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

Good morning, and welcome to the X4 Pharmaceuticals Investor Webinar. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the X4 website following the conclusion of the event. I'd now like to turn the call over to Dr. Paula Ragan, President and Chief Executive Officer of X4 Pharmaceuticals. Please go ahead, Paula.

Thank you, everyone, for joining us this morning for our event highlighting the promise of mavorixafor across chronic neutropenic disorders and the exciting results of our Phase Ib clinical trial. 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 Form 10-K and Form 10-Q on file with the SEC. We will begin today's program with a brief overview of chronic neutropenia, followed by a discussion of the current treatment paradigm and patients' significant unmet needs. We'll then present the positive clinical data from our Phase Ib clinical trial and touch briefly on our future plans and expected upcoming milestones. Throughout our event today, we will be hearing from chronic neutropenia patients. We'll also be hearing from leading physicians who treat patients with CN daily, and most importantly, their views on our Phase Ib data. Now let's meet these patients and our clinician commentators.

I'm Peter Newburger. I'm a Pediatric Hematologist-Oncologist with a particular interest in neutropenia and neutrophil disorders. I'm Professor of Pediatrics and Molecular, Cell and Cancer Biology at the University of Massachusetts Medical School and a visiting lecturer at Harvard Medical School. I see patients at both University of Massachusetts Medical School and at Boston Children's Hospital. In my clinic, I see 1 to 4 patients with neutropenia weekly. Some are repeat patients so I estimate that I see about 75 patients with neutropenia each year. Most of those have idiopathic or autoimmune neutropenia and a few have congenital neutropenia, including cyclic neutropenia. I would say that the number has increased quite a bit over the last decade, and I think that's due to both increased recognition of neutropenia and referral to me as a specialist in the disease.

Hi, my name is Jolan Walter, and I'm the Division Chief and the Chair of Pediatric Allergy and Immunology at John Hopkins All Children's and University of South Florida. And as an allergist-immunologist, I work very closely with hematologists and we share patients. And I would say probably currently in my practice, I take care of around 30 patients with this disease, but there're way be more out there who haven't come to us yet for evaluation. I believe that neutropenia patients have several unmet needs. The first one is delayed diagnosis. Many of the neutropenia patients will not have a proper evaluation for the course of their neutropenia, and that could be requiring laboratory testing and genetic evaluation. The second unmet need is that there is no therapy offered to them regarding how to improve their neutrophil count that is sustainable long term. And they don't have alternatives to choose from, and they don't know when to use and how to use medications for the neutropenia. So there is a major diagnostic gap currently in their needs and also treatment of [indiscernible].

Living with neutropenia, it's a constant awareness. It's understanding like germs and what's out there and hearing people cough or listening to them sneeze and just not being -- wanting to be around them. From day-to-day chores of going into a store of what you touch and where you touch it, it's like thinking of living like a germaphobe. Recently, last Thanksgiving, I was hospitalized for the common cold, the rhinovirus, and quickly developed pneumonia as a result of just having a common cold.

So I was diagnosed when I was back in 2001. I was 16 years old. I remember going in for spinal taps and bone marrow biopsies and having to stay home when others were going out and recovering from those and having a spinal headaches from my spinal tap. When I did get some viral infections that were significant, I would end up in the hospital. I remember a lot of my adolescents being home sick and being home recovering from either illnesses or spinal taps or bone marrow biopsy or doctors' appointments.

As you've just heard, chronic neutropenia is a very severe condition with high unmet needs. As a quick refresher on white blood cells, neutrophils are a type of white blood cell that circulate in the blood and survey for foreign invaders. Neutrophils are necessary for successfully fighting infections and creating a healthy immune response. Abnormally low neutrophil counts, or ANC, are those measured below 1,500 cells per microliter of blood. The table in the lower corner of the slide highlights key ranges and risks. ANCs are tracked carefully because the lower the count, the higher the risk of infection. In fact, severity of neutropenia has been well proven to correlate with the risk of serious infections in a number of immunocompromised patients, including bone marrow and solid organ transplant populations, as well as HIV populations. Our own research specifically examining infection risk in patients with chronic neutropenia show that CN patients have a twofold to fourfold increased risk of serious life-threatening infections versus those with normal neutrophil counts. There are various etiologies of chronic neutropenic disorders, which include idiopathic, cyclic and congenital neutropenia, among others. There's only 1 treatment option for chronic neutropenia currently, recombinant injectable granulocyte colony-stimulating factor, or G-CSF, for short. It was approved back in the early 1990s for the treatment of severe chronic neutropenia. Administration of G-CSF for injection has been shown to cause debilitating side effects like bone pain and muscle cramps. Additionally, we learned that there's an increased risk of cancer in certain subpopulations after years of chronic dosing. It is clear there's a significant need for an oral efficacious therapy with low burden of administration and good tolerability. We believe that mavorixafor has the potential to address this important need. As many of you may know, the CXCR4 receptor is known to be a master regulator of immune cell synthesis maturation and mobilization, including neutrophils. These specialized cells are produced in the bone marrow in large quantities. Majority of them are held in reserve and maintained in the bone marrow, and it's estimated that more than 100 billion neutrophils exit the bone marrow per day to perform the job of immune surveillance. Downregulation of CXCR4 leads to both maturation and rapid mobilization of neutrophils from the bone marrow into circulation, happening in just a matter of minutes to hours. In the various disease settings of chronic neutropenia, the condition of the bone marrow reserve has been considered as negatively impacted. However, our Phase Ib study was designed to partially test this assumption, and our results have shown us an exciting and important findings as you'll soon see in just a moment. Our lead candidate, mavorixafor, is an oral investigational CXCR4 antagonist that has been shown across a number of clinical studies to downmodulate the CXCR4 receptor and robustly increase the mobilization of white blood cells, increasing the absolute neutrophil count, or ANC, in the blood. Mavorixafor has also demonstrated good tolerability, with some patients from our Phase II trial in WHIM syndrome being treated for nearly 4 years. More than 200 patients and healthy volunteers have been dosed with mavorixafor to date, with only low-grade adverse events deemed treatment-related and none impacting our compliance for long-term use. As I have mentioned, there's been little to no innovation in the treatment of chronic neutropenia, and there's only 1 FDA-approved treatment, G-CSF for injection, which is only indicated for those with severe but not moderate chronic neutropenia. G-CSF was approved based on its ability to increase neutrophil counts above predefined threshold. For those who can tolerate G-CSF, most patients inject the treatment once daily and oftentimes suffer through debilitating side effects. There are no alternative therapies except bone marrow transplantation in patients with extremely severe disease presentation. I'll now pass to hear more from our physicians and patients, this time sharing their experiences with G-CSF.

The decision about whether or not to use G-CSF is highly individualized, and so is the dose and schedule. And this has to be determined by titration at the time of therapy initiation for every patient, and then often readjusted over the course of treatment of this chronic disease. The titration period to determine the best dose can take weeks to months. For adults, it can be a very prolonged process because the dose has to be adjusted for both efficacy, the absolute neutrophil count, and toxicity, primarily bone pain. And often, the effective dose is also a toxic dose, so you have to slowly back down off the dose, and that can take many months, usually with weekly blood counts. When I speak with patients either in my clinic or through the National Neutropenia Network, the major objections to G-CSF therapy are the daily injections, the bone pain and the inconvenience of the frequent blood counts and injection procedures. I think that patients would tremendously welcome, in fact, they often state that they wish there would be an oral drug as a substitute for the injected drug.

What I noticed is that patients who, again, are followed by us on G-CSF have to have neutrophil counts repeatedly checked at least once a month or every 2 weeks depending on how stable the neutrophil count is. And, of course, the goal is to have the minimum amount of G-CSF to administer to the patient with the least possible injections. So it's a long and tedious process, requires a lot of visits to the doctors, and it may not be a steady dosing schedule. As the patient goes through [indiscernible] or other complications in life, they may have to revisit the G-CSF treatment schedule. And this is exactly why our patients were so excited about this study since many of them elect not to use G-CSF on a regular basis. And knowing that the neutrophil can be corrected or even stabilized with a monotherapy, based on the data, I can probably confidently say to them that there is a potential for them to receive a monotherapy and do well with their neutrophil count long term.

The treatment plan was administering Neupogen. Early on, we had to figure out how often and how much. So that process was pretty painful, and I would experience a lot of bone pain, like debilitating, like I would just feel like my body was like tense, like severe back pains like -- because it's produced through your bone marrow. So it literally feels like your inside muscles are just like cramping down and you can't move.

As of right now, I'm using Neupogen to -- as my treatment plan to manage my neutropenia. I use that daily on a low dose. If I get the extreme bone pain that does sometimes come through, I am unable to sleep, I get cold sweats, I have to take hot showers because I get body pain. Yes, it's unreal. It's some of the worst medication that I could put into my body, but it's a medication that I know I need to be on to be able to live a semi-normal life.

To better understand the treatment burden of chronic G-CSF use, we reached out to the patient community in the U.S. In mid-2022, X4 worked with our patient advocacy groups and conducted a survey of people living with chronic neutropenia to learn more about their experiences with chronic G-CSF treatments. Of the 100 responders, 91 had previous experience with taking G-CSF. Many of them had to discontinue its use. 51 of the 100 have been able to tolerate continuing on G-CSF despite side effects, but the incidence of these side effects is significant, with 76% of those on treatment experienced bone pain and 75% also describing muscle pain or cramping. As a reminder, this is a chronic, lifelong, daily treatment. And as we've just heard from Kevin and Vanessa, bone pain and muscle cramping, not to mention the pain of injection, are daily burdens endured by these patients. With such a compelling need to transform patient treatment, we initiated a Phase Ib clinical trial to study mavorixafor across a number of chronic neutropenic disorders as listed here. These are the same CN disorders indicated for G-CSF treatments. The U.S. prevalence has determined through X4's ICD-10 code research showed idiopathic neutropenia to be the most prevalent of the chronic neutropenic disorders with about 40,000 patients in the U.S. The term idiopathic speaks to the fact that no underlying cause has been identified for this largest CN population, the majority of whom are adults. The cyclic and congenital category is combined for an additional prevalence of about 7,000 patients in the U.S. Those with congenital neutropenia are often the most difficult to treat and require higher doses of G-CSF. I'm now going to pass the presentation over to our Chief Medical Officer, Dr. Diego Cadavid, to go through the results of our successful Phase Ib study. Diego?

Thank you, Paula. And thanks to all of you for joining us this morning. Based on our previous experience and the results to date of our clinical development of mavorixafor for the treatment of WHIM syndrome, we hypothesized that mavorixafor has the potential to treat chronic neutropenic disorders broadly beyond WHIM, and that it could be used either as monotherapy or concurrently with lower doses of G-CSF. To investigate this, we designed a Phase Ib study in chronic neutropenic disorders, including patients with idiopathic, cyclic and congenital neutropenia. The main objectives of this study were to examine the safety and tolerability and the ability of a single dose of mavorixafor to increase the neutrophil counts as monotherapy or concurrently with G-CSF. Based on the population enrolled, we were able to complete 3 sub-analysis that further elucidated the broad potential of mavorixafor in all of these populations. The first assessed the impact of mavorixafor monotherapy in patients with severe chronic neutropenia who were not on G-CSF. The second analysis examined patients with moderate neutropenia treated with subtherapeutic doses of G-CSF to determine if mavorixafor could elevate their neutrophil counts to normal levels. The third analysis examined patients who were successfully been treated with chronic G-CSF therapy to determine if mavorixafor could further increase their neutrophil counts, so that in the future, they could potentially be treated with mavorixafor and tapered off of G-CSF. This slide shows our trial design, which assessed the impact of a single dose of mavorixafor on blood neutrophil levels, also called absolute neutrophil count, or ANC. On day minus 1, eligible participants entered the study on the standard of care, either stable G-CSF therapy or no background treatment. ANC was determined by drawing blood at multiple time points over an 8-hour period to define their average baseline neutrophil levels prior to treatment with mavorixafor. The following day, day 1 at time 0, study participants were given a single dose of 400 milligrams of mavorixafor. Their ANC was again measured by drawing blood samples at the same time points as those taken on day minus 1, so that day minus 1 and day 1 data could be directly compared. For each study participants, their pretreatment neutrophil counts were plotted alongside their post mavorixafor treatment levels over the 8-hour assessment window. Big change in ANC relative to the average baseline value was the metric chosen to determine treatment response and the magnitude of that response. The study has enrolled 28 patients across all 3 CN disorder subtypes. Today, we are presenting the data on the first 25 patients enrolled. The mean age of a participant in our trial was 36 years old. 2/3 enrolled were female, and about 3 quarters of participants were on a chronic dose of G-CSF. Of those on chronic G-CSF, their median dose used in their daily injection was about 1 microgram per kilogram. We believe this data reflects the reality of current treatment where G-CSF is significantly underdosed due to lack of patient tolerability and to attempt to reduce the risk associated with chronic treatment. Here, we also give an overview of the safety and tolerability in the study. The safety assessment of mavorixafor in this CN population is consistent with the experience in prior clinical studies of chronic dosing of 400 milligrams mavorixafor once per day as monotherapy in WHIM syndrome. Mavorixafor was well tolerated. Most adverse events were low grade, and there were no treatment-related serious adverse events reported. Here, we present the increase in ANC in each individual study participant, showing that everyone responded to mavorixafor with an increase in ANC. These results demonstrate the ability of mavorixafor to consistently increase the neutrophil count across all 3 types of CN disorders we examined. Importantly, this increase in ANC following a single dose of mavorixafor occurred regardless of whether or not the patient was being treated with G-CSF. As you can see that every patient had large increases in ANC, with the majority increasing by at least 1,000 cells per microliter at peak. We are very excited to see these results as they established for the first time the potential for mavorixafor as a broad treatment for people with chronic neutropenic disorders beyond WHIM syndrome. Notably, given the well-established relationship of reducing neutropenia with reduction in infection risk, we believe these results, if confirmed with long-term treatment, are clinically meaningful and will address an important unmet medical need. Here, we present the impact of mavorixafor treatment across the 3 types of chronic neutropenic disorders: idiopathic, cyclic and congenital. These were the same types of chronic neutropenic disorders studied in the pivotal G-CSF trial in the early 1990s. As you can see, across all 3 disorders, mavorixafor increased the ANC in blood circulation at peak by more than 3,000 cells per microliter. This consistent large increase across all types of chronic neutropenic disorders confirms the presence of a large bone marrow reserve of neutrophils in all study participants regardless of their type of neutropenia. We shared this data with doctors Newburger and Walter. Here are their initial impressions of the results.

I found the 100% response rate to be extraordinary. I was expecting a fairly high response rate, but close to 100% is much better than what I expected. The numbers are small, but certainly indicative of a very high response rate.

My first reaction to the data was that I was very pleased to see the response, and I expected that to happen because the way I see mavorixafor, a CXCR4 antagonist, is that it helps to have the neutrophils emerge or be released from the bone marrow more readily. And as long as there're neutrophil precursors and neutrophil development in the bone marrow, we should be able to release those neutrophils to the peripheral blood.

Having observed a 100% treatment response at the individual level and consistent and robust responses across all 3 types of chronic neutropenic disorders, we next examined the treatment response in 3 different populations of participants to help further confirm the wide potential of mavorixafor in this indication. Here, we provide details on the 3 different groups of participants within this sub-analysis. Of the 25 participants included in this analysis, 6 were severely neutropenic at baseline, with a mean ANC of just 420 cells per microliter and not receiving any G-CSF therapy. They inform on the potential of mavorixafor to treat chronic neutropenia as monotherapy. The second group consisted of 8 participants who had moderate neutropenia at screening with mean ANC of about 1,000 cells per microliter despite being treated with G-CSF. But as you can see here, their average dose of G-CSF was well below their recommended label dose. We look to these patients to inform us on the potential of mavorixafor to fully correct the neutropenia when used in combination with G-CSF. Finally, there was a third group of 11 participants whose neutropenia had resolved on a steady dose of G-CSF. They had a mean ANC of 4,300 cells per microliter, receiving an average daily dose of about 1 microgram per kilogram of G-CSF. As I mentioned, we included this population to specifically assess whether mavorixafor could further increase the ANC, and therefore, enable the tapering of G-CSF and possibly transitioning to mavorixafor monotherapy. Let's now look at the data from our first sub-analysis, which examined mavorixafor as a monotherapy treatment in participants with severe chronic neutropenia, not on G-CSF. In the left plots, you can see the ANC over the 8-hour assessment window. The red dashed line corresponds to the patient's baseline neutrophil level prior to mavorixafor treatment on day minus 1. With the extremely low neutrophil counts, ideally, these patients should be on some form of treatment, but they are not, which speaks to the risks and tolerability problems associated with chronic G-CSF use. The blue solid line represents the ANC on day 1 following dosing with 400 milligrams mavorixafor. You can see from the kinetics that there was a rapid rise in neutrophil count that ultimately reached normalized levels by 2 hours post treatment. Additionally, you can see the consistent and significant separation between the ANC on day minus 1 and day 1 across the time frame of measured neutrophil counts. In the right-hand bar graph, the results show that mean ANC increased at peak, which was more than 2,500 cells per microliter following mavorixafor treatment versus the untreated baseline value. This is a meaningful increase in ANC levels at peak, moving patients out of severe neutropenia and into the normal range. Here, we break this data out by individual patients to demonstrate the consistent severity of their disease at baseline as shown by the red portions of the bar graph. Every patient had baseline ANCs of less than 500 cells per microliter, corresponding to severe neutropenia. The blue portion of the bar graph demonstrates the consistent impact that mavorixafor dosing had on each individual patient. 100% of patients responded with elevated ANC counts and 100% of patients achieved normal neutrophil levels. We'll now hear from Dr. Walter and Newburder regarding their impressions of our monotherapy data.

I was very impressed about the level of neutrophil count and how it increased within the time frame that was examined in this study. And I must say that one of my patient who was actually in the study mentioned to me that she felt energized, more energized after the time when she received the treatment. The following days, she felt stronger and it was beneficial to her to get the therapy and she were looking forward to getting to the next phase of the study. So I believe that not only the patients which were stronger and more energized, but they will be able to have neutrophils maintaining their periphery to fight infections and take care of their wounds or any kind of healing that they need in their body.

The responses of patients who are not on G-CSF, but achieved excellent peripheral blood absolute neutrophil counts with mavorixafor was very impressive. I think it tells us something about the pathophysiology of the disease as well as the potential use of the drug for therapy. There has always been some debate as to whether the problem in idiopathic neutropenia, in which you see quite a few mature neutrophils in the bone marrow, whether the pathophysiology involves the failures of release those neutrophils or the death of those neutrophils as they enter the circulation. The success of mavorixafor suggests that it is largely, at least in these patients, a matter of release from the bone marrow. I think that it has very important implications in terms of future monotherapy if you can correct the absolute neutrophil count with an oral drug in patients without any use of G-CSF. It would avoid many of the toxicities of G-CSF, all the toxicities of G-CSF for that matter, and provide adequate absolute neutrophil counts, which I think would be a surrogate for freedom from infection.

In these next few slides, we will review the effect of mavorixafor in moderate or severe neutropenic participants who are currently treated with G-CSF. As you can see from the graph on the left, the average baseline neutrophil counts for these participants as shown by the red dashed line are close to 1,000 cells per microliter. While they have higher ANCs as compared to the severely neutropenic patients, their counts remain below normal even while on G-CSF. The blue solid line demonstrates the effect that mavorixafor had on this group. As you can see, neutrophil counts rapidly rose into the normal range and were maintained at normal levels throughout the 8 hours of blood sampling. The bar graph to the right shows the significant increase of almost 3,000 cells per microliter on average at peak following treatment with mavorixafor, with the blue bar highlighting this robust increase. This next slide shows the individual 8 participants in this group, their baseline ANC levels while on G-CSF and their individual responses to mavorixafor. All patients had below normal ANC counts, and 5 of 8 participants presented with moderate or severe neutropenia even though they were being treated chronically with G-CSF. The consistent and large increase in ANC was demonstrated in every participant, 100% responded to mavorixafor treatment and 100% achieved normal neutrophil counts following 1 dose of mavorixafor. These results indicate that for patients still having neutropenia despite chronic treatment with G-CSF, mavorixafor has the potential to normalize ANC and possibly reduce dependence on G-CSF. Here, we present our final sub-analysis, where we examined the impact of mavorixafor on neutrophil counts in participants who are on chronic G-CSF and who had ANC counts in the normal range. Again, the purpose of studying the ANC impact of mavorixafor in these participants was to support the rationale of tapering down G-CSF to reduce side effects or potentially replace it with mavorixafor monotherapy. As you can see from the plot on the left, baseline neutrophil counts before our mavorixafor treatment, depicted by the red dashed line, were in the normal range with some variability throughout the 8-hour evaluation on day minus 1. The blue solid line represents the increased ANC in these same participants after mavorixafor dosing on day 1. As in all others, those with mavorixafor to date, we saw a consistent rise and sustained increase in ANC. Importantly, there were no exaggerated increases in ANC, something that can occur with G-CSF alone. In the bar graph to the right, the difference between the blue and red bars show a mean increase at peak of more than 5,000 cells per microliter after treatment with mavorixafor. We believe this very large increase supports exploring a reduction or potentially elimination of G-CSF dosing in these patients. Now let's hear how the physicians treating these patients reacted to this data.

The responses of patients who were already on G-CSF, but showed very significant increments in absolute neutrophil count on mavorixafor suggests that the drug would be very useful in this setting. The clinical implications of decreasing the G-CSF dose are potentially very important. First of all, from a toxicity point of view, the lower dose is less likely to produce bone pain. And in the long run, there is a relationship between dose and risk of development of acute myeloid leukemia or myelodysplastic syndrome. So I would expect, although it certainly hasn't been proven yet, that a decrease in the dose of G-CSF would reduce those risks.

So I do believe that the combination of G-CSF in mavorixafor could be very helpful for patients who are currently on G-CSF therapy, but would like to wean their therapy or they are looking for possibly transitioning to an oral medication, just having an alternative that can bridge the transition from an injectable G-CSF to an oral medication and combining it for a while and then tapering off G-CSF could be a great alternative for many of our patients.

Some excellent insights from our physicians as we head into our conclusions. As we've just shown you, we believe our Phase Ib study has delivered very impressive results on the potential of mavorixafor to treat chronic neutropenic disorders broadly beyond WHIM syndrome. You have heard from us, as well as from clinical experts, that we achieved our primary objective and demonstrated the breadth of mavorixafor's ability to increase and normalize ANC levels in the 3 main types of chronic neutropenic disorders: idiopathic, cyclic and congenital. 100% of the 25 participants robustly responded to the single dose of mavorixafor, with sustained increases in ANC. Perhaps most impressively, we've demonstrated that monotherapy treatment with mavorixafor normalized neutrophil counts in patients with severe chronic neutropenia. This is a very positive outcome as we believe this could potentially lead to a new treatment option for patients who cannot tolerate G-CSF, those who do not want to accept its long-term risks and also prefer an oral option. Additionally, we've demonstrated that mavorixafor can robustly increase ANC levels in patients chronically treated with G-CSF, including patients who are still moderately or severely neutropenic despite G-CSF treatment. We believe that this significant increases support the exploration of tapering patients to reduce or eliminate G-CSF therapy altogether. And finally, once daily oral mavorixafor was well tolerated, similar to what we have seen in patients with WHIM syndrome, some of whom have been receiving treatment for nearly 4 years. Let's now hear some final insights from the clinicians, and then I'll turn it back to Paula for her final thoughts.

The most important point that needs to be kept in mind about the Phase Ib trial was that it was a single dose, and augmentation by 500 or 1,000 would be adequate for clinical purposes of preventing infection and maintaining the oral mucosa and dental health. So those data will be very interesting and important to see in the future, but I think the single dose experiment shows great promise in terms of therapeutic efficacy even in the long run. I believe that, I, as a single clinician, and most others in the field, as well as patients, would welcome the availability of mavorixafor as an oral drug to treat neutropenia. I would certainly consider it for every patient currently on G-CSF. And would certainly consider it as well assuming the toxicity profile remains very low for patients who are not currently on treatment, but who have worries about the risks of neutropenia or who have some ability to form neutrophils at the time of infection, but not have neutrophils on a daily basis. I think they would benefit from having a steady normal neutrophil count.

Mavorixafor, once it's available, can really change the life of many of our pediatric patients. I definitely would like to try it in patients who are treatment naive regarding G-CSF just to bring their neutrophil count in the more acceptable range, and therefore, we could avoid emergency room visits and hospitalizations. So this is a very important alternative. I also would advocate for this medication among patients who are on G-CSF and bring to their attention an alternative that could be taken easily and they could travel with it easier and potentially decrease the side effects that they are experiencing with their current treatment.

Thank you so much to our commenting clinicians and to Diego for that summary of our exciting results. I'd like to spend just a few more minutes putting these data into context of our broader mavorixafor clinical development program, including some of our important expected upcoming milestones. Based on all of our mavorixafor clinical trial results to date across both safety and efficacy measures, we believe mavorixafor has the potential to become the standard of care across chronic neutropenic disorders, including WHIM syndrome, which we've not focused on today, but is our lead indication for mavorixafor. WHIM syndrome is a rare primary immunodeficiency, with one of its key symptoms being chronic neutropenia. We continue to anticipate presenting results from our Phase III clinical trial in WHIM patients treated with mavorixafor in the fourth quarter of this year. We believe these and our previous results derisk this program significantly given mavorixafor's strong history of tolerability with long-term chronic dosing to date. And we're very excited to continue clinical development of mavorixafor in chronic neutropenic disorders given that this large patient population is thoroughly in need of therapeutic innovation, including an oral well-tolerated option. Today, we presented a major step forward for X4 with clinical data supporting mavorixafor as a potential treatment of patients with chronic neutropenia. In addition to the anticipated announcement of our pivotal Phase III WHIM results in the fourth quarter, we also plan to initiate an amended protocol to the CN Phase Ib clinical trial, which we expect to generate additional data through the first half of 2023. This amendment is intended to enable us to assess durability of response and the effects of tapering patients off G-CSF, as well as to assess long-term tolerability in a larger and broader set of patients with CN disorders. We anticipate discussions with the FDA on these Phase Ib data to inform our regulatory path going forward. We will share further information when we have more clarity from regulators, currently anticipated in the first half of 2023. Provided the Phase III WHIM data are positive, we expect to be in a position to file our first NDA of mavorixafor for the treatment of WHIM syndrome early in the second half of next year, a significant accomplishment for our team, and hopefully, a large step forward for these patients in need. We believe this will put us on sound footing to launch mavorixafor commercially in WHIM as our first indication, with a broad and bright future ahead in chronic neutropenic disorders on the horizon as well. In closing, we thought we'd leave you with some forward-looking thoughts from our interviewed patients, highlighting why we are so excited to advance mavorixafor in chronic neutropenic disorders.

What I'd like to see with neutropenia would be a different way to administer the medicine, honestly. Nobody likes needles, nobody likes to get shots. Giving yourself a shot every day isn't the best. You kind of become numb to it, and it's just like a thing. But if I had to take a pill as opposed to giving a shot, I'll take that 100%.

I dread injecting every day. I dread it. It's the worst part of my day. I do it because it gives me a normal life. If I would be able to have a medication or a treatment that gives me that same outcome with just an oral pill would be outstanding.

We'll now we move into the live portion of our program. Unfortunately, Dr. Walter cannot join us today for the live Q&A, but we're joined by Dr. Newburger, whom you've already heard from, as well as Dr. Julia Warren, a hematologist with the Division of Hematology at Children's Hospital of Philadelphia, who will first give us a quick overview of her background and then will provide her reactions to the data you've just seen. She will also be available to answer any questions you may have. We are now also joined by our Chief Scientific Officer, Dr. Art Taveras; our Chief Financial Officer, Adam Mostafa; and our Chief Operating Officer, Dr. Mary DiBiase. Dr. Warren?

Yes. Thank you for inviting me today. I'm a pediatric hematologist here at the Children's Hospital of Philadelphia and a System Professor at the University of Pennsylvania and sort of breathe and sleep neutropenia, neutrophils all day every day. Since I've been here, actually, I think they're really tickled to have somebody excited to see neutropenic patients. It's been all of my clinics. And honestly, this is such a compelling problem. Patients who have both congenital or cyclic neutropenia, but also patients with idiopathic neutropenia. You heard in that last patient's voice, I think, she was almost on the verge. She was getting emotional about just the thought of having something oral to take, and that's something I've heard from so many patients that G-CSF is -- can work, and it's just really -- it can be really challenging to administer and to be on. And so as far as reactions to the data go, as the other clinicians had mentioned, I was really, frankly, astounded to see the response from all of the patients. I think we certainly don't have the preclinical mouse models to help us understand some of these diseases to the degree that we'd like to be able to. And so we have to ask the questions in human. And the idiopathic neutropenia patients, I think we were expecting to see them respond, but to see the same response in especially congenital neutropenia patients I was surprised and really pleased by. So that there could be a path forward for these patients is really encouraging.

Thank you, Dr. Warren. I think at this time, we'll be opening up questions for others.

[Operator Instructions] So our first question comes from Stephen Willey from Stifel.

You guys can hear me okay?

Yes.

Perfect. Appreciate the presentation. Congratulations on the data. I guess maybe one for the company first. I know you've talked about amending the protocol here. Would further development contemplate BID dosing as well? There's obviously some variability in patient ANC increases, and I think it looks like there's just a couple of patients on mono who are just crossing the threshold of normal at the 8-hour period. So do you think that those patients would benefit from a second mavorixafor dose just based upon what you know about PKPD?

Steve, I'll ask Diego to field that one.

Yes, Stephen. We have actually looked carefully at whether a twice per day could yield a better response than once a day. We did this in the context of WHIM syndrome, which, as you know, it's one of the diseases that cause chronic neutropenia. And we found that there's really no advantage to the twice per day dosing. You just need to get the neutrophils out of the marrow, and they will get to the blood and move to tissues. So we don't expect that we have to do further dose ranging beyond. Obviously, the single dose of mavorixafor has responded really well across all these various patients, which speaks to the ability of single day dose to actually do the job.

And Art, would you like to add a little bit? I know you've looked at some of our year -- many year line data as well.

Of course. Steve, thanks for the question. So as you know, we've studied mavorixafor in multiple clinical trials, and then we've looked at the ANC values in peripheral blood across patients, more than 200 patients in all of those trials. And what we've seen is that there's an elevation of ANC that sustained in many patients -- actually, all patients, by 2, for some patients up to 4 years. So we already know that a single dose 400 milligrams of mavorixafor can already achieve the goals of the ANC counts in the peripheral blood of these patients.

That's helpful. And then just given the 6-month dosing in the proposed protocol, should we expect this to also include an analysis of venture and outcomes pre and post initiation of mavorixafor therapy where you're looking at infection events, antibiotic use and hospitalizations? And then I guess, maybe for the clinicians, can they maybe speak to how important that data would be in terms of your ability to generate that prior to perhaps entering into a registrational study?

So maybe Diego can comment on the data that we're collecting, and then, of course, the physicians can comment on what's important to them. So, Diego?

Yes, definitely as part of this amendment, which now would include chronic dosing, we're working with the clinicians to actually begin collecting data in clinical outcomes, infection-related events, patient-related outcomes and others. So that will be part of the next stage of the trial. But perhaps Dr. Warren can comment further on why this is important and how we're working to accomplish that.

Yes, definitely. And I sort of would think about, for example, the infection question in almost 2 buckets because there's going to be patients who are already on G-CSF potentially able to participate in this study, and it may be difficult to see infection-related outcomes in those patients because in their look-back period, hopefully, their G-CSF is helping improve their ANC to the point where they haven't had significant infectious events. Then those patients, I think, what we could really have the opportunity to see is with the titration down or potentially even off G-CSF do we see the same sort of maintenance of infection-free days or minimal infection events, minimal antibiotic use. But I think really importantly, in those patients, tolerability, so side effects, quality of life measures and especially like fatigue scores for those patients. And then for the patients who aren't on G-CSF, there may be an opportunity -- more of an opportunity in some of those patients who, in a look-back period of, for example, something like a year, 6 months to a year, may have had infectious events that are either requiring unplanned medical attention, hospitalization or antibiotic use. And in those patients, we may be able to use infectious outcomes as a measure. But I think, especially in those patients, quality of life measures are going to be really important in addition to the ANC parameters.

And Dr. Newburger?

I agree completely that quality of life and toxicity measures will be as important as infection measurements or perhaps more important because that is what makes a big difference to these patients, especially those already on G-CSF who will have few infections. I would add that clinicians are very accustomed to using and trusting surrogate endpoints. So for us, seeing a response in the ANC would be interpreted as a decreased risk of infection, even if the period of observation was too short to see a statistical difference in the number of infections or the severity.

From Mayank Mamtani from B. Riley.

You hear me okay?

Yes.

Congrats on yet another potentially [indiscernible] data for mavorixafor. So maybe staying with the clinicians first and then going to the company. So Dr. Newburger or Dr. Warren, could you just comment on historical G-CSF studies published in moderate to severe chronic neutropenia that helps put in context the response rates we are seeing could be real-world studies? And then along the same lines of multiple dosing cohorts, as you think pragmatically, the taper down population, the sub-responders but also the congenital, pediatric, like what are sort of things you would want to see in that 6-month time period that allows you to also study that in broader population?

So I think just to summarize from Mayank to the clinicians. The first question is, how do you interpret our response rates in the context of what you see with responses with G-CSF? And then I think the second question is on what would success look like with G-CSF taper in the Phase Ib? I hope I got this right, Mayank?

And maybe the last part on pediatric, congenital, what would we like to see the chronic exposure.

If you like to go ahead, Dr. Warren.

Sure. Yes, I mean, I think I could comment a lot of patients with chronic idiopathic neutropenia can respond to G-CSF therapy. I think the problem is the side effects and the tolerability, and that what is -- as far as just kind of the ANC being able to increase, I think what I could comment on my experience and then on some published data is that not every single patient will respond to G-CSF, but many patients will. But more -- I think more importantly, the tolerability and the side effects and especially the impact on quality of life, I think on one of the slides there was that data from Tom Michniacki in the University of Michigan-led study on quality of life in chronic neutropenia patients. And really with the safety profile of mavorixafor, how well it was tolerated, to me, that's where the comparison really shows a huge difference -- a potential for a huge difference in those 2 groups. As far as congenital neutropenia, again, I think it would be really exciting to be able to dose more patients with congenital neutropenia with mavorixafor and to understand how they can respond especially over the long term, and whether or not this could augment G-CSF therapy to the point where we can get below some of those threshold doses that we know are associated with increased side effects, and in that particular patient population, with a longer-term increased risk for the development of myeloid malignancy. So could we decrease the dose to see a minimization of those side effects and toxicities from the G-CSF? I think from a molecular pathogenesis standpoint, I'm really interested to see if those patients could come off G-CSF. I don't know if that would be possible for those patients. And so for me, I wouldn't necessarily have that as a benchmarked outcome in congenital neutropenia patients that I would say success is coming off of G-CSF. I would say success is coming down on G-CSF. But again, I was surprised to see that these patients could have such a good response to mavorixafor. So there could be something that we just don't fully understand there about how this drug is helping those patients have, hopefully, functional, mature neutrophils circulating in their periphery.

Dr. Newburger, would you like to add anything?

Yes. I also work with a lot of adult neutropenia patients through my role as Chief Medical Adviser to the National Neutropenia Network, the patient and family organization. And for the adults, bone pain is a dose-limiting toxicity. It's almost universal. And many patients could achieve an adequate ANC with G-CSF, but can't tolerate it. So the promise of decreasing the dose is very important to them. And I think many of them could go off G-CSF judging from the initial data. For those with congenital neutropenia, I agree with Dr. Warren that the objective would probably be decreasing rather than eliminating G-CSF because many of them or most of them have a defect in maturation of the neutrophils. So you would need G-CSF to get their neutrophil maturation beyond the promyelocyte stage to provide mature neutrophils to be released from the marrow by mavorixafor. But I think that it would likely have a benefit, both in terms of bone pain, although that's less of a problem for congenital, but the risk of AML and myelodysplastic syndrome is definitely dose-related. And I think that it would take many years to see that difference, but I think it would be very likely to be proven eventually.

And maybe just a quick follow-up for Diego or Paula. In the idiopathic chronic neutropenia data you presented at ASH last year, there was, I believe, breakdown of other cell types, white blood cells. Did you also look at that data as part of this analysis? And if yes, would love to hear if a conference presentation or something you're planning where we can see the full data set on this?

Sure. I'll start to comment, and then Diego can add. So yes, we certainly have a full panel of all white blood cells examined in the study. We have -- we look forward to publishing that data at a medical conference, and stay tuned on that one. But Diego, do you want to add anything?

Yes. No, that's exactly right. We have looked at all white blood cells, but the additional data will be presented at a medical conference, yes.

The question comes from RK from H.C. Wainwright.

It just was an excellent presentation and really appreciate some of the comments from Dr. Newburger. A quick question -- quick couple of questions. First one, has there been any studies done to increase neutrophils from the bone marrow -- the release of neutrophils from the bone marrow as you were stating that mavorixafor probably is doing that particular function in terms of -- in these patients.

Sorry. Okay. I wasn't sure if I understood your question. Are you asking if there have been other drugs that have been studied for neutrophil maturation or release?

Yes. Yes.

Okay. There has. It's called G-CSF, but I'll actually turn it to the clinicians because I would expect they have a better understanding of the broad landscape. So Dr. Newburger, would you like to comment?

Thank you for raising that critical point. The reason we're so excited about mavorixafor is there hasn't been any other drug that we know of either tested or even in development to have that same effects. So the alternatives now are G-CSF, G-CSF and G-CSF.

Dr. Warren, do you have anything more to add?

No, I agree.

Our next question comes from Eva Xia Privitera from Cowen.

Congrats on all the data. Our question is about how you're thinking about the regulatory path in chronic neutropenia-s? Will you pursue monotherapy in G-CSF in tolerant or refractory patients or have a randomized trial against G-CSF? And are there particular patient populations that you would prioritize?

Sure. I'll start at high level, but of course, I'll invite Diego in. So this data plus our WHIM Phase III data and then, of course, the additional Phase Ib extension that we're undergoing will create a really very robust data set to help inform us as we approach the FDA. I think we're certainly planning on pursuing a registration trial, which the details are still yet to be sorted out. But I'll turn it over to Diego to add further on that.

Thank you, Eva. So now that we've looked at this exciting data, we're obviously beginning to have conversations with all our key stakeholders, importantly, of course, the clinicians who are working to help patients every day. We are also obviously planning to have the conversations with the FDA. As Dr. Newburger said, there has been no drug development in this space in 3 decades. So I -- we anticipate that we're going to have really productive discussions with regulators and find a clear path forward. Our recent experience working with the FDA and other regulatory agencies in WHIM syndrome is very relevant as the main characteristic of WHIM is the chronic neutropenia. So we will draw from those experiences, those conversations. There is also the previous experience with G-CSF, in which the primary endpoint was actually based on the ANC count. So all this will come together. As Paula said, we expect to have some clarity in the first half of next year about what the next steps could be in terms of a registrational trial.

Our next and final question comes from Leland Gershell from Oppenheimer.

A couple of questions which are related for the physicians. With G-CSF being a titratable drug, wondering if you use other information besides ANC count, for example, infection rates or other outcome measures in guiding? How you use it with respect to dosing? And how might that play into any preference of G-CSF or use of G-CSF with mavorixafor versus fixed dose mavorixafor, at the same time, mavorixafor oral and so that may avoid skip doses or other nonadherence on patients part?

So maybe, Dr. Warren, if you could start first. And just to reiterate, I think are there any metrics that you use other than ANC as you find the right dose for your patients, and then how would you think about mavorixafor as a fixed dose in that context?

Yes. I mean, at least the approach that I take is what is the absolute lowest possible dose of G-CSF that I could give to all of the patients across the spectrum of diseases, because I think it's in kind of the congenital neutropenia bucket at least, we're attempting to achieve an ANC that leaves patients free of the symptoms of their neutropenia, while maintaining as low a possible dose to hopefully mitigate the long-term toxicities -- or the short- and long-term toxicities of G-CSF. And so for me, it's really a goal in congenital neutropenia patients to minimize total exposure to G-CSF with the goal of just maintaining an ANC that's able to accomplish reduced, or hopefully, no infections and no other neutropenia symptoms. I would say for chronic idiopathic neutropenia patients, especially in kids, the goal is pretty similar. I don't have 1 ANC that I'm targeting. Especially in those kids, a lot of times, if we're putting them on G-CSF, it's because they're sort of symptomatic enough from their neutropenia. And so to me, again, it's sort of, those kids tend to have a pretty robust response to G-CSF. And so I'm just targeting what's the lowest dose of G-CSF, what's the lowest dosing frequency that can achieve what we want to achieve in there? I'm really targeting kind of a trough ANC. And so when they're due for the next longest spaced out G-CSF dose, are they maintaining ANC that I think would leave them in a range of not experiencing symptoms from their neutropenia. And that does not have to be an ANC above 1,500 in those kids. I think it's an ANC that -- it might sound funny, but it's an ANC where they feel better. They have less fatigue. They don't have mouth sores. And especially in little kids, we'll hear a lot about buttock folliculitis, if they're still diapered. And so really, I think for me, in those kids, it's a lot about symptom -- symptomatic improvement on the lowest possible dose.

Dr. Newburger?

I would just add that for adults and some children, it's a very delicate balance between adequate dose and tolerable toxicity. So that often in those patients falls to a rather poor ANC because they can't tolerate the dose sufficient to raise the ANC. I would also add that the data from the international registry and from the French registry indicates that over 10 to 12 years, there is still 8% to 10% sepsis mortality in patients with congenital neutropenia who are theoretically on G-CSF. But I believe that much of that is due to poor adherence in teenagers and young adults. And having an oral drug, I think, would make a major improvement that could indeed be lifesaving.

If I could comment about the fixed dose part of the question. To me, a huge benefit to that is we should be able to achieve ANCs that are going to be in ranges that help people feel better with minimal side effects. So that also brings with it the benefit -- hopefully. So that also brings with it the benefit of not needing to monitor their ANCs to its same very frequent degree that we're often having to do that, sometimes over the span of months or even 6 to 12 months up to a year to try to get people on an ANC -- I'm sorry, on a G-CSF dose that they can actually tolerate that's effective enough for them. And so this would -- that might sound trivial, but having to go to a lab, call a request, make those visits, take time off work, take your kid in, kids getting poked, then they associate negatively with other medical encounters that they have to have in their life. And so it might sound small, but I think not needing to do as frequent monitoring would be really huge for this population.

We haven't talked much about cyclic neutropenia, but in those patients, they require twice to thrice times weekly blood counts in order to titrate the dose. And they would certainly welcome avoiding that.

Well, thank you so much, Dr. Newburger, and thank you, Dr. Warren, for joining us today. It's always inspiring to be with the clinicians who treat these patients. And so with that, we'll be concluding, and we wanted to thank all of you for joining us today, and we do apologize if we weren't able to get to all of your questions. But please feel free to reach out to us at X4, and we'll be happy to follow up. And so with that, I wish everyone a wonderful day.