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

Good morning, and thank you for joining X4 Pharmaceuticals Investor Day. As a reminder, this event is being recorded. Before we begin, I would like to remind you that during today's call, we will be making certain forward-looking statements. Various remarks that we make during this call about the company's future expectations, plans and prospects constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors. Please refer to the risk factors described in our most recent annual report on Form 10-K, quarterly report on Form 10-Q and other SEC filings, which are available on our website as well as the cautionary statements on Slide 2 of today's presentation. In addition, any forward-looking statements represent our views as of today, and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements in the future, we specifically disclaim any obligation to do so even if our views change. Today's event is accompanied by a slide presentation, which is available in the Events section of X4 Pharmaceuticals' Investor Relations website at x4pharma.com. A replay will be available on the website later today. [Operator Instructions] Leading our discussion today is Dr. Adam Craig, Executive Chair of X4. Previously, he was CEO of CTI BioPharma, where he oversaw the approval and launch of the company's first product and guided its $1.7 billion acquisition by Sobi. Dr. Craig is a physician specializing in pediatrics and pediatric oncology, and holds a PhD in molecular oncology. I would now like to turn the call over to Dr. Craig.

Thank you, Remy, and thank you all for joining us this morning. We have a great lineup of speakers today and appreciate the key opinion leaders joining us to share the expertise on the treatment of chronic -- primary chronic neutropenia. With me today is John Volpone, our President and Chief Operating Officer. John brings more than 2 decades of drug development leadership across oncology and rare disease. Most recently, he was the Executive Vice President and Chief of Staff at CTI BioPharma. And before that, he held business development roles at Bristol Myers Squibb and ZymoGenetics. We also have David Kirske, our Chief Financial Officer, with us today. David has 20 years of strategic financial and operational experience, most recently as CFO of Stratus Therapeutics. Prior to that, David was Executive Vice President and CFO of CTI BioPharma, where he played a central role in the Sobi acquisition. I'm pleased to introduce Michael Massello, our Senior Vice President of Market Strategy and Development. Michael has nearly 30 years of commercial medical experience in biopharma and has led more than 12 commercial launches in hematology, oncology and rare disease companies, including CTI BioPharma, Amgen, Onyx, Lilly and Seattle Genetics. Most recently, Michael was Global Head of Commercial Strategy and Vice President Markets at Autolus where he helped lead the launch of the company's first cell therapy. Also honored today to have Dr. Julia Warren, a pediatric hematologist and physician-scientist at CHOP Hospital of Philadelphia with us, and she is an Assistant Professor of Pediatrics at the Perelman School of Medicine. Dr. Warren sees patients in CHOP's Comprehensive Bone Marrow Failure Center and Cancer Predisposition Clinic programs, with a specialized interest in patients with chronic neutropenia. Finally, we welcome Dr. Shreyans Gandhi, a Consultant Hematologist at King's College London. Dr. Gandhi is focused in the field of myeloid disorders -- his practice is focused in the field of myeloid disorders with a primary interest in bone marrow failure, cytopenic disorders and PNH, including cellular therapies and stem cell transplantation. Please note, Dr. Warren and Dr. Gandhi are Consultants to X4 and the views they express today are their own. For reference, you can access speaker biographies on the right side of the screen or via the button in the top right corner. So first of all, I'll go through the agenda today. Once I finish with the opening remarks, John Volpone will present the mavorixafor clinical program to update you on the 4WARD trial and introduce to you for the first time the 4STEPS trial of dose adjustments to G-CSF in the presence of mavorixafor. We will then move on to the market opportunity in primary chronic neutropenia, presented by Michael Massello, who will present to you today our market research that has established the market opportunity for mavorixafor in chronic neutropenia. Following Michael's presentation, we'll move on to a fireside chat, which I'll host with Dr. Gandhi and Dr. Warren. And then we will move on to a Q&A session where you can ask questions. The aim of the company is to deliver on the promise of CXCR4 antagonism through mavorixafor. To do that, the company has had to go through quite substantial corporate transformation, as many of you know, in '25 and '26, 2025 and 2026, but we're now focused on -- able to focus on the completion of the pivotal Phase III 4WARD trial in primary chronic neutropenia. We aim to complete full enrollment by the end of Q4 2026 and expect top line on the primary data in Q1 2028. If successful, that could lead to a U.S. FDA approval in late '28 and '29. This year, we've also been working on the Phase II trial, the 4STEPS program that I mentioned earlier. And that's a trial to demonstrate if we can safely reduce G-CSF dose in patients with chronic neutropenia following the initiation of mavorixafor. Next slide, please. So mavorixafor is an oral agent designed to alleviate neutropenia. Its target is CXCR4, which is a -- which regulates the movement of white blood cells throughout the body. If CXCR4 is antagonized with an agent such as mavorixafor, it results in white blood cell migration from the bone marrow into the circulation. And as a result of that, the mavorixafor increases the levels of neutrophils and lymphocytes in the bloodstream. It's this effect that we believe will have an impact on infections in patients with chronic neutropenia. And it's that -- this is what we are testing in the Phase III 4WARD trial. Next slide. I'd like to introduce John Volpone, who is going to present the clinical program.

Thank you, Adam. I'll begin with an overview of our pivotal Phase III 4WARD trial in primary chronic neutropenia or PCN, and then introduce 4STEPS, our Phase II study designed to evaluate whether G-CSF dosage could be safely reduced in patients who have started treatment with mavorixafor. 4WARD is a global double-blind, placebo-controlled trial with a target enrollment of 126 patients. We designed the inclusion criteria to enroll patients in whom a potential treatment benefit can be clearly measured. Participants must have a diagnosis of congenital, autoimmune or idiopathic chronic neutropenia and an absolute neutrophil count, or ANC, below 1,000 cells per microliter. This is defined as moderate or severe disease. Participants must also have at least 2 infections requiring intervention in the previous 12 months. These are patients with serious recurrent infections who need better therapies to manage their disease. Patients are randomized 1:1 to receive mavorixafor or placebo in each case with or without G-CSF. ANC is assessed at baseline and at months 1, 2, 3, 6, 9 and 12. The trial has 2 primary endpoints: ANC response defined as an ANC above 500 cells per microliter and annualized infection rate. With 126 patients, the study is powered at 93% and 89%, respectively, for these endpoints in the intent-to-treat population. Secondary endpoints include severity of disease of infections, antibiotic use, fatigue, quality of life and safety. We expect to complete enrollment in the fourth quarter of this year with top line data expected by the end of the first quarter of 2028. Now I'd like to share the baseline patient characteristics for 4WARD based on blinded pooled data as of September 2026. Enrollment is evenly divided between moderate and severe disease with median age of participants in the trial of 36 years old and 70% of participants are female. Median baseline ANC is 483 cells per microliter, well below the trial's entry criteria of 1,000. 68% of participants have 3 or more infections at baseline. 4WARD requires at least 2 infections in the prior 12 months for entry, so this is a population with a meaningful burden of infection. 37% of participants are on concurrent G-CSF. As a reminder, we are evaluating mavorixafor as both a monotherapy and in combination with G-CSF. Importantly, we have not seen any new safety signals to date. Taken together, these baseline characteristics give us confidence that we are enrolling the right patients in 4WARD and the patients we believe scan to benefit the most from an oral treatment option. Today, I would like to introduce our planned 4STEPS clinical trial that is designed to complement 4WARD. In 4WARD patients who entered the study on G-CSF keep the same G-CSF dose for the entire study. So any clinical benefit of mavorixafor can be clearly measured. However, with real-world usage, we expect that patients and physicians will want to reduce the use of G-CSF once mavorixafor started, citing the burden of frequent injections and side effects such as bone pain and fatigue. 4STEPS is designed to evaluate whether G-CSF dosage can be safely reduced while maintaining stable neutrophil counts after mavorixafor has been started. 4STEPS is a single-arm, open-label multicenter Phase II study. We plan to enroll approximately 25 patients with acquired primary autoimmune or idiopathic chronic neutropenia. Patients must be on stable G-CSF therapy at study entry and have a baseline ANC of at least 1,000 cells per microliter, which makes this a different population from 4WARD. The study will be conducted at approximately 25 sites in the U.S. and the U.K. The primary safety endpoint is the safety and tolerability of mavorixafor. There are 3 primary efficacy endpoints, each measured at 6 months, the percentage of patients who stopped G-CSF entirely, the percent reduction in average daily G-CSF dosage and the percentage who reduced their G-CSF dosage by 75% or more. Here's how the study is designed. Patients start with a 4-week observation period on G-CSF alone. Mavorixafor is then added for an 8-week run-in, which gives it time to reach the full effect. Next comes a stepwise G-CSF reduction period of 16 to 20 weeks. Patients can step down to reductions of 25%, 50% and 75% and finally stop G-CSF altogether. At each reduction visit, the physician follows the simple ANC-based rules shown on the table at the bottom of the slide. If a participant's ANC is at least 1,000 cells per microliter, the G-CSF dose is reduced. Between 750 and 1,000, it stays the same, between 500 and 750, the physician considers an increase and below 500, the dose is increased. The primary analyses, including the percentage of patients who have stopped G-CSF takes place at approximately 6 months. A 24-week maintenance period then follows to determine the durability of response. The next 18 months are full of important milestones for X4. We expect to complete enrollment of 126 patients in 4WARD in the fourth quarter of this year. We then expect to enroll the first patients in 4STEPS in the first quarter of 2027. Top line data from both 4WARD and 4STEPS are expected in the first quarter of 2028. If positive, the 4WARD results could support a potential FDA approval of mavorixafor in primary chronic neutropenia in late 2028 or early 2029. With that, I'll turn it over to Michael Massello, our Senior Vice President of Market Strategy and Development, to discuss our work on establishing the commercial opportunity of mavorixafor. Michael?

Thank you, John, and good morning, everyone. I'm excited to talk to you today about what is happening at X4 with regards to the commercial opportunity with mavorixafor in primary chronic neutropenia. To begin, I want to address the impact of this disease on patients and physicians and the limited treatment options available in PCN. PCN is a rare chronic blood disorder defined by neutrophil counts below 1,500 cells per microliter for more than 3 months. PCN varies from patient to patient and is a heterogeneous disease that occurs in 4 forms: idiopathic, congenital, cyclic and autoimmune. PCN is a large underserved market, and this disease is often underdiagnosed and misdiagnosed. This disease affects every aspect of a patient's life. This is a deeply personal and deeply psychological disease, where patients are immunocompromised and are constantly worried about getting severe infections. Current treatment options for PCN are extremely limited with patients basically left with a mix of options that are often off-label, unproven or difficult to use. Therefore, PCN remains a very high unmet medical need. Our goal is to reshape and rethink the way PCN is treated today as it has been 30 years since a new treatment has been approved. Importantly, there is no current FDA-approved oral agent for PCN, and we're looking to change this with mavorixafor here at X4. We have conducted extensive amounts of market research for the past few months covering both the current market dynamics that exist today as well as physician and patient reaction to the clinical research on mavorixafor. I have to tell you, the more research we do, the more excited we become. To allow us to size the PCN market opportunity, we have established rigorous market research. To this end, we have undertaken a two-pronged approach, deep claims analysis and direct physician and patient research. On the claims side, we started with a Veeva claims analysis covering 2023 to 2025 to identify the symptomatic PCN population. We then confirmed that figure with a second independent source, the Komodo claims analysis over the same period. We then went a step further looking at these claims longitudinally to map the patient journey. That includes how patients are newly diagnosed and what drives diagnosis, the referral dynamics to specialists, what triggers treatment and who makes those decisions. And lastly, how G-CSF and antibiotics are used. In parallel, we went directly to our potential customers, including hosting advisory boards with both physicians and patient groups. In addition, we conducted a qualitative demand study of 100 physicians looking at unmet medical needs and sources of business. We complemented that with qualitative disease state messaging with 50 physicians and qualitative patient journey research with 30 physicians. We also heard directly from patients through the CONNECT PCN burden of illness and burden of treatment survey with 110 patients who are all treated with PCN and about 90% of whom were on G-CSF. This provided us with their perspective on how PCN affects quality of life and where their social and medical needs remain unmet. Taken together, these insights have clearly established our view of the U.S. PCN market opportunity for mavorixafor. Just as importantly, they have confirmed our belief that mavorixafor is well aligned to address the unmet medical needs for PCN patients. PCN drives substantial health care utilization and cost. Recurrent and serious infections can lead to complications such as pneumonia, bronchiectasis and sepsis. These often result in emergency room visits and hospitalizations. As you can see on the right, infections can affect nearly every part of the body from the mouth, throat, ears and sinuses to the lungs, skin, gut and bloodstream. Our recent Komodo claims analysis found that approximately 1 in 4 or 6,300 U.S. patients with PCN were hospitalized due to infections in 2025 with a mean stay of 4 days per infection. These hospitalization stays are not only expensive, they stress the health care system. This truly exemplifies the importance of treating this disease effectively and in a timely manner. The overall burden of this disease is immense. Existing therapies have real limitations, which leaves a high degree of unmet medical need and a great deal of dissatisfaction amongst both patients and physicians. In 2026, we conducted a burden of illness survey with 110 patients with PCN exploring the impact of this disease, the challenges with treating it and what they look for in a new therapy. From this, 4 themes emerged. First, PCN has a profound emotional impact. Fear of the next infection drives social withdrawal and feelings of isolation. Second, patients have a high motivation to manage their disease despite the heavy burden. Patients are determined to control their disease even with the frequent challenges of injections and antibiotics. Third, the unmet medical need. Serious infections and hospitalizations remain common despite available therapies. And fourth, a strong desire for an oral option to fit their lifestyle that is simple, safe and effective and offers sustained disease control. As I mentioned earlier, PCN affects every aspect of a patient's life. Patients living with this disease restrict everyday life just in order to cope. In our research, we found that 9 out of 10, or 88%, avoided crowded places such as restaurants and large events at least some of the time. 81% felt especially alert or on guard around others. 78% avoided public transportation, 74% avoided social gatherings and 69% avoided traveling or taking vacations. Many of these patients suffer in silence. They feel isolated and they want to give up the very activities that make up normal life that many of us probably take for granted. Adults with PCN report a significant impact on work. Among surveyed adults, 64% missed work with a mean of 9.6 days missed over the past year. 54% reduced their work hours and 20% missed a promotion or chose not to pursue a new role. This matters. Caregivers report a profound emotional toll on adolescents and children. Parents describe the tremendous burden of managing this disease in their children. The physicians who treat the young patients also tell us the psychological impact is often underappreciated. According to caregivers, 60% of adolescents missed school days, 53% reduced their participation in after-school activities and 60% avoided interacting with others. Just stop for a moment and think about the impact on children with this disease and how these numbers translate into real life for parents and their kids. And you'll hear more later from our key opinion leaders, Dr. Warren and Dr. Gandhi about the impact of this disease on adults and adolescents. Despite this burden, there has been little or no innovation in this space and no new class of therapy being approved in more than 30 years. Two main treatment options exist today. G-CSF injections, first approved in 1994, remain the only treatment that raises neutrophil counts and antibiotics are often used to treat or prevent bacterial infections, but do not address the underlying neutropenia and they're not specifically indicated for PCN. And our claims analysis shows that roughly 1/3 of symptomatic patients are treated with G-CSF and roughly 1/2 are treated with antibiotics and some patients receive both. Many other patients are managed with a watch-and-wait approach often because they are reluctant to take the burden of daily injections. Patients are actively looking for a new treatment option because of the limitations of what is available today. G-CSF comes with inherent limitations and the injections carry a significant burden. These injections are frequent, recurrent and painful and 63% of G-CSF patients in our survey told us that they have injection fatigue and adolescents are just needle phobic. There are often gaps in protection because neutrophil counts rise and fall between doses and are very inconsistent. Importantly, there are also long-term safety consequences. In congenital neutropenia, the Severe Chronic Neutropenia International Registry data, or SCNIR, shows that for patients on the long term, high-dose G-CSF have a cumulative risk of acquiring myelodysplastic syndromes or acute myeloid leukemia of approximately 21% at 10 years. And finally, there's a huge negative quality of life impact. 57% on G-CSF report bone pain and 61% report fatigue. Bone pain can manifest in as little as 1 week. Together, these side effects and long-term safety concerns may be why only 1/3 of patients are on G-CSF because it's so challenging for patients to take injections literally every day for the rest of their life. Antibiotics can treat infections, but they do not address the underlying neutropenia. They are usually prescribed based on a suspected pathogen and often rotated through to help prevent resistance, but they do nothing to raise neutrophil counts. In our research, about half of the PCN patients are prescribed antibiotics either prophylactically or chronically. Cumulative exposure brings its own side effects and drug interactions. Most importantly, long-term use can drive antibiotic resistance and gut microbiome disruption. Physicians tell us this is a key reason they are reluctant to rely on repeated or chronic antibiotic use. As you can see, there is a well-defined market today that is riddled with 2 main therapeutic options that don't offer the true protection patients need and want. In our market research, we've also mapped the patient journey, which has 3 main steps depicted on the left side of the slide. First, patients usually see a primary care physician, then the diagnosis is confirmed by a hematologist/oncologist, or hem/onc for short. Treatments are then administered with G-CSF predominantly prescribed by hem/oncs, while antibiotics are managed by both primary care physicians and hem/oncs. Here's an example. A primary care physician sees a patient and they find that they have an ANC below 1,000. The physician may monitor the patient for a month or 2 and then retest. If the counts remain low, the physician may prescribe antibiotics and refer the patient to a community or academic hematologist. The specialist then rules out other causes with bone marrow aspirate and confirms the PCN diagnosis. As the middle chart shows, about 87% of patients on G-CSF received their prescriptions from hematologists. About 80% of G-CSF is given in prefilled syringes and 20% by vial, both require injections. On the top right side of the slide, it shows only 27% of antibiotics are prescribed by hem/oncs. Strikingly 100% of patients requiring hospitalization or ER visits received antibiotics. And among these patients, about 72% required IV or injectable administration. Hematologists and patients agree on what they want from a new treatment. Hematologists told us they want fewer and less severe infections and hospitalizations, the ability to raise and stabilize neutrophil counts and a therapy that is safe and well tolerated. Patients want the same things. They want to stay injection-free and out of the hospital. They want relief from fatigue, pain and the constant vigilance, and they want a treatment that fits into their daily life over the long term. I'd like to share a few quotes with you from recent market research we conducted that paints a picture of how individuals feel about treating or living with this disease. One hematologist told us, "We are so frustrated for patients who have no other treatments than just a few modalities. We're ready to embrace anything new to treat this disease." Another simply put it, "An oral would be a game changer in PCN." We also heard this profound quote from a patient, "I'm scared to go out of my house, I'm scared to go on vacations. I won't leave the house without 3 antibiotics. I want control of my life back, and I want to focus on the moments that matter." So these quotes really speak to the frustration on the physician side and how desperate and scared patients feel when living with PCN. I've been in this industry a long time, and I can tell you this disease is ready to be disrupted. We believe mavorixafor is a highly differentiated investigational therapy and to our knowledge, is the first and only therapy in development for PCN that can potentially treat the underlying biology of the disease. It is a once-daily oral therapy. It has a novel mechanism of action as a CXCR4 antagonist that mobilizes neutrophils into the circulation. This is vastly different from how G-CSFs work. Mavorixafor is being evaluated both as monotherapy and in combination with G-CSF in our Phase III 4WARD trial and will be evaluated as a G-CSF sparing agent in our planned Phase II 4STEPS trial that you just heard from John, giving physicians the potential flexibility to use it alone or alongside existing therapy with the potential of coming off G-CSF. In our research, physicians and patients describe mavorixafor as being a highly differentiated product with quantifiable and tangible differences over what's readily available today. For hematologists, the #1 differentiator was an oral route of administration. As we heard earlier, an oral therapy would be a game changer. The #2 differentiator was the potential for greater infection control as physicians believe mavorixafor may be able to reduce both the number and severity of infections. In our quantitative survey of 100 hematologists after reviewing a target product profile that assumed FDA approval, approximately 90% said they intend to prescribe mavorixafor and 87% rated it favorably, scoring it above 5 on a 7-point scale. Now let me go deeper on prevalence. We recently confirmed our estimates with longitudinal analysis of Komodo claims data, which is widely regarded as one of the most complete sources of U.S. claims data. Komodo sources data directly from more than 500 payer organizations and covers pharmacy and medical claims, including Medicaid and Medicare. At the base of the pyramid, we identified approximately 95,000 patients aged 12 and older with confirmed primary chronic neutropenia diagnosis code who were active in 2025. This group includes both symptomatic and asymptomatic patients with ANC less than 1,500. Moving up one step, approximately 30,000 of these patients had one or more infections in 2025 that were symptomatic with ANC less than 1,000. At the top of the pyramid, approximately 15,000 patients who had 2 or more infections, including ER visits and hospitalizations. These patients were also symptomatic with ANC less than 1,000. Taking a closer look at our base case, we have high conviction in this core segment of approximately 15,000 patients who closely mirror those we are enrolling on the 4WARD trial. Specifically, we are enrolling participants 12 years and older with recurrent or serious infections. This segment has been validated by the claims data. And if mavorixafor is approved, we believe physicians will be rapid adopters of mavorixafor in this population. PCN has a significant initial market opportunity with potential for upside. If approved, our initial commercial focus for mavorixafor will be on the approximate 15,000 symptomatic patients with ANC below 1,000 and 2 or more infections in a year. We don't need to convince these patients that they have this disease. They know it and they know how it makes them feel. Beyond this initial group, our latest market research suggests the opportunity for mavorixafor is larger than previous estimates, potentially up to 30,000 patients with an ANC below 1,000 and one or more infections subject to FDA labeling. We look to potentially maximize this segment. Physicians tell us that for a PCN patient, even one infection, the next one could be life-threatening. Physicians who have lost patients to sepsis or pneumonia feel strongly about intervening earlier, and we've heard in our recent market research, and it's very saddening to hear the true consequences of what PCN can do when someone loses a loved one. In closing, our goal at X4 is to reshape and rethink how PCN is treated. We believe, if approved, mavorixafor is uniquely positioned to transform the treatment landscape for patients with PCN, those on G-CSF and those on antibiotics. We continue to learn more about this market with research to date strongly supporting the opportunity to use mavorixafor in this 15,000 to 30,000 symptomatic patient population with PCN. Thank you for your attention. And with that, I'll turn it over to Adam.

So thank you, Michael. Thank you for a great presentation. There clearly is a great opportunity for mavorixafor. So now to provide the clinicians viewpoint, we're honored to have with us today 2 leading hematologists in the area of PCN. Dr. Warren and Dr. Gandhi, if you would -- you've joined us now to make sure your audio is on. What I'd like to do is start with maybe Dr. Warren, you could describe your practice, what patients you see, how your patients are referred. And then obviously, the same question to Dr. Gandhi. Dr. Warren?

Yes, of course. Thank you for having me today. My practice here at the Children's Hospital of Philadelphia is my outpatient practice is primarily children, which we would consider anyone under the age of 21 with chronic neutropenia and other bone marrow failure disorders. And we do see a pretty good mix of germline genetic causes, meaning congenital neutropenia or cyclic neutropenia or patients with chronic idiopathic neutropenia. Patients are -- come to see me either through their entry through our hospital system as primary referrals to myself from community, pediatricians. And I will say that because I have specialized expertise in neutropenia, I do often perform second or third consultation opinions for patients with neutropenia from both the Philadelphia area, and I will say from around the country as well. And I do also see adults with chronic neutropenia as onetime consultation visits to provide additional expertise for their care and partner with their local adult hematologists.

All right. Thank you. Dr. Gandhi, same question.

Thank you, Adam, and the X4 team. Shreyans Gandhi, I'm an adult hematologist based at King's College Hospital in London. And we are a large tertiary teaching university hospital. We receive referrals. U.K. being a smaller country and this being a rare disease, we receive referrals from around the country. I see these patients also from the primary community, referred by GP, referred by primary physicians. Again, it's a mixed bag of patients with inherited bone marrow failure syndromes, congenital neutropenias, but also we have a substantial practice for patients with common variable immunodeficiency syndromes. And last but not the least, an important sector is the rheumatological causes associated with autoimmune neutropenias.

So if I could ask you, Michael was talking about the impact of the disease from our market research. What's your -- Dr. Gandhi, what's your perspective on the impact of the disease, primary chronic neutropenia in patients? What do they tell you?

Thank you, Adam. I think it strikes a chord with me because I mean all of the things that he talked about, particularly the emotional burden, the aspect about people missing out on job opportunities, people waiting, waiting, waiting, women having particular anxieties with regards to getting on with their lives. This is something that sadly we have seen for so long, and we've really never had any kind of research opportunities to kind of investigate and look beyond G-CSF, which in itself has got its own issues and problems, but it's the best we could do and it's the best we've been able to offer up until so far. So -- and sadly enough, I think one of the things John mentioned was also about the loss of patients, which is -- does not just strike -- I'm sure it strikes in a very profound way to patients, families, but it does strike us as well to lose one patient is lose too many, and it stays with you.

Yes. I looked after chronic neutropenia when I was a pediatrician, so I have some experience of that. Julia, the pediatric experience from your perspective, what are the parents and the adolescents and the children telling you?

Yes. I mean this is a very difficult disease for the entire family unit. Of course, the children are suffering. And I do really want to use that word. Our patients are truly suffering from their symptoms, and that includes painful oral ulcers, mucositis. Those ulcers can appear along the entire intestinal tract. Fear of infection is very real and actual infection can carry significant morbidity, mentioning even things like skin infections can leave long-lasting scars because our patients also have difficulty with wound healing. And so really, the symptom burden is very high. And then the emotional burden on the patients experiencing the disease themselves, knowing what it feels like when they feel at their worst or knowing what it feels like to go to the hospital can then actually propagate quite a lot of anxiety for the patient. But then as a parent, if you can even just imagine being in that position of being told every time your child has a temperature over 101, that could represent a life-threatening infection. You have to drop what you're doing and you need to be in the emergency room within 30 to 60 minutes or your child could die. And so I think for any parent to try to put yourselves into those shoes, you can then understand and we saw that in some data forms that I can say really reflects in my practice, too, that parents really diminish their social circle and the social interactions for both themselves and their children. And they miss out on birthday parties, family events, social gatherings, really a lot of fear of being out in public, a lot of fear of being around anybody who might be sick. And I do want to also just call out that I see a significant impact on educational opportunities for both young adults and also work opportunities from a pediatric perspective that impact the parents. And I do see really disproportionately impact the mothers in the family unit who may elect to leave a work setting so their child can stay home from daycare or even sometimes be home schooled or are forced to leave the work setting because they had to miss so much work to bring their children for urgent visits. So it's very impactful.

Yes, this is all we've heard. I've heard this from conversations with you and others. There is -- it's time to have something different. We'll get on to that in a second. Can I ask you generally, what's your view? Michael mentioned some patients are watch and wait, some patients have antibiotics, some patients have G-CSF. Generally, how do you treat these patients? And how do you make the decision? And obviously, Dr. Gandhi, it will be the same question for you.

Yes, I could start. So the only approved therapy right now is G-CSF. And in my own practice, that's really the only prophylactic approach that I take. I do recognize and sometimes see patients for second or third opinions who may have received other therapies, including prophylactic antibiotics, which our opinion is that any potential benefit of that has actually not been borne out in retrospective analyses of available data and additionally, as was mentioned, carries the significant side effects of long-term antibiotic use, including the potential to develop antibiotic resistance. So that is not a part of my current practice. And then I also do see some patients come to me in less -- with less typical approaches such as intravenous or subcutaneous immunoglobulin replacement therapy, even if their immunoglobulins are normal sometimes in an effort to somehow modulate the immune system or -- and I'm very displeased when I see this chronic steroid use, which has, of course, a very, very high long-term symptom burden. So really, when I see a patient who requires treatment, my practice is to reach for really the only approved medication, which is G-CSF.

And I'll ask you, how easy do you find it to administer it? Obviously, you have a large age group range from small children all the way to adolescents. Do the parents administer it? Do the adolescents self-administer? Do you have young people who go on it and then go off because they don't like the injections? What's your experience here?

The experience is wide. I could say, of course, for the little children, the parents have to administer it. For some parents, that's fine. For some parents, that actually causes significant distress. I could say, again, when we talk about family units, I have many families where one parent sort of becomes the injector and that creates a lot of tension between the parents, between one parent child, it really affects the family unit. Older -- young teens, tweens and teenagers may start self-administering. Some of them find that to be helpful to be in control of the situation. Some of them really never do kind of cross that threshold to be able to do it. And I will say I don't have lots of data on this, but in my experience, I do see a lot of young adults with chronic neutropenia in almost sort of a failure to launch state, right, where they -- maybe they go to school, but they stay nearby and they live at home and their parents are still helping with their injections well into their 20s. And so a needle phobia is definitely a very significant thing that can occur as well. And I will just say that we do struggle sometimes, too, with insurance understanding that it's not a prefilled syringe for a child. Having to sort of dispense a vial that's a single-use vial when you use maybe 1/10 of that volume can actually increase the sort of cost burden of treatment for the families.

Yes. Thank you. Thank you for that. Dr. Gandhi, your experience with the adults, do G-CSF antibiotics, watch and wait? What's your -- how do you treat these patients?

I would completely concur with what Julia has already mentioned. We do not advocate regular usage of prophylactic antibiotics. There's too much of issues with side effects, resistance, so on and so forth. We do advise some of our patients to keep a stash of rescue antibiotics as somebody has already pointed out, the door-to-needle time has to be 60 minutes, less than 60 minutes preferably. And sometimes patients struggle because you go up to ER and you could struggle convincing the ER registrar, "This is a neutropenic state. I need to have my antibiotics. You can do the triaging later on." And so many -- we have audits done that show that so many patients consistently miss that target, the 1 hour target to receive antibiotics. But the second aspect is that although these are now adults, fully speaking, adults, but there are so many behavioral issues and anxiety-related issues. We had the COVID pandemic, which did not help, but particularly patients who were neutropenic through that phase have spent 1 year, 1.5 years, 2 years in complete total and absolute isolation. And it's been very hard, as you can imagine, and people needing to go for counseling and therapies thereafter, that's a significant burden. And also having to write to employers, people missing out on opportunities or sometimes almost nearly losing a job is a big ask because you're always writing to their employers. "She was over here in ER. We had to admit her. This was the admission date. She got discharged on this day." And it's not often mentioned because there are strong employment laws these days. But in spite of all the occupational health assessment and others, I get a feeling that there's some kind of unfavorable outlook towards people who have these kind of conditions to take on as an employee. So the psychiatric element of it, the anxiety element of it, the self-rationalization, you would have patients who will have the self-rationalization because they try to balance out the 2 risks. I want the increment in my neutrophil count, but I'm feeling particularly okay, there are too many side effects that I'm getting with G-CSF. Perhaps I could go with a few more days without a G-CSF injection or a week without G-CSF injection and how far they push themselves is a risk in itself actually. So they do live with a lot of uncertainties, anxieties alongside all of the social and emotional aspects that John has already talked about.

Yes. I greatly appreciate these comments from both of you because we -- one of the things we wanted to get across today is this is a hard disease to have, both for patients, families, caregivers, everyone. And thank you for putting that very clearly. So the obvious question then, Dr. Gandhi, first is that how would an oral agent like mavorixafor fit into the treatment landscape if the 4WARD trial was positive and if the drug was approved in the U.S. and obviously for you in the U.K. How would it fit in? How would it change things?

Well, I particularly am quite hopeful that we see good responses because there is an -- I mean, I couldn't shout louder from the rooftop actually. There is an absolute desperate need to have therapies in this arena, really, really, really needed. I'm sure everybody is going to be in agreement on that one. I hope the results are positive such that we have something that develops that can be offered to our patients. I mean the fact that we can achieve neutrophil counts and our patients know that because some -- a lot of our patients are almost as well educated as we are about neutrophils, whether we need to have neutrophil counts above 500, greater than 1,000, they understand those risks and they titrate those G-CSF doses accordingly. Having an oral agent definitely helps. And the long-term anxiety that they have with regards to evolution to MDS, as you rightly pointed out, the median age in our cohort has always been about 33, 34 years with all sorts of things. So they practically have their whole social professional academic lives in front of them. So to the point where some -- up until so far before we've had these kind of studies, some patients have contemplated considering a stem cell transplantation for people who've had such profound infections and cytopenia. So I'm particularly very, very keen to see evolution of newer therapies in this area.

Yes. I think in our Phase II, the median age was about 30 as well, just illustrates how long these patients potentially have treatment. Dr. Warren, same question to you. How do you think an agent, an oral agent like mavorixafor would fit into the landscape in your pediatric and young adult practice?

Yes. If I can answer this kind of with respect to 2 buckets of populations of patients. First would be the patients who currently are not on treatment. And I would put a prophylactic antibiotic receiving patients in that category as well. So really patients who are not on a therapy aimed at raising the neutrophil count. So for those patients, I would absolutely offer them mavorixafor as the starting intervention for them because I think that they would benefit from having the opportunity to use an oral agent and benefit from the mechanism of action of having something that helps to release the neutrophils that are present in the marrow, potentially could support the formation of neutrophils. I think we need to learn more about that. And then something that they could take by mouth would be easier for them to fit into their daily life, et cetera. So I think for patients who have never been treated or who are no longer treated with G-CSF due to kind of intolerability. So those are the patients I would absolutely offer mavorixafor to as monotherapy and see how they do. And then for patients who are currently on G-CSF, I do -- I can say I would have a conversation with every single one of them about what are their goals related to their therapy and how could mavorixafor sort of fit into those goals. And so if they would have a goal to say, I'd like to try to be off of G-CSF, then we can trial sort of addition of mavorixafor and titration down of G-CSF. If I have somebody who has a goal to say, maybe they have an inherited form of neutropenia where there's a long-term increased lifetime risk for the development of malignancy, and we know there's an association between longer-term use of G-CSF or dosage of G-CSF, they may have as a goal to be on a lower dose of G-CSF or space out the frequency of G-CSF dosing. And we would discuss can we add mavorixafor on and see what we can achieve as far as being able to lower the G-CSF dose. I'm really excited to see the results of both the 4WARD study and then 4STEPS to help us as prescribers better understand what that journey could look like when somebody is already on G-CSF. But I really cannot think of a single situation even for somebody who is already on G-CSF therapy where I wouldn't offer them mavorixafor addition. And then we would work together with goals of is your goal to try to come off or is your goal to try to dose reduce and we can kind of have a partnership in achieving those goals.

That's great. I'm glad you see -- you acknowledge the importance of the 4STEPS trial. We really do need to generate data to guide physicians on how to reduce the G-CSF dose whilst maintaining mavorixafor that as its primary aim. One of the -- Dr. Warren, one of the questions we get asked quite often is about the toxicity of the drug in the product label. There is some GI toxicity mentioned. What's your experience of toxicity? And how do you handle it when you've given patients the drug on clinical trials?

Yes. We did observe that in some of the patients that we treated on the Phase II, and what I could say is that the #1 thing that helped with that was informing patients that, that was a possibility ahead of time. That was sort of the experience that we gained and that patients who did experience that side -- so the majority of patients did not experience GI toxicity. The patients who did, as long as we have provided that education upfront to say, hey, this is a possibility, this is the pattern of the GI side effects we've seen and these are the interventions that we know can help with those side effects, those side effects were very manageable. I could say as well that our experience was that after somewhere between 1 to 2 months of mavorixafor therapy, those side effects actually waned. And for the very small number of participants who did require something like an over-the-counter medication to help with the GI side effect. And I do just want to add, I never -- I don't believe I did personally ever have to prescribe any medications to help with GI side effects. It was all sort of treatable with anything over-the-counter or required no intervention. Eventually, those participants were able to stop whatever over-the-counter medication they had because those symptoms had improved. So overall, I do believe that was a very tolerable side effect for subjects who did not know about that, and we had sort of one experience with that, that we then educated ourselves about just that very brief, hey, you might experience this, here's how we'll deal with it, led to a sort of much better experience with the medication. And again, those side effects resolved.

Yes. Thank you. I've experienced this with drug development of other drugs, some early GI toxicity that resolved. And I completely agree with you, informing the patient, informing the families is really important, so it's expected. Dr. Gandhi, your view, your experience of the drug from a toxicity point of view, from a safety point of view?

No, I think it's much the same actually. So I wouldn't know the randomization per se, but speaking to patients, some patients in the first month would come and ask us, "I feel a little bit of nausea," and they're actually happy about it because they see this perhaps as a sign that they are on the active compound. And there's no way of telling that actually. But we've not had -- we've recruited, I think, a good number of patients actually, amongst the largest, I would think. And we've not had any patients who discontinued. We've not had any patients who've complained beyond the first month. But having said that, I wouldn't know whether they are on a placebo or a compound, but some symptom treatments initially in the first few days, first few weeks with some anti-sickness. And since then, I think we've not had any issues.

Yes. Thank you. And I think we should say that Dr. Warren has treated patients on the Phase II and the Phase III, so you have some unblinded open-label experience. And so a common question I've discussed with you both before is what is a meaningful benefit with respect to a reduction in infection rate. The study is powered, the 4WARD, for about a 1/3 reduction in the annual infection rate. What do you think is meaningful? Dr. Gandhi, what do you think is a meaningful outcome for the trial?

Number of infections, important, but reduction in the severity of infections equally important. So I would think that patients generally, when they cross the threshold of 500, you're getting into the somewhat -- not somewhat actually, quite a safe territory. You're less likely -- you may still get infections, but you're less likely to get really serious infections that would warrant hospitalization or ITU admissions. So the severity of infections perhaps would be as important as the reduction in the number of infections. Just speaking to the cohort of patients that we have seen, we don't know. Again, this is blinded to us. But when people come and tell us that, "My median of infection was needing 10 courses of antibiotics a year has come down to 2 a year. Does that mean I've been on the compound?" And I say, look, I don't know. I'm glad that you've had just the 2 infections this year compared to the 10 infections that you had last year, but I really don't know. We'll have to wait for the trial data to come through. So 1/3 would be very good, but I would perhaps be more optimistic, and I hope to see results that are better than that, and we probably will, and also the severity of infections.

Yes, of course. Dr. Warren, the same question.

Yes. I want to answer in 2 ways, if I could. Dr. Gandhi, you really said something that really resonated with me earlier, which was that, that next one infection can be the infection that kills your patient. So -- I'm paraphrasing, but to me, one fewer infection is meaningful. In all honesty, I'm speaking as myself and not as, of course, the Food and Drug Administration or whoever else might not be treating these patients personally because that one next infection could be the infection that really either has significant morbidity, or unfortunately, mortality for our patients. I think as far as what would be meaningful to our patients would also include something that I wouldn't necessarily categorize as an infection, but the ability to go home from the emergency room because a lot of our patients are admitted for febrile neutropenia. And although we may not consider that to be a documented, confirmed infection, a patient might have fever that could be even just related to the neutropenia itself, they get all these evaluations to search for any potential causes of infection when their ANC or neutrophil count is under 500, then they get -- very often get admitted to the hospital, get placed on very strong antibiotics, which themselves have side effects in an effort to make sure that the patient is safe. And so even if we raise the ANC to above 500 and for presentation of fever, that means a patient could avoid hospitalization and avoid long durations of antibiotics. Even in the absence of what might not have been a documented infection, I think that will be highly meaningful. I suspect that beyond even being able to see a reduction in admissions for febrile neutropenia, I just suspect that fewer patients will even be presenting to the emergency room with fever because we do think that fever -- we don't understand this well, but that fever by itself without a concurrent infection can occur when the ANC is under 500, especially when it's under 200. And so I think though that might not technically or officially be one fewer infection, I think it -- we would be very meaningful to also see if patients either go to the hospital, but don't have to be admitted or may even have fewer hospital presentations.

Yes. No, thank you. I appreciate that. We are, of course, collecting a lot of data, not just annualized infection rate, we'll collect other data on severity and other things. And for the people who've joined us today, the infection rate on the trial is adjudicated by a blinded committee. It's not adjudicated by the company. So I'm hoping for a very robust data set. Julia, there is one question I've discussed with you before, which was following our change to the sample size and the 1-quarter delay in completing enrollment, some of our investors felt that this was a reflection of the pole market opportunity. It was because there weren't enough patients around. I wondered what your thoughts on that are.

Yes. So our experience is that patients were sort of clamoring to participate in this trial, really excited when we opened the study. Some participants who, for whatever reason, were unable to participate in the Phase II, we had a lot of referrals. And I think our experience was not a lack of patients to treat or patient willingness or availability, it was really more that at least here in the United States, our prescribing patterns are -- and I could say maybe at least especially in our region, our prescribing patterns are really to favor use and early use of G-CSF. And so it's really a very rigorous requirement to have ANCs under 1,000 and to have at least 2 significant infections every year when the prescribing patterns, especially in our region are to reach for G-CSF early and to try to target higher ANCs. And so in the Phase II, of course, participants could -- really did not have that infection requirement for entry on to study. And so I think -- I would disagree with that sentiment that was about either patient -- I understand it, but I can see where it could come from, but I would not say that would reflect our experience. Patients were very -- they're around, and they were very interested in participating. And I think really, it's kind of the stringency of eligibility to me that for us -- well, go ahead.

Yes. The protocol -- I think so people who have joined us today, the -- we should say the protocol is designed for an FDA approval, and it's designed as a confirmatory study for the WHIM approval, has some complexities in it that make it harder. And I personally, and I think you've said this saying, it doesn't quite represent the real world, but it's a regulatory requirement. Dr. Gandhi, have you found slightly different health care system, obviously, but have you found enrolling patients in the 4WARD trial?

Extremely, extremely easy. I think it's been a privilege actually to speak to people directly, sometimes the medical monitors and other people to kind of look at certain aspects of eligibility and all. It's just a phone call away. You speak to them. And it's been very, very, very busy. We've screened so many patients. Some did not meet the screening criteria, but they -- it's just a testament to how many people want to come forward once they've heard about the trial, once they know that there's something else that's happening in this field. Some have had self-referrals, some have come through their hematologists from different parts of the country. U.K. being a smaller country, but even so people traveling 300, 400 kilometers to come to your place. We've had a massive amount of interest. Adam, we've shared thoughts on this on many occasions. And just to kind of carry on with what Julia has just mentioned, in terms of the reduction in numbers, the way I look at it is that I cannot wait for the results to come out. It's not substantially changed the goalpost. But if it makes that slight difference where we get the results out earlier, we have the data out earlier, completing the trial earlier. And once it's out, we have -- we could have a compound that's available for us for our patients, not just patients who met the trial eligibility criteria. So to me, I think I couldn't wait for the results to come out earlier, and that just suits me actually.

Thank you. Well, you've both been great. And always end sessions like this to see if you've got any closing remarks, anything else I haven't asked you, you want to say before we move to Q&A. Julia?

Yes. I just do want to say that the patients have not had access to trials, access to opportunities for new medications in this space for over 30 years. And the enthusiasm from the community has been very high. People in my practice who heard about this through various -- either marketing opportunities, Facebook groups, word of mouth, were really very disappointed if they did not meet the criteria to be able to participate and are continuing to ask me about this medication when we have routine clinical follow-up. So I do think the community, which is very connected online, especially here in the United States, the community is very, very interested. And so I do think were the results to be positive and were there to be FDA approval that the neutropenia -- chronic neutropenia community, at least here in the United States, has an awareness of this medication, certainly, and there would be sort of high enthusiasm to at least discuss it with their provider.

Great. Thank you for that. Dr. Gandhi, closing remarks from you.

I put the same things what Julia has said. I think the enthusiasm is really high. We are very keen ourselves. We couldn't wait for the results to come out. And we see a huge, huge potential, a huge market, but also lots and lots of patients who could benefit from this therapy if it shows the benefit that we hope it shows.

Excellent. Well, thank you, both. It's been an absolute pleasure interacting with you over the last year and meeting you in your -- in various parts of the world. I also thank you for everything you've said today. I think we've had some very unique insights for our investors and analysts to hear. I really appreciate it. So now Remy, I'd like to go to Q&A, and I'll turn it back to you.

Yes. So that would be great, Adam. Thank you. We're going to transition to Q&A. Dr. Warren and Dr. Gandhi are going to stay with us. David, John and Michael are also going to join us for the Q&A portion, and I see their cameras are all on. So Adam, I'll turn it back to you to moderate the discussion.

Yes. So we've had a number of questions. I'll try and sort of group them into the right categories. The first question is going to go to you, Michael. It's from Derek Archila of Wells Fargo. And Derek has asked, how has the new market research informed your view of the estimated 15,000-patient U.S. target market?

Well, thanks so much, Adam, and thanks, Derek, for the question. So initially, we worked with the Veeva claims in 2023 to '25 to validate the work that was done. And we validated this again with Komodo claims in 2023 to '25. And they have more precise algorithms that really allow us to accurately capture the PCN patients. So we're confident with the data regarding the patient numbers for PCN. We're going to use those for commercial purposes. And I can tell you that having led blockbuster hematology brands, we view this as an underserved market. You think of PNH, you think of some of these other areas. So we know that physicians once they get experience will use mavorixafor more frequently and in additional areas. So we're confident with that base case based on what we're seeing in our market research.

So the second question -- thank you, Michael. The second question again is from Derek, and it says, could you share more color on the mavorixafor product profile used in the survey that showed 90% of physicians' intent to prescribe?