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

Greetings, and welcome to the X4 Pharmaceuticals Conference Call and Webcast. [Operator Instructions] As a reminder, this webinar call is being recorded. It is now my pleasure to introduce Dr. Paula Ragan, Chief Executive Officer of X4. You may begin.

Thank you, operator, and thank you, everyone, for joining us for our investor event today. Next slide, please. Before we begin, I'd like to remind everyone that on today's call, we'll 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. Next slide, please. Here, we provide a brief snapshot of our therapeutic focus here at X4, where we aim to deliver targeted treatments for rare diseases of the immune system, including primary immunodeficiencies and certain lymphomas. The common thread you'll see throughout today's presentation is how we believe CXCR4 antagonism creates significant opportunities to meet the unmet needs of patients in these 2 broad disease categories. Next slide. So today, we'll be focusing on primary immune deficiencies, we will be sharing some of our recent ASH data, our investment over the last year have resulted in our largest presence ever at a medical science conference. We are very pleased to be able to put all our promising data into context on this call today by sharing views from several experts and our team at X4 to help everyone truly appreciate, not only the unmet need in primary immunodeficiencies, given that the current standard of care are limited to injectable and infusion treatment options that address only some of the needs, but also the potential that we believe mavorixafor have to change the landscape of treatment for many of these patients. Next slide. On today's call, we have representatives from X4, including myself, our Chief Medical Officer, Dr. Diego Cadavid; our Chief Scientific Officer, Dr. Art Taveras; and our Chief Financial Officer; Adam Mostafa. We are also very fortunate to have 2 outside experts to support and help educate on this important topic, Dr. Teresa Tarrant from the Duke University; and Dr. Neal Sondheimer from the University of Toronto. Next slide, please. As many of you know, we are an established global R&D center of excellence, focused on modulating the CXCR4 receptor, which is known to be a master regulator of immune cell maturation and trafficking. Our lead candidate, mavorixafor, is an investigational CXCR4 antagonist that has been shown to safely and effectively modulate the CXCR4 receptor across a number of clinical studies to date. As you can see here, we're advancing our broad pipeline of oral CXCR4 targeted candidates that aim to benefit rare disease patients. Today, you'll hear about our WHIM syndrome Phase II and Phase III program, as well as the first data from our ongoing Phase Ib clinical trial in chronic neutropenia. On Saturday, we presented additional positive data from our ongoing Phase Ib trial in patients with double mutation Waldenstrom's macroglobulinemia, a rare B-cell lymphoma. We believe these are strong proof-of-concept data, and we'll be happy to take questions on those data at the end. Next slide. Today, we're looking forward to discussing on the unmet needs and the breadth and opportunity of mavorixafor and primary immunodeficiencies. We'll be opening up the meeting with our guest speaker, Dr. Teresa Tarrant, who will provide an overview on primary immunodeficiencies, a complex landscape for patients and physicians. There has really been little focus in this area, both from industry and academia despite the continuing unmet need. We will then flow through the remainder of the agenda with Art, Diego and myself talking about mavorixafor, the new data supporting a broadening target patient population, specifics on addressing WHIM syndrome, including some of the progress we've made on patient diagnosis and disease definition and prevalence, as well as our first clinical data set in chronic neutropenia patients. Dr. Neal Sondheimer will participate in that segment as well, providing some insight into our exciting research around newly identified CXCR4 mutation of variants and what that could mean for patient prevalence. Diego will then host a fireside chat with Dr. Tarrant, who will give us some greater color on the physician perspective and patient journey as they confront immunodeficiency diagnoses. And then we'll wrap up and open up the call to questions. Next slide, please. It's now my honor to introduce our first guest speaker today, Dr. Teresa Tarrant, is an Associate Professor of Medicine, Rheumatology and Immunology at the Duke University School of Medicine, where she focuses on understanding why and how autoimmunity and immune deficiency disorders developed, a practicing clinician for research investigates immune targets that may either impact the development of immune disease or help identify new therapies for patients. Importantly, Dr. Tarrant is also a key author on our ASH abstract, highlighting a case study of a WHIM patient with a novel [indiscernible]. As you can see, she is a great fit for our discussion today as we seek to help our audiences understand the presentation and diagnosis of patients with immunodeficiencies, the mechanisms underlying some of those immunodeficiencies and how our advancement of CXCR4 antagonist could potentially benefit this broad patient population. Terri?

Thanks, Paula, for the kind introduction, and thanks to everyone for joining us on the call today. It's really my pleasure to be here to provide a brief overview of primary immunodeficiencies, which I'm going to refer to moving forward as PIDs, a field that's often poorly understood due to its complexities and variabilities, characteristics that create challenges, both for physicians and for patients. As you can see here, PIDs are a large group of rare chronic conditions. They are most often caused by a hereditary genetic mutation, that results in a dysfunctional immune system. They can affect anyone regardless of age, gender or ethnicity. The hallmark symptom of PIDs is infections, but the types of infections are variable and dependent on the phenotype of the specific condition. Patients with PIDs can be susceptible to specific bacteria, viral, fungal or mycobacterial infections, and the pattern of those infections is different, depending on what genes or immune cell is affected at the age of onset. Infections can cause morbidity and mortality, either through severity or recurrence. These patients may also carry an increased risk of cancer and can often have inflammatory disease, blood disorders, including anemia, neutropenia, lymphopenia and antibody deficiency. And depending on when the PID is diagnosed, they can experience delayed growth in development. It's estimated that there are approximately 250,000 people in the United States diagnosed with PIDs. But due to their variable presentation is also understood that there are likely many more patients that go undiagnosed or under-recognized. Next slide, please. Although infancy is when most genetic PIDs are recognized and diagnosed, many patients can have a delayed onset or a delayed diagnosis into adolescents or adulthood. Many of these PIDs are adult and onset, particularly those that are idiopathic, such as common variable immunodeficiency or chronic idiopathic neutropenia. And many other chronic immunodeficiencies can be secondary, such as due to bone marrow disease like myelodysplastic syndrome or autoimmune conditions. The reason for the often delayed diagnosis are several, including lack of recognition and understanding of rare diseases by treating physicians and due to the fact that the same genetic defect can present differently in different patients. For example, some patients are severely affected, while others have a more mild presentation. Another confounding factor in rare disease diagnosis is that, most physicians are taught when you hear hoof beats, think horses, not zebras. But in fact, patients with primary immunodeficiency diseases can be the zebras of the medical world, which is why this is the mascot for the Immune Deficiency Foundation. Early diagnosis is critical. The Immune Deficiency Foundation, or IDF, reports that the average time from symptom onset to diagnosis is usually between 9 and 15 years of age. During this gap, more than 1/3 of patients end up with permanent impairments, including lung disease. With earlier diagnosis, we believed that the patients with the diseases listed here, chronic neutropenia, particularly the congenital types, common variable Immunodeficiency, or CVID; and WHIM syndrome, which I know many of you are familiar with [ through your interest ] in X4, have a clear unmet and could -- need and could be much better served. Next slide, please. This slide presents a little more granular detail on diagnosis. Well, about 1/4 of patients are diagnosed between the ages of 1 and 5 years, 60% aren't diagnosed until after the age of 18. And as I just mentioned, this can cause morbidity and even permanent disability in these patients, while also increasing their risk of cancer and sometimes death. Next slide, please. Here, we provide a little more color on the most common conditions experienced prior to diagnosis. As you can see, upper respiratory and ear infections are the most common, symptoms like sinusitis, bronchitis, pneumonia and otitis topping the list. But we also see GI effects inflammatory effects and most serious disease, including meningitis, hepatitis and as I've been discussing previously, cancer. As noted, it's been reported that significant increases in lymphoma have been seen with men and women both experiencing 8 to tenfold increases when the PIDs were diagnosed and observed. Next slide, please. So how is this broad range of disease treated? As shown here, the treatments are broad because the conditions are and typically include replacement therapies such as intravenous immunoglobulin, or IVIG. This can also be administered subcutaneously now for these patients, and granulocyte-colony stimulating factor, or G-CSF, as it's commonly called. This is being used most commonly. While generally well tolerated, these treatments are infusions and injections. And in my experience, patients do experience challenges in trying to use these therapies chronically. Immune modulation is the second mode of treatment for those PIDs with an inflammatory or autoimmune component, high-dose IVIG can be used in this indication as well, as well as a range of immunosuppression or anti-inflammatory medication. Broad immunosuppression is considered for some PID patients, although this may seem ironic. These therapies include corticosteroids, which have long-term side effect sequela and newer treatments, including steroid-sparing agents. Many of these are off-label. And again, are not standard of care and based on the individual patients. Lastly, hematopoietic stem cell therapy or as many people in the lay public would call a bone marrow transplant, is being studied in some of these patients, as well as emerging gene therapy, which some of you may be familiar with for certain patients with specific PIDs. But there is very limited experience with this technology and it's only been explored in a few diseases. It has been shown that being gene therapy to be helpful to replace the protein is absent due to a genetic defect, but it has not been tested in PIDs where the protein is hyperfunctioning like in WHIM and needs to be turned off or turned down. This brings us to our next slide, where I'll briefly talk about WHIM syndrome and the potential for intervention to treat the root cause of the disease through CXCR4 antagonism. Next slide, please. As most of you know, WHIM stands for warts, hypogammaglobulinemia or low antibody levels, infection and myelokathexis, which is a hypercellular bone marrow. It's a rare immunodeficiency caused in most known cases by what are called a gain of function mutation in the CXCR4 receptor. These mutations cause the receptor to remain in an on-state when it binds to its ligand. This leads to retention of the white blood immune cells inside the bone marrow. They're effectively trapped. Visits referred to as the m of myelokathexis because the patient's bone marrow filled up with immune cells, in particular, neutrophils, as well as lymphocytes. As you can imagine, being trapped means they're not in the blood and reducing the body's ability to mount a healthy immune response to infection. Because of this, patients develop multiple chronic recurrence infections that can lead to devastating an irreversible morbidities, including, but not limited to, hearing loss, repeated pneumonia, chronic obstructive pulmonary disease and fibrosis, bronchiectasis, which is a thickening of the walls resulting from recurrent infections and inflammation. In addition, many WHIM patients suffer from low levels of B-cells and hypogammaglobulinemia, again, that being low antibodies. A condition that's marked by these low antibodies and having reduced antibody production, which further prevents patients from mounting a proper defense against pathogens, and it limits the response to vaccination. And lastly, the most visible manifestation of WHIM is the presence of severe recurring warts. These are primarily driven by infection called HPV or Human Papilloma Virus, and it significantly impacts the patient's quality of life. Worst if left untreated, these HPV infections can increase the patient's risk of developing anogenital cancer, as well as head and next cancer. The majority of WHIM patients have one abnormal copy of CXCR4, while the other is typically normal. CXCR4 is a g protein-coupled chemokine receptor, that's on the outside of immune cells, and it is critical for the differentiation of early hematopoietic cells that become white blood cells and also in the egress of those mature white blood cells once they're made in the bone marrow to leave the bone marrow and get into the blood. We're going to explore this in more depth on our next slide. Next slide, please. When normal CXCR4 binds to its ligand, as I had discussed earlier, the CXCL12 protein, the cell can undergo many different functions. This includes proliferation, normal development into different types of immune cells and then its retention in the bone marrow as it matures. Internalization of the receptor from the cell membrane, allows those white blood cells to migrate out of the bone marrow, meaning that you have to turn off that signaling in order for them to get out. Once they get out, they're circulating normally in the blood between the other lymphoid organs that being the lymph node and the spleen and also being able to migrate into infected tissues when needed. All of this is through CXCR4 signaling that should be normal in people that is not in WHIM. Abnormal CXCR4 affects all white blood cells. This includes neutrophils. These are the immune cells that are most important in initially fighting off bacterial infection. This includes B-cells. These are the immune cells that fight off infections and can mature into antibody-making cells and that's the hypogammaglobulinemia of WHIM. It also can affect how T-cells and NK T-cells work. These cells are critical in fighting off viral infections and in cancer immune surveillance. So the consequence of having an overactive CXCR4 is that, first, immune cells do not develop in the bone marrow normally. And second, immune cells do not migrate out of the bone marrow. And then finally, immune cells may have dysregulated differentiation migration, which could ultimately lead to immune surveillance for cancer and increasing your risk for cancer, as well as infection. In WHIM, for example, the abnormal CXCR4 gene leads to a receptor that's overactive. Therefore, it doesn't desensitize or turn off and internalize normally. As a result of this, the turnoff mechanism being abnormal, the white blood cells are retained in the bone marrow. One potential approach to treating WHIM is through antagonizing this hyperfunctioning receptor, thus antagonizing CXCR4. These will bind to the protein on the cell surface and inhibit the binding of the naturally producing CXCL12 ligand. Therefore, it can turn it off and allow that receptor to internalize and turn down those signaling interactions that are hyper functioning. As a result of therapeutic dampening of CXCR4 function in WHIM, the immune system is able to function more normally. Thought that the severe cytopenias that characterize WHIM syndrome, as well as myelokathexis, could be reduced or eliminated via the thick CXCR4 antagonism as it would be able to treat the root cause of this disorder. It's also important that because CXCR4 antagonism may work to increase both the maturation and the mobilization or the [ exodus ] of white blood cells from the bone marrow in people with wild-type CXCR4, it might have the potential then to be useful across a broad range of immunodeficiencies and conditions. X4 actually presented some early promising data on this, supporting the hypothesis at this ASH meeting in adult patients with chronic idiopathic neutropenia, which you're going to hear about shortly. Next slide, please. So in summary, I hope this overview has been helpful in better understanding PID. And just to kind of wrap up on this message, there are many patients diagnosed with PIDs and likely many more that go undiagnosed. PIDs are unfortunately poorly understood in the general physician community. Early diagnosis is key to preventing long-term serious complications. While there are advances being made in the treatment of these patients, they remain -- there remains a significantly unmet need for many of them with chronic immunodeficiency. I do believe that there's hope, though, new innovations in [ stem cell ] therapies and gene therapy is being advanced. And as you're going to hear about today, the X4 pathway creates an opportunity to potentially target many of these neutropenic subsets of patients with an oral CXCR4 antagonist. With that, I'll pass it back to X4 to discuss their late-stage clinical CXCR4 antagonist, mavorixafor. Thank you.

Thank you so much, Terri, for all of your insights. This is Diego Cadavid, Chief Medical Officer of X4. Now that Terri has provided some background on primary immunodeficiencies and touched on the potential of CXCR4 antagonism as a mechanism to improve the lives of people with PIDs. Let's turn to our lead candidate, mavorixafor. Next slide. As most of you know, we are developing mavorixafor across a number of therapeutic indications. Mavorixafor is a novel oral, small molecule antagonist of the CXCR4 receptor, and it has a durable half-life that supports once-daily dosing. Mavorixafor safety profile to date supports long-term chronic administration with more than 200 patients and subjects dosed, with some patients in our trials treated for as long as 4 years. Next slide, please. We are excited to share with you today some of the first data that show the effect of mavorixafor across multiple disease states, multiple white blood cell types [ on over ] chronic dosing. One of our posters just presented at ASH shows for the first time that mavorixafor is able to raise total counts of all the key white blood cells necessary to mount an appropriate immune response across a wide spectrum of diseases over both short- and long-term treatment periods. Data were presented from ongoing clinical trials in clear cell renal cell carcinoma, Waldenstrom's macroglobulinemia, WHIM syndrome and for the first time, early data from our ongoing Phase Ib trial in patients with chronic neutropenia. Here, we highlight some of the data presented in the poster, combined with some published data from a previous study in healthy individuals. As you can see, white blood cells, including neutrophil counts increase anywhere from 2 to sixfold across all indications and in healthy subjects, and the lower the baseline counts, the higher the elevation. Early data from our chronic neutropenia trial mirrored these results. We'll be focusing on those data later in our presentation today. It's a compelling set of consistent responses irrespective of the [ C state ] and mutation status. In aggregate, this data encourage us to think much more broadly about how mavorixafor could impact larger numbers of primary immunodeficiencies, whether caused by CXCR4 mutations, as in the case of WHIM syndrome, or the antagonism of the wild-type CXCR4 signaling pathway in many other primary immunodeficiencies. Next slide, please. And here, we show some impressive long-term data, very unusual for a drug at this stage of development. But having data in patients that have been treated with mavorixafor for up to 4 years and looking at how neutrophil and lymphocyte counts track over those years of usage, we believe is a meaningful data set to appreciate. It speaks to the durability of effect. You can see here how over time patients' neutrophil counts almost double. And these are patients with normal white blood cell counts to begin despite having cancer. So again, it gives us a view of the capabilities of mavorixafor to potentially address patients with chronic cytopenias. Next slide, please. And it's certainly important to, not only look at cell counts but also the resulting impact on and correlation of cell counts with the incidence of infections. For this, we have data from our WHIM Phase II clinical trial. I just highlighted neutrophil counts on the prior slide. And here, we see that as neutrophil counts increase, there is a corresponding decrease in the annualized infection rate in the Phase II study. This correlation data were just presented at ASH. So again, it continues to build mounting evidence both from our studies, as well as others that mavorixafor rapidly and durably mobilizes white blood cells, including neutrophils and can greatly reduce the risk of recurring infections, the hallmark of people affected by primary immunodeficiency disorders. Next slide, please. In summary, with the totality of this data, we are excited and feel confident that mavorixafor has the potential to become standard of care across, not only in WHIM syndrome, but also potentially many other immunodeficiencies. As I just highlighted, mavorixafor has been shown to increase all major types of white blood cells. Regardless of the patient's mutation status and whether or not it's in combination with other treatments in multiple disease settings for long periods of time. In aggregate, this data continue to give us confidence that reduction in cytopenias can translate in to reduce infection burden and may ultimately reduce cancer risk in some of these patient populations, ultimately improving overall long-term patient health and quality of life. Now that we've talked more broadly about mavorixafor, let's drill down into our lead clinical indication, WHIM syndrome. Next slide. As you heard from Dr. Tarrant earlier, WHIM syndrome is a disease that ties very nicely to the mechanism of action of mavorixafor. In most patients, CXCR4 gain-of-function mutations cause white blood cells to become stuck in the bone marrow, causing combined immunodeficiency and a spectrum of clinical manifestations and susceptibility to recurring infections and cancer. Interestingly, and as you'll hear more about shortly, physicians are increasingly recognizing WHIM to really be a spectrum of clinical and genetic presentations and are diagnosing patients, both clinically and genetically and identifying either new CXCL mutations or other genes entirely. Next slide. So with that, let's review the updated data from our ongoing open-label, long-term extension of our Phase II clinical trial in WHIM. This data were presented last weekend at the ASH meeting as well. As you can see, mavorixafor continues to show durable increases in neutrophils, lymphocytes and monocytes with a mean duration of treatment of nearly 150 weeks and has been well tolerated by all patients. As we showed earlier, sustained improvements in infections correlates well with the time above threshold for absolute neutrophil count or TAT ANC. Importantly, TAT ANC is the primary endpoint in our ongoing and now fully enrolled global Phase III registrational trial in WHIM syndrome. We are very pleased that this data continues to support the potential success of this trial and the clinical relevance of this biomarker endpoint as well. With top line results from the Phase III trial expected in the fourth quarter of next year, we are in an excellent position to start looking forward to what we believe is a clear and favorable regulatory path and hopefully to launch mavorixafor in WHIM syndrome. Next slide, please. I'd like to quickly review our status in terms of regulatory designations. With being granted in the U.S. breakthrough therapy, fast track, rare pediatric disease and orphan drug designations for mavorixafor for the treatment of WHIM, we also have orphan drug designation in the EU. And just to highlight, we are eligible for priority review voucher. This is something that we expect could translate into around $100 million should we choose to monetize this meaningful voucher if mavorixafor is approved for WHIM. As I mentioned, the Phase III WHIM trial is now fully enrolled. We actually exceeded our target enrollment, and we'd like to briefly highlight the efforts and thank the patients, physicians, our partner, CRO and other vendors, along with our team here at X4, who all surpassed our expectations despite a very challenging global pandemic environment. As reported in an abstract published at ASH, the enrolled patients in the Phase III trial are about 50:50 children aged 12 to 17 versus adults, supporting that rare pediatric disease designation. As I mentioned, we are very much looking forward to top line data late next year. Importantly, we've begun to focus on our potential label for mavorixafor and have had early discussions with the FDA. Based on these discussions, we expect the drug to be indicated for the treatment of WHIM syndrome in patients 12 years of age and above. We also expect not to be required to have a companion diagnostic or genetic test included in our label. As we begin to increasingly focus on this broad potential label for WHIM, we thought it would be particularly helpful here to provide greater detail about the evolving understanding of the definition and diagnosis of WHIM syndrome and how that is guiding our pre-commercial efforts, both now and in the near future. Next slide. Let me remind you here that if approved, mavorixafor will be the first disease-modifying therapy for the treatment of WHIM syndrome. There is no definite definition of disease, and there are no formal treatment guidelines for WHIM. As you can appreciate, we are very engaged with the medical and patient communities and involved with regulatory agencies and payers, as they discuss the disease definition and ICD-10 code for WHIM syndrome. We are also working hard to support education and awareness across both the physician and patient communities. What's becoming clear is that, the diagnosis of WHIM syndrome includes at its core, a clinical phenotype of combining immunodeficiency with presentation of 1 or more of a variety of clinical symptoms. Combining immunodeficiency in WHIM syndrome refers to having one or more of abnormal neutrophils, lymphocytes, monocytes and/or hypogammaglobulinemia. Once physician say it is general patient clinical and laboratory profile, patients are then further started to find out whether they do have a CXCR4 mutation that causes gain-of-function as we've been discussing, and/or they look at the bone marrow to see whether they have evidence of myelokathexis. Many, but not all patients are found to have 1 or more of CXCR4 mutations and myelokathexis. And finally, an interesting and evolving piece of this puzzle is that, when patients are diagnosed with neither of the above 2, there's emerging information around additional genes that may be presenting as a WHIM phenotype and impacting the CXCR4 [ multi-gene ] such as GCPR kinases. This may explain the finding of WHIM patients who fit the clinical and laboratory profile, but who do not have CXCR4 mutations. As we talked about last year, this phase of WHIM is like a [indiscernible], but with our ongoing research and that of the physician, scientists and patient communities, that is increasing clarity as the understanding of the disease continues to evolve as is often the case with many rare diseases. With a better understanding of the diagnosis of WHIM syndrome, we can now focus on education and awareness with physicians and patients. We also engage with payers to facilitate eventual market access and ultimately, hopefully, support patients appropriate for treatment with mavorixafor, if approved. Next slide. We'll now turn our focus to some of our recent insights into the prevalence of WHIM, expanding on the disease definition and updating our prevalence assumptions based on some of our scientific findings and patient identification initiatives. Next slide. This slide provides some additional detail on how we've been and continue to identify potential WHIM patients. To date, we've been successful at finding patients for enrollment into the Phase III trial, but also through other approaches such as our free genetic testing program, PATH4WARD, through physicianal reach and through our newly established commercial team of patient diagnostic liaisons, which Paula will talk more about shortly. Many of the newly identified patients have gone through analysis to understand their genotype. Basically, we examine patients with a clinical and laboratory presentation of WHIM and question whether or not they have a CXCR4 mutation. If they do, we then analyze whether it's a known mutation consistent with that in the literature, or if there are novel variants. If there are novel variants, we do a full characterization for pathogenicity in vitro in comparison with non-WHIM mutations. Today, we will be sharing with you what we've learned from our ongoing genotype/phenotype study results and share with you an important novel variant that we've recently discovered in collaboration with Dr. Tarrant and others. Next slide. In a recently published ASH abstract, we present our first case study of this novel variant, what's now called D84H. Here, I'm going to walk you through some of the phenotypic highlights of this patient. Our Chief Scientific Officer, Art Taveras, will then walk through some of the more interesting genotypic highlights and functional assays from the work coming out of our world-class CXCR4-focused research group in Vienna. Next slide, please. We believe this patient is quite important and relevant, as she is presenting with a novel phenotype, one that wouldn't initially or automatically have been considered WHIM based on the more classic phenotype and genotype presentations. This patient is a 40-year-old female who originally presented with severe cancer, starting at the age of 20. It was diagnosed as recurrent vulvovaginal and anal dysplasia and carcinoma consistent with HPV infection. In addition, she had very low NK T-cells and mild thrombocytopenia. Interestingly, she only had moderate neutropenia and only mild bacterial infections during her early adulthood, but nothing that would be considered typical for a classic WHIM patient. Upon bone marrow analysis, it was found that she did have bilobed neutrophils, which provides evidence of myelokathexis. Dr. Tarrant, who you will hear more from later on will give you more color on these patient, but it was certainly critical that Dr. Tarrant referred her for genetic testing. This is how the D84H variant of the CXCR4 receptor was found. And we've now started identifying additional patients with this mutation variant. Next slide. Within our clinical network of physicians, we've learned from a second physician, Dr. Svetlana Sharapova at the Belarusian Research Center for Pediatric Oncology that she also had identified the D84H mutation in several of her patients, each with a WHIM-like phenotype. Of relevance here is also the history of blood transfusions, lung bleeding, thrombocytopenia, all of which are expanding our understanding of the clinical phenotype of WHIM syndrome in patients with the D84H variant. As with [ mind ] through the broader literature and some of the databases, we've continued to learn that the D84H mutation is showing up in additional patient populations across the world. If you go to the next slide, based on this another continuing research, we're now starting to think more broadly about the phenotypic diversity of WHIM syndrome. It is becoming clear that WHIM goes beyond the original classic report of warts, hypogammaglobulinemia, infections and myelokathexis. Other findings such as thrombocytopenia may be part of the WHIM spectrum. Of course, we and our collaborators will continue to do additional work to learn more about this. And while these questions are still outstanding, I'd like to introduce our Chief Scientific Officer, Dr. Art Taveras, who will tell you why the D84H variant is also different from the mutations traditionally reported in WHIM syndrome. Art?

Thank you, Diego. As mentioned, I'm going to touch briefly on the results of our research into the D84H mutation. While we're really excited about sharing this case study with you, we also want to note that we have a long list of additional mutations that we are working through. So this is just one story of many more to come. For today, we thought it's important to highlight this one variant as a great example of our expanding research into the genetics driving WHIM syndrome. The D84H variant represents the first mutation reported that is located outside of the C-terminus or tail of the receptor leading to WHIM. Until now, only CXCR4 mutations in the tail region have been traditionally thought to cause WHIM. This amino acid D84 is involved in signal initiation and propagation and located away from the tail region in the second transmembrane domain. It plays an important role in keeping the receptor in its inactive state and supports normal CXCR4 signaling following binding to its natural ligand CXCL12. I'll now walk you through the data, demonstrating that D84H mutation results in a gain-of-function or over-signaling of the receptor in similar ways to the well-known CXCR4 WHIM mutations. Next slide, please. As a quick reminder, CXCL12 is the natural ligand of CXCR4, where binding to CXCR4 causes internalization of the receptor. Internalization is a way of recycling the receptor to appropriately end its signaling. This leads to normal CXCR4 signaling and cell migration, also known as chemotaxis. Two of our assays that we use to determine the impact of new mutations, characterize receptor internalization and chemotaxis. In the case of bone marrow, chemotaxis leads to cell retention in the stroma. So here, you see that D84H demonstrates a defect in CXCR4 internalization, which can be seen by the lower rate of CXCR4 in internalization with increasing CXCL12 concentration compared to wild-type cells shown here in green. This is similar to what is seen in cells with WHIM mutations in the tail of the receptor, which we just presented in a poster at ASH. Additionally, in a second assay, lymphocytes isolated from D84 patient blood were found to migrate much more toward a CXCL12 concentration gradient, consistent with the CXCR4 internalization defect seen in these patient cells. Collectively, these data show that D84 mutation results in defective CXCR4 receptor internalization and enhanced chemotaxis, demonstrating functionality in vitro that D84H is a pathogenic variant. Next, we wanted to explore if any particular subtypes of white blood cells might be uniquely impacted that would better help us understand the more unique phenotype of the patients with the D84 mutation. Next slide, please. Specifically, we examined Natural Killer T-Cells, or NK T-cells, given that they are associated with cervical cancers and this D84H study is of a patient who has had multiple surgeries due to refractory cervical cancer. And experimenting with the NK T-cells derived from this D84H patient, we observed a significantly increased chemotactic response compared to that of wild-type donors. And this hyperactive response was far greater than that seen with any other types of lymphocytes from this patient. This observation is particularly interesting since in HPV-associated cervical cancers, infiltrating CD4 positive NK T-cells are reported to promote tumor progression and the cervical cancer cells are known to inhibit the functional activity and killing effect of infiltrating NK T-cells leading to increased CXCR4 expression. Together, these data provide a link to potentially helping us further elucidate why this particular patient's dominant presentation of WHIM syndrome is around warts and HPV-associated cancers. That's an important scientific connection between the pathogenicity of D84H and the phenotype of the patient. Next slide, please. To assess whether mavorixafor can correct the gain-of-function chemotactic defect of D84H patient leukocytes, we first tested the ability of mavorixafor to inhibit CXCL12 binding to the D84H mutated CXCR4 receptor. Mavorixafor was found to potently inhibit the D84H variant with an IC50 of 3.9 nanomolar, a concentration easily attainable by our current dosage of mavorixafor in WHIM patients in the ongoing Phase III trial. Next, we treated the lymphocytes isolated from this D84H patient with mavorixafor and characterize its ability to correct the chemotaxis abnormality in the mutant cells. Mavorixafor potently and fully decreased the pathogenic chemotactic phenotype of all leukocyte subsets, including T, B and NK T-cells. We conclude that these results support the use of mavorixafor, not only in patients presenting with classical C-terminal WHIM mutations but also with other novel mutations like D84H. Further, our work demonstrates that simple in vitro laboratory assays can be used, not only to determine the pathogenecity of a given mutation but also can evaluate whether mavorixafor can block a pathogenic response in patient cells with these mutations, thereby identifying potential candidates for mavorixafor therapy. Additional work is needed to understand the potential effect of this mutation on platelets. Next slide, please. So with that, I'm very pleased to pass it over to Dr. Neal Sondheimer, who will lead the next portion of our presentation, focusing on better understanding the prevalence of these interesting end new mutations using genomic analysis and publicly available databases.

Good morning. My name is Neal Sondheimer. I'm a Physician-Scientist at SickKids Hospital. And I'm here today to talk a little bit about approaches to understanding how common variants are for rare disorders. My background is that, I [ made ] clinical and research geneticist with experience in rare disease discovery and also in the use of large genotype data sets for the analysis of phenotype and for risk assessment. I've done consulting activities previously using publicly available data sets to help to estimate disease prevalence. Next slide, please. When asked to determine the prevalence of an allele that may cause risk for disease, one approach is to use large publicly available database is to try to identify allele frequencies. So various studies that have largely been funded within the United States. Have looked at Exome-wide allele frequencies. And collected these data with occasionally some phenotype information, but often with no phenotype information. And the actual purpose of these databases is to help us when we're performing clinical sequencing to determine whether an allele is common or rare within a population because that can give us a sense of the potential of the allele to have pathogenicity. So in approaching the particular problem, which I'm going to be talking about today, which is looking at the allele frequency of the D84H allele, we used 3 of these databases to determine whether there were individuals present in a control population who had the allele. Now a little bit about what I mean by control population. These databases, by and large, aren't intended to identify people with a rare disease. So they take generally all-comers of people who have been sequenced in a range of either research or clinical studies and these individuals are not supposed to have primary genetic disorders. But, of course, they may have subclinical problems that haven't been reported or problems that are unrelated to the original purpose of the study. So for instance, one of the data sets that we'll be looking at is gnomAD, which is based on the Exome and now genome sequencing of around 140,000 individuals, and they are supposed to not have severe disease. The gnomAD data set is reflective generally of the U.S. population splits in ethnicity, it does skew slightly older than the true population, and there is a small over-representation of men in the data set as compared to women. The next data set we'll be talking about is TopMed. This is 150,000 individuals, and they were compiled from several different population studies that were aggregated together. There was no specific intent in the TopMed study to exclude disease. There are no age statistics, but most of the people in these data sets are adults. And African-Americans are slightly overrepresented in TopMed. And the last project is the Exome Sequencing Project from NHLBI, and this is 200,000 individuals. And again, this is an aggregation of multiple studies, largely of cardiovascular phenotypes. And again, the population is biased somewhat towards adults. And in these analyses, what we're trying to do is look for concordance of the estimates of any given allele. That is, we want to see the estimates come fairly close to each other to suggest the true population frequency of an allele. And of course, as these data sets grow and merge over time, these estimates will gain in confidence. So in particular, for the D84H allele, we can see these allele frequencies, which are on the right side of this slide. And they actually do paint a pretty compelling picture of the true allele frequency and the population by surrounding sort of the same number of about 4x10 to the negative fifth. If we want to convert these allele frequencies to the number of people who have the allele, we just have to multiply by 2 because we each have 2 copies of the gene. And here, we're talking about a dominant disorder and then multiply that by whatever population we're interested in. And so for the United States, if you want to look at this allele, this would suggest that there's around 25,000 individuals who have the D84H allele in heterozygosity. Next slide, please. The next task, of course, in understanding how important this allele is in the overall spectrum of disease is thinking about penetrance, which is the percentage of individuals who are actually going to manifest features of a disease based on their genotype. The first thing to note is that it's clear that D84H is not going to be 100% penetrant for WHIMS disease itself. And the reason that we know this is sort of twofold. First, the allele frequency is really much too high in comparison to the C-terminal truncating alleles that were used to define the disease. And when we're talking about something that is going to define the disorder, usually the most common alleles that cause severe disease are going to be found first because they're the easiest to identify when we're sort of getting our hands around a new disorder. So related because the allele frequency is so high, we would have clearly stumbled across people with the D84H allele first, if it was fully penetrant for WHIMS disease. At the same time, we know from research that's presented by other colleagues that the D84H allele does cause disease, so it's not in penetrant. So the real question is, how many patients would this allele add? And sort of the sub-question here is for this allele, what really matters is what percentage of individuals are going to be potentially treatable with an investigational agent rather than the percentage that have a complete WHIMS phenotype. And again, this is something that we see in the rare disease literature, which is that often a disease is defined by the most severe and obvious form of the disease, but only later do we recognize more subtle forms of the disorder, which still may require treatment but weren't immediately apparent when the original studies of the disorder were done. So far, we've used a fairly conservative estimate of around 5% to 10% penetrants for the D84H allele. Now, this is not based at this point on any direct evidence. This is just a conservative estimate. And this would give us around 1,250 to 2,500 patients in the United States who might have a treatable disorder based on the D84H allele. Next slide. There are many ways to improve this penetrance estimation, which, of course, is critically important. And several of these approaches are probably underway. The first is the use of family studies. If we have kindreds where we know the D84H allele is present, and we can genotype enough individuals in those families, this can give us a direct calculation of penetrance. That is how many exact genotype individuals manifest a phenotype. One problem with this approach is that, if you do it based on a single family or a small number of families, it can be challenging because of delayed onset, so that is some patients who might go on to develop disease may not have symptoms at the time you're studying them. And also, there can be a risk that other features of the genetic background of the family may either inflate or suppress the true penetrants number because it affects the potential to have disease. There are 2 other factors that can be used to refine penetrants estimates using family studies. And these are based on the assumption that the incidence of the disease is stable over time, which is generally a safe assumption for human disorders. And these calculations are reproductive fitness, which is a measure of how often affected individuals have children and the other calculable factor is the de novo mutation rate. That is how often is the D84H allele new in the proband and not present in other individuals. The other approach, in general, is different types of studies in large databases. The databases that we used in calculating the prevalence of the mutation don't have sufficient linked phenotype information for us to know whether someone in the population who has the allele has a phenotype of interest. And here, we might think of infections or abnormalities and blood count or the presence of disease as a phenotype we would be interested in. But if we use different types of databases, which are, again, growing in availability, where we do have linked phenotypes, we could use this information to get a more robust estimate of penetrant, which would also have the benefit of evening out the impact of the genetic background of individual families. So these 2 approaches are going to be used in the understanding of this allele and will improve our estimate of the penetrants of the D84H allele and will allow us to provide a robust calculation of the number of patients who are potentially treatable.

Thank you, Neal. It's been a privilege to work with you, and we appreciate you speaking on behalf of the research that we've been doing around prevalence of CXCR4 mutations in the general population. As I mentioned, D84H is just one in a group of more than 40 new variants that we are identifying, characterizing in our labs. We expect to report on additional results beyond what was presented at this year's ASH meeting, examining, not only known CXCR4 mutations, but also additional genotypes and phenotypes and forming gain-of-function CXCR4 activity, whether caused by CXCR4 mutation or not and confirming mavorixafor activity against all of the mutations and cell types identified. We anticipate reporting on additional case studies like this [ D84H1 ] in the future. I'll pass it back to Paula now to talk about how this research is helping advance our pre-commercial planning and activities in WHIM. Paula?

Thank you, Art. As you've just heard, our bench-to-bedside research is showing up a number of WHIM causing variances on the rise and adding to our understanding of the breadth of disease symptoms. Because of the success we've seen with this genotype/phenotype work, we are building further momentum to support patient diagnosis in 2022 and beyond across a number of important areas. Keying off of Dr. Sondheimer's guidance, we'll be pursuing a better understanding of the penetrance of the D84H and other mutations by researching family profiles and utilizing larger databases. And we're expanding our support of both physician and patient education, hopefully bringing this new information under clinical and laboratory presentation and genetic profile into their understanding. We're specifically adding a targeted group of field force members called Patient Diagnostic Liaisons or PDLs. Their mandate has helped raise awareness and reduce the time to patient diagnosis. And importantly, we'll continue to invest in genetic testing, including our recently expanded PATH4WARD program to allow for patient-initiated testing or PIT. This enables any person to request free testing through the program. Please go to the next slide. You can see from the tremendous breadth of our ongoing activities as we think about the different pieces of the puzzle that are needed to be ready for what will hopefully be good news from the regulators. Of course, building a sustainable rare disease business is not fully rooted in supporting patients and physicians. There's much more beyond that that we need to deliver on and we're well on our way. We have made great progress in adding leadership to the company with our VP of U.S. Commercial and our new Board Director, both with significant life science commercialization experience. More key hires, including a Chief Commercial Officer, are slated for 2022. In terms of our ultimate commercial product, we have taken the appropriate steps in terms of registration and validation batches to support our NDA filing and are advancing our work for mavorixafor's future commercial trade dress and third-party logistic providers to enable a successful U.S. launch. Finally, and importantly, given the disease-modifying impact that mavorixafor may have on this rare WHIM syndrome population, we are engaging payors with research and education in the U.S. and key European territories. All of these platforms and initiatives are working in concert to enable us to be ready to deliver for our patients in the event of our first approval. Next slide. So when we think ultimately about what the future holds for us, it's not only about WHIM, it's about primary immunodeficiencies more broadly. All of those commercial efforts that I just shared with you are part of the sustainable build to support the continuum of patients that could be treatable with mavorixafor. We talked about classic WHIM and how that's now expanding through our re-U.S. work, research and some of our broader research into other diagnostic criteria. Importantly, you'll hear in a few minutes about our expanding programs and focus on chronic neutropenia. It's yet another indication supporting a patient population that is larger and potentially treatable with mavorixafor and that can be reached by the same commercial infrastructure we are building for the launch of WHIM. We believe the future is quite bright for us in that a commercial investment even in the next year or 2 will be that fundamental building block that will allow us to deliver mavorixafor to any patient that can benefit across the spectrum of primary immunodeficiencies. Next slide. So I'll now pass it on to Diego to talk more about mavorixafor's potential and chronic neutropenia, including our first data set from our ongoing Phase Ib clinical trial that was presented at ASH. Diego?

Thank you, Paula. On this slide, we provide a brief introduction to chronic neutropenia or CN. Chronic neutropenia refers to a condition of sustained or recurring abnormally low neutrophil counts lasting at least 3 months. A study in Denmark has found that about 6 in 10,000 people in the general population have chronic neutropenia, which can present in a variety of severities; mild, moderate or severe. The main problem with chronic neutropenia is that it increases the risk of serious and recurring infections, infections that can affect any organ but occur more often in the skin or on the respiratory tract. Next slide. X4 recently completed an electronic medical record study to understand the risk of severe infections in people with chronic neutropenia in the U.S. For this, we used the medical records of 44 health care organizations treating approximately 66 million patients that allowed the identified patient level medical records to be used for research. Neutropenia was defined as mild, moderate or severe using standard cutoffs. The analysis looked for patients who had experienced at least 2 serious infections following a finding of neutropenia in each calendar year of interest and compared with those who did not have neutropenia. Serious infections were defined as any infection that require hospitalization, intravenous antibiotics or resulted in significant disability or death. We excluded all subjects who received chemotherapy treatment and any of the known drugs or infectious agents known to induce transient neutropenia. The results show that the incidence rate of frequent serious infections per 100,000 person days was increased for all levels of chronic neutropenia. It was 2x greater for patients with any chronic neutropenia defined as an absolute neutrophil count of less than 1,500 cells per microliter blood than for the non-neutropenic general population and 4x greater for patients with severe chronic neutropenia defined as less than 500 cells per microliter of blood. The results were consistent for all the calendar years we examined. It was very clear that the risk of serious infections increased with the worsening of neutropenia. Next slide. This EMR research was also helpful to inform on the estimated number of patients with chronic neutropenia in the United States. Extrapolation from the approximate 66 million patients to the total population of the U.S. found approximately 20,000 patients with chronic neutropenia or about 7 per 100,000. This is very similar to the report from Denmark in the literature. Importantly, about 25% of them had at least 2 serious or severe infections in the calendar year examined. All of this was done pre-COVID. Next slide. The current standard of care for management of severe chronic neutropenia is granulocyte-colony-stimulating factor or G-CSF. G-CSF is an injectable medication given once or twice daily. However, due to low tolerability, the approved doses and frequency of administration are often reduced by physicians to help patients with convenience and to increase tolerability. Bone pain is a frequent problem that limits compliance. There is a high unmet need for an oral and well-tolerated treatment for chronic neutropenia and we believe there is an unmet need for anyone with chronic neutropenia as long as they are having recurring infections. Given its profile, we believe mavorixafor has the potential to treat chronic neutropenia either alone or in combination with lower or less frequent doses of G-CSF. Next slide, please. X4 is currently conducting a Phase Ib open-label proof-of-concept study of mavorixafor for in patients with moderate or severe chronic neutropenia. The study is enrolling patients with congenital, cyclical or idiopathic neutropenia. Patients receive 200 milligrams if they are 12 to 17 years old and weighed less than 50 kilos or 400 milligrams for adults or adolescents with weight greater than 50 kilos. Patients are dosed for 1 or 14 days and mavorixafor can be given as monotherapy or concurrently with stable doses of G-CSF. One important goal of this study is to determine the initial safety and tolerability of mavorixafor across a broad spectrum of chronic neutropenic disorders. Another key goal of the study is to determine the ability of mavorixafor to increase the neutrophil count in the peripheral blood, which is a measure of bone marrow reserve. Positive results from this trial could support discussions about advancing mavorixafor into a registrational trial for treatment of chronic neutropenia, which we expect to have greater clarity on in 2022. Next slide. This past weekend we presented at the ASH Congress initial data in patients with chronic idiopathic neutropenia treated with the first dose of mavorixafor. As you can see here, 4 adult patients with chronic idiopathic neutropenia taking stable daily injections of G-CSF had their blood cell counts examined, including absolute neutrophil, lymphocyte and monocyte counts over 6 hours the day before and on the following day right before and after administration of the first dose of mavorixafor. The results show a very clear and consistent elevation of white blood cell counts, including the neutrophils, the lymphocytes and the monocytes in all 4 patients, which was seen already after 1 hour of taking the drug and was sustained for the 6 hours of the assessment. Next slide. Given these results, we believe there could be a significant opportunity for mavorixafor in the treatment of other causes of chronic neutropenia beyond WHIM syndrome. Given that there is a population in the multiple thousands in the U.S. alone with chronic neutropenia who are not well set with the current treatment options and we are having serious or frequent infections. We look forward to continuing to report on our ongoing clinical trial in chronic neutropenia with data expected in the second half of 2022. Next slide, please. It's now my pleasure to reintroduce Dr. Teresa Tarrant, who we heard from earlier. She and I will now kick off the fireside chat portion of our program where we'll focus on the patient journey and physician perspective.

With that, let's start with the first question. We'd like to get your sense of a typical patient experience when confronted with a possible immunodeficiency diagnosis. How do patients typically present to you? What is your process for diagnosing primary immunodeficiencies, WHIM syndrome? What is the treatment paradigm for the cases that you follow?

Thank you, Diego. The patient with primary immunodeficiency has a unique journey and a lot of this will depend on what type of immunodeficiency they have. Typically when they are presenting to me, they have seen numerous physicians. These physicians range from their primary care doctors, perhaps hematologist/oncologist, infectious disease specialists. And the question is often posed is there an underlying defect that could explain why they have been having so many clinical problems most commonly with infection. And in our training when we learn as allergists/immunologists how to approach these patients, the types of infections are really what provides the clues to the diagnosis and how you begin to work a patient up. So a large portion of our first visit in evaluating them is understanding their history, understanding when they started having infections, how severe they were? What types of treatments have been used that worked and did not work? Did these infections come back? How old were they when they started having infections? And then the severity, some patients have been hospitalized for very severe infections. So we start by trying to understand that. Family members are typically present during these initial interviews because sometimes these types of conditions do run in families and for many patients, they started having problems as very young children. And so having a family member there to help recall the data is quite helpful. And then after learning about what types of infections or in some cases cancer these patients have had, we typically order immune studies and some of these include the number and type of white blood cells that they have, functional studies about how well these white blood cell or infection fighting cells work and occasionally, we will order also genetic testing depending on if the pattern that we're hearing sounds like a known published primary immune deficiency disorder. But we're limited somewhat in what a clinician can order and adjudicate with respect to the immune system. It's typically white blood cell enumeration, how they function and then antibody production. And that's kind of how we start off the workup and then determine based on that and the history whether or not we should pursue genetic testing.

And could you comment briefly on the treatment paradigm you most often would follow?

That one is probably nuanced in the type of disease you end up diagnosing. In general for antibody disorders meaning that you don't make normal antibodies to protect yourself, for those types of disorders we can replace low antibodies or dysfunctional antibodies with immunoglobulin and this can be either administered intravenously monthly or it can be administered weekly subcutaneously. So that's probably the most readily approachable disorder that we have a treatment for. For patients that have cellular defects meaning that their cells are not working properly due to an underlying immunogenetic defect. That is typically something we cannot replace or restore without something very severe like a bone marrow transplant. And depending on the age and the number of infections the patient has or whether or not they have had cancer, we sometimes don't have that as an option. So there is supportive therapy for these patients and continuing to try to aggressively treat their infections with antibiotics, antifungals or antiviral.

What are your thoughts regarding the unmet need in patients with WHIM syndrome or some types of chronic neutropenia that you're familiar with? What would be the goal of the treatment?

So in WHIM syndrome because their genetic defect in CXCR4 affects all immune cells, they have a much broader unmet need for treating them. If they have low antibodies which some can, we can replace that with the intravenous or the subcutaneous immunogloblin as I discussed and that's an approachable therapy. But the unmet need has to do with their cellular defects. Their neutropenia can be profound and although we certainly can for WHIM and for chronic neutropenia provide them with G-CSF or granulocyte-colony stimulating factor, which is kind of a growth factor for neutrophils, although we can definitely provide them with that, that is not something typically that's given on a chronic basis. So it makes that therapy somewhat limited. And usually, you're using that only during a severe infection to try to help that immune system fight off the infection. As a preventative, most people would not do that. So you're kind of limited for those patients and you're really only able to treat them in those periods where they're severely affected. There's not a lot that gets at the underlying problem for them.

Can you share any tough patient story to illustrate what these patients are facing?

Absolutely. So with respect to -- I'll share 2 stories with you, one is a WHIM patient and the other is a patient that I treat and follow for chronic neutropenia from autoimmune cause. So for my WHIM patient when she presented to me, she has seen upwards of 10 doctors and had a very challenging experience for the last 10 years with cancer. And she told me that she had upwards of 20 surgeries in her perineal area because she has refractory cervical and anal cancer. And no matter what the doctors were doing to help her, it seemed that there was not a cure and it kept coming back. And as you can imagine as a young woman in your 30s, dealing with this emotionally is really, really difficult. And she has battled with anxiety and depression and a real fear of her mortality with doctors saying we don't know how to make you better with respect to this. So I think that was a really moving story for me for my WHIM patient. She actually had not had as many problems with infection throughout her life. Her problem was more with the cervical dysplasia from HPV, which is human papillomavirus, and that's what causes cervical cancer and is a particular virus that WHIM patients suffer from not only in the cervical region but also just on their hands and on their feet. And HPV can be an important pathogen that leads to squamous cell carcinoma. And so that was a particularly heartbreaking patient for me and we continue to work with her gyn/oncologist to try to prevent future surgeries that she may need. And she certainly was absolutely elated when she found out about this medication that could potentially be a game changer for her and we are hoping for the best with respect to that moving forward. My other challenging patient is a neutropenic patient that I take care of. She has myelodysplastic syndrome and she is older, she's in her 60s, and she did not have neutropenia throughout her lifetime. When her bone marrow became somewhat abnormal with this condition that's thought of to be as kind of a pre-cancer situation, she developed autoimmune cytopenias that were very severe and her neutrophil counts have really never gotten above 200. And I think what's been frustrating for this patient is we use a lot of immune suppression in autoimmune neutropenia because if you can treat the underlying immune problem, perhaps you can have the neutrophils not be attacked and destroyed. And we really run through the gamut for this patient in terms of trying to find something that could be helpful. And her neutrophils are so low that it has now enabled her to have to retire prematurely. She was involved as a teacher taking care of early elementary children and because as you could imagine, many people get lots of infections when they're working with small children who get sick a lot, this became something that was not going to be medically feasible for her moving forward. So she had to retire early and this was heartbreaking for her because she really enjoyed her job and she is subsequently not going to be able to work because her neutrophils are so low that just kind of going outside without a mask on is a risk to her.

Thank you. Let me ask you about the definition of WHIM syndrome. What do you think are the implications of the case reported as an abstract for the ASH Congress this year on your patient with a novel CXCR4 mutation that has had somehow different phenotype and genotype than the more classic patients with WHIM syndrome? How important do you think is genetic confirmation for diagnosis of WHIM syndrome?

I think that in all primary immunodeficiency disease, which I would argue my patient has, like you said does she meet all of the clinical criteria for WHIM. She has features that are very clearly WHIM and then features that don't fit with the original description of the patient. And I think that's something we all have to remember that we didn't have genetics when WHIM syndrome was originally recognized as a disease. And so we probably weren't appreciating historically the full spectrum of what CXCR4 mutations as well as other proteins involved in that pathway with CXCR4 can do. So although I believe that most immunologists feel that genetic confirmation is a very important piece to diagnosing primary immunodeficiencies, I think we are now appreciating the spectrum of what those genetic diseases can be and that not all patients look exactly the same. And that probably WHIM syndrome is a much bigger collection of clinical presentations that have portions of that name to it, but all I think we could say are certainly primary immunodeficiency disorder. In general with all diseases, there's a spectrum and I think we should always at the foremost of the diagnosis, the individual patient is what is most important. And if their symptoms and their infections are lining up and they have a genetic defect that may be even classic, but still could be conceivable, I think we need to think of that patient as WHIM. So I guess our patient really illustrates to us the spectrum and how probably there are a lot more people out there with WHIM and CXCR4 mutations than we previously recognized.

What do you think is the level of awareness among physicians in general about WHIM syndrome or other types of primary immunodeficiencies that you are familiar with?

I think in general the average physician who's in primary care, I think that that is quite low. I think that hematologists, oncologists infectious disease doctors and immunologists like myself, I think there is awareness amongst our group. And I think those patients although may be under-recognized initially do ultimately get to one of us who are more familiar with these diseases. But in general, there is a lack of awareness about rare diseases. Now what I can speak to is an experience that I have with other primary immunodeficiencies that I treat in the clinic. We had one in particular, which is called hereditary angioedema, and a lot of people didn't know what that disease was but a medication became available for those patients. And the knowledge and the awareness that was reached out to the broader medical community with publications about a drug target that works for these patients made the awareness actually much greater. So there is a lot of potential for WHIM and chronic neutropenia to be better recognized by physicians when we can educate them that we have drug therapies to help them.

Could you please share your impressions of the mavorixafor data from the WHIM syndrome Phase II trial, including the recent data presented at the ASH Congress?

In general, I'm incredibly enthusiastic about the data that I have been able to review that are presented as posters at the ASH conference. There's just a huge unmet need for these patients. And post the safety, the efficacy and the primary endpoints of neutropenia being met are very exciting. And I think that the evolution of having an antagonist for CXCR4 has been in the works for a long time and to see the fruition of that research and to see the fruition of the bench to bedside now making it to patients and showing some clear clinical impact is very exciting.

Thank you. Could you also provide your impression on the mavorixafor data on elevation of why build cells across multiple disease areas as recently presented also at the ASH Congress? If you could comment on the durability of the observed effect and the impact on neutrophils, lympocytes, monocytes?

Yes. I mean CXCR4, as I think we've alluded in other ways during this conference and during this conversation, is just critical to the function of all immune cells. So although neutropenia is something that is being presented at ASH and is being kind of focused on, like you said there are effects on these other immune cells as well that are very positive. Not all patients including WHIM patients have isolated neutropenia, sometimes all of their blood cell counts are low and abnormal and it is exciting to see that this corrects several defects for several different immune cells where CXCR4 is not functioning normally. So I think that it definitely broadens the potential therapeutic indications because as I had alluded to before with respect to cellular correction for immunodeficiency, we really have nothing with the exception of pulmonary transplantation and in a very few rare instances gene therapy has been explored. But that's not available to most clinicians. So the limitation is really quite extensive and this really fills that unmet need of perhaps being able to affect the abnormal immune cells not just the antibody.

And what is your opinion on the potential of a novel CXCR4 antagonist such as mavorixafor if approved? Do you think long-term treatment may be needed for patients who have WHIM syndrome or other chronic neutropenias that the drug may be able to help?

I do think that that is conceivable. There are many things about the formulation of the drug that are very amenable to chronic therapy. The other therapies we have discussed are intravenous or injection. And to have an orally bioavailable therapy is much more amenable for chronic therapies and obviously far less expensive from a health care cost system. So something like that is very attractive to both physicians and patients in terms of the way to kind of treat someone. And really at the end of the day if you think about WHIM, that defect is permanent. That is a genetic defect that someone is born with. And so it makes sense that you would want to treat those patients chronically because although infections come and go, you could maybe prevent some long-term complications that many of these WHIM patients experience, that specifically being cancer. So as a preventative therapy, that is very exciting. In the case of my patient who has the chronic neutropenia for myelodysplastic syndrome, that condition of hers is not going to go away. So in that patient, I could see how a chronic treatment with CXCR4 could be very helpful for her. This would allow her from staying in her house and only leaving it with a mask on to maybe being able to live her life again. So I think that there is definitely the possibility of chronic therapy. That will ultimately have to be tested in the patients who are in the clinical trials we have designed and then following them long term, which is done in many diseases, both autoimmune and immunodeficiency where patients start treatment and we study them and learn over many years what happens down the road.

Thank you. And finally, could you discuss briefly on other potential possibilities of studying and addressing additional immunodeficiency unmet needs with mavorixafor in the future?

So in general I think for neutropenia or diseases -- PIDs that have neutropenia in it that do not have a way to have their gene defect corrected, this could potentially be a therapy for them. So this might be where you have a different PID and neutropenia is a part of that and this may be something that could address that. At the end of the day, the PIDs where there are known genetic defects, we ultimately want to treat the genetic defect itself. That is the goal. I think we're only in the infancy of being able to do that, which is why WHIM is so exciting because it is directly correcting the problem that these patients have pharmacologically. Otherwise, if that can't be done, which is the case for most PIDs, you're treating them symptomatically and trying to prevent infection. So there could be instances where diseases have no treatments other than antibiotics available to them where CXCR4 antagonism could be helpful. Those will obviously have to be studied. I find it very exciting to think about autoimmune patients or patients with myelodysplastic syndrome or malignancies, I think that's another very broad area where there's a lot of exciting potential for this particular target.

Thank you so much, Dr. Tarrant, for your participation in today's event. Your insights into the field are incredibly valuable to us and our audience. We are lucky to have had so much of your time. So thank you again. I'll now turn it back to Paula to provide a summary of today's presentation and then we'll open it up to questions. As a reminder, Dr. Tarrant and Dr. Sondheimer will both be available during the Q&A session. Paula?

Thank you, Diego and Terri, for that incredibly insightful conversation about various primary immunodeficiencies including WHIM and chronic neutropenia and providing additional context to our ASH data with mavorixafor. As we head into wrap-up and Q&A, I hope we've created some key takeaways for you, including the fact that patients with primary Immunodeficiencies absolutely need more treatment options. The 2 injectable treatments of immunoglobulins and G-CSF are just not enough. We believe mavorixafor holds promise to be the first oral broadly applicable treatment for a number of primary Immunodeficiencies because of its well-tolerated ability to increase white blood cell counts across the board both acutely and chronically and irrespective of mutation status. WHIM syndrome is our landmark indication where we believe we have a high probability for approval and where the magnitude of patients that could benefit from mavorixafor appears to be growing through the better understanding of patient genotype and phenotype. And finally, today we introduced you to chronic neutropenia as the next immunodeficiency disease that we hope to change for the better. Thousands of people with chronic neutropenia experience multiple severe infection events per year in the U.S. We are beginning the journey to assess if mavorixafor can reduce these life-debilitating or life-ending events for these patients and our favorable clinical data presented at ASH is the first step. Next slide. X4 is at an exciting point in its growth towards developing its first franchise in immunodeficiency treatment. Within the next 2 years, we expect to gain our first approval in WHIM in the U.S. and help more than 3,000 estimated patients with the disease. In the following 3 years, we expect to grow rapidly with ex-U.S. approval of WHIM in various markets as well as expanding approval into chronic neutropenia, an estimated market of more than 15,000 patients worldwide. 5 years and beyond, we hope to be expanding into broader primary immunodeficiency populations to treat tens of thousands of more patients. And we'll keep going with the goal of helping as many of the 250,000 plus PI patients as our research supports. And now we'll open up the meeting to Q&A.

[Operator Instructions]

So as I mentioned earlier, we'd open up the meeting for questions regarding our ASH presentation of our Phase Ib Waldenstrom's data and we'll take the time now to answer some questions that we've already received and open up Q&A on Waldenstrom for 1 or 2 additional questions and then we'll take audience Q&A directed to our primary immunodeficiency review and to our KOL given the special opportunity that we had today with their participation. So with respect to our Waldenstrom's trial, 2 key questions that we've heard so far are can you clarify how you see the efficacy emerging from your trial and provide relevant benchmarks? And can you share more about the safety events that were reported, including the Grade 5 fatality and the cryptococcal pneumonia case? So we prepared a few slides to address these questions and I'll speak to the efficacy and benchmark question and Diego, our Chief Medical Officer, will speak to the safety. Next slide. As a very brief reminder, we have an ongoing Phase Ib study in Waldenstrom's patients where we are dose escalating mavorixafor in combination with ibrutinib. We have completed the low and mid-dose stages of the trial and are currently enrolling the highest dose. The efficacy data at ASH are primarily from the low and mid-dose treated patients and the safety data includes all patients enrolled in the study at any dose. Next slide. So as you may recall, Waldenstrom is a B-cell lymphoma where cancerous cells produced a blood protein called IgM at levels fivefold to fiftyfold higher than normal and reductions in serum IgM are that first indication that patients are responding to treatment and IgM can be assessed every few weeks or via a blood draw. Here we present our ASH Phase Ib data along with the 2 relevant benchmarks also in relapsed/refractory patients with double mutations. The light blue line is the benchmark when these patients are solely treated with ibrutinib. IgM initially reduces, but then plateaus out after a few months. Our study data are represented by the dark blue line treating the same population so it's an apple to apples comparison across these studies. By month 4, you can see a clear separation and improvement in IgM decreases versus the light blue line and we've not yet reached our plateau of responses nor have we reached our maximum dose in the study. Another important benchmark is the dark purple line and this is really what drives home the point that we have proof of concept. The purple line are Waldenstrom patients who fortunately do not have a second mutation in CXCR4. Treatment with our CXCR4 antagonist, mavorixafor, has shifted IgM reductions in double mutant patients, initially they looked like the shape of the light blue line, to respond similarly to patients without any CXCR4 mutation shifting to track with the dark purple line by 4 to 6 months of treatment. This is incredibly exciting and precisely supports the mechanism of our drug, blocking the enhanced pathogenicity caused by CXCR4 mutations and the double mutuant in Waldenstrom patients. Next slide. So now on to response assessments. Overall response is a metric that is assessed between the first 3 to 6 months on treatment and every 3 months or so thereafter. These assessments take longer because they involve imaging and other clinical metrics. Therefore, overall response assessments lag IgM reduction simply due to the fact that this needs more time to be completed. Here we present the overall response data from the 10 patients that were on treatment long enough to be assessed. We are thrilled to see that 100% of our patients respond to treatment. This means the drug is having a clinically positive impact in all of the patients that were response evaluable. Specifically, in the relapsed/refractory patients, this is dramatically better than ibrutinib monotherapy benchmark where after 6 months of treatment, the overall response rate is just 60% versus our 100%. This is yet another indicator to show that we are separating from ibrutinib monotherapy in a very meaningful way. Next slide. Next key metric is called major response and a major response is defined as responding patients who have had at least a 50% reduction in IgM versus his or her baseline. Here the response assessments for each of our 7 individual relapsed/refractory patients are represented by 7 bars in this waterfall plot. The green bars are 3 patients who have had major responses, including 1 patient with a VGPR. The light blue lines or bars are our 4 patients with minor responses and as you can see, they're edging up to potentially convert to major responses. In fact, 3 out of 4 of these patients are within a few percentage points to convert to major responses and I'd like to point out that these patients have been treated for a shorter period of time, 30 weeks versus 52 weeks, and all of these patients are continuing on treatment. So additional time on treatment as well as dose escalating to our highest dose provide an opportunity to further deepen these responses for patients. It is so clear to us why these data are so exciting. And so with that, I'll turn it over to Diego to help clarify the questions regarding safety. Diego?

Thank you, Paula. Next slide. At the recent ASH Congress, we also gave an update on the safety and tolerability of ibrutinib in combination with mavorixafor in this study in patients with a double mutation. I will briefly comment on this. Our overall assessment is that ibrutinib in combination with mavorixafor continues to be tolerated with a manageable safety profile. The majority of adverse events have been mild. 2 study participants had serious adverse events recently. One of them was found to have evidence of cryptococcal infection in the lung and in the brain. However, it turned out this infection was already present before initiating treatment. The infection responded well to treatment and the patient remains on the study receiving ibrutinib and mavorixafor at lower doses. Many cryptococcal infections have been reported with ibrutinib and none with mavorixafor until this case in combination. The other participant who developed serious adverse events, unfortunately, died soon after developing pneumonia and sepsis during the first 3 weeks of treatment and the family withdrew care. This happened while receiving the full dose of ibrutinib and the low dose 200 milligrams of mavorixafor early after enrollment. This patient had multiple comorbidities at study entry, all of which likely contributed to this event including older age, having a severe relapse of the lymphoma that required treatment with plasmapheresis for very high serum IgM levels that were rising rapidly and even blood transfusion for moderate anemia right before enrollment into the trial. Plasmapheresis removes all antibodies that are needed to fight infections. Also relevant, this study participant had a history of recurring respiratory infections including in the lung and bronchi that resulted in discontinuation of maintenance therapy with rituximab the previous year. We do not believe these unfortunate events related to mavorixafor. It was called by the study team at the site possible related to both ibrutinib and mavorixafor on the basis that they could not rule out either drug. Most importantly, these data have been revealed by the Data and Safety Monitoring Board and submitted to the FDA and other regulatory authorities. The Data and Safety Monitoring Board supported continuing dose escalation and treatment continues in the study without modification. Also very important, there has been no impact to any of our other studies as a result of these events. Next slide.

Thank you, Diego. And so with that, we'll open it up to Q&A, maybe 1 or 2 on Waldenstrom and then direct the rest of the Q&A to the broader questions around primary immunodeficiencies.

And our first question comes from Stephen Willey with Stifel.

Thanks for hosting us this morning and thanks for breaking out the patient-specific data on the Waldenstrom side. I guess specifically to Waldenstrom, can you just speak to what's happening now with the 600 mg dose level? And I know that there's going to be an attention to titrate our patients on to 600 mg in an effort to deepen some of those responses. But are you also interested in initiating therapy at 600 mg just to try to expedite the kinetics of it?

So I'll start and then I'll turn it over to Diego. But we are well on our way. Actually, in the poster, we described 4 out of 4 patients already enrolled at the 600 mg dose. So we're close to achieving what we need to move forward and declare that the maximum tolerated dose. And then we're expediting enrollment as quickly as we can with some adjustments to the protocol. But of course, Diego, I'll turn it over to you.

Yes. Thank you, Stephen. Yes, as you currently point out, we have now sufficient experience initiating treatment at the 200 milligrams. So we have amended the protocol. The amended has been approved. So treatment initiation once the 600 milligram dose clears will begin at 400 milligrams. So this will definitely accelerate kinetics. And we're looking forward to see the results of both initiating treatment at a higher dose 400 milligrams, but also escalating to 600 milligrams, which should be happening soon if the ongoing study supports that.

Okay. So I guess the objective then is to start patients at 400 milligrams then regardless and titrate them up to 600 milligrams or is there a plan to actually start patients at 600 milligrams at some point once the dose levels in cleared?

Yes, we will reassess how it goes. And of course, the tolerability allows it, the potential is there to just start at 600 milligrams. But we have to wait for the data to guide us.

Our next question comes from Mayank Mamtani with B. Riley Securities.

Appreciate the detailed presentation and covering some of the work you've been doing on the broader PID side. So maybe if I can start there and come back to Waldenstrom with a brief question I have. So for Dr. Sondheimer, for this work that you're doing on characterizing the WHIM disease like phenotype that might be tied to D84H a little. Could you just sort of comment specifically how do you anticipate this initial 5% to 10% present estimate to kind of move? What sort of work streams you have ongoing? And is there any other rare disease that comes to mind where as we think about understanding implications of CXCR4 beyond the C terminal truncating mutations?

Thanks for your question. So I outlined some of the approaches that I think X4 is going to look into to improving those estimates as long as well as the reasons for using a very cautious estimate for penetrance initially. It's hard to predict what direction those numbers will move. It's going to be based on data coming from families where the mutation has been identified and also from other databases that X4 is considering looking at, which may have linked phenotype identifiers. Clearly, the mutation can cause a phenotype, and there's data here showing how it may be treatable, but we need better information as we're moving through understanding this mutation.

Excellent. And then maybe for Art or Dr. Tarrant, either of you can kind of respond to this. So if you think about responders to mavorixafor, and you talked to some interesting biomarkers in the preclinical work around B or T cell against cell profiling. Could you just talk to like, in this initial work you're doing to understand either expanding from a WHIM syndrome standpoint to broader mutation type or just looking at the broader chronic neutropenia indication, like what are some of the early biomarkers that makes sense to look at? And then if you'd look to segment by baseline characteristics of these patients, again, in terms of phenotype, like how do you think about that?

Yes. Thanks, Mayank. Maybe I can start with the work that we're doing to characterize the pathogenicity of these various mutations and expanding it to other PIDs. So we have set up in our labs a bunch of different assays that are really characterizing the defect in CXCR4 internalization. We're also looking at hyper signaling of AKT and ERK. And we're looking at calcium utilization and chemotaxis and all of these ultimately give us a picture of what the defects are, and what they're looking like and how aggressive they are. And then you treat cells that have those various mutations with mavorixafor, and we look at the responses to mavorixafor. So for us, then we're able to characterize which mutations are more pathogenic from the in vitro work that we've done and which ones can respond to mavorixafor, and we'll be reporting on all of that next year for sure. But so far, what we've seen, it looks like these mutations, there are plenty of them that actually are pathogenic, and they appear to be responding to mavorixafor. So that's the first step, and that's related to the CXCR4 mutations and WHIM disease. For the work that we're planning to do for next year is actually expanding that to other primary immunodeficiencies with other mutations that have nothing to do with CXCR4 mutation. And what we found is that, there are many different primary immunodeficiencies, there is a connection to CXCR4 through up-regulation of the CXCR4 pathway, and that's actually how we're anticipating that mavorixafor will be working there. So we'll do that work, and we'll report on it. But so far, the work that we've done looks very promising. I'll invite Dr. Tarrant if she has any additional comments from the other phenotypic questions that you asked, Mayank. Thank you.

Yes. So this is Terri Tarrant. And thank you for your question. I think -- I hope that I'm answering the question that you posed that in terms of in vitro characterization, which I think was very well described that allows you to understand the function of the CXCR4 protein, whether it is mutated or not. And that is a very valuable quality control series of assays that explain pharmacologically in the cell at the cellular level, what is going on. Now obviously, patients are collections of cells and disease is another thing. So in terms of being a clinical immunologist and the patient who is looking at us across the table and how we decide whether or not to treat them, that has to do with different types of endpoints. So ultimately, they are usually symptomatic. So they're having recurrent infections or their blood counts are very, very low, leading to infections or at least being very concerning that they could get serious infections. So those are some of the things we're looking at in terms of phenotypically characterizing these patients. And in terms of biomarkers that we use in the clinic, oftentimes since this is a very neutrophil-targeted therapy, if their [ nutrionals ] are quite low, that is a very easy thing for doctors to check in the clinic. Just a CBC or a complete blood count with a differential can allow you to monitor therapy clinically. So I think export is validating protein regulation and protein function at the cellular level. But what's nice is that, if this drug were to come to market and be available for patients, doctors are going to be able to monitor cellular responses using the clinical assays that are available to us already.

Very helpful detail there. And then maybe the final question for Paula or Diego. Appreciate the color on the safety threshold with the high dose. It's good to hear you're getting close there. But with -- Paula or Diego, if you are able to share sort of the expectation on the IgM depth and duration and whatever metric, MR or VGPR you're looking at, as you think about having a clear separation from BTK monotherapy that would make sense to basically move on to the next stage of development and obviously, appropriately engage the regulatory bodies.

Yes. I'll start, and then I'll certainly invite Diego to chime in. But -- so we've not had conversations with the regulators about a trial design, but we can use at least benchmarks of recent study. So zanubrutinib used major response rate, I believe, at 1 year that supported their recent approval in Waldenstrom's. So if you use that same metric for at least the refractory population, which we're seeing initially the strong signal emerging is that the major response rate for ibrutinib alone is around the 50th percentile. It's in that same reference that we put in our slide deck today. So certainly, we hope to beat that. We certainly need our data to certainly mature and also ultimately achieve our highest dose, should that be possible. So again, we're really excited. I think our data are already looking incredibly positive with those 7 refractory patients kind of in the race to cross over that major response line, and that would certainly be very meaningful step forward. So Diego, I don't know if you have anything to add?

I would just add, Paula, that the 2 earliest indicators that you want to look at to find out in vitro is having an effect, which is the change on the serum IgM levels and the impact on overall response. Those 2 boxes are already checked. So we are at a really good place, and we look forward to continuing dosing patients longer, hopefully, dose escalating. So we can explore a higher dose and then obviously, take this data to regulators who understand not only this is a rare lymphoma, but it's the sub-population of Waldenstrom that has the most severe phenotype, and they don't respond to ibrutinib in the way that it's needed. So we look forward to next year and further data and updates to you on all this.

Actually, if I can squeeze in like one final question. Are there any other patients with pre-existing respiratory issues or crypto-positive, things like that on the study currently? Sorry, this came from an investor, so I thought I'd squeeze it.

Not that we're aware.

[Operator Instructions] Our next question comes from Eva Privitera with Cowen.

I was wondering if you could put the mavorixafor [indiscernible] data in the context of the recent data from the CXCR4 antibody plus ibrutinib? And then I have another question on the CSN -- SCN trial.

So I'll do that briefly. But we, certainly, with our KOLs on the call, we'd like to make sure we can get through the primary immunodeficiency questions. But just briefly, the way we view the antibody data is it continues to affirm proof-of-concept for the mechanism. That trial had a different set of requirements than ours where patients were allowed to be plasmapheresis while on study. So that obviously impacts the dramatic drop of IgM that was reported. So it's a bit challenging to compare. So I think big picture, we're excited for the proof-of-concept of the trial. It's not really -- I think the benchmarks are somewhat difficult to interpret. And then finally, those patients had grade 3 for thrombocytopenia, which is a problem -- certainly problematic with patient population. So I think we're in excellent shape with the profile of our drug and what we're already seeing in terms of our response rates. Questions on the primary immunodeficiency side of the equation?

Yes. So in the Phase Ib SCN trial, what metrics and what time points are most important? And what's the bar for moving forward?

Yes, Diego, do you want to take that?

Yes. This is a clinical pharmacology study. The key question, of course, is how people with different types of neutropenia tolerate and respond to mavorixafor. We think that it will -- it should go well based on our experience in WHIM syndrome. The second most important is, what's the type of white blood cell elevation that we observed because it's key that there must be a bone marrow producing cells. It may not be a normal level, but there should be enough production for the CXCR4 inhibition to improve from that production and release. So that's full change, like we have seen in the ASH poster, it's exactly what we're looking for. We believe it will translate into clinical benefit by reducing infections, and that's how we're thinking about next steps.

Our next question comes from Leland Gershell with Oppenheimer.

Thank you for holding this comprehensive event. Actually, just one question for Dr. Tarrant. As we think about mavorixafor for WHIM, obviously well supported there. And presuming that comes to the market, what do you see kind of as the key hurdles for uptake, given its efficacy and safety, would you look at particular mutations as being drivers of use in certain patients? Would it be diagnosis that is going to be perhaps a gating factor? Can you just help us understand the initial trajectory as we think about mavorixafor? And then I have a follow-up question for the team.

Yes. So I think in the beginning, when patients certainly who are on the study, will likely want to continue if they're having good experiences. And so there will likely be still continued study of those patients who continue on the drug for long-term safety and clinical efficacy endpoints. And I think as new patients get diagnosed, certainly, it will now be something that we can offer to patients, whereas previously, it really is pretty much antibiotics or IVIG, if they have low antibodies or G-CSF in the setting of a severe infection to help them get over it. So I think that the potential is that, it can be thought of more as a maintenance drug, something that can actually correct a wrong pharmacologically, and it would be my expectation that patients would be -- maybe using this long-term and not as an often on therapy. So they would be maintained on this chronically. Many people use genetics as a part of the diagnosis of WHIM. And I think when a disease, particularly an orphan disease, has a drug target that becomes available to it, we are going to see a lot more genetic testing of patients, awareness of the disease. And I think more patients will get recognized that probably weren't being recognized. But I think for many of us in the community where we might have a patient who, let's say, has a normal CXCR4 genetic tests, but clinically looks like woman has neutropenia, I would not be surprised, and I think based on consensus talks with some of the folks who work with X4, that we will be treating those patients as well. So I do not think we will be limiting this drug to patients who have only a genetic diagnosis. I actually think those that meet clinical criteria of WHIM have severe neutropenia, I would expect that those patients would be tried on this drug.

And then a question, just kind of -- just to clarify, maybe Paula maybe chime in that. In terms of the use of mav in non-mutated wild-type CXCR4 patients with PID, could -- would there be a role there? Or would you really only be looking at those patients who are experiencing PID due to driving mutations in CXCR4, I think there's been data in the past that shows that even wild-type CXCR4 could be targeted by antagonist and there could be a therapeutic role?

Yes. I mean, our job at X4 is to support the physicians and patients for those choices. But what we're hearing from our physicians is that they believe that even for non-CXCR4 mutated patients with WHIM phenotype that they believe those patients could be candidates for the drug. So it's really -- the decision is always in the hands of the physicians in terms of diagnosis and then a suggestive treatment. But all of the research that we're doing is to enable them to make the best decision. And certainly, what we're hearing is, they're open to that, as you just heard from Dr. Tarrant.

All right. Great. Thanks very much for the additional information.

Our next question comes from Zegbeh Jallah with ROTH.

And congrats on the data. Really nice update. I think for me, it's just some general questions. I think a lot of them have been asked. And if I'm duplicating questions, please do let me know. The first one is just about how you plan to turn the handle, some of the variability we're seeing in the WHIM data.

So when you speak of variability, could you be a little more specific?

Just patients -- differences in patients' baseline characteristics, how do you plan to kind of tackle that?

So I think when we set out on our journey to study WHIM, we were focused on sort of the most consistent criteria that all WHIM patients appear to share, which is the chronic neutropenia and chronic lymphopenia and monocytopenia. So I think we're happy in terms of like the study is designed to measure those and then also more broadly assess through some additional secondary endpoints to various clinical features of the syndrome, the work counts, the infection rates, where I have some exploratory endpoints as well. So I think the very -- we always defer the physicians on how they define the WHIM patients, but we think our study design will certainly be able to address and measure the full spectrum of the disease as these patients are assessed. I hope that answers your question.

Yes. That was helpful. And then the follow-up one is just on Waldenstrom. And Paula, I apologize, you may have said this in your interim questions that you've been getting. I'm just wondering, is there a way to kind of definitively determine the source of the grade 5 AE? And then a follow-up to that, if you were not able to escalate to the 600-milligram dose or not move forward into pivotal studies with that dose? How confident are you in the efficacy that you're currently seeing if you were to have to move forward with that?

Yes. So maybe we'll take the dose, first. I mean, so far, all systems are cleared that we are continuing to dose escalate. So I don't expect there to be any variations based on the 4 patients we've already seen. So -- and then again, in the event that 400 is our dose, which I think is highly unlikely at this point. It's -- we're still seeing the great efficacy that we've already presented today. So longer durations of treatment will certainly benefit the overall study. So again, low probability is on the 400, but we, of course, need to achieve the data. And then with respect to the grade 5, this was, as Diego highlighted, it was a very severe cancer patient who entered our study. And of course, we're always trying to follow what the physician and patient wishes are. Unfortunately, there was this negative outcome for the patient and really the cancer profile combined with their immunosuppression due to plasmapheresis as well as their background history with severe infections. Unfortunately, we think that paints the picture of the unfortunate outcome for those patients.

And then the last 2 is just on the SCN program. The first one is just as the opportunity kind of gets more broad, how are you thinking about the regularity strategy around that, look at a pivotal study even look like for that broad indication of chronic neutropenia?

I'll ask Diego to speak to that.

Yes, thank you for the question. So we -- there is already a precedent, I'd say, some 30 years ago. The FDA approved the first G-CSF in chronic neutropenia on 3 different populations with a randomized crossover design. That is just one example where you can measure not only the effect on the cell counts, which was the primary endpoint, but also clinical impact like febrile neutropenia, frequency of infections, duration of hospitalizations. So there's already a clear benchmark that we can follow, of course, we will bring this discussion to the agencies, and we are already engaged with receiving input from really amazing doctors who see the unmet need and are working with us to, hopefully, one day, improve the medical care of this patient population.

And then the last one, again, and I'll just have a broad one, since we have the clinicians on the line. The last one, Paula, for you, is just about as you think about PIDs more broadly, certainly looking like a bigger opportunity. So I was just wondering if I'm beginning to think about maybe potential partnerships with large pharma as this opportunity kind of broadens. And then for the clinicians on the line, I was just curious if you're seeing greater patient or physician awareness about genotyping, technology or great awareness that have actually made it more feasible. And I think if you have any additional commentary on how likely it is that we're going to be able to find these patients will be helpful.

I think that question is for me. So I'll take a stab at it. So in terms of finding these patients, I think the first thing that happens is most doctors, even primary care doctors notice the profound neutropenia. So that is the first step, and that is a really easy thing to do. A lot of people have blood counts done for many different reasons. And in terms of the journey of my patients and how they got to me, it just started with a simple blood count with differential. And the neutropenia was low, and someone said, we've got to figure out what's going on there. So typically, even just screening your annual physical, we can find defects that then get further explored. Oftentimes, maybe even before someone has infections, which is great, who would like to think you could pick people up earlier. Typically, those patients are going to then get referred to either a hematologist/oncologist or an immunologist like myself. And I would say that we are very much involving genetics and genetic screening as well as bone marrow valuation for hematology/oncology and the evaluation of these patients. So I actually do think that there will be a lot of people picked up and recognized, and I don't see that as a barrier.

And in terms of genetic evaluations of complex patients, this increases dramatically year-after-year as we find more genetic variants that have impacts on disease and guided treatment. We are moving through an era of using exome sequencing rather than panel sequencing for many disorders just because of price, and that will lead to genome-level sequencing inevitably in the next few years.

And I'd like to add one comment as I discussed with the electronic medical record study we recently completed. And now with -- this is really widely available in the U.S., and we were able to very rapidly find 25,000 patients with chronic neutropenia that are linked to a hospital. So there is really a change in our -- related to identify and approach patients who may have an unmet need and who could potentially benefit.

And then Paula, just about the partnership?

Sure. So certainly, we -- the vision for the company is to globally commercialize and build this franchise in primary immunodeficiencies. I think that's something that we've seen successful with other long-term successful biotechs. In terms of partnerships, we do think that the exciting proof-of-concept with our drug in Waldenstrom's actually have broader implications in lymphomas. And as I'm sure people are aware that the changing standard of care and complex standard of care in lymphomas continue to evolve. So I think that's an exciting area for us, given how well our drug combines with a number of approved therapies. We'll actually be reporting more out on the first half of the year. Next year, Art and his team has done a phenomenal job looking at the mechanistic sort of synergies between our drug and a number of approved treatments. So more to come on that.

[Operator Instructions] Our next question comes from Stephen Willey with Stifel.

I guess, maybe to Dr. Tarrant, you talked a little bit about the genetic testing component of this. And just curious as to whether or not you believe a lack of a requirement for genetic testing as per some of these initial labeling discussions, how that may impact use amongst prescribers, if at all? And then I have a follow-up.

So I think I understand your question, but I may not, so I'm going to try my best here. So in terms of how we treat diseases, ultimately, no disease is definitively defined, but based on its genetic defect per se in immunology. Meaning that it is a part of the diagnosis, but it is not absolutely essential for the diagnosis. Certainly, again, there have been WHIM patients that have been followed by very prominent immunology centers in the world that have normal CXCR4 sequence. And sometimes we end up discovering new genetic mutations, and we learn more about pathways. So CXCR4 is not a protein that is involved in doing its function in isolation as it was kind of discussed downstream signaling molecules like AKT and ERK, GRKs, G protein coupled receptor kinases. There are lots of interactions that proteins have with other proteins when they're activated and causing us all function in a certain way. So we may find that there are defects in the pathway of CXCR4. And I see that as a big plus. But I don't see it as -- if you don't have a CXCR4 mutation, we wouldn't offer a therapy that we think could be helpful to a patient. So I don't think genetics limits us. I actually think genetics only expands and makes the broader physician community more aware about this disease. But I don't think it's going to be something where we would require a CXCR4 mutation to be eligible for this therapy. I think it's just going to make some physicians feel more comfortable with the diagnosis. But again, I don't think anybody would limit therapy to a patient who needs a drug based on their genetic sequence.

I'm currently showing no further questions. I'd like to turn the call back over to Dr. Paula Ragan for closing remarks.

Well, thank you so much. We really appreciate everyone's attention and excellent questions today. We certainly thank our 2 experts, Dr. Tarrant and Dr. Sondheimer. We wish you all an enjoyable day, and please feel free to reach out separately if you have any additional questions. Thank you again, everyone, and happy holidays.

This concludes today's conference call. Thank you for participating. You may now disconnect.