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

Greetings, and welcome to the X4 Pharmaceuticals conference call and webcast on the Phase Ib results being presented today at EHA 2021. [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.

Thank you, operator. Good morning, everyone. I'd like to welcome you to our EHA 2021 conference call and webcast. We appreciate all of you joining us today as we share the exciting initial results from our ongoing Phase Ib study in Waldenström’s macroglobulinemia. Before we begin, I'd like to remind everyone that on today's call, we will be making forward-looking statements regarding our regulatory and product development plans. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in our most recent Form 10-K and Form 10-Q on file with the SEC. We have an exciting session ahead of us. As you can see, the flow of today's conference call is outlined here. Overall, we can expect the formal part of the call to last about 40 to 45 minutes, including our fireside chat with Dr. Christian Buske, who's considered to be one of the top physician scientists in Waldenström's clinical research. We will then open up the meeting for a live question-and-answer period, including the chance to hear directly from Dr. Buske. X4's management that is joining us for today's call, in addition to me, are Chief Scientific Officer, Dr. Art Taveras, who will provide relevant insights into the critical role that CXCR4 plays in diseases of the immune system as well as provide introduction to our lead candidate, mavorixafor. X4's Chief Medical Officer, Dr. Diego Cadavid, will educate us on the disease mechanisms and unmet need in Waldenström’s macroglobulinemia and provide an overview of the data presented in our Phase Ib EHA poster, Dr. Cadavid will also facilitate the fireside chat with Dr. Buske. Our CFO, Mr. Adam Mostafa, will join us to share an outlook of upcoming events, and then we'll open up the meeting to audience Q&A. And with that, I'll now share a brief corporate overview. Here on Slide 5, we provide a snapshot of X4. X4 Pharmaceuticals is a public Boston-based company focusing on delivering targeted treatments for rare diseases of the immune system, including primary immune deficiencies and rare blood cancers. We are an established global R&D center of excellence focused on modulating CXCR4 receptor, which is known to be a master regulator of immune cell trafficking and maturation. Mavorixafor, our lead candidate, is a CXCR4 antagonist that has been shown to safely and effectively modulate the CXCR4 receptor across a number of clinical studies. Our focus that is relevant to today's discussion is regarding the development of mavorixafor to treat a genetically defined subpopulation of patients Waldenström’s macroglobulinemia, a rare form of non-Hodgkin's lymphoma. We will look forward to sharing an overview of our exciting initial Phase Ib data shortly. In addition to Waldenström's, we are studying mavorixafor in a number of rare diseases of the immune system including inborn diseases with few existing treatments, such as WHIM syndrome and severe congenital neutropenia. Combined, we believe mavorixafor has the potential to make a meaningful difference in more than 10,000 patients across the severe set of diseases. We believe our strong balance sheet provides a long runway and the support of development of mavorixafor and our preclinical pipeline into this quarter of 2022. At X4, we are leveraging what we believe to be a well-positioned platform to build a global rare disease company, where we are performing important translational research to further the breadth of our platform and support the pursuit of additional novel therapeutics. So why are we focused on CXCR4? I'm going to turn it over to X4's Chief Scientific Officer, Dr. Art Taveras to explain. Art?

Thanks, Paula, and thanks to all of you for joining us on the call today. As background for our discussions today, CXCR4 is one of the main drivers of normal immune cell surveillance and maturation. It is a well-validated target across a number of human diseases of the immune system and dysfunctional CXCR4 signaling has been shown to be a driver across a number of rare diseases that impact more than 10,000 patients, as Paula mentioned. Initially, we are focusing on enriched patient populations defined by genetic profiles to optimize for the success of our lead development programs, such as the primary immunodeficiency called WHIM syndrome, and the rare lymphoma, Waldenström’s macroglobulinemia, where a gain of function mutations in the CXCR4 gene, underlying the pathogenesis of these diseases and cause severe and refractory disease. In Waldenström’s specifically, sequestered B cells remain in the bone marrow and our belief to be protected from treatment, producing elevated levels of immunoglobulin M or IgM, that puts patients at risk of severe complications. In patients with CXCR4 mutations, there is even greater bone marrow involvement and significantly enhanced IgM production associated with prolonged downstream signaling. Further, as these trap cells crowd out the bone marrow, they impede normal hematopoiesis, causing a reduction in hemoglobin levels. By inhibiting CXCR4, B cells can mobilize to the periphery, which may facilitate cancerous B-cell killing by BTK inhibitors and other therapies, thereby reducing blood IgM levels and providing room in the bone marrow for normal hemoglobin production. We believe that these proof-of-concept studies in WHIM and in Waldenström’s, create the cornerstones for possible broader application of CXCR4 antagonism in large patient populations with immunodeficiencies and lymphomas. Mavorixafor is a first-in-class, orally bioavailable, small molecule antagonist with high potency and high selectivity for the CXCR4 receptor. Mavorixafor binds allosterically to CXCR4 receptors expressed on the surface of cell membranes and not only induces mobilization of leukocytes expressing CXCR4 but also inhibits detrimental and hyperactive downstream signaling. As a small molecule with a 22 hour half-life, we are developing mavorixafor as a once-daily oral capsule. Mavorixafor has now been studied for several years and in more than 200 patients in healthy adult volunteers, demonstrating dose-dependent mobilization of neutrophils and lymphocytes in these patients. With a favorable safety profile and multiple points of clinical validation through our successful Phase II trials in WHIM syndrome and in clear cell renal cell carcinoma, and now in this Phase Ib clinical trial of mavorixafor in Waldenström's. We believe mavorixafor has the potential to be a significant drug for patients and for X4, if approved. The FDA has recognized the importance of this drug and the unmet medical need of patients with WHIM syndrome. By granting X4 valuable key designations to support mavorixafor's advancements, including breakthrough therapy, fast track and rare pediatric disease designations. Fast track and rare pediatric designations create eligibility for X4 to obtain a priority view voucher, should we gain approval in WHIM syndrome. In terms of market exclusivity to support our commercial business, we have received orphan drug designation and also have multiple issued U.S. patents on composition of matter that extends through 2038. With that overview, I will now pass it over to Diego Cadavid, our Chief Medical Officer, who will provide some background on Waldenström’s and review the poster data presented today at the EHA meeting. Diego?

Thank you, Art. And to all of you on the call today, we are very excited to be presenting this data to you today and thought it would be helpful if we started with a little background on the disease itself. As Art touched on earlier, Waldenström’s is a rare B-cell lymphoproliferative disorder, primarily characterized by increased clonal IgM secreting cells. This elevated IgM can cause a number of serious complications, including hyperviscosity syndrome, which I'll explain upon in just a moment. Patients often experience pancytopenia, along with fatigue as a result of anemia. Greater than 90% of patients with Waldenström's have somatic mutations in the myeloid differentiation Factor 88 or MYD88 gene and a subset. Roughly 30% to 40% also have WHIM like activating mutations in the CXCR4 gene. It is estimated that there are approximately 4,000 to 5,000 of this high unmet need double mutation Waldenström's patients in the U.S. and Europe. Waldenström's patients have an approximate 8 to 10 year survival rate post diagnosis. With double mutation patients having shorter progression-free survival. The presence of both the MYD88 and the CXCR4 mutations impacts this patient's response to BTK inhibition. We are conducting our Phase Ib clinical trial of mavorixafor plus the BTK inhibitor, ibrutinib in this double mutation patient population because we believe CXCR4 inhibition with mavorixafor can improve the response of this double mutant Waldenström population to ibrutinib. Here on Slide 10, we provide a quick look into the complications facing these double mutation Waldenström patients. These patients tend to have delayed response, an inferior depth of response to BTK inhibition and shorter progression-free survival. As you can see, these patients typically present with higher levels of IgM diagnosis, which proportionately increases the patient's risk of developing hyperviscosity syndrome. From a clinical perspective, we list here some of the complications of living with hyperviscosity syndrome, providing the rationale for keeping serum IgM levels low in the long term. As seen here on the left, previous studies of ibrutinib monotherapy in double mutation patients indicate that this patient group, on average, starts at higher IgM levels than single mutation patients and have more severe bone marrow involvement. As you can see, response poorly to ibrutinib monotherapy, whether they are treatment naive or rituximab refractory. On the right, we've broken out some of the key clinical outcomes from previous studies of ibrutinib monotherapy in double mutation Waldenström's patients. This show a slow time to response of 6 to 7 months and only 28% to 38% of patients are able to achieve greater than 50% reduction in serum IgM at 6 months, which is a key criterion on defining a major response. So what does this mean from a clinical and regulatory perspective? This next slide, #12, helps to put the greater than 50% response into context. For Waldenström’s, clinical responses measured across very specific criteria that includes both biomarkers and clinical manifestations. A major response is defined as achieving a greater than 50% reduction in serum IgM, reduction in extra [indiscernible] disease is present at baseline and no new or worsening symptoms. As you can see from the visual here, a major response includes both the partial response of 50% to 90%, plus a very good partial response of greater than 90% decrease in serum IgM. Complete response is defined by normal levels of IgM and no signs of disease, including on bone marrow biopsy. For context, ibrutinib is only drug currently approved by the FDA for treatment of Waldenström’s macroglobulinemia, either as monotherapy or in combination with rituximab. So with that background, let's dig into today's poster presentation. The poster presented today summarizes the preliminary data from our ongoing Phase Ib clinical trial of mavorixafor in combination with ibrutinib in Waldenström's patients with confirmed MYD88 and CXCR4 mutations. It is a multinational study with endpoints examining safety, pharmacokinetics, pharmacodynamics and monthly assessments of serum IgM, hemoglobin and other blood parameters. We are also measuring objective responses every 6 months, including assessments of extra [indiscernible] disease and bone marrow biopsies. Patients are initiated on mavorixafor 200 milligrams, the low dose and ibrutinib 420 milligrams, both oral and dosed once daily. Mavorixafor escalation to 400 milligrams, the mid-dose or course after 28 days, if fewer than 2 dose-limiting toxicities are observed. And then to 600 milligrams, the high dose after 400 milligrams is deemed tolerable. Here, we provide details of the 8 patients who had been enrolled as of the April 15, 2021 cutoff date. As you can see, the min age is 67, 6 of the 8 patients are male, and patients have a mean duration of disease of 4.5 years. This trial includes a mix of treatment naïve or frontline and refractory patients. Patients had median baseline serum IgM levels of 39.75 grams per liter, where the normal range is 0.5 to 2 grams per liter, with levels hiring from [indiscernible] refractory patients. Patients had median baseline hemoglobin levels of 110.5 grams per liter, where normal ranges fall between 138 to 172 for males and between 121 and 151 for females. 3 of the 8 patients were diagnosed with extra [indiscernible] disease at baseline indicating [indiscernible] and/or splenomegaly. The majority of patients had moderate or high-risk disease based on IPSS scores, generic analysis of the patients, CXCR4 mutations show that half had nonsense mutations and half had frameshift mutations. On this next slide, 15, we show patient disposition. Of the 8 patients enrolling the study as of April 15, 7 were in Cohort A, with 6 of the 7 patients remaining on 400 milligrams of mavorixafor after the escalation from 200 milligrams. 1 patient in Cohort B has been escalated to the 600-milligram mavorixafor dose. However, due to the timing of the cutoff, now 600 milligram safety data are included in the poster. For patients were treated for more than 6 28-day cycles, with a median duration of treatment of 156 days. In terms of safety, no serious adverse events have been reported, and preliminary results demonstrate that mavorixafor plus ibrutinib therapy is well-tolerated. Adverse events related to use of mavorixafor occurred in 2 patients, over Grade 1or 2. Mavorixafor and ibrutinib exposures were consistent with previous single agent studies and no apparent drug-drug interaction between mavorixafor and ibrutinib were observed. Turning now to Slide 17. If you recall back to our discussion earlier of the mechanism of action of mavorixafor, that it mobilizes leukocytes from the bone marrow, you can see here evidence of dose-dependent increases in total white blood cells that track with mavorixafor exposure and confirmed target engagement. The observed dose-dependent increase in total white blood sales with mavorixafor is different from the isolated lymphocytosis that can occur during the first few weeks of ibrutinib monotherapy that results after a median of 8 weeks. Most importantly, all patients in this study saw a decreasing serum IgM during treatment at the low and mid-dose levels and there was no progression of disease for any of the patients while on treatment. On the left here, you can see the median absolute serum IgM levels decreased to 9.9 grams per liter for the 4 patients that reached the 6-month measurement. This is an approximately 60% drop versus their medium baseline level and a 75% drop versus the medium baseline of the total of 8 patients who started on the trial. And on the right, you can see that at 6 months, 2 of the 4 patients had a greater than 50% reduction from baseline and 1 of 4 was able to achieve absolute IgM levels within normal range, which is very initial in patients with a double mutation. Moving on to Slide 19. As we noted earlier, [indiscernible] fatigue are characteristic of patients with Waldenström's. Here, we present efficacy data on blood hemoglobin levels, which is a key biomarker of bone marrow health. As you can see of the patients with baseline hemoglobin below normal, all patients saw a steady rise with median hemoglobin increasing by greater than 20 grams per liter at 6 months. So to put all of this into context, on Slide 20, we presented our preliminary data compared to previously published studies of ibrutinib monotherapy in double mutation Waldenström's patients. While not completely apples-to-apples and based on a small number of patients, this preliminary data begin to give us a sense of the added beneficial effects of mavorixafor in combination with ibrutinib versus ibrutinib monotherapy. They include a substantial drop in IgM levels at the 6-month time point. We look forward to seeing the effects of the higher dose of mavorixafor as we dose escalate. To conclude, we are very encouraged by this data, which show that the combination of mavorixafor and ibrutinib at the low and mid doses is well-tolerated and results in clinically meaningful benefits in reduction of serum IgM and increases in hemoglobin. At the 6-month standpoint, the combination therapy showing signs of superiority versus previously published data on ibrutinib monotherapy in double mutation patients. And we are further encouraged by the 1 patient who reached normalized levels of IgM within a 6-month treatment window. This rapid normalization of serum IgM in 1 of 4 patients is [indiscernible] power studies with ibrutinib monotherapy show that only about 1 out of every 10 patients can achieve 90% plus reduction of serum IgM and only after about 11 months on treatment. These encouraging initial results report on the low and mid doses of mavorixafor and believe there is potential for even more robust outcomes with a higher 600-milligram dose. We are looking forward to presenting additional data later this year as we advance our Cohort B through the 600-milligram mavorixafor dose and then assuming safety broaden the high dose to all patients in the trial as we aim to enroll up to 18 patients in total. In summary, we believe that this Phase Ib study will enable us to define the optimal dosing of the combination with ibrutinib and help inform the design of further clinical trials in the double mutant population. With the ultimate goal of providing a meaningful novel treatment option for this most difficult-to-treat Waldenström's patients. With that, I will conclude and will begin our guest speaker segment. We're very pleased to have Dr. Christian Buske with us today for a fireside chat. Dr. Buske is a world-renowned expert in treating clinician in Waldenström’s macroglobulinemia. And we're going to have a series of questions with him. To begin, Dr. Buske. Could you please provide an overview of your background and experience in general and specifically to Waldenström?

Yes. Thanks a lot. Yes, I'm happy to do so. So my background, I'm a hematologist oncologist at the University Medical Center in Germany. I am a senior consultant in the hematology/oncology department and a professor. And now, my background is that I'm involved for a long time in clinical research, in non-Hodgkin's lymphoma, in particular, for Waldenström’s macroglobulinemia. I'm the founder of the European consortium for Waldenström’s macroglobulinemia and I'm running this consortium with my colleagues, including all relevant European clinical study groups. I'm also President of the -- one of the largest clinical study groups in Europe with regard to lymphoma, the German lymphoma alliance and I'm also responsible for national and international treatment guidelines in indolent lymphoma and particularly Waldenström’s macroglobulinemia.

Thank you, Christian. With that background, I think you can really give us a good overview of the general unmet need in patients with Waldenström. In general, and also specifically in the patients who also happen to have the CXCR4 gain of function mutations.

Yes. In general, what we have to be aware is that Waldenström’s macroglobulinemia is a disease where we have, at the moment, no curative treatment options. So this is a major drawback. So also with BTK inhibitors, such as ibrutinib, we actually are not achieving complete remissions in this disease. So this is for clear, something which we have to improve. The unmet medical need at the moment is despite this. To guarantee these patients live with Waldenström’s macroglobulinemia. So live where we control the disease without compromising quality of life. So this is, I think, very important when we look at Waldenström's patients. So we have certain subpopulation of patients who have particularly an unmedical need. So it's not that frequent, but we have Waldenström patients with certain genetic alterations, such as [ p53 ] divisions on mutations who show quite aggressive clinical cause. But I think a major subfraction of patients with a clear-cut need for improved treatment are the patients with the so-called CXCR4 mutation. So you mentioned this. So why is this so important? Because the CXCR4 mutation is very frequent, much more frequent. For instance, the mutation I just mentioned before, which hits up to 40% of all Waldenström’s patients. And what we know is that the CXCR4 mutation or the CXCR4 mutated patients have a clear-cut reduced sensitivity towards ibrutinib singular agent treatment, and they also have certain clinical characteristics, which are indicative of the more aggressive clinical cause. So as said, there's much room for improvement. And in particular, in the sub fraction of a subpopulation of patients with CXCR4 mutation, we have not, let's say, an ideal treatment so far for this highly relevant subgroup of patients.

Thank you. One of the clinical issues faced by the Waldenström's patients who also have the CXCR4 mutation is higher levels of serum immuno globin M. Could you comment as to why that is of clinical concern and why it would be important to make sure that these high levels are reduced and why doing that promptly is important?

Yes, that's exactly what I just alluded to. So as you said, so these patients with CXCR4 mutation and Waldenström's disease. So what we know is they have certain clinical characteristics. And they differ from patients who do not have the CXCR4 mutation. So one is that they have a significantly higher level of bone marrow disease which is important because the higher the bone marrow disease, the more the likelihood that you have a suppressed normal [indiscernible]. So as I said, they have a significantly higher serum IgM. I will come back to this in a second, why this is important. I'm also referring to your question. And what we also know based on these things, that they present much more often with a symptomatic disease requiring treatment. So in particular, higher IgM levels of concern in patients with Waldenström’s macroglobulinemia, because we know that a high IgM serum level can cause a lot of problems in these patients as when the IgM level rises to a certain level, the risk for hyperviscosity is dramatically increased. So hyperviscosity can actually then end up in a so-called hyperviscosity syndrome, so in a symptomatic hyperviscosity and this is actually an emergency case in Waldenström’s macroglobulinemia and requires immediate treatment. So this is why we have let's say, an eye on CXCR4 mutated patients. So with the notion that they have a more active disease, there is a higher dynamic of disease progression, and they are because of this higher serum IgM, more at risk to go into a symptomatic hyperviscosity.

On that point, could you please comment further on how do you think CXCR4 antagonist could potentially help with the treatment of this Waldenström patients who have the double mutation?

Yes. I think the concept of CXCR4 antagonist is indeed smart. Now I think it's a very nice example how biological insights -- into biology insights in the disease can really transfer to clinical implications. So what we know is that, as I said, 40 -- up to 40% of patients have this activating CXCR4 mutation. We know that clinically, I just mentioned the CXCR4 mutations are associated with a more aggressive disease via serum IgM. We also know from the lab that CXCR4 mutations are triggering the proliferation of Waldenström's macro glomera cells. So the concept to antagonize CXCR4 makes absolutely sense also from the biological perspective. And as said, it's not a rare mutation, but it's actually hits not half, but up to 40% of the patients or the concept to develop drugs, which are able to antagonize this activating CXCR4 mutation, I think, is very increasing.

Could you also comment on any benchmark data or even your own experience of what happens when these patients who have the CXCR4 mutation are treated with ibrutinib monotherapy? And specifically, what -- how do they respond in terms of lowering the serum IgM?

Yes. I think from our own experience, but I think it's very well confirmed by independent data sets, many investigators. We know that when you use ibrutinib single agent, that you have problems with CXCR4 mutated patients. So what we know is that when you compare CXCR4 mutated versus CXCR4 non mutated patients, that the rate of major responses. So of significant responses, clinical responses in patients dropped by nearly 30%. So you have nearly 100% [ major ] response rate, which is partial remission or better. When you have CXCR4 for wild-type, which drops then below 70%, just around 68%, when you have this double mutation. So what we also know, and is very important for patients is the time to response because you have to imagine patients are suffering from Waldenström. They want to go into remission because they want a relief of their symptoms. And we know that CXCR4 mutated patients respond to treatment much slower. It's a delayed response of the major responses achieved around a median of 5 months, whereas it's less of 2 months in the CXCR4 wild type patients. So what we also know is when we look at serum IgM, and we discussed this before, that with the wild type patients, you have around 70% reduction of IgM after half a year, whereas when you have a CXCR4 mutation, this drops down to 30% reduction of the serum IgM. So you see that you have many parameters, which demonstrate that CXCR4 mutated patients are a problem with a single agent ibrutinib.

One of the investigators on the ongoing combination study of mavorixafor with ibrutinib. Could you please share your general impressions of the mavorixafor data being disclosed as part of the EHA Congress?

I think these are encouraging data, of course. It's a very -- these are very early data. It's a limited number of patients. Of course, which is typical for this level of clinical trial. But what we see is the clear-cut efficacy, in combination with ibrutinib in the CXCR4 mutated patients. We see a clear anti lymphoma activity. And of course, it's difficult to compare to historical data with ibrutinib single agent. But when we do this, it looks like, of course, we have to be cautious, but it looks like that this combination of ibrutinib with the CXCR4 antagonist is quite effective in lowering the serum IgM levels, for instance. So what is also important when we look at the data is toxicity or the safety profile. And again, this is what we see with this number of patients, it's very encouraging. So we don't see any added toxicity when you compare to ibrutinib single agent so we don't see any new toxicity signal. And I think this is a very important take-home message because as said, Waldenström is -- cannot be cured so far by standard treatments. Which means quality of life is very important also for patients under treatment. And as it looks like, we do not compromise the quality of life of these patients compared to ibrutinib single agent treatment. And I think that's very important.

As the trial continues to enroll, including into the higher dose, and we plan to present later more on clinical response. What is your view of what success could look like into the future for the potential of this combination?

It's a great question. I think what we see already now is -- and I refer to this in my formal responses. But actually, yes, so the IgM dropped -- what we see with this, of course, limited number of patients is quite high. So it's up to 70% at 6 months in the 6-year for mutated patients. So compared to the numbers I just told you before, so around 30% reduction at 6 months for IgM and the CXCR4 mutated patients by ibrutinib single agent. And of course, we have to be cautious. It looks like that it's higher with the CXCR4 antagonist mavorixafor plus ibrutinib. So this is encouraging, but you're right. So this would be an important signal. But of course, we would love to have other success parameters in future studies or when we have, as I said, dose escalation in more patients. So what would be a clear-cut signal. So as I said, a major response rate with ibrutinib single agent is below 70% when we go in CXCR4 mutated patients. So now by adding the CXCR4 antagonist, mavorixafor, it would be great when we move this mega response rate above 80%. I think this would be a very nice signal of course, with our goal to have major response rates in the CXCR4 mutated patient population, which approaches at least the rate of major responses in the CXCR4 non mutated patients with ibrutinib single agent. So PFS, so the PFS with ibrutinib single agents, the 5-year PFS is around 38% with ibrutinib single agent in the [ CXCR4 ] mutated patients. So I think to move the 5-year PFS from 38% up to 60%, similar to what we achieved with ibrutinib single agent in the CXCR4 non mutated patients would be also a great signal. So the core message is a great signal would be that by adding your CXCR4 antagonist, you overcome the inferior sensitivity of CXCR4 mutated patients achieving similar response rates and progression for survival as seen in CXCR4 non mutated patients. So this would be a great signal.

And I think the final question a bit thinking towards the future, assuming that the data continues to support further clinical development and eventually inform an approval. How do you think you all and others could potentially use CXCR4 inhibitors such as mavorixafor in the Waldenström patients and how perhaps genetic testing could be done more widely and earlier?

I think when mavorixafor shows these signals we just discussed, I think it will be widely used. Because as said, for the patient, it's very important to go into remission because remission, it's such a theoretical term. But for the patient, it means a rise in hemoglobin, he's not -- he has no fatigue anymore. He has a better quality of life. It means lowering of IgM, less risk of hyperviscosity. And also what I just mentioned before, time to response is with this then shorter, the time to relieve of symptoms. So for the patient, it has clearcut practical implications. And based on this, I'm quite convinced that such a drug, which is already given. That's also very important. It's not an IV application. It can be given on an outpatient unit, such a compound would be widely used, as said, for patient subpopulation, which comes for around nearly 40% of all Waldenström patients.

Thank you very much, Dr. Buske for all your comments and the valuable information and your work on the trial. It's now my pleasure to introduce our CFO, Adam Mostafa to close out the formal portion of our event. Adam?

Thank you, Diego, and thank you to Dr. Buske for the engaging fireside chat. Looking ahead on Slide 23. We had a very exciting juncture in exports corporate growth. With a strong cash runway through the end of 2022, we are on the cusp of a series of transformative catalysts that we believe will shape the business for years to come. In Waldenström's, building on the excitement around today's data release, we will continue to enroll and dose escalate with a more fulsome data set, including response measures, expected to be revealed later in 2021. In our Phase III program in WHIM syndrome, we are nearing an important enrollment update. And later in the year, what we believe will be more confident building information on WHIM prevalence and patient identification. Along with a look into new long-term data from the open-label extension portion of our Phase II study in WHIM. As we broaden and diversify the business, we look forward to announcing initial data from our severe congenital neutropenia trial this year as well as providing updates across our R&D efforts and pipeline. This will all set the stage for a fast approaching 2022 when we expect to be able to announce top line Phase III data in WHIM as we grow into a commercial organization while maintaining an exciting and growing preclinical and clinical pipeline. Today marks the launch of a season of catalysts, long in the making at X4. We hope you'll join us for the journey. With that, operator, why don't we open up the call to questions?

[Operator Instructions] Our first question comes from Zegbeh Jallah with Ross Capital Partners.

Just had a quick question and more of a clarification, I guess. The subsequent patients being dosed after the 600-milligram dose is cleared, would they start at 200-milligram and then go directly to 600 milligram. So skipping 400 milligram? Or would they have to escalate to 400 milligram and then 600 milligram?

This is Paula. Nice to hear your voice. Diego, would you like to comment about the protocol?

Yes. Sure. Thank you for the question. So currently, there is dose escalation through 200 milligram, 400 milligram, 600 milligram. The patients that once cleared 400 milligrams are all going into 600 milligrams and once 600 milligrams is clear, there is still an intra-patient dose escalation. But we probably will work on further dosing that does not require that. It's been done just early as part of the safety assessment, but we don't believe that will be necessary down the road.

Perfect. And then just a quick follow-up. How many additional patients do you intend to enroll? And then how do you think the curve might shift assuming that patients eventually get to stride at 600 milligrams?

Yes. Thanks. Sorry, Diego. I'll make a quick comment, and then I'll turn it over to Diego. So I mean, I think [indiscernible] designed for 12 to 18 patients, so at least those initial 12 will help inform us about dose, which is certainly the major driver of the study, dose and safety. We certainly are excited about looking at higher doses, given the greater exposures of mavorixafor at 600 milligrams. And we believe certainly greater exposures can blunt the signaling that's driving part of this cancer forward even more meaningfully. But at the end of the day, we have to generate the data. But -- Diego, please, I'd appreciate if you add some additional comments.

Yes, that's right. The positive [indiscernible] today mostly reflects the initial dose at 200 milligram and then sustained treatment at 400 milligrams. So definitely, once Cohort B is enrolled and analyzed, we will look at what's the effect of the 600 milligrams dose. And as Paula said, of course, there is a potential to gain additional efficacy.

Thanks, Diego. I also thought will be interesting in terms of how rapidly patients respond when they're dosed at the 600-milligram dose. So it will be interesting to see, but congrats to the team on all the progress.

Our next question comes from Stephen Willey with Stifel.

Congrats on the data. I was wondering if you could maybe speak to the actual percent changes in IgM reductions that you're seeing in those 4 patients that are out to 6 months? I know you have, I guess the normalized CR patient, which is, again, I think, pretty impressive in this disease setting. But just curious where, I guess, the sub 50% patients are falling out in terms of IgM reduction?

Yes. Again, Stephen. What we're excited about is the fact that the cohort of patients that are treated for 6 months are really getting to IgM levels that are below what you've normally seen historically quite significantly. And I think in terms of any individual patients, I think what we want to do in the future is just, again, continue to show the overall totality of the impact across all patients. Like all the historicals, it's kind of best to look at the total cohort. I don't know. And then, of course, we're extremely excited about the normalized IgM in that 1 patient that we saw within the 6-month treatment period. But Diego, I don't know if you'd like to comment and add further insights there.

No, that's right. I think it's clear that at 6 months, we are seeing individual patient responses that are better than the published benchmarks. So we look forward to getting additional data later in the year. But so far I think there is a very nice results at the 6 months.

Yes. So can I add to this, I think -- it's Christian here. So the hematology. So I think the patients data, of course, are still very limited. So we have to be cautious, but just that you get a flavor. So what we would expect in ibrutinib single agent treated patients with mutation, you would expect around 30% IgM drop at this time point. And what we see here, again, we have to be cautious, it's 60% to 70%. So it's encouraging. So when this would hold true, this would be, as I said also in the interview before, this would be a very good signal.

Okay. And then I was also wondering, I know, again, it's very small patient numbers, but it was anything that you could detect between patients that have nonsense versus frameshift mutations? I know that there's been some suggestion in the literature that these nonsense mutation patients have a worse prognosis, I guess, both with respect to outcomes and baseline characteristics. And so was just wondering if you can speak to whether or not you see anything in this admittedly small data set? And then maybe Dr. Buske could comment on his thoughts around mutational type and whether or not that matters?

No, I think it's a great point, and you're aware and front. So it's absolutely true. So that seems to be a difference in the biology between frameshift and nonsense. And as you pointed out, with the nonsense to be associated more with a more definite outcome, but we have also to say that this data parts also in the literature are very limited and are originating actually just from one very important and phase group from Steve Treon's group. But -- so it's still limited data on this. But you're right, it might be that nonsense patients have inferior outcome. Actually, I have to give the question back to all our -- because I'm not aware of whether you had the chance to look at specifically at the 4 patients who had a nonsense versus frameshift, whether there was any major difference in IgM drops or whatever. So I don't have the data.

Thanks, Dr. Buske. Actually, Art, would you mind commenting because we certainly -- certainly start to look at that data, although, obviously, it's a limited data set.

Sure. Happy to. Steve, so we've looked at that and we looked at all the patients, and we looked at the starting serum IgM level as a function of what the mutation status was. We looked at the relative drops and the end status. And so what we see from all the 8 patients, it's literally 50-50 mix between the nonsense and the frameshift. There is no clear correlation at all of the starting IgM level. So we have frameshifts that are super high, and many of the patients are already starting at incredible levels of serum IgM that obviously puts them at significant risk of HVS. We looked at the drops and there was no clear correlation at all between the frameshifts and the nonsense. So the -- all the drops, the significant drops, it's literally 50-50 in terms of nonsense and frameshift. So right now, based on our own data and analysis, there's no clear correlation between frameshift and nonsense in terms of the starting IgM level or their relative rate of drop. So it's not clear in terms of the biology guess but what we do know is that we're dropping [indiscernible] for all patients.

That's really helpful commentary. And then just one quick last follow-up. Have you enrolled any additional patients since the cutoff date?

Diego, you want to add?

Yes, Steve. Enrollment continues, and we look forward to reporting data on additional patients, not only longer follow-up of the current A patient. So the answer is yes.

Our next question comes from Leland Gershell with Oppenheimer.

A few questions for Dr. Buske. Clearly, it seems like the data validate the utility of mavorixafor with BTK inhibitors for Waldenström. We know with BeiGene's ibrutinib, [indiscernible] now in review for [indiscernible] expansion to Waldenström's. I wanted to ask what your interest would be in seeing a combination studies with that agent with mavorixafor. And also wanted to ask, given these data, although they're early, there is, obviously, a competitive space of candidates out there being built for this indication that don't necessarily relate to CXCR4, but have shown encouraging data, BCL2, [indiscernible], other approaches. I want to ask, given these data and given the mechanism, would any patient with CXCR4 mutations in Waldenström's pretty much put mavorixafor as [indiscernible] choice at this point given the mechanism and the data. And my last question is, do these data at all will affect your outlook on the ability of mavorixafor to provide benefit in severe congenital neutropenia, which the company is also looking at?

So probably I didn't get -- we did not get everything acoustically. So -- so yes, when I understood you correctly. So there are, of course, other compounds being developed or present environment from [indiscernible], but and you ask for combination partners. And I think also the landscape a little bit in Waldenström's and competitors, when I understood it correctly. So I think the concept to combine it with ibrutinib was and is the right concept because ibrutinib, as you -- if you like, like a backbone of treatment nowadays. So -- but what chemotherapy was before a backbone, and we try to optimize chemotherapy. Now it's a little bit like with ibrutinib. It's the backbone, and we try to optimize ibrutinib. So I think the concept to combine it with ibrutinib, it makes a lot of sense because ibrutinib has these limitations. And there are also new second-generation BTK inhibitors such as zanubrutinib or acalabrutinib. And at least for zanubrutinib that also the second-generation BTK inhibitors have difficulties in CXCR4 mutated patients. So it makes absolutely sense to use this drug in the CXCR4 mutated patient population. So there are other compounds such as venetoclax. As I said, so it's not fully published. So we have to wait for this. But the venetoclax efficacy in Waldenström is great. This was an abstract and an oral presentation at different meetings, but also in the CXCR4 mutated, venetoclax shows an inferior outcome. So meaning that new drugs do not make or let's say, eradicate the need for CXCR4 antagonist because they seem to have the same problem. This also means it makes sense in later trials also to think about combining mavorixafor with other compounds, such as venetoclax, for instance. I hope this was the right response to your question because the acoustics are not perfect. And the second was, I think, with regard to congenital neutropenia or something?

If the data -- if these data support your outlook on the potential for mavorixafor to have a benefit in that -- those patients [indiscernible]

So you mean the data we have for congenital neutropenia, whether they support the use in Waldenström or?

No, no. Just -- if these data incrementally provide support for -- given that it's another hematologic disorder, given SCM...

For other hematologic disorders. Okay. That's also -- I think what we can say is that CXCR4 is a great surface protein to targets because CXCR4 plays a major role in a variety of tests. And so we know that CXCR4 is a driving force for cancer stem cells for a variety of solid cancers. And we know when we stay with hematological new players, we know that CXCR4 acts also as a clear-cut growth signal in other lymphomas, such as [indiscernible] leukemia. We know that, for instance, in acute myeloleukemia, which is driven by leukemic stem cells, [indiscernible] is a key signal for maintaining and for growth of acute myocyte cell clones. So we discussed this before. I think for CXCR4, they have a great potential to act beyond Waldenström. And Waldenström is very intriguing because you have these activating mutations. But we also know that without being mutated, CXCR4 plays a major role for the maintenance and survival of [indiscernible] clones and other cancers.

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

Congrats on the progress. So just a couple of quick ones on the study for David, maybe. So on the 4 patients that my understanding are beyond the 6-month follow-up, could you comment on how far along the remaining 4 are? And and then also, how should we think about your next update, possibly before ASH, assuming the declines here remains kind of the dose-dependent signal we are seeing here?

Yes. Diego, could you take that?

Yes, that's right. The dosing continues in all the patients. So the ones that -- by the April cut off across 6 months. Of course, now there are several more months into treatment. Other patients are being enrolled. Dose escalation is proceeding to the 600 milligrams and as Paula mentioned earlier, we are doing a full assessment of clinical response at 6 months, including bone marrow biopsies and whole body CTs for those who had [indiscernible] at baseline. So when we present data later in the year, you're going to get data on more patients, longer treatment as well as clinical responses. The poster we are presenting today, as you saw, is focus in terms of efficacy on the emerging data on serum IgM and hemoglobin, but more to come.

Great. And then as you mentioned, that total of 18 patients, is it kind of fair to assume that the remaining somewhere closer to 10 would be on the highest dose. Is that kind of what we should think about?

So the way the study is designed cohort, Cohort A was designed to clear 200 milligram and 400-milligram doses, and we have completed that. That's the data you've seen in the poster. Cohort B, is designed to clear the 600-milligram dose. Once that happens, the 600-milligram dose will be offered to everyone. And the sample size is 12 to 18. So we have the opportunity to enroll additional patients. We believe a minimum that we need is 12. And if the safety allows, we will get everybody on 600 milligrams and see what happens.

Okay. Great. And Dr. Buske, appreciate the comprehensive update. So just trying to make sense of the impressive IgM kinetics and then think about the clinical responses. Like what would you like to see before you sort of gain confidence to move this into a pivotal trial? Like how much -- what sort of MR or VGPR that you think makes sense there. And maybe there is a comment on the ideal treatment setting where you can start out with, but you can see this being beneficial for patients, maybe even in the first-line setting, if that makes sense?

Yes. So I think I would not wait too long to go for pivotal or trial. So it's in -- as we heard, it's a very early phase trial dose escalating, which, of course, major purposes to look at feasibility and toxicity. So what I would like to see, probably at this stage, I would take an early parameter. I think it's impossible to take progression-free survival. So an event with parameter for the decision to move forward or not. I think when you see that you have no added toxicity compared to ibrutinib single agent. And when we see that the IgM drops in the range what we see with ibrutinib single agent in CXCR4 wild type patients. So when we see that the major response is in the range above what we see with ibrutinib single agent, I would have the courage to go into a larger trial, which clearly aims at validating this early response parameter and adding an event-driven parameters such as PFS. So this will be my concept. Yes. So you have early parameters, IgM drop, hemoglobin rise, major response rates, which will allow you to have confidence that it's worth to go to a larger Phase II randomized Phase II trial. So I think the basic concept is actually very clear. So with ibrutinib, you have a chemotype mutational type depending activity. And this is a clear limitation. So with adding the [indiscernible], we want to break through this genotype depending activity of a ibrutinib single agent, yes. So you want to be as good as in CXCR4 for wild type patients. And I think you have the parameters to judge this.

Our next question comes from RK with H.C. Wainwright.

Most of my questions have been answered, but I have really 2 quick questions. Number one, how many patients are still on the study? And of the 8 patients that reached 3 cycles of treatment. How many of the 8 patients that reached the 3 cycles of treatment have greater than 25% IgM reduction?

RK. Sorry about that. Just try to repeat your questions. You're just saying how many patients are still on study? So again, we're providing the April 15 cutoff. We're continuing to enroll, and then we'll provide updates on the full cohort towards the end of the year. And then in terms of how many patients had greater than 25% reductions in IgM. I don't think we've broken out the data specifically in the poster, but all I can say is it's continuing to look very encouraging. Certainly, to a degree that give us the continued confidence that we're separating from ibrutinib and showing something meaningfully different, but not sharing any of that level of detail. Diego, do you want to add anything to that?

No, no, that's right, Paula.

Okay. Then my last question is, looking at the curves, and trying to understand what's going -- what's happening pharmacodynamically between the months 3 and 5 or between the second and third of the mid dose, the 400 milligrams, where we actually see [indiscernible] and even hemoglobin numbers. And then rapidly drops. So I'm just trying to understand biologically what's going on? And do you think in real life, you might have to do some sort of titration just to make sure that says smoothening of the drop?

Yes. RK, I'll repeat the question. I think you're asking -- you're wondering about, is there -- there a need to dose titrate patients up just based on looking at the IgM kinetics?

Yes.

My initial response is, no. The reason why we're dosing [indiscernible] is to ensure safety and also maximize the information that we can get on a per patient basis, given how rare the disease is. But certainly, as we clear safety threshold, we'll feel comfortable dosing patients with the highest dose of the safety of course. And again, Diego, I'd invite you in to add some further color to that, as you feel appropriate.

Yes, that's right. We don't have really any evidence that we need to titrate mavorixafor. We've been cautious here in agreement with regulators because we are dosing with ibrutinib and there is always the potential to alter the PK. But as we said so far, we have not seen that. So that's encouraging. Down the road, if everything continues away this, I don't believe we will have a titrate.

Our last question comes from Laura Christianson with Cowen.

My first is just specific [indiscernible] of patients who experience hypertension of any grade with the combination and then additionally, the percentage that it had in anti hypertensive added on their treatment therapies.

Sorry, do you just want a little bit more color on that patient? Is that the direction of your question?

Yes. I mean, it's based on -- yes, in the abstract, you guys first, just so the patient who had the dose, the hypertension that ibrutinib does, is associated with hypertension and typically can be controlled with anti hypertensives, but I just wanted to see if you were seeing a higher rate of hypertension with the combination?

Yes. Sure, Diego, do you want to take that?

Yes. Laura, no, we haven't. We've had that case that we presented in the poster. It seems to be pretty typical of what you see in ibrutinib monotherapy and responded nicely to anti hypertensives. And maybe Dr. Buske can comment in general about hypertension with ibrutinib and any issues handling it?

Yes. So I think it's a known side effect, which can be actually handled very well by a normal treatments, we know from internal medicine, let's say. And so it's a side effect. I think it's absolutely validated that ibrutinib has this side effect, also when you compare to second-generation BTK inhibitors, they have less -- they induce less hypotonic values. But from the daily clinical life, so this is not a major indication to use ibrutinib. I think we have to say. So it can be well managed. And for us, it's not a major limitation to use ibrutinib to the side effect.

Perfect. That's helpful. And then my final question is just if you're able to share how responses vary between treatment naïve and treatment-experienced patients?

Yes. Thanks, Laura. We haven't broken out those data just yet. And obviously, the patients are starting at a decent range of IgM levels. I think we're really excited because we've seen reductions in all of our patients as we reported. And then I think, certainly, as there's a larger cohort of patients, we'll be able to comment on what line of treatment. But just to remind you, CXCR4 mutations seem to impact response ibrutinib or regardless of line of treatment as we've kind of shared with our benchmarks. So thus far, we're seeing a reaction to the combination equally independent, meaning we're seeing nice IgM drops across all those populations. But Diego, would you like to add some more color to that?

Yes. No, that's right. So far, again, low numbers, but no apparent difference, and we are enrolling from both. And as we report data later in the year, we probably will give you more color on that.

And this concludes our Q&A session. I would like to turn the call back to Paula Ragan for her final thoughts.

Well, thank you so much, everyone. We really appreciate your participation in today's conference. If you have any further questions or for any further information, please don't hesitate to reach out to us. Thanks again, and have a great weekend.

Thank you, ladies and gentlemen. This concludes today's program. You may now disconnect.