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

Greetings, and welcome to X4 Pharmaceuticals Third Quarter 2022 Conference Call. [Operator Instructions] As a reminder, this conference call is being recorded. It is now my pleasure to introduce your host, Dan Ferry from LifeSci Advisors. Please begin.

Thank you, operator, and good morning, everyone. Presenting on today's call will be X4's Chief Executive Officer, Dr. Paula Ragan; and Chief Medical Officer, Diego Cadavid. We all see here briefly from the company's new Chief Commercial Officer, Mark Baldry, and company Board Member and incoming Interim Chief Medical Officer, Dr. Murray Stewart. Following prepared remarks, we will open the call to your questions and will be joined by Chief Financial Officer, Adam Mostafa; Chief Scientific Officer, Arthur Taveras; and Chief Operating Officer, Mary DiBiase. As a reminder, on today's call, the company will be making forward-looking statements regarding regulatory and product development plans as well as research activities. 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 X4's most recent filings with the SEC, including this quarter's 10-Q, which is expected to be filed after market close today. I'd now like to turn the call over to X4's President and CEO, Dr. Paula Ragan. Paula?

Thanks, Dan, and thank you, everyone, for joining us on the call this morning. As we shared in the press release this morning and as Dan just mentioned, Diego will be transitioning out of his role as Chief Medical Officer and becoming a Senior Medical Consultant to X4 and our Board Member, Dr. Murray Stewart, former Chief Medical Officer of GSK and Rhythm Pharmaceuticals, will be joining X4 as Interim CMO. At the end of today's call, Murray will say a few words of introduction. As we welcome new team members, we are extremely excited to share the progress that we've been making as we sharpen our focus as a company with a mission to develop therapeutics to treat the broad patient population with chronic neutropenic disorders, including our first potential indication of WHIM syndrome and where we believe there is a significant need for an oral efficacious therapy with low treatment burden and good tolerability. With no oral therapeutic approved for approximately 50,000 chronic neutropenia patients in the U.S., we believe that mavorixafor, if approved, could represent a new opportunity to transform the treatment landscape and create a new standard of care. Today, the focus of the call will be to provide updates on mavorixafor progress in our global pivotal Phase 3 trial and WHIM syndrome, and to highlight how we are getting appropriately prepared to ramp into commercial launch. Mavorixafor is being studied in an ongoing Phase 3 for the treatment of WHIM syndrome, which is a population of people with severe neutropenia as well as other immune system deficiencies. WHIM syndrome is considered a combined immunodeficiency because patients with WHIM not only have profoundly low neutrophil counts, but also low lymphocyte and monocyte counts, and sometimes low antibody production, which is referred to as hypogammaglobulinemia. We believe that mavorixafor has the potential to favorably impact the combined immunodeficiencies of those with WHIM syndrome and also has the potential to favorably impact a potentially broader population diagnosed with chronic neutropenic disorders. I'd like to take a minute now to review WHIM syndrome and how patients are diagnosed. Next slide, please. As I mentioned, WHIM syndrome is a combined immunodeficiency impacting people from birth. Patients have profoundly low neutrophil counts as well as abnormally low lymphocyte and monocyte counts and in many cases, low immunoglobulin levels. The WHI and M of WHIM represents the variable presentation of the disease, which can range from severe work presentations, the W; and HPV-associated disease to low immunoglobulin levels, the H for hypogammaglobulinemia; increased susceptibility to frequent infections, the I; and retention of neutrophils in the bone marrow called myelokathexis, the M, which explains the severe chronic neutropenia. Patients can present with one or more of these disease manifestations in addition to low neutrophils, lymphocytes and monocytes. In view of this variable and complex clinical phenotype, a range of inputs is utilized by clinicians to diagnose WHIM syndrome. According to leading experts in this field, one of the most reliable ways to begin the journey of diagnosing WHIM is to examine total white blood cell counts, which includes neutrophils, lymphocytes and monocytes, and look for multiple decreased white blood cell types referred to as panleukopenia. As a consequence of the panleukopenia, people with WHIM syndrome experienced lifelong risk of bacterial, fungal and viral infections with particular susceptibility to refractory warts due to infection by human papillomavirus, which can evolve into HPV-related cancers. Infections can be severe, including sepsis. Bone marrow biopsies can be utilized in the diagnostic journey. Although it may not always be done due to the pain of potential morbidity associated with this needle-based invasive procedure. Upon microscopic evaluation, the hyper mature or hypersegmented neutrophils in the bone marrow are important findings to corroborate the diagnosis of WHIM syndrome. In fact, the disease was initially called myelokathexis before there was knowledge about genetic mutations. Genetic testing to look for gain-of-function mutations in the CXCR4 receptor is the confirmational assessment most often used. Interestingly, genetic analysis in patients with a clinical diagnosis of WHIM syndrome, but without CXCR4 mutations, have identified new genetic mutations, including mutations and genes associated with the signaling half cascade such as CXCR2. In fact, in these individuals, neutrophil shared functional alterations of CXCR4-mediated responses despite the lack of CXCR4 mutations. Finally, a family history of WHIM syndrome also supports the ultimate diagnosis in any individual patient due to the autosomal dominant nature of the disease for those with CXCR4 mutations. We continue to support the needs of the medical community to facilitate awareness and earlier and accurate diagnosis of WHIM syndrome via multiple approaches, including knowledge of the variable clinical manifestations, pathologic abnormalities in the bone marrow, genetic mutations and family history assessments. Importantly, there are no approved treatments specifically for WHIM syndrome. Existing treatments only address individual components of the disease, such as giving high-dose immunoglobulin to treat the low antibody levels or G-CSF injections to treat the neutropenia, which is often poorly tolerated for chronic use. We recently completed the randomized placebo-controlled portion of the Phase 3 study of mavorixafor in WHIM, which is testing for the first time in a registrational study a targeted treatment that specifically addresses the root cause with the potential to improve the full spectrum of problems associated with the disease. I'll now turn it over to Diego to review our Phase 3 study design and our historical data that supports why we are so excited about our pending pivotal trial results. Diego?

Thank you, Paula. I'll now briefly review the study design of our 4WHIM global registrational trial assessing mavorixafor as a potential treatment of WHIM syndrome. As Paula mentioned, the design is a randomized placebo-controlled and double-blinded study. We completed enrollment in Q3 of last year over enrolling the trial with 31 patients from 12 countries. We have now completed the last patient, last visit for the placebo-controlled 52-week period and are diligently working towards database lock. The study inclusion criteria required that all patients enrolled had a confirmed absolute neutrophil count or ANC, less than or equal to 400 cells per microliters during screening. For the 31 patients enrolled in the trial, the average pretreatment ANC was 220 cells per microliter, an indication of the severity of chronic neutropenia that characterizes WHIM syndrome. Recall that an ANC less than 500 cells per microliter is considered severe neutropenia, indicating that this population was severely neutropenic as they enter the study. Importantly, almost half of the patients enrolled were pediatric between 12 and 17 years of age, which supports the potential for us to receive a rare pediatric disease priority review voucher or PRV upon approval of mavorixafor, a significant potential value to the company. At the end of the placebo-controlled portion of the study, all participants were eligible to roll over into the open-label extension or OLE study. Notably, more than 90% of eligible participants elected to continue on and receive mavorixafor treatment in the OLE. We are continuing to collect data from this ongoing portion of the trial. Safety from the trial has been monitored regularly by a data safety monitoring board, which has endorsed the continuation of the study without any protocol modifications due to safety or tolerability. As I mentioned, we have now completed last patient last visit in the placebo-controlled portion of the trial. The blinded data are being reviewed by an independent adjudication committee and database lock is soon to follow. We continue to expect announcing Phase 3 top line data in the fourth quarter of this year. Next slide, please. We have a robust series of metrics to assess the efficacy and safety of mavorixafor in WHIM patients in this Phase 3 trial. The primary endpoint is a metric called TAT ANC, which is time above threshold, or TAT for short, for absolute neutrophil count, or ANC. It is an assessment of mavorixafor's potential to raise neutrophil counts above the severe neutropenia threshold over a 24-hour period. Participants in the study were dosed once daily for 52 weeks with either placebo or mavorixafor. The 24-hour TAT ANC was measured 4x during the 52-week treatment period, approximately once every 12 weeks. The study's first key secondary endpoint is time above threshold for absolute lymphocyte counts or TAT ALC. Calculations follow the same approach as for TAT ANC. Assessment of TAT ALC is important for WHIM patients who suffer from significant lymphopenia and hypogammaglobulinemia. Recall that lymphocytes are mostly BMT cells and are key for mounting effective immune responses. The graph here presents how time above threshold is calculated. Patients undergo a series of up to 12 blood draws over a 24-hour time frame, and levels are measured via standard CVC methods and plotted versus time. Time above threshold is the amount of time in hours that neutrophil or lymphocyte counts are equal to or above certain thresholds. Here, 500 cells per microliter for neutrophil and 1,000 cells per microliter for lymphocytes. Finally, there is a comprehensive list of clinical endpoints, both key secondary and exploratory endpoints, to assess the clinical impact of mavorixafor over placebo during the first year of treatment. A few of them are listed here organized by category. One category is patient and physician-reported outcomes, or PROs. The second category is related to infections and warts. The third category is response to vaccine and the fourth category is safety, tolerability and PK. There are also several prespecified subgroup analysis. This robust and comprehensive study design reflects the guidance provided by the FDA over a number of consultations, and we will share more specifics on this in a few slides. Next slide, please. As you can see here, the Phase 2 endpoints closely mirror our Phase 3 end points and the success of this trial, along with results from the Phase 2 open-label extension study, has formed the basis of our confidence in Phase 3 success. The positive Phase 2 results not only inform the Phase 3 trial design, but also served as the basis for the power assumptions for the primary and the top secondary endpoint of the Phase 3 trial. Based on the blinded baseline ANC and ALC of the 31 subjects enrolled and the high retention rate in this study, the primary endpoint of the Phase 3 trial in WHIM syndrome is powered to greater than 95%. In the Phase 2 study, we saw that all patients responded to mavorixafor treatment with increased neutrophil and lymphocyte counts. Increases in both TAT ANC and TAT ALC upon treatment with a 400-milligram dose, which was the dose selected for the Phase 3 trial, ranged between approximately 2 and 24 hours. Importantly, these observed increases in TAT ANC and TAT ALC in the Phase 2 trial were associated with clinical benefit, including positive patient-reported outcomes, reductions in both the rate of infections and the wart burden, and equally importantly mavorixafor was well tolerated throughout the study, including the long-term extension. Recall this favorable Phase 2 results resulted in the FDA granting us breakthrough therapy designation or BTD for mavorixafor for the treatment of WHIM syndrome. Also recall that the hurdle for BTD is high and required preliminary clinical evidence from our Phase 2 study that indicated that the drug may demonstrate substantial improvement on a clinically significant endpoint or endpoints over available therapies. The totality of the Phase 2 data was shared with the FDA and supported the award of BTD for mavorixafor in WHIM. On this slide, we provide a patient-specific view on the impact of once-daily oral treatment of mavorixafor in a participant in the Phase 2 study. This study participant was a 24-year-old female with a long history of large refractory warts that had a major negative impact on her quality of life and cancer risk. She also reported frequent sinus infections. In this close up, you can see the large compound warts encasing her nail and part of her thumb. Additional warts of even larger sizes were distributed over her hands and feet. A dramatic reduction in the subject's white lesions was evident over a time during the Phase 2 study. These images captured this favorable change. The thumb image on the left shows the wart lesions prior to treatment. The image on the right shows the same thumb after the subject was treated for almost a year with a 400 milligram once daily dose. We can see that in many areas, the lesions are almost completely resolved. Similar reductions were visibly evident across most of our other lesions as well. This same patient was interviewed after more than 3 years of treatment. She reported on her experiences as overall reducing her infections and wart burden, and reported an improvement based on the Patient Global Impression of Change, or PGIC, questioner. We have included the PGIC assessment among other patient and physician reported outcomes in our Phase 3 trial. Next slide, please. Since the initiation of our INV for mavorixafor in WHIM syndrome, we have had ongoing interactions with the FDA, and frequent engagement with the agency has continued under breakthrough therapy designation and in the context of an orphan-drug designation. Importantly, the FDA has provided clear guidance that has informed our study design endpoints and plant analysis. They have recognized the variety and heterogeneity of WHIM syndrome and have guided us on our endpoints, including combining assessments of infections and warts into a single composite endpoint to optimize the potential for the trial to show a difference between mavorixafor and placebo on infection-related metrics with the available sample size. X4 has followed all of the guidance provided by the FDA and we are looking forward to announcing top line results later this quarter. Once the data are unblinded and analyzed, we plan to share data that will include the primary endpoint, TAT ANC, and likely the first key secondary endpoint, TAT ALC, along with the trial safety assessments. I'll now turn it back to Paula.

Thank you, Diego. We believe mavorixafor before is well positioned to make history by being the first treatment specifically developed for the treatment of WHIM syndrome. Based on our discussions with the agency, we expect our label to be focused on those aged 12 and older diagnosed with WHIM syndrome. It has been an ongoing commitment of X4 to support education, awareness and ultimately, the diagnosis of WHIM syndrome in the medical and patient communities. As previously described, the diagnosis of WHIM requires a clinical assessment, consistent with one or more of the various phenotypes of the WHI and M in a setting of combined immunodeficiency that is neutropenia, lymphopenia, monocytopenia and/or hypogammaglobulinemia. And can potentially include bone marrow examination as well as genetic testing assessments and family history information. We've been investing in a breadth of activities to support the clinical and patient community as outlined here, and I'd like to highlight a few more recent efforts. We've begun collaborating with a bone marrow pathology expert with the potential to establish a Myelokathexis Center of Excellence. In the future, we envision such a center could be a place where physicians can send bone marrow samples for a second opinion to be analyzed by those experienced with mild kathexis to aid in a potential diagnosis of WHIM syndrome. Additionally, we have hired a patient education liaison, a medically trained professional, who can compliantly engage directly with patients and their families to support the potential for genetic testing amongst individuals or kindred members within the same family. And finally, we are excited to support the International Patient Organization for Primary Immunodeficiencies or IPOPI in establishing a global registry for people with WHIM syndrome. By bringing together those working across a breadth of existing immunodeficiencies, including a patient foundation, patient community representative, experts in WHIM syndrome and academic centers in the U.S. and abroad, we believe this registry has the potential to be a great resource for the WHIM patient community, their physicians and for drug development companies such as X4 to learn even more about the disease. Next slide, please. I hope you can now see why we are so excited for the unblinding of our Phase 3 trial results. Assuming a successful Phase 3, we are already gearing up for an NDA submission in the early part of the second half of 2023 and if approved, preparing for the U.S. launch of mavorixafor in the first half of 2024. EMA filing is expected to follow our U.S. filing by about 12 months. And if approved, we expect commercial launch would be initially focused in the top 5 to 7 European markets with others to follow. We may consider partners to support the launch of mavorixafor in territories outside of the U.S. in these key European countries. We will update you at a future point when we have clarity into any potential partnerships. Next slide, please. As Dan mentioned earlier, we are joined on this morning's call by Mark Baldry, our new Chief Commercial Officer. Today is actually Mark's first day at X4, we couldn't be more pleased to welcome him. As a quick background, Mark comes to us with more than 30 years of experience in global life science commercial strategy and operations, having launched multiple orphan and rare disease therapeutics. He's particularly skilled in building and coordinating global teams and equally importantly is as passionate as we are about innovating for patients in need. We consider ourselves very fortunate to have someone with Mark's background joining us at this critical time in our corporate evolution and are looking forward to getting Mark's up to speed on our mavorixafor program and continuing to advance our commercial readiness as we approach the unblinding of our Phase 3 4WHIM trial. Welcome Mark, to your first day at X4.

Thank you, Paula. I'm really pleased to be here, and I'm looking forward to digging in. This is such an exciting time at X4. And as you've just outlined, a great opportunity for me to help support 3 commercial efforts. And hopefully, the commercial launch of mavorixafor and its first indication. I spent much of my career focused on launching innovative therapeutics that we're able to transform the lives of patients around the world who are living with rare diseases. And I've joined X4 because I can clearly see the potential of mavorixafor to not only become the first therapy for people with WHIM syndrome, but also to become a new standard of care for those with chronic neutropenic disorders who face considerable challenges with currently available therapies. So I'm really looking forward to working with you and the whole X4 team.

As a remark, thanks. Next slide, please. As you would expect, preparing the product, the market and the company for commercialization to ensure mavorixafor treatment reaches patients with WHIM syndrome is well underway in anticipation of the Phase 3 data and leading up to planned 2024 launch, if approved. Here, I want to share some additional ongoing activities and near-term planning and highlight several spokes to building the commercial wheel and getting it rolling. I've already mentioned the team of people we have in place out in the field, PDLs and PEL and in the home office. In its pre-commercial phase and under Mark Baldry's leadership, we intend to right-build the commercial team as we enter into the next phase of preparation. These customer-facing people are actively engaged with health care professionals, patients and patient communities to raise awareness of WHIM, educate on recognizing and diagnosing disease, and communicating the potential of mavorixafor through medical channels. We have also conducted primary payer research with U.S. and European payers to understand the issues and opportunities to gain market access. We've begun to identify the capabilities we need to build and define the full spectrum of health care value that mavorixafor may demonstrate and ensure access for patients. On the manufacturing front, registration batches have been completed. The key requirements, core components and partnerships are well underway to ensure a stable and efficient commercial supply chain and specialty distribution network. And lastly, from a marketing standpoint, we have secured conditional approval of a brand name with the FDA, an exciting step for mavorixafor. Additionally, we have conducted early health care professional market research focused on targeting the physicians most likely to have a WHIM or potential WHIM patient, introduce tools available to the patient and ACPs on disease awareness, and are developing full branding. Next slide, please. As we move towards an anticipated approval in WHIM, we would like to highlight that our time and commitment to launching in WHIM will be leveraged towards improving our potential future success in developing mavorixafor for indications that may treat the broader chronic neutropenia community. The same physicians that treat WHIM syndrome also treat those patients with chronic neutropenic disorders. The same patient foundations that support WHIM patients also support those with chronic neutropenic disorders. In fact, we've already seen these synergies benefit patients and physicians. For example, our free genetic testing program called Path Forward has enabled physicians to diagnose new patients across the full range of chronic neutropenic disorders, including WHIM syndrome and other congenital neutropenias. Additionally, we see the synergy of potentially translating into support for the additional enrollment in our amended Phase 1b2 and anticipated CN Phase 3 trials, and of course further expanding our network of medical experts that diagnose, manage and care for these patients. Finally, we expect highly leveraged distribution channels for drug supply and payer interactions to support market access to optimize our future sales for the WHIM indication if approved and our bottom line. Next slide, please. We believe that mavorixafor had a great feature ahead. If approved for the WHIM indication, we intend to continue to develop mavorixafor in additional indications where we believe it has the potential to become the only oral treatment approved for an array of chronic neutropenia disorders. As presented over the last few years in the context of various clinical trials, we've seen dramatic and sustained increases in neutrophil counts with all patients responding to mavorixafor, including across all of the CN disorders we studied thus far. As a result, we plan to study whether mavorixafor has the potential to treat up to 50,000 patients currently diagnosed with idiopathic, congenital and cyclic neutropenia in the U.S. And we are on the cusp of a potentially positive Phase 3 trial that could support a U.S. launch in 2024. The launch that could not only begin to generate meaningful revenue for X4, but can also set the company up to maximize success in chronic neutropenia disorders beyond WHIM syndrome. In closing, you can see that we expect a steady cadence of milestones ahead of us, starting with our potentially transformative WHIM Phase 3 data later this quarter, followed by additional expected CN data and potential initial clarity on the regulatory path forward for mavorixafor in CN in the first half of 2023. Assuming positive Phase 3 results in WHIM, our NDA filing for mavorixafor is on track for early in the second half of 2023, and we're aiming to be Phase 3 ready to move forward with advancing a CN registration trial following the expected filing of our NDA and WHIM. As I mentioned at the beginning of this call, we believe mavorixafor is poised to change the treatment landscape in chronic neutropenia, starting with WHIM, and expanding into idiopathic cyclic and congenital neutropenia, and X4 is ready for this transformation. We are ready to go. And one last thing before we conclude. We'd like to officially welcome Dr. Murray Stewart as our interim CMO. He has a wealth of experience in the development and launch of rare disease therapeutics from his previous CMO role at GlaxoSmithKline and Rhythm Pharmaceuticals, and he has helped guide multiple successful NDA filings throughout his career. We are fortunate to have him join us during this exciting time for X4. Murray is on the call with us today. Murray, would you like to say a few words?

Thanks, Paula. I'm really pleased that I'm able to support X4 at this time and look forward to working with the whole X4 team as we're poised to unblind the Phase 3 data and advance as quickly as possible to an NDA submission. Having been part of the X4 story for several years now, I'm really excited to help the company bring an important new treatment option to patients.

Thank you, Murray. And with that, why don't we now open the call up for your questions. Operator?

[Operator Instructions] The first question is from Stephen Willey with Stifel.

And I appreciate the update and the overview ahead of data. I know that it was mentioned, I guess, the average ANC count of patients pretreatment. Do you happen to know also what proportion of patients pretreatment were severely lymphopenic as well in terms of what the average ALC was?

Steve, it's Paula. Thank you so much for the excellent question. I think my understanding is they are quite severely lymphopenic as well. The actual number I think is escaping us at this moment, but I believe we published in an abstract back in April some of the details. So we're happy to take that offline with you and make sure you get that information.

Okay. No, that's fine. I can dig that up. And then have you been able to see just the blinded infection rate that's been observed in the trial to date? Just curious as to whether or not that's information that you're privy to, and I guess whether or not that's kind of tracking to expectations.

Yes. So we are able to look at overall blinded safety-related events, which, of course, infections are one of them. I'll refer to Diego to provide any more context on that.

Yes. This is something that the team has monitored, as Paula said. And yes, we have seen infection events. Of course, we're completely behind it. We have a very rigorous process of central adjudication and they are actually working now to finish that, and that will poise the trial to help us. It's one of the metrics of clinical benefit that we are tracking, obviously, among several others. But yes, I think we've seen a good number of infections that we believe is consistent with what we expect now that the pandemic impact has been somehow mitigated.

That's helpful. And then just lastly, maybe a little bit of a bigger picture question, but I know that you're kind of now talking about the addressable patient opportunity as being, I guess, in the 50,000 range. I know that you had previously indicated or estimated that the proportion of patients, I think, in the U.S. who were on chronic G-CSF was maybe somewhere in the 2,500 range. How do you think about the disconnect between those 2 numbers? How do you close that gap in chronic neutropenia specifically? And then how does that 50,000 number factor into your thoughts around this initial mavorixafor price set?

Yes. So a couple of things, Steve. Thank you for highlighting that disconnect. So the 2,500 number that we threw out previously was really based on registry data. So of course, it doesn't really capture the average utility out in what I would call the commercial setting, #1, and it's very difficult. So G-CSF is used intermittently in many patients. So how you define chronic, semi-chronic is another challenge for us as we consider the number of patients on GE, then also to highlight only about half of them can tolerate it based on our patient surveys. Of course, we don't even know what we're not capturing underneath that approach as well. So I hear you on the disconnect. I'm actually not worried about the overall market size for folks with chronic neutropenia. It's a massively underserved market with a treatment that is incredibly painful to take on a daily basis. So we think there's certainly a lot of opportunity to further uncover these patients who really need something new.

And then just how that factors into how you're currently thinking about the pricing decision on mavorixafor, with the understanding that you're still a ways away from having to make that decision?

I mean, I think we've done enough price sensitivities even around WHIM to appreciate that even numbers in the tens of thousands are relatively consistent with ultra-orphan pricing around WHIM. I mean, there's examples of this in the field already with the Vertex CF molecules certainly getting into the tens of thousands of patients that they serve and commanding the price points of that particular treatment. So I don't think there's really a sort of a deep consideration that we need to make as we think about the broader chronic neutropenia markets.

The next question is from Eva Privitera with Cowen.

Congrats on all the progress. Can you remind us of the powering assumptions to 4WHIM trial? Are there any updated assumptions given the high enrollment numbers?

As we said during the call, we use the change in the TAT ANC observed in the context of the Phase 2 trial for powering the Phase 3 trial. So based on the increase in the TAT ANC that we observed in Phase 2, of course there was a range, but we took that into consideration and concluded that to have at least 90% power we needed around 18 patients minimum. As you heard, we ended up enrolling 31. We have excellent retention. So that's why we said earlier that right now we believe that we're powered on the primary endpoint is greater than 95%. And the same goes for the top secondary endpoint. As Paula said, it's really important to show that we are impacting not only neutrophils, but also lymphocytes because that goes to the core of this disease.

And what's the latest estimate on the prevalence of WHIM based on all the research you've done? Are there any updates on new genetic variance or anything?

Yes. No. I mean we continue to feel very comfortable with guiding to 1,000 or higher with WHIM syndrome. It's actually fascinating some of the publications that will be coming out or have come out around additional genes even beyond CXCR4 such as CXCR2. So we think we're just at the very beginning. Our physicians are incredibly excited about potentially supporting their approach to diagnosis of which, obviously, genetics is a component and we'll keep you updated as we refine that any further.

The next question is from Mayank Mamtani with B. Riley Securities.

I look forward to working with you a summary to it. So just maybe first question, as I was comparing between the baseline characteristics for Phase 2 and Phase 3 beyond having now a pediatric cohort which you didn't have, could you just give us a little bit more color on the clinical presentation of the patients that you have there in Phase 3 versus the Phase 2? And just remind us of what presentation was required for all patients at baseline? And also if you excluded any product exposure to mavorixafor or if you permitted any ongoing treatment for G-CSF in the study, if you could remind that, that would be great.

Mayank, sorry, I'm just going to repeat your question back to if I hope I got it right here. I think your fundamental question sounds like what's different or similar or different between your patient populations between Phase 2 and Phase 3 since we've included pediatrics in there. So Diego can highlight that. And then I think the second element of that was around G-CSF use and how was it addressed in the Phase 3. So Diego, I'll turn it over to you for those 2 Phase questions.

So regarding the first question, so Phase 2 and Phase 3 populations are actually quite similar in the sense that they're all required to have WHIM syndrome. All of them actually had a CXCR4 mutation. The pretreatment ANC counts actually were almost identical. The main difference is that we open up Phase 3 to pediatric, 12 to 17, while Phase 2 was only adults. You ask what type of clinic phenotype. As we -- Paula mentioned earlier, WHIM comes in different ways. So we did not restrict by whether they have this overview or all 4 letters. They had to be clinically diagnosed with WHIM, genetically confirmed, and they had to have severe neutropenia, which they all had. So we feel that Phase 3 pretty much follows Phase 2. You also asked about G-CSF. G-CSF is used mostly intermittently, it's not well tolerated. So we only allow the use of G-CSF as rescue therapy in WHIM Phase 3. And it's something that really the doctors don't like much. So essentially, we have mostly a mavorixafor versus placebo trial randomized, fully blinded, very high quality that we're very proud of.

And just Diego, you might want to comment on the approach that we took to make sure we weren't confounding neutrophil counts with TAT ANC and G-CSF use.

Yes. If somebody received G-CSF as rescue therapy, we postponed the timing of the TAT ANC assessments to avoid a compounding.

Got it. And maybe just to clarify, any prior exposure to mavorixafor and also thinking because there was one patient on your Phase 2 which had an early rash, he had prior exposure to predict. So did you exclude that also in the study?

So we did not enroll anyone in Phase 2 who had been previously exposed to mavorixafor. And in terms of rashes or dermatology safety segments, we really have not seen much of that. I mean we're blinded. But based on blinded assessment, we have not seen much.

Nor did we exclude anybody for that basis as well.

Correct.

Sorry, I had meant -- I did not mean mavorixafor under the CXCR4, the rejectable. And then my follow-up on the steps forward after the top line data. Could you just lay out between the December top line data and then the early filing of assuming the NDA filing in early second half. What are sort of the activities that you undertake on the WHIM side? And then if there is any overlap, you also talk to the regulators about chronic neutropenia indication, [indiscernible] durability data becoming available there. Could you just kind of help connect the dots there, how the interactions will progress on these 2 fronts?

So it sounds, Mayank, I think you're trying to kind of piece together the various kind of evolutions of WHIM and CN and regulatory. So we'll try to lay those out clearly. So the Phase 3 data will come in Q4. On average, it takes about 6 months to file an NDA, give or take. So that's where we're putting it in the early part of second half of 2023. We're in excellent shape there in terms of just moving it forward and of course, working with the agency as closely as needed. The important thing around chronic neutropenia, of course, is the amended protocol has been completed. We're moving forward with operationalizing that, which always takes a couple of months at these sites. So we think we'll have some early data in the extension study around durability in CN. Of course, the WHIM Phase 3 will have a lot of durability data given its one year dosing course. So that totality of data will be useful as we go in to approach the FDA regarding a chronic neutropenia registration trial. So the timing isn't finally tuned, but we believe WHIM plus CN data plus regulatory conversations should be happening in the first half of next year to prepare us to then, of course, file the NDA and WHIM, and shortly thereafter, complete that registration clarity and kickoff advancing a CN Phase 3 trial subsequent to the NDA.

The next question is from Trevor Allred with Oppenheimer.

Just wanted to ask a question on Waldenstrom's. Any updates here on potential partnerships that might be developing?

No updates for this morning. We'll come back and update as we make progress. We continue to focus on upcoming WHIM data and the excitement around product neutropenia.

The next question is from RK with H.C. Wainwright.

And most of my questions have been asked, but I just want to have an idea of what sort of data would be presented at the top line announcement this quarter? And what else needs to get done in terms of analysis between now and your filing in the sense I'm trying to figure out if there will be additional update before you file the DLA?

So as we can appreciate top line is typically the primary endpoint plus safety. However, we're adding our first key secondary endpoint in there to specifically highlight the unique approach of mavorixafor as a targeted therapy for all the combined immunodeficiency effects of WHIM syndrome. So we're looking forward to sharing a little bit more than usual. In terms of the totality of the data of the entire trial, of course that's incredibly important to preserve for publication rights. So we do think that we'll be having an update at a relevant medical conference or via a publication, and we'll try to provide more guidance when we have clarity on that. And then, of course, I'll be rolling into our NDA submission early in the second half of next year.

And then as you stated in the late summer that you're focusing on the chronic neutropenias in diseases at this point. When would be the next update on the chronic neutropenia study itself? And do you think we'll get additional clarity after we get through the 4WHIM study? Or will there be any updates on those studies?

Yes. So we plan for additional data updates on the CN trial in the first half of next year. Again, I'll try to provide clarity under what format or possibility medical conference, but it's an exciting trial to be moving forward quickly with. And as we generate some interesting data under that, we'll take a cut and share it. Most importantly, I think for us, we really want to work with the agency. So it's really about the totality of data to support our regulatory conversations. We're all very bullish on moving this forward as quickly as we can to a CN registration trial. So stay tuned and we look forward to providing those updates in the first half of next year.

This concludes the question-and-answer session. I would like to turn the conference back over to Paula Ragan for any closing remarks.

Well, thank you so much for joining today. I did want to make one additional comment since it's now past 9:00 a.m. As you probably know, ASH 2022 abstracts were just published and we're very happy to announce that our abstract on our Phase 1b chronic neutropenia study has been accepted for an oral presentation at this year's meeting. In addition, we've had several additional abstracts accepted for poster presentation and these include 2 on chronic neutropenia, one on U.S. prevalence and then the other on the voice of the patient, and one additional on the morphology of myelokathexis and WHIM syndrome. So a very productive ASH for us. We look forward to seeing some of you in New Orleans in December. And with that, we're concluded, and I hope everyone has a wonderful day. Thank you.

This concludes today's conference call. You may disconnect your lines. Thank you for participating and have a pleasant day.