X4 Pharmaceuticals, Inc Q3 FY2022 Earnings Call

Greetings, and welcome to X4 Pharmaceuticals third quarter 2022 conference call. At this time, all participants are in a listen-only mode. A question and answer session will follow the formal presentation. 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 will also hear 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 Art 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. 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. 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. We are extremely excited to share the progress that we've been making as we sharpen our focus on the 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's 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 US, we believe that mavericksphore, 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 mavericksphore's progress in our global pivotal phase three trial in WHIM syndrome and to highlight how we are getting appropriately prepared to ramp into commercial launch. Mavericksphore is being studied in an ongoing phase three 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 have not only 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 mavericksphore 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 represent the variable presentation of the disease, which can range from severe wart 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 this panleukopenia, people with WHIM syndrome experience a 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 and potential morbidity associated with this needle-based invasive procedure. Upon microscopic evaluation, the hyper mature or hyper segmented 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 in genes associated with the signaling cascade, such as CXCR2. In fact, in these individuals, neutrophils share 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 administering high doses of immunoglobulins to treat the low antibody levels, or GCSF injections to treat the neutropenia, which is often poorly tolerated for chronic use. We recently completed the randomized placebo-controlled portion of the phase three study of mavericksphore 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 three study design and our historical data that supports why we are so excited about our pending pivotal trial results.

Thank you, Paula. I'll now briefly review the study design of our global registrational trial, assessing mavericksphore as a potential treatment of WHIM syndrome. As Paula mentioned, the design is a randomized placebo control 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 inclusion criteria required that all patients enrolled had a confirmed absolute neutrophil count less than or equal to 400 cells per microliter during screening. For the 31 patients enrolled in the trial, the average pretreatment count was 220 cells per microliter, an indication of the severity of 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 entered 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 mavericksphore of 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 study. Notably, more than 90 percent of eligible participants elected to continue on and receive mavericksphore treatment in the OLE. We continue 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. As I mentioned, we have now completed the last patient last visit for 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 three 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 mavericksphore in WHIM patients in this phase three trial. The primary endpoint is a metric called TAT ANC, which is time above threshold or TAT for short, for absolute neutrophil counts. It is an assessment of mavericksphore'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 mavericksphore. The 24 hours TAT ANC was measured four times 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 ANC 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 neutrophils 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 mavericksphore versus 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 vaccines, and the fourth category is safety, tolerability, and pharmacokinetics. There are also several prespecified subgroup analyses. 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 two endpoints closely mirror our phase three endpoints, and the success of this trial, along with results from the phase two open-label extension study, have formed the basis of our confidence in phase three success. The positive phase two results not only inform the phase three trial design, but also served as the basis for the power assumptions for the primary and the top secondary endpoint of the phase three trial. Based on the blinded baseline ANC and ALC of the 31 subjects enrolled and the high retention rate in the study, the primary endpoint of the phase three tracking WHIM syndrome is powered to greater than 95 percent. In the phase two study, we saw that all patients responded to mavericksphore 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 three trial, ranged between approximately two and 24 hours. Importantly, these observed increases in TAT ANC and TAT ALC in the phase two trial were associated with clinical benefit including positive patient reported outcomes and reductions in both the rate of infections and the wart burden. Equally importantly, mavericksphore was well tolerated throughout the study, including the long-term extension. Recall that these favorable phase two results resulted in the FDA granting us breakthrough therapy designation, or BTD, for mavericksphore for the treatment of WHIM syndrome. Also, recall that the hurdle for BTD is high and requires preliminary clinical evidence from our phase two study that indicated that the drug may demonstrate substantial improvements on a clinically significant endpoint or endpoints over available therapies. The totality of the phase two data was shared with the FDA and supported the award of BTD for mavericksphore in WHIM. On this slide, we provide a patient-specific view on the impact of one's daily oral treatment of mavericksphore in a participant in the phase two 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 wart lesions was evident over time during the phase two 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 her other lesions as well. This patient was interviewed after more than three 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 questionnaire. We have included the PGIC assessment among other patient and physician-reported outcomes in our phase three trial. Next slide please.

Since the initiation of our IMD formal mavericksphore 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 planned 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 mavericksphore 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 is embedded and analyzed, we plan to share data that will include the primary endpoint TAT ANC and 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 mavericksphore 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 W, H, I, and M in a setting of combined immunodeficiency that is neutropenia, lymphopenia, monocytopenia, and/or hypogammaglobulinemia, which can potentially include bone marrow examinations, 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 myelokathexis 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. 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 representatives, 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 three trial results. Assuming a successful phase three, 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 mavericksphore in the first half of 2024. EMA filing is expected to follow our US filing by about 12 months, and if approved, we expect the commercial launch would be initially focused in the top five to seven European markets, with others to follow. We may consider partners to support the launch of mavericksphore in territories outside of the U.S. and these key European countries. We will update you at a future point when we have clarity into any potential partnerships. Next slide, please. As Sam 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, and 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 up to speed on our mavericksphore program and continuing to advance our commercial readiness as we approach the unblinding of our phase three for WHIM 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 the commercial efforts and hopefully the commercial launch of mavericksphore and its first indication. I spent much of my career focused on launching innovative therapeutics that were able to transform the lives of patients around the world who are living with rare diseases. I've joined X4 because I can clearly see the potential of mavericksphore 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 are we, Mark. Thanks. Next slide please. As you would expect, preparing the product, the market, and the company for commercialization to ensure mavericksphore treatment reaches patients with WHIM syndrome is well underway in anticipation of the phase three 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 PELs, and in the home office. In this pre-commercial phase, and under Mark Baldry's leadership, we intend to rebuild the commercial team as we enter into the next phase of preparation. These customer-facing people are actively engaged with healthcare professionals, patients, and patient communities to raise awareness of WHIM, educate on recognizing and diagnosing the disease, and communicating the potential of mavericksphore 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 healthcare value that mavericksphore 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. Lastly, from a marketing standpoint, we have secured conditional approval of a brand name with the FDA, an exciting step for mavericksphore. Additionally, we have conducted early healthcare professional market research focused on targeting the physicians most likely to have a WHIM or a potential WHIM patient, introduced tools available to the patient and HCPs 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 developing mavericksphore 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 one B2 and anticipated CN phase three 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 mavericksphore has a bright future ahead. If approved for the WHIM indication, we intend to continue to develop mavericksphore 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 mavericksphore, including across all of the CN disorders we've studied thus far. As a result, we plan to study whether mavericksphore has the potential to treat up to 50,000 patients currently diagnosed with idiopathic congenital and cyclic neutropenia in the U.S. We are on the cusp of a potentially positive phase two trial that could support a U.S. launch in 2024. A launch that could not only begin to generate meaningful revenue for X4 but could 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 three data later this quarter, followed by additional expected CN data and potential initial clarity on the regulatory path forward for mavericksphore in CN in the first half of 2023. Assuming positive phase three results in WHIM, our NDA filing for mavericksphore is on track for early in the second half of 2023, and we're aiming to be phase three 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 mavericksphore 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 roles 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 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 three 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. And with that, why don't we now open the call up for your questions?

Thanks for taking the questions and 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?

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.

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?

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.

This is something that the team has monitored, as Paula said. And, yeah, we have seen infection events. Of course, we're completely blinded. We have a very rigorous process of central adjudication, and they are actually working out to finish that, and that will inform the trial regarding its clinical benefit tracking. We have seen a good number of infections that we believe is consistent with what we expect now that the pandemic impact has been somewhat mitigated.

And then just, lastly, maybe a little bit of a bigger picture question, but I know that you're 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 US, who were on chronic GCSF was maybe somewhere in the 2,500 range. How do you think about the disconnect between those two numbers? How do you close that gap in chronic neutropenia specifically? And then how does that 50,000 number factor into your thoughts around the initial mavericksphore price set?

Yes, 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, number one. And it's very difficult. So GCSF has been used intermittently in many patients. How you define chronic, semi-chronic is another challenge for us as we consider the number of patients on G, and also to highlight that 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. 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 a pricing decision on mavericksphore 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. You know, there are 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 deep consideration that we need to make as we think about the broader kind of neutropenia markets.

The next question is from Eva Privitera with Cowen. Please go ahead.

Hi, thanks for taking our questions, and congrats on all the progress. Can you remind us of the powering assumptions for this WHIM trial? Are there any updated assumptions, given the high enrollment numbers?

As we said during the call, we used the TAT ANC that was observed in the context of the phase two trial for powering the phase three trial. So, based on the increase in the target ANC that we observed in phase two, of course, there was a range, but we took that into consideration and concluded that to have at least 90 percent power, we needed around 18 patients minimum. As you heard, we ended up enrolling 31. We have excellent retention. We believe our power on the primary endpoint is greater than 95 percent, and the same goes for the top secondary endpoint. It’s really important to show that we are impacting not only neutrophil counts, 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 variants or anything?

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, and our physicians are incredibly excited about potentially supporting their approach to diagnosis, of which, obviously, genetics is a component. We'll keep you updated as we refine that further.

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

Thanks for taking our questions, and look forward to working with you. Just maybe first question, as I was comparing between the baseline characteristics for phase two and phase three, 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 here in phase three versus the phase two? And just remind us, what presentation was required for all patients at baseline? And also, if you excluded any prior exposure to GCSF or if you permitted any ongoing treatment for GCSF in the study?

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

So regarding the first question, the phase two and phase three 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 were almost identical. The main difference is that we opened phase three to pediatric patients aged 12 to 17, while phase two was only adults. You asked what type of clinical phenotype. As Paula mentioned earlier, WHIM comes in different presentations. We did not restrict by whether they have the W or all four 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 the phase three cohort pretty much mirrors the phase two cohort. You also asked about GCSF. GCSF is used mostly intermittently; it's not well tolerated. So, we only allow the use of GCSF as rescue therapy in WHIM phase three. It's something that really the doctors don't prefer much. So essentially, we have mostly a mavericksphore 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 GCSF use.

If somebody received GCSF as rescue therapy, we postponed the timing of the TAT ANC assessments to avoid any compounding.

And maybe just to clarify, any prior exposure to mavericksphore, and also thinking because there was one patient in your phase two with an early rash, would you include that patient as well?

We did not enroll anyone in phase two who had been previously exposed to mavericksphore. In terms of rashes or dermatology safety signals, 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 on that basis as well.

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 the NDA in the early second half? What are sort of the activities that you'd undertake on the WHIM side, and then if there is any overlap? You also talked to the regulators about chronic neutropenia indication with multi-dose durability data becoming available there. Could you just help connect those dots regarding how the interactions progressed on these two fronts?

So, it sounds - you're trying to piece together the various evolutions of WHIM and CN and regulatory aspects. So, we'll try to lay those out clearly. The phase three data will come in Q4. On average, it takes about six months to file an NDA, give or take. That's where we're putting it in the early part of the second half of 2023. We're in excellent shape there in terms of just moving things 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 with these sites. We think we'll have some early data in the extension study around durability in CN. Of course, the WHIM phase three will have a lot of durability data given its one-year dosing course. So, that totality of data will be useful as we approach the FDA regarding a chronic neutropenia registration trial. So the timing isn't finely 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 file the NDA on WHIM, and shortly thereafter complete that registration clarity and kick off advancing a CN phase three trial, subsequent to the NDA.

Great. Thanks for taking my questions, and it's been great working with you, Diego. All the best for your next adventure.

The next question is from Trevor Allred with Oppenheimer. Please go ahead.

I just want to ask a question on Waldenstroms. Any updates here on potential partnerships that might be developing? Thanks.

We'll come back and update as we make progress. We continue to focus on upcoming WHIM data and the potential for ongoing neutropenia.

The next question is from RK with H.C. Wainwright, please go ahead.

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? I'm trying to get a sense, trying to figure out if there will be additional updates before you file the NDA.

So, as you can appreciate, top line is typically the primary endpoint plus safety. However, we're adding our first key secondary endpoint to specifically highlight the unique approach of mavericksphore, the targeted therapy for all the combined immunodeficiency effects of WHIM syndrome. We're looking forward to sharing a little bit more than usual. In terms of the totality of the data from the entire trial, of course, that's incredibly important to preserve for publication rights. We do think that we'll be having an update at a relevant medical conference via a publication, and we'll try to provide more guidance when we have clarity on that. 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 late summer, that you're focusing on the chronic neutropenia studies 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 WHIM study, or will there be any updates on those studies?

We plan for additional data updates on the CN trial in the first half of next year. Again, we'll try to provide clarity under what format or possibly at a medical conference. It's an exciting trial moving forward quickly, and as we generate interesting data under that, we'll make sure to share it. Most importantly, 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. Stay tuned and we'll look forward to providing those updates in the first half of next year.

And I know it's an exciting quarter, so good luck with everything.

Thank you. It is very exciting.

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

Thank you so much for joining today. I did want to make one additional comment since it's now past 09:00 AM. As you probably know, ASH 2022 abstracts were just published, and we're very happy to announce that our abstract on our phase one B 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, including two on chronic neutropenia, one on U.S. prevalence, and 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.