X4 Pharmaceuticals, Inc. (XFOR) Earnings Call Transcript & Summary

Good afternoon, and welcome to the X4 Pharmaceuticals webinar. [Operator Instructions] 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 to review and discuss the exciting data from our Phase III trial of mavorixafor in WHIM syndrome. Before we begin, I'd like to remind everyone that on today's call, we will be making forward-looking statements regarding our regulatory and product development 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 Forms 10-K and 10-Q, both on file with the SEC. We will begin today's program with a brief overview of our lead investigational candidate, mavorixafor and its potential to address the many unmet needs of individuals with WHIM syndrome and our exploration of its potential in additional chronic neutropenic disorders. We will then discuss the key challenges that people with WHIM face, followed by a presentation of our new data from our Phase III clinical trial which focused mostly on the beneficial effects that mavorixafor had on the rate, severity and duration of infections. We will then provide an update on our regulatory path forward on mavorixafor and WHIM and on other possible indications, including CN disorders before concluding and taking your questions. Throughout our event today, we will be hearing from both WHIM patients and from leading physicians who treat people with WHIM and/or a range of chronic neutropenic disorders and who study the underlying biology of these immunodeficiencies. Joining us today to comment on the Phase III results and the unmet medical needs of WHIM and CN patients are a mix of immunologists, hematologists and rheumatologists, all of whom have expertise in treating immunodeficiencies and several of whom who are investigators in the 4WHIM Phase III trial. You'll be hearing commentary today from Dr. Charlotte Cunningham-Rundles, a professor and immunologist at the Icahn School of Medicine at Mount Sinai; Dr. Jean Donadieu, a pediatrician in the Hemato-Oncology Department of Trousseau Hospital in Paris, and importantly, Coordinator of the French Registry for Chronic Neutropenia; Dr. Peter Newburger, Professor of Pediatrics and Molecular, Cell and Cancer Biology at UMass Chan Medical School; Dr. Akiko Shimamura, Director of the Bone Marrow Failure and Myelodysplastic Syndrome Program at Boston Children's Hospital and Professor of Pediatrics at Harvard Medical School; and Dr. Teresa Tarrant, Associate Professor and Director of the Clinical Immunology Laboratory at Duke University School of Medicine, and Vice Chief of Translational Research for Rheumatology and Immunology. We will also hear the unique perspectives from 3 individuals: Gabrielle, Willow and Courtney, all of whom have been diagnosed with WHIM and who have been experiencing WHIM symptoms since birth. We are honored that they all agreed to speak with us and share their insights with our investor audience. Joining me during the main program will be our Interim Chief Medical Officer and current X4 Board member, Dr. Murray Stewart. During the Q&A session, we will be joined by Drs. Shimamura and Tarrant, along with the rest of our leadership team: Chief Scientific Officer, Dr. Art Taveras; Chief Commercial Officer, Mark Baldry; Chief Financial Officer, Adam Mostafa; and Chief Operating Officer, Dr. Mary DiBiase. We believe mavorixafor has the potential to play a historic role in transforming the current treatment landscape for those affected by a range of chronic neutropenic disorders, first beginning with WHIM syndrome. Since the mid-1950s when the first congenital neutropenia disorder was described, just a single treatment, one only available by injection has been approved for certain forms of chronic neutropenia. Amazingly, there has been no innovation in this field in almost 30 years. Our belief in mavorixafor is based on demonstrated improvements seen in clinical trials to date across a wide range of immunodeficiency measures in WHIM and in certain chronic neutropenic disorders. Mavorixafor has demonstrated the ability to increase white blood cell counts, including improvements in neutrophils, lymphocytes and monocytes and has been well tolerated in long-term studies to date with more than 200 individuals now dosed with mavorixafor, some for as long as 4 years now. Mavorixafor earned Breakthrough Therapy Designation with the FDA based on clinical impact seen in our Phase II trial, and has received other favorable designations as well, including Orphan Drug Designation in both the U.S. and in Europe. At the end of 2022, we presented the first data from our global pivotal Phase III trial of mavorixafor in WHIM syndrome, the 4WHIM trial, showing that the trial met its primary and a key secondary end point. The field is ready for a breakthrough, and we believe that as an oral, once-daily, well-tolerated treatment, mavorixafor could significantly improve the lives of WHIM patients, if ultimately approved. At X4, we serve as an advocate to improve treatment options for the close to 50,000 patients across certain chronic neutropenic disorders, including idiopathic, cyclic and congenial neutropenias and WHIM syndrome. One of the main shared clinical experiences of these patients is the increased risk of frequent, severe and long-lasting infections due to a dysfunctional immune system. Today, we're announcing that mavorixafor treatment demonstrated statistically significant and clinically meaningful improvements across a number of infection measurements in those diagnosed with WHIM syndrome in our pivotal Phase III trial. This benefit, which will be readily apparent in the coming presentation is yet another step in delivering that breakthrough that is deeply needed and deserved for those diagnosed with WHIM and provides further inspiration to us to advance mavorixafor as quickly as possible for those with broader CN disorders. So what exactly is WHIM syndrome? Here is a quick overview. WHIM is most often an inherited combined immunodeficiency that creates significant hardship for people from birth. Their weakened immune system results from bone marrow overcrowded with all types of white blood cells, including neutrophils that remain stuck there and unable to perform immune surveillance, a necessary role in identifying and fighting infections. This weakened function often leaves the people less able to successfully resolve infections and as a result, those with WHIM syndrome experience much more frequent, more severe and longer-lasting infections than unaffected individuals. These increased infections typically impact the lungs and ears, the heart and skin among other body parts. Repeated infections in these areas can lead to permanent organ damage, and can increase morbidity and mortality and lead to a higher risk of developing certain types of cancers. In addition to infections, the I in WHIM, people with WHIM can experience warts resulting from the infection with HPV, hypogammaglobulinemia or low levels of circulating immunoglobulin or antibodies and/or myelokathexis the condition that describes the failure of neutrophils to leave the bone marrow and move into the bloodstream. As mentioned, WHIM syndrome creates hardship from birth. Symptoms start within the first year of life and increase as years go by, as shown in this graph, which captures the natural history of symptoms. By the time people are entering their 20s, nearly 90% are experiencing chronic neutropenia and infections. Here, you can see the dark red line representing infections tracks with other symptoms of WHIM syndrome, neutropenia, hypogammaglobulinemia and lymphopenia. While graphs and data help our understanding of the progression of disease, we can never truly appreciate the disease burden until we hear it firsthand from patients and their physicians. Let's take a few minutes to learn directly from these experts.

My name is Gabrielle. I am 27 years old. I work as an associate scientist, and I was diagnosed with WHIM in 2019. Growing up, I had always been sick a lot as a child with lots of infections, strep throat, the flu, colds, it was almost constant. My doctors would brush it off a lot as I was in school with a bunch of kids that spread germs around, and it was nothing to be concerned about. However, when my mother was diagnosed with an immune deficiency in 2016, the immunologist decided that my sister and I needed to be tested. And it turned out we both had hypogam. The most burdensome symptom would have to be the infections. Even now with my diagnosis and being on IVIG treatment, I still get infections quite a bit. And I have to miss work. I had to miss school growing up. Or when I was in college, I would get infections and miss class. It impacted my grades, and now it impacts my income.

I'm Willow Finley. I was diagnosed with common variable immune deficiency in 2017, when I was 17, through genetic testing. In 2019, that was updated to WHIM syndrome. I would describe WHIM syndrome to those unfamiliar with it by saying that my immune system does not produce enough of what it needs to fight off infections as well as producing things like warts and other problems. My initial symptoms were recurring infections, things like ear infections when I was a kid, strep throat, mono, other infections like that as I got older. The impact on my daily life from reoccurring infections has been generally missing school, getting behind on schoolwork, like that ,and then just general fatigue.

My name is Courtney Empeson. I was diagnosed with WHIM in 2019. Growing up, I'd always have symptoms of colds and pneumonias, and every time I would get sick, I would get very sick. My sister would get a cold and she would be better in a couple of days. I would get her cold and I would end up on high-dose antibiotics or in the hospital, and it would take weeks for me to recover. Frequent respiratory, sinus infections and there is always just something wrong with me continuously. I would probably say I'm in and out of the hospital probably 4 or 5 times a year and sometimes it's for a couple of days and sometimes it can be for a couple of weeks. And so due to the WHIM syndrome, I'm frequently experiencing infections. And due to that, I'm on antibiotics quite frequently, which is very challenging and devastating on my body in that I have a very difficult time tolerating most of the antibiotics and so if I'm placed on antibiotics, I usually have to have an additional 2 or 3 medications to support the side effects that I have from the antibiotic with the WHIM syndrome that kind of ebbs and flows with infection and severity which is difficult because there's so much uncertainty in this illness. There's not a linear path in that you get sick, you get the medicine and you get better. That's not the journey for a patient with WHIM. You are constantly sick, and it's just a matter of how sick for how long.

The biggest problem in WHIM syndrome, of course, is recurring infections. And that's going to be bronchitis, sinusitis and over time, what that does is it actually hurts the lung and then you get this inflammation picture in the lung called bronchiectasis. And that's, I would think one of the things that physicians worry about quite a bit.

Infections are the [Foreign Language] of immune deficiencies. In patients with inborn errors of immunity involving neutrophils, such as WHIM syndrome, bacterial infections are the most important cause of morbidity and mortality.

First challenge is infection, which are not that short term because we have some way to manage the short-term infection. But the recurrence of infection and the consequence of recurrent infection on several organs, like the lungs, like the sinus, and led to the HPV infection and wart, so that's the first challenge. The second challenge is the challenge of the secondary malignancy in such a group of patients, which is later in life, after the age over 30, which are also related to several kind of viral infection like Epstein-Barr virus infection or HPV infection. So that's the 2 main challenge, I think, for the patient with this disease.

We are coming to appreciate that WHIM means different things in different individuals. Infections probably is the #1 burden of disease for most patients. I think that -- and infections can mean many things. So it can be skin infections, it can be warts that are difficult to treat. It can be pneumonias, it can be very difficult to treat sinusitis. And it's not just that each infection may be more severe. So there's this piece of the infections are more severe than the average person, but they also happen more often. And I think that's something we do not always appreciate as people who have normal immune systems.

I hope that you can appreciate from these insights why X4 was so motivated to study mavorixafor in WHIM syndrome and aim to reduce the heavy burden of infections, which was a key focus of the 4WHIM Phase III trial. I'll now turn it over to Dr. Murray Stewart to review the trial design and present our very promising results.

Thank you, Paula. We designed our 4WHIM global registrational trial to assess the potential of mavorixafor to impact neutropenia and lymphopenia, 2 of the hallmarks of WHIM as well as other clinical metrics of this chronic syndrome. The 4WHIM trial was a randomized, placebo-controlled, double-blinded study. The study's inclusion criteria screening required that all patients enrolled had the diagnosis of WHIM and a confirmed absolute neutrophil count or ANC less than or equal to 400 cells per microliter. Remember that less than 500 cells per microliter is the definition of severe neutropenia. Participants aged 12 and above were eligible to enroll. As you can see here, the median ANC at baseline was about 200 cells per microliter. So this population was severely neutropenic. As we described last November, the 2 arms of the trial, treatment and placebo, were very well balanced by gender, age, degree of neutropenia and lymphopenia and by previous or ongoing immunoglobulin use. Participants would assess for the primary endpoint of TAT ANC or the time above threshold for the absolute neutrophil count at weeks 13, 26, 39 and 52. Similar assessments at the same time intervals were completed for the calculation of the key secondary endpoints of mean TAT ALC or absolute lymphocyte count, to assess mavorixafor's effectiveness against lymphopenia which is defined as less than 1,000 cells per microliter. At the end of the placebo-controlled portion of the trial, all participants were eligible to roll over into an open-label extension or OLE. Notably, more than 90% of eligible participants elected to continue on and receive mavorixafor treatment in the OLE. Today, we'll be focusing on the robust data set measuring differences in various clinical outcome metrics related to the rate, severity and duration of infections among others. Importantly, all metrics related to infection were determined by central blinded adjudication committee. This rigorous approach, which minimizes bias, utilized an independent group of physicians who reviewed blinded participant data generated under the trial. All safety data were also assessed by an independent board. Previously, we shared that the trial met its primary endpoint of TAT ANC with dose of mavorixafor achieving 15 hours versus 2.8 hours on placebo and a p-value of less than 0.0001. Similar benefit was achieved in the first key secondary end point, TAT ALC. Additionally, we shared that mavorixafor was well tolerated with no treatment-related serious adverse events. No treatment-limiting toxicities and no treatment discontinuations due to lack of efficacy or safety. Today, we're announcing that mavorixafor treatment demonstrated significant and clinically meaningful improvement in infections in those diagnosed with WHIM syndrome in the 4WHIM trial, including the rate, severity and duration. Today's event follows this morning's publication of our late-breaking abstract that was submitted to the Clinical Immunology Society. As we've announced previously, the abstract was accepted as an oral presentation at the CIS Annual Meeting, which is taking place May 18 through the 21st in St. Louis. Dr. Raffaele Badolato, Professor of Pediatrics at the University of Brescia in Italy and an investigator in the 4WHIM clinical trial will present these and some additional data at 11:30 a.m. Central Time on Sunday, May 21. Although the session is only accessible live to conference attendees, we will be posting the presentation slides onto our website concurrent with the presentation. We'd also like to note here that an abstract we submitted to the European Hematology Association was also accepted for presentation at EHA's upcoming annual meeting. Dr. Donadieu, who you've been hearing from today, will be presenting the data for our 4WHIM trial in an encore oral presentation of the results being presented at CIS. With that, let's move on to today's data presentation. This first new data set that we're presenting today demonstrates mavorixafor's ability to improve white blood cell counts in the trial as demonstrated by the top graph. The total white blood cell counts are represented here as the mean plus the standard deviation over the 24-hour assessment, measured at weeks 13, 26, 39 and 52. Across all time points, mavorixafor treatment significantly elevated mean total white blood cells versus placebo. In fact, white blood cell counts reached almost near normal levels with mavorixafor treatment, demonstrating stability in the Phase III trial to improve panleukopenia that is one of the hallmarks of WHIM syndrome. A similar graph specifically quantifying absolute neutrophil counts over time is shown in the bottom half of the slide. Similar to the impact on total white blood cell counts, mavorixafor significantly improved mean ANC counts over most of the 52 weeks of the trial, improving the severe neutropenia presented by these patients at the start of the trial. White blood cell neutrophil counts are quite meaningful assessments for this patient population, and it's key that mavorixafor significantly elevated these counts. Importantly, benefit in clinical outcomes was also observed. As we've just heard, infections are the most important sequelae of the impaired immune system in WHIM patients. So let's now move on to our first data set demonstrating the impact of mavorixafor on the rate of infection in the 4WHIM trial. We are very pleased to share that mavorixafor treatment resulted in a 58% reduction in annualized infection rates when compared to placebo, which was statistically significant with a p value of less than 0.01. As a reminder, the trial was conducted during a global pandemic during which most of trial participants were social distancing or isolating. We believe this underscores the strength of the drug effect we're seeing. In fact, if we move on to the next slide, here, we show that reductions in annualized infection rates were greater over time on treatment with mavorixafor. In this graph, the first set of blue and red bars on the left shows that mavorixafor reduced infection rate over the first 6 months of the study to 3 infections per year versus 4.5 for those in placebo. During the following 6 months of the trial, as depicted in the second set of blue and red bars, an even greater reduction of infection was achieved. Participants treated with mavorixafor had an infection rate of less than 1 per year, while the infection rate of 4.5 was unchanged for those in placebo. The difference in the second 6 months was statistically significant with a p-value of less than 0.005. We next examined the various subgroups within the study to better understand what might be driving the observed changes. The subgroup analysis shows that the reduced infection rate observed across the full study was also observed across all key subgroups, including age, gender and for those on or off immunoglobulin treatment. In all cases, infection rate reduction was consistently observed in those treated with mavorixafor as compared to placebo. We'd also like to share that trial participants in mavorixafor also had fewer recurrent infections versus placebo although we don't have time to review those data today. We also examined infections in various organ systems, consistent with the clinical symptoms of WHIM. This benefit seen with mavorixafor in the 4WHIM trial is consistent with the overall reduction in infection rates. More specifically, as shown in the graph, the number of infections in patients treated with mavorixafor in the trial, shown by the blue bars, were reduced across almost all infection types as compared to placebo and improvements were reported across bacterial, viral and fungal infections. Notably, large reductions occurred in upper and lower respiratory tract infections with reductions of 60% and 100%, respectively. Skin infections were also dramatically reduced in the trial by more than 90%. We also examined preexisting wart lesions, 3 lesions per patient on the arms, legs and/or trunk regions of the body by taking photographs of the selected lesions at baseline and at weeks 26 and 52. Our blinded central adjudication committee reviewed the photographs and scored visual changes in existing lesions for worsening, no change or improvement. Although there were no differences measured between the 2 arms, both arms did show minor improvements across the 52-week trial. Observations of new warts were also assessed. Patients on mavorixafor had either no or fewer new warts compared to patients treated with placebo, which was encouraging. Overall, mavorixafor showed improvement across most metrics related to location and type of infection. We'll now hear from our physician experts to provide their perspectives on these data.

One of the most compelling features of the WHIM trial was the reduction in infections that was noted that was associated with the improvement in the white blood cell counts, the lymphocyte counts, the neutrophil counts.

The data showed a very significant decrease in the rate of infections in WHIM patients taking mavorixafor. And I think that has major implications both for health and for quality of life.

Well, I think that the reduction of infection globally will offer to the patient a more normal life, and so -- normal meaning that they will not be hampered by this infection. And so they will recover social capacity on many aspects of what is social life. So that's probably the best results we may expect for the patient.

To speak to a WHIM patient about the impact of the trial and how mavorixafor reduced infection rates threefold or more, to explain that to a WHIM patient would be to kind of talk about how we hope to bring your immune system back to within normal range for what normal people experience, people without CXCR4 defects or WHIM. So we're optimistic that this medication can have you be more like the normal human experience with respect to infections.

In addition to frequency of infection, the assessment of severity of infection is also an important metric. As we've just heard, these infections often need antibiotic treatment or even hospitalization and can lead to permanent tissue damage and long-lasting effects. So let's now go through the data examining mavorixafor's impact on the severity of infections in the Phase III trial. First, we'd like to only take you to the definition of severity applied here. The blinded central adjudication committee utilized the standard definitions for Grade 1 through Grade 5 infection severity as set by the U.S. Department of Human Health Services. These are standard definitions utilized across all clinical trials. X4 defines severe infection as those Grade 3 or higher. According to Dr. Newburger, and I quote, "Grade 3 and above represents infections that have very significant morbidity, frankly, make people feel very sick and have an increased risk of permanent tissue damage and long-lasting effects." In that context, it's particularly important to reduce the numbers of these more severe infections because they have the most immediate and long-term morbidity and potential for mortality. This is the rationale behind our focus on infections Grade 3 or higher in this study. As seen in this bar chart 29%, or 5 of the 17 of those on placebo experienced Grade 3 or higher infections which only 7%, only 1 out of 14 patients of those on mavorixafor experienced a Grade 3 or higher infection during the trial. Importantly, the single Grade 3 infection in the mavorixafor treatment arm occurred during the first 3 months of the trial. After that first 3 months, there were 0 serious infections for the remainder of the study in all participants treated with mavorixafor, whereas the frequency of severe infections on placebo remained unchanged. Additionally, we looked at antibiotic usage in the 2 arms. These data demonstrated that participants on placebo needed more medical intervention, which makes sense given the higher rate and greater severity of infections in the placebo group. Here, we see that 10 of the 17 participants on placebo were treated with antibiotics over the course of the study, whereas only 3 of the 14 receiving mavorixafor were given antibiotics. Again, let's hear reactions to these data from our physicians.

On the mavorixafor trial, there was a reduction in both the frequency and severity of infections. And this has significant clinical impact. Frequency of infection, of course, impacts quality of life in that patients require treatments or even hospitalizations more frequently, which translates in children to time lost from school or in adults, time lost from work.

The long-term consequence of severe infection is destruction of some function of the body, like lung function, respiratory like also maybe CNS functioning. And so -- or maybe joint infection. So we will change major -- the future of the patient in terms of quality of life because we preserve the entire body. And so this is a good perspective for the patient, not at short term, but also for the rest of his life.

The data showing reduced use of antibiotics in patients receiving mavorixafor compared to those on placebo are actually quite important because the prolonged and frequent use of antibiotics leads to antibiotic resistance. And they use more broad spectrum or more and more expensive antibiotics. So from the patient point of view, almost all patients prefer to have less antibiotic use. Most antibiotics have some side effects, particularly GI and they also are aware of the risks of development of resistance.

Naturally, we are also pleased that the data revealed that mavorixafor reduced infection rate and severity in the trial. And now we're at the final data set, which reveals results on the duration of these infections. We've heard that infections can prevent people with WHIM from participating in important life activities. And as you'll see in the next slide, the results quite clearly favor the mavorixafor-treated participants in the trial. Here, you can see the mavorixafor treatment reduced the total duration in days of infections by more than 70% as compared to placebo. In fact, those on placebo were sick for a mean duration of 7 weeks throughout the year of the trial versus a mean of only 2 weeks for those treated with mavorixafor. So not only did mavorixafor treatment participants get fewer infections that were less severe, but the total number of days they lived with an infection during the trial was dramatically reduced. Furthermore, this impact on duration of infections was evident in the patient exit interviews we conducted. We'll not be presenting the details of these data today. However, we can summarize that those on mavorixafor reported better quality of life outcomes versus those on placebo. Let's again hear the reaction of our physician panel to these data.

The difference between 7 weeks and 2 weeks is really rather striking if you think about it, because 7 weeks is the best part of 2 months. And if you're missing, for example, you're in school and you're missing a number of lectures, you're missing classes for close to 2 months in the middle of the calendar year, that could be a big problem. From the standpoint of an employee working in job circumstance, missing close to 2 months of work, again, is even if it's scattered out throughout the year, that's really quite a bit of time. 2 weeks is something which is really much more of a handleable period of time to not lose not only school but work issues, I would say.

The duration of infection is a very important measure. and the decrease in duration associated with mavorixafor as opposed to placebo is very impressive. The longer and infection less, the more tissue damage and long-term sequelae are likely to occur as well as the duration of antibiotic use and risk of development of resistance.

The implications of that data are several. First, the patients' -- the quality of life and what they are experiencing in those extra 5 weeks is not to be trivialized. So being sick for 7 weeks or effectively 2 months, is extremely impactful, not only in how you're feeling physically, but in your mental health. And then I think the other piece that is important to remember is that the longer you are sick, the more likely there is for the opportunity to develop chronic, permanent damage. So clearing an infection more quickly, there is less likely to be perhaps permanent lung damage or scar then there would be in someone who is recurrently sick with a disease burden of 2 months. So I think that, that result is very meaningful for WHIM patients in terms of not only just what they experienced in one year and in the individual days of being ill, but also in the repercussions that, that could lead to down the road many years from now.

Let's now turn briefly to review the safety data from the trial. As a reminder, when we disclosed the top line data last November, we also shared that mavorixafor was well tolerated in the trial, with no drug-related serious adverse events, no treatment-limiting toxicities and no discontinuation due to safety. About 90% of patients continued on into an open-label extension study, which is ongoing. Most adverse events related to the background disease. The next slide will provide some further details. In this table, it's a part that the placebo arm had dramatically more infections and infestations as well as respiratory tract disorders, in fact, about 4x as many when compared to those treated with mavorixafor. As you can see, this is consistent with infection benefit with mavorixafor treatment in the trial that we just outlined in the prior slides. The mavorixafor treatment arm showed an increase in skin disorders, which was mostly characterized as mild rash, eczema and acne. GI disturbances were higher in the mavorixafor arm versus those in placebo. The nature of these issues were infrequent nausea and vomiting. With both skin and GI disorders, all events were mild in nature, all resolved and all patients continued on mavorixafor treatment. All other safety assessment showed either a balance between mavorixafor and placebo arms or were considered not drug-related. We believe these data continue to support the potential use of mavorixafor as a chronic treatment for WHIM syndrome. We're pleased to report that we recently completed our pre-NDA meeting with the FDA. X4 provided the clinical data reviewed here today, along with other relevant data supporting a potential U.S. new drug application submission. The meeting was positive and productive. Given this positive interaction, we are advancing our NDA preparation and are on track to submit early in the second half of 2023. As a reminder, should mavorixafor be approved for WHIM syndrome, X4 is eligible for a Priority Review Voucher, which we would expect to monetize to provide funding to support our commercial launch and continued growth of the company. I'll now turn it back to Paula to share a bit about our preparation for U.S. launch. Paula?

Thank you so much, Murray. As you just heard, we're nicely on track for the U.S. NDA submission in the early part of the second half of 2023. In parallel, X4 is executing on the next steps to bring our innovative science to the market, now backed by this meaningful clinical data in WHIM syndrome. As we prepare for a potential launch in WHIM syndrome, possible in the first half of 2024, if all continues to go well, we are focused in the following areas. Building WHIM syndrome community. Establishing X4 as a trusted partner with both the physician and the patient advocacy communities. As we actively engage with those physicians who are likely to see WHIM patients in their practice, we are helping to drive earlier patient diagnosis through disease awareness and genetic testing. Based on our previously presented market research, we remain confident that there are many more WHIM patients than is currently estimated in the literature. It is our hope that our early outreach to the WHIM community will help us rapidly identify patients which could lead to better outcomes for these patients. We are also working to enable broad patient access, clearly articulating the mavorixafor value proposition and setting out to ensure that every patient who wants treatment has access to it, not only through our manufacturing and supply chain preparations but also through a rapid and smooth reimbursement process. It is important to us that the patient feels supported on their entire journey. Lastly, as we as a company continue to evolve, we are taking a thoughtful approach to the implementation of systems and processes that are fit for purpose to support a launch in WHIM syndrome. With the ultimate goal of leveraging all of our investments not only to prepare us for a successful launch in WHIM but also to lay the foundation for a potential future indications, such as chronic neutropenic disorders, and possibly other primary immunodeficiencies and across different geographies. Let's hear from our experts their final thoughts on the potential future for mavorixafor.

Targeting the CXCR4 pathway has the potential to improve neutrophil counts even in patients who lack a mutation in CXCR4, W.e see improvements in neutrophil counts in patients treated with plerixafor, for example, and the pilot data with chronic neutropenia of a variety of causes also gave an encouraging signal that this may be efficacious in treating neutropenia more globally.

The most compelling information is that, of course, a single pill may reverse neutropenia in this group of patients. Of course, not completely, we should have more data, more situation, a more genetic background for this demonstration, but it's a very promising approach for many chronic neutropenia. A single dose of mavorixafor may improve the neutrophil count. And so it should -- we should demonstrate all the consequence of this in terms of infection. But it's the first step is to show that it acts on the neutrophils. And so we are full of expectation. I also will present this in terms of action for probably all kind of human beings because this pathway is something universal. We know that we can't reverse the immune efficiency, but probably it opened the gate to have a treatment able to improve the situation in various situation like other kind of neutropenia.

As you can appreciate, we and the WHIM-related communities are very pleased to see the significant impact that mavorixafor had on correcting neutropenia and reducing infection rate, severity and duration in our WHIM Phase III trial. And we believe these data further support our moving forward as rapidly as possible to advance our trials in CN disorders. While those with chronic neutropenia by definition have low ANC, our research indicates that many of them also experience higher rates of infections than the general population. In fact, this morning's CIS abstracts include our research on this very topic, what we believe is the first study performed confirming the correlation between the annual incidence of serious infection events, or SIEs, and the severity of chronic neutropenia. A poster presentation of this robust research will be included at the CIS meeting on Saturday and will be also added to the Publications page on our website. As we previously discussed, we currently have an ongoing Phase II study assessing for durable increases in absolute neutrophil counts in those with various CN disorders, including idiopathic, cyclic and congenital with chronic treatment of once-daily oral mavorixafor. We expect to provide data from this ongoing study in the second or third quarter of this year. Additionally, we plan to engage the FDA to gain their input on a Phase III trial design and registration path for mavorixafor in CN disorders in the same second quarter, third quarter time frame. As we continue to generate what we believe could be a robust data in CN, we remain committed to seeing just how many patients this mechanism could impact, hopefully leading to a long-awaited and well-deserved innovation for the broader CN disorder communities. To conclude, we continue to believe that mavorixafor has all the components to potentially deliver a transformative new option to people with CN disorders, first starting with WHIM syndrome. We have just successfully completed our first registration trial, demonstrating clinically relevant increases in white blood cell counts and clinically significant impact on infections. We have a path forward to an NDA submission to support the potential U.S. launch in WHIM syndrome, and we are pulling out all the stops to advance the study of mavorixafor in the broader CN disorders. However, we suspect that there are even more patients we could support. As we continue to evaluate the data from the WHIM Phase III trial, we are learning more about mavorixafor's impact on additional components of the immune system, the innate and adaptive components. We believe mavorixafor has the potential to treat additional subsets of patients with primary immunodeficiencies. This entire group of patients is in need of innovative new treatments and we're committed to being there for as many patients as possible. As we conclude the prepared portion of our presentation today, we'd like to thank you all for joining us and to leave you with some final last words before we take your questions.

The mavorixafor Phase III trial is an exciting one because I think the molecular target of CXCR4 has the potential to serve not only the WHIM immunodeficiency community, but really does have the potential to expand into -- as an immunomodulatory agent in other diseases affected by the immune system. So I was very excited that the safety profile was so good, that the efficacy in reduced infections and the primary endpoint of ANC were met because I think that this oral CXCR4 antagonist has the ability to be impactful beyond WHIM.

I want to express my gratitude for recognizing that we are people and that we are just as important. And even with an ultra-rare disease, it's so wonderful to know that people are actually looking at ways to help us.

Thanks to Dr. Tarrant and to Courtney for their meaningful remarks, highlighting the importance of our work, on behalf of those with rare diseases, and communicating the excitement for the potential of mavorixafor treated patient populations even beyond those with WHIM. Before we head into Q&A, we'd like to mention a couple of things. One quick correction to our program, which we clearly have pre-recorded. We just learned this morning that CIS has pushed out its abstract publication date until this Thursday, May 18, so the abstract is not currently on their website. Given the last minute change, they've granted us an embargo waiver for this event. The oral presentation is still being given by Dr. Badolato this Sunday at 11:30 a.m. Central Time, and we will be uploading those slides to the posters and presentations page on our website. One other update, as we announced earlier today, we are very pleased to have completed a significant financing, raising $65 million in gross proceeds from an at-the-market private placement to further advance our development of mavorixafor. This was done with the support of some new top-tier investors, including Adage, Stonepine and Kingdon Capital along with the strong support of our existing investors, including NEA, Bain, Acorn Bioventures, OrbiMed and others. Now with these impressive data demonstrating the efficacy of mavorixafor in the 4WHIM trial, a strong balance sheet to support our business into the fourth quarter of 2024, along with the potential to monetize a Priority Review Voucher in 2024, we believe we are well positioned to continue to grow our business, advance our clinical and commercial efforts around mavorixafor and deliver this potentially groundbreaking treatment to as many patients as possible. We'll now open the event to questions.

[Operator Instructions] So with that, we'll go ahead and take a question from our first analyst here, Ted Tenthoff at Piper Sandler.

Can you hear me okay?

We can.

Well, thank you for just a fantastic presentation today. I really appreciated all the detail both from the clinicians as well as the patients on what it's really like to experience WHIM. And I had 2 questions on -- maybe they're a little bit different. But firstly, in how much does it cost to care for WHIM's patient? Do we have that kind of data? And how relevant are those cost savings going to be for potential payers who will ultimately reimburse this? And I was intrigued to see sort of the flip side of the mechanism of actually having some skin issues. I don't think they were too severe and I just wanted to ask the physicians who are logged in, if that raises any questions or if that might require any monitoring on their part, just to keep an eye on any kind of autoimmune-like syndrome.

Sure, Ted. So I think what I heard was a little bit of how do we think about the value proposition of WHIM in the context of the background disease and our treatment. And then second one was around the skin-related findings, and we'll ask, perhaps, Dr. Tarrant that question. So I'll take the first one and ask Mark Baldry to join. But really, the exciting thing that we're at right now is we've just completed placebo-controlled trials. So what we're really excited about is to determine the true clinical impact of the drug. No one has studied WHIM long term to understand the burden of care, both in terms of costs and patient impact. You heard a lot of the commentary about the long-term sequelae of having repeated infections. So I think we need to just take this data and really do our health economic outcomes research to bring the true value proposition to the payer systems and really capture that as best possible. But of course, these data are a great step forward. I'll now actually ask Dr. Tarrant to please comment if she could, since she was involved in the trial, on any perspectives on safety.

So in terms of, I guess, also to speak to the value of having a medication to prevent long-term complications, to contextualize, I am an internist, so I actually take care of the adult side of immunodeficiency, which is unusual because a lot of folks are in the pediatric space. And I end up seeing these patients with some of the long-term health chronic outcomes in primary immune deficiency. And I agree with Paula, this is really hard to put a dollar statement onto that because as you've learned about WHIM, it's so incredibly variable in terms of people's experiences, so I don't know if there's just an average patient that you can really speak to, to do economics on. But as you can imagine, multiple hospital admissions for IV antibiotics in the case of my patient, one of the patients I care for, she has had maybe 10 or 15 surgeries for HPV, which is the virus associated with the warts. She has had multiple surgeries and cancer treatments for the cancer, cervical cancer and vulvar cancer that have become extensive since she is in now in her 40s. And we'd love to think that when you're addressing a root cause, which the CXCR4 or mavorixafor antagonist is, if you're addressing the root cause of a disease that you could potentially prevent many of the complications that these patients do suffer from long-term to get it back. And then was there something more you wanted me to speak to with the skin?

Just with respect to the -- I guess, is there any way that we could actually promote almost autoimmune-like syndrome if we turn on the immune system too much?

Okay. So I think if I'm understanding correctly, it's can one develop autoimmune sequelae from being on chronic administration of mavorixafor? Is that -- am I paraphrasing correctly?

Ballpark, yes, kind of from the mechanism. And again, I don't think there's any signals that from the clinical data yet, but is there something in your head that you might be worried about?

It is not. I am a rheumatologist. So in addition to allergy immunology, I'm also boarded as a rheumatologist, and I take care of autoimmunity is kind of the main purview under rheumatology. And we don't really think of this target as necessarily being involved in the autoimmune access of many of our autoimmune diseases. And I would speak to psoriatic arthritis, rheumatoid, multiple sclerosis, inflammatory bowel disease. I have no concerns there as a clinician and someone who's an expert in autoimmunity. You'll never know. Obviously, in a year-long trial, you have only a certain amount of clinical data that you can see in the trial. But both WHIM itself and the target itself do not concern me for enhancing autoimmunity.

The next question comes from William Wood at B. Riley.

And many congratulations on the impressive infections data disclosure today. On your FDA interactions, glad to hear you've had a pre-NDA meeting already. And wondering if you were able to get any insights on how they may think similarly or differently about severe chronic neutropenia relative to WHIM in terms of choice of ANC endpoint, but also the relevant clinical outcomes. I know there have been some GCF studies done in the CN, whereas, obviously, you did have insight in WHIM, although they are quite old. So maybe if you could just give us any extra color there that would be helpful. And then one follow-up.

Sure. Murray, would you like to kind of paraphrase where we're at with our regulatory strategy in CN?

Yes. So in CN, we've obviously got the Phase I data showing an increase in ANC. We're doing Phase II to show whether that's durable. And the plan would be to go and discuss with the agency our Phase III plans. We've already had some preliminary discussion with them regarding what the study would look like, and they agreed that it should be on top of standard of care and rather than versus GCSF, given the challenges with the variable doses people are on. So we're mapping out a plan of mavorixafor versus placebo on top of standard of care, which may or may not include GCSF, and we are submitting questions to the FDA, and the plan will be to discuss that in the next few months.

Great. I greatly appreciate that. And then for the second question for the experts. The infection data looks quite impressive in different ways you look at it. Are you able to provide similar color on how the wart disease burden is being thought of and maybe if we could also characterize the skin adverse events that were noted here?

Dr. Tarrant would you like to take that?

Yes. So with respect to the warts, one of the things that I think was really outstanding about the way the trial was designed for WHIM is that it was one of the first times that we had a placebo arm. And really, I think we didn't understand the nature of CXCR4 antagonism and warts in general in terms of how to study them, how to measure them, how to follow them over time. And we actually learned that warts in and of themselves go up and down regardless of treatment. So I think previously, we've made some assumptions as clinicians that may not have been correct that medicines that we were using made the warts go away when actually the natural history is such that they recede and they come back and they recede and they come back. And as you saw from the data, in the group that was on mavorixafor, there were not any evolution really of new or worsening warts. So it didn't necessarily make the warts that they had recede in a kinetic that maybe looked different for the brief time shot that we looked at. So remember, this isn't the lifetime of a patient. It's a 52-week trial. So for that snapshot in time, we saw no new recurrence of warts. So there's many ways you can look at that data. You can say, number one, the natural history of warts, which is very poorly understood, we might need longer time spans to understand the true impact of the drug. That's one thing. The other thing you could look at is perhaps CXCR4 antagonism works better as a preventative than as a treatment strategy. That makes a lot of sense. So that may be. And again, what we might find in these patients that are in the extension, and we're following them much longer, that those patients may have their warts go away and they may not develop any new ones. So I think there's still a lot of questions but CXCR4 is something that in terms of skin and cutaneous manifestations, we are still learning a lot more about. And so I think that, that's just an area still of scientific investigation. But certainly, the data only looked promising. It did not look in any way discouraging.

Got it. Appreciate that extra color. And congratulations again on the great information we saw today.

The next question comes from Kristen Kluska at Cantor Fitzgerald.