenges of the regulatory bodies, but certainly we welcome your input, Dr. Newburger.
Yeah. From my point of view as a clinician, I think the objective of using mavorixafor would be to be able to reduce or eliminate G-CSF therapy. But I believe that, and Christophe can probably comment on this, that this is more a matter of study design for the regulatory requirements.
Yes, so Dr. Newburger, you're correct. So for regulatory requirement, we do need to have a stable dose in order to not have confounding factors with regard to our primary endpoint. Having said that, as Paula presented, in some of the slides, this addresses the large number of population treated with G-CSF, as well as the 50% of the population that is not treated with G-CSF. So demonstrating an effect in monotherapy and in addition to G-CSF on the infection rate will be really supporting the indication and the use in all these different populations.
Okay. Okay, thank you very much for taking my questions.
Thanks for the questions. I'll turn the call over to Dan Ferry at LifeSci Advisors for any questions that may have come in through the webcast.
Thank you. So Paula, a couple of written questions here from the audience. The first would be: What are some other rare diseases that could see a benefit from raising neutrophil levels, and will X4 be able to tap into these? And then as a follow-up question, how are current partnerships going for ex- U.S. and that potential to expand worldwide?
Sure. So thanks for the questions. So, the bone marrow, of course, certainly has various ranges of deficiencies, and we think that mavorixafor could help support those that have cellular-based immunodeficiencies. We're not getting more specific than that. But certainly, you heard Dr. Newburger's, you know, overall practice certainly supports a broad spectrum of patients, and we look forward to expanding as quickly as we can in more relevant populations. And then, with respect to the ex-U.S. partnering, we're certainly excited about these data, as well as our pending submission for our MAA in Europe. So with these data and that trajectory in hand, we will be able to update folks on an ex-U.S. partnership as more information emerges.
If I may add to that, there are a number of syndromes that include neutropenia that have not been included in the current studies. These include Shwachman-Diamond syndrome, Pearson syndrome, Cohen syndrome. They're rare, although Shwachman-Diamond, it's a significant number, and those, I think, would be potential future subjects.
Exactly. Yeah.
Okay, great. All right, Paula, it looks like we have time for one more question here. This question pertains to the Phase 3. It took months to get 15 patients. How long will it take to find 150 patients for the Phase 3?
Yes, we're excited about announcing patients are already enrolling in our Phase 3 study. Phase 3s are very different from Phase 2s, and that it's really about opening a large number of sites across a large number of countries. Christophe and our team has done a phenomenal job opening that funnel as wide as we can, as quickly as we can. So we continue to maintain that we'll expect a 1-year enrollment for the study and followed by 1 year of treatment, so 2026, second half for top-line data.
Thank you, Paula. This concludes the question and answer session. I'll now hand it back to you, Paula, for concluding remarks.
Thank you so much. Well, once again, thank you all for joining us for this presentation of the exciting data that we have from our ongoing Phase 2 trial in chronic neutropenia. A heartfelt thanks to Dr. Donadieu and Dr. Newburger for participating in the program and, of course, to Dr. Newburger for joining us live today. If we didn't get the chance to answer all of your questions, please feel free to reach out to us, and we really appreciate your attention. Hope everyone has a great day.