X4 Pharmaceuticals, Inc Q3 FY2024 Earnings Call

Greetings, and welcome to the X4 Pharmaceuticals Call and Webcast. 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. Thank you for joining us today for the special earnings call during which X4 will focus on providing a business update and, importantly, data and results from its now completed Phase II study of mavorixafor in chronic neutropenia. As a reminder, on today's call, the company will be making forward-looking statements regarding regulatory and product development, commercialization plans, as well as research activities and financial projections. 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 year's Form 10-K, which was filed on March 21, 2024, and in the company's Form 10-Q for the third quarter, which is expected to be filed shortly. Presenting on today's call will be Dr. Paula Ragan, X4's President and CEO; and the company's Chief Medical Officer, Dr. Christophe Arbet-Engels. I'll now turn it over to Paula Ragan to run through today's agenda.

Thank you, Dan, and thank you all for joining us. Today, we will provide an update on our operational achievements, including activities supporting the launch of XOLREMDI in the U.S. and the substantial progress to date with our ongoing Phase III clinical trial of mavorixafor in people with chronic neutropenia or CN. In addition, we're excited to present the positive data from our recently completed Phase II study of mavorixafor in CN. These results include the final mavorixafor monotherapy data, which remains very encouraging and consistent with the data we presented in June from the interim Phase II analysis. We will also be presenting new data from the study. Results show that most of the participants who were treated with mavorixafor and G-CSF ended up having their G-CSF dose adjusted downwards during the study, while the mean neutrophil count for this group remained in the normal range. These data provide a first glimpse into how mavorixafor could be used in the real world if ultimately approved in CN. Equally exciting are the new insights we've gained from assessing the functionality of circulating neutrophils in a subset of the Phase II study participants as well as healthy donors for comparison. We'll briefly review this updated safety data from the study as well. We'll then conclude and open it up for your questions when we will be joined by our Chief Commercial Officer, Mark Baldry; our Chief Financial Officer, Adam Mostafa; our Chief Operating Officer, Dr. Mary DiBiase; our Chief Scientific Officer, Dr. Art Taveras; and our Head of Corporate and Patient Affairs, Jose Juves. So let's quickly run through the operational update as we know you're all eager to hear about the CN Phase II study results and analysis. As you know, we received U.S. FDA approval in late April for our first product, mavorixafor, branded XOLREMDI, for the treatment of WHIM syndrome, a rare primary immunodeficiency disease. As with ultra-rare disease launches, our initial commercial strategy has been focused on disease awareness to support patient identification and diagnosis. While we do recognize that sales appear to be flat quarter-over-quarter, we want to remind everyone that some of the sales in the second quarter were product stocking with our specialty pharma, which is typical during initial launch. I'm pleased to report this past quarter, we hit our most important launch goal, having engaged with all 3,400 of the initial immunologists and hematologists targeted for the first phase of our launch. These visits and digital engagements are bearing fruit, as you can see here. Recently completed market research comparing pre- and post-launch metrics indicate that knowledge of WHIM syndrome and these likely XOLREMDI prescribers has increased and is now at more than 75%. In addition, an increasing number of physicians are screening their patients for WHIM, and 80% of healthcare professionals surveyed report that they would consider prescribing XOLREMDI for their WHIM patients. Over the past six months, we've also stepped up our conference attendance, launched a peer-to-peer speaker program, and initiated a patient-focused campaign, which includes a website, new materials, and an HCP discussion guide. Reimbursement and access continue to go well, with favorable policy decisions resulting in more than 150 million lives now covered. So very good progress there. Importantly, the activities we are conducting in WHIM are yielding insights that may support our efforts to advance mavorixafor into the much broader indication of chronic neutropenia. While our commercial efforts are exclusively focused on WHIM today, we do see a significant overlap between the WHIM and CN communities. Based on our claims analysis and experience in the field, we observed that a majority of hematologists that we're calling on for WHIM also see chronic neutropenia patients, and of course, there's overlap within the patient advocacy communities we engage with as well. If mavorixafor is approved for use in CN, we certainly expect to be able to leverage our commercial infrastructure and relationships within the WHIM community to support a potential launch into chronic neutropenia. As you all know, success in CN will be dependent on the results of our global pivotal Phase III trial, which is progressing well, and currently participants are being screened and dosed across multiple countries. Our 4WARD, as we've named it, is a global trial that will engage patients and physicians across 20 to 25 countries. We can report today that we have already received health authority authorizations to initiate the trial in approximately 85% of these countries. We can also now report that approximately 40% of our planned sites worldwide are initiated, and we expect to have the majority of sites initiated in early 2025. This trial is expected to enroll 150 participants at 90 to 110 sites with a planned enrollment of one to two participants per site, which is typical in a rare disease clinical trial. Most importantly, we are on track and continue to expect full trial enrollment in mid-2025.

Thanks so much, Paula, and hello to everyone on the call. Let me begin with a quick refresher on chronic neutropenia. The hallmark of chronic neutropenia is abnormally low levels of circulating neutrophils, which are the defense mechanism our body uses to fight pathogens. As we've presented previously, there is a well-established correlation between circulating levels of neutrophils or absolute neutrophil count (ANC) and the risk of frequent and/or serious infection. Note that the lower limit of normal for neutropenia diagnosis is 1,500 cells per microliter. Below that, grades are divided based on the infection risk in increments of 500 cells per microliter from mild to moderate to severe. As you can see, severely neutropenic patients have ANC of less than 500, and this corresponds to the highest risk of infection. To reduce the risk of infection in these patients, it is critical to move them from the most severe grade towards a less severe grade to achieve as normal a level of neutrophil as possible. Therefore, an increase of 500 cells per microliter is an important clinical practice objective. Through its mechanism of action, mavorixafor has been shown to precisely do that, increasing the number of circulating neutrophils. This ability is clearly stated in the mavorixafor label from the FDA approval in WHIM syndrome based on results from a pivotal Phase III trial. These results demonstrated that mavorixafor sustainably raised ANC over the 52 weeks of the trial and consequently reduced the annualized rate of infection along with the duration and severity of infections in trial participants. This infection benefit was achieved through an increase in mean ANC of more than 500 cells per microliter. These results and the WHIM approval in the U.S. provide confidence in our plan to potentially bring mavorixafor to those with other chronic neutropenic conditions where significant unmet needs remain. The gap in addressing these unmet needs results from the significant lack of innovation in the field. The only currently available therapy is G-CSF, which was approved almost 30 years ago. It's an injectable drug that is associated with dose-dependent and often treatment-limiting side effects, as well as long-term risk of certain malignancy. As you've heard in our previous investor presentations, CN patients and the physicians that treat them are dissatisfied with G-CSF and its side effects, especially fatigue and bone and muscle pain. Unfortunately, these side effects are often dose-dependent and can limit the use of G-CSF or prevent its use at a fully effective dose. We believe there is an urgent need for a new innovation like mavorixafor, which data now suggests could be used, if approved, as a monotherapy or in combination with G-CSF while also allowing for reduced doses of G-CSF to limit side effects and long-term cancer risk. Our market research indicates there are approximately 50,000 people diagnosed with CN in the U.S. Of this population, it's estimated that about 15,000 have high unmet need, including recurrent infection despite the available standard of care. Our Phase III 4WARD trial focuses on this population with the highest unmet need, enrolling adolescents and adults with ANC below 1,500 cells per microliter and a history of recurrent and/or serious infection. To meet the multiple needs of this population, we envision two potential opportunities for oral, once-daily mavorixafor within this market. One, it could be used as a monotherapy in newly diagnosed CN patients or to replace G-CSF treatment; and two, in combination with G-CSF, enabling a meaningful reduction in G-CSF dosing, thus lessening pain, discomfort, and long-term risk of malignancy. Our Phase II CN study set out to evaluate those opportunities. As you will see in just a minute, we believe the data from this study supports the potential for mavorixafor to transform the chronic care of this neutropenic population. The main goal of the Phase II study was to confirm the durability of the Phase Ib results that showed a 100% response to a single dose of oral mavorixafor plus or minus G-CSF across multiple CN types. We also aimed to assess the long-term safety and tolerability of mavorixafor use, with and without G-CSF, in people with CN. In addition, we wanted to explore the feasibility and willingness of physicians to safely reduce G-CSF with mavorixafor; and a key goal was also to inform the design of our Phase III pivotal trial, thus de-risking it. The Phase II study was a six-month study with monthly visits and comprehensive assessment at baseline in months one, three, and six. Two quick notes on the design of this study: first, since the neutrophil life cycle is about 10 to 14 days, we believe that a study of this length provides a good indication of the bone marrow's long-term ability for stable neutrophil production; and second, modifications to G-CSF dosing were permitted in the combination group following participants' month two visit. So the first assessment of those on an adjusted dose would have been at the month three visit. These adjustments were decided between physicians and their patients and were not protocol mandated. Let's start by looking at the final participant disposition in the study, a population typical of those with chronic neutropenia and high unmet need. We enrolled a total of 23 participants in the six-month, single-arm, open-label study with the mix of idiopathic and congenital CN and even a few with cyclic presentation. There was a typical gender distribution in the study and a mean age of 34 years. We also note here that there was a good mix of genetic backgrounds within the congenital group, representative of what you might see across the full CN population. We analyzed the data in two groups: mavorixafor monotherapy comprising 10 participants; and the mavorixafor plus G-CSF group with 13 participants, nine of whom ended up having their G-CSF dose reduced in the study. Additionally, we evaluated neutrophil functionality pre- and post-treatment in a sub-study population of nine evaluable participants and compared those results to a group of healthy individuals. To address the unmet needs existing with current chronic CN therapy, our objective is to sustainably increase circulating functional neutrophils using oral mavorixafor. Thus, the results presented today are focused on answering the following four questions. One, in the monotherapy group, did mavorixafor increase and durably sustain ANC at clinically meaningful levels? Two, in the combination group, were physicians willing and able to adjust their patients' G-CSF dose when adding mavorixafor? Three, could G-CSF be reduced while maintaining clinically meaningful ANC levels? And four, are the neutrophils mobilized into the peripheral blood by mavorixafor functional throughout the six-month study? First, let's look at the monotherapy results. Consistent with our data presentation in June, mavorixafor durably and meaningfully increased mean ANC, bringing levels into the normal range at month three and month six. As an oral, once-daily treatment delivering this level of ANC increase, you can begin to appreciate the potential for mavorixafor as a monotherapy. Additionally, mavorixafor also durably and meaningfully increased mean ANC levels in the severe CN study participants. Those starting with levels below 500 cells per microliter had more than a two-fold increase in mean ANC compared to baseline throughout six months of mavorixafor treatment. As a reminder, such an ANC increase in our Phase III WHIM trial led to a decrease of 60% in the infection rate. So this similar ANC increase here is not only clinically meaningful, but it also helps increase our confidence in achieving a positive infection rate readout for this monotherapy population in the ongoing pivotal Phase III trial in CN. Let's move now to the combination results. In this group, we started with 13 participants entering the study on G-CSF at baseline. One dropped out almost immediately, so we had 12 eligible to have their G-CSF dose reduced following their month two visit. Notably, clinicians chose to reduce G-CSF in nine of these 12, with three being fully taken off G-CSF prior to their six-month visit, finishing the study on mavorixafor monotherapy. Thinking back to the market opportunity and unmet need slide, you can now see why we're so excited about the data. This is the first look at how physicians could potentially use mavorixafor in their CN patients who are already on G-CSF, should it gain approval. Today, we're not presenting the data from the three participants who remain on stable dose G-CSF. However, the final data set from this group was consistent with the results we shared this past June, showing robust and sustained increases in mean ANC from baseline levels. As shown here, the G-CSF reductions were quite substantial, and mean ANC were maintained at normal levels throughout the study. At month three, eight of the nine had been adjusted; physicians were comfortable lowering G-CSF by 52% on average. This average increased to 70% reductions by month six, with three of the nine adjusted dose participants taken completely off G-CSF. Anecdotally, physicians and academic experts have informed us that they believe a 25% reduction in G-CSF would be clinically meaningful to their patients. Observing this level of G-CSF reduction reinforces the potential benefit of mavorixafor and its role in the treatment of CN. We now turn our attention to assessing the functionality of the increased levels of circulating neutrophils in the Phase II sub-study. As mentioned, the purpose of this sub-study was to assess the percentage of functional neutrophils in people with CN, including those with congenital genetic variations associated with neutrophil maturation arrest. We used two well-accepted functionality assays: the phagocytosis assay, which assesses the neutrophil's ability to engulf pathogens; and an assay for ROS (reactive oxygen species) production, the ability to damage or kill pathogens that have been engulfed. These neutrophil function studies were conducted on samples from nine eligible participants with a mix of CN types and monotherapy and combination use. We also recruited five healthy individuals to provide a benchmark for comparison. For simplicity, we are only showing the phagocytosis data today, but we note that the ROS assay results closely mirrored the phagocytosis results. While participants with chronic neutropenia have fewer neutrophils than healthy donors, you can see here that those neutrophils that do make it into circulation are functional with a similar percentage of functionality between the neutropenic and healthy donor population. Note that the bars represent the percentage of neutrophils that demonstrated phagocytosis after challenge with opsonized bacteria. We've also broken out the congenital CN subset to see if genetic variant affects functionality differently than in the other groups. Looking now at the full results, we see that the percentage of functional neutrophils in healthy donors, the full participant group, and the congenital CN subset are essentially the same following six months of mavorixafor therapy. Note that while we are showing data for fibrocystic function, we generated very similar data on the percentage of neutrophils generating ROS after bacterial challenge. Recall in our 52-week WHIM Phase III clinical trial, we saw that an increase in circulating mature neutrophils corresponded with a 60% reduction in the annualized infection rate, as well as a reduction in the severity and duration of infection. By increasing the number of functional circulating neutrophils, we believe that mavorixafor treatment could correspondingly reduce the infection rate in the larger chronic neutropenia population. We are hopeful to see similar results in our ongoing registrational Phase III chronic neutropenia trial. Mavorixafor with or without concurrent G-CSF therapy was generally well tolerated throughout the study. The overall safety profile was consistent with previous studies, and the most frequent treatment-related, treatment-emergent adverse events were GI-related nausea and diarrhea, which were mild to moderate and typically resolved over time. As we noted in our June presentation, we did see three discontinuations in the study. These occurred early in the execution of the study. After implementing an education program on possible GI side effects, there were no further discontinuation. Rest assured, we have incorporated this education into the Phase III CN trial. In summary, we could not be more pleased with the results of this Phase II study, having met all of the goals we set forth. We have shown that mavorixafor can durably and meaningfully increase mean ANC as a monotherapy, even in the most severe CN population, and can do likewise when dosed in combination with G-CSF. We show that mavorixafor enabled clinicians and their patients to meaningfully lower the use of G-CSF while maintaining mean ANC at normal levels. Critically, we showed that mavorixafor increased the total count of functional circulating neutrophils even in the most difficult-to-treat individuals with CN. Importantly, we demonstrated that mavorixafor was generally well tolerated on its own and in combination with G-CSF. These results give us great confidence in the chance of success of our ongoing Phase III trial and mavorixafor's potential to reduce infection rates. They also provide hope that mavorixafor could be the innovation that the CN community is looking for. As you've heard previously, through our interviews with physicians and CN patients, what they need and want is a well-tolerated oral option, one that can enable them to safely reduce the use of injectable G-CSF. Thus far, our results have shown that mavorixafor fits that profile well as either a monotherapy or in combination use.

Thanks so much, Christophe. Great job sharing our exciting update on mavorixafor's potential in CN. To conclude, over the last six months, we have made significant progress as a company in bringing innovation to the immunodeficiency community. By gaining approval for and launching XOLREMDI in the U.S. for WHIM syndrome and by exploring additional geographies for mavorixafor's approval and distribution in WHIM, we are seeking to maximize the global opportunity to help those with WHIM. By completing and reporting out these positive Phase II results and initiating our pivotal Phase III trial of mavorixafor in those with chronic neutropenia, we are seeking to further expand the market opportunity for mavorixafor and have a positive impact on a much larger potential patient population. In terms of our financial results, I direct you to our press release from this morning and our 10-Q to be issued shortly. We ended the third quarter of 2024 with cash and equivalents of almost $136 million. We continue to believe this gives us the runway into late 2025, and note that this does not include the expected ramp-up of sales of XOLREMDI throughout next year. As always, we thank you for your continued support and would now be happy to take your questions.

Thank you. We'll take our first question from Kristen Kluska with Cantor. Please go ahead. Your line is open.

Hi. Good morning, everybody. Congrats on these new great data you shared with us. Really appreciate it. So questions that I have are related to the new data today. I wanted to ask what the biggest criteria were in the trial that made the physicians comfortable to reduce and lower the G-CSF usage? While I recognize it wasn't a formal endpoint measured, I'm curious if the doctors had any anecdotes to share about any early signals of reduced pain or better convenience benefits for patients.

Yeah, Kristen. Thank you for the question. I'll start and then Christophe will add some color. The important thing about the Phase II study is we really put the choice in the physicians' and patients' hands. There is a wide variety of patients, and they have real-world experience with them. What gave them comfort to adjust G-CSF dosing was the high and robust ANC responses due to the addition of mavorixafor. That is confidence in data, and of course, they acted on that. But Christophe, why don't you give some more color on that?

Sure. Yes, we are really happy with the results and the choice that 75% of those physicians with their patients have decided to decrease G-CSF. This is a really high percentage of those decisions without any mandates from the protocol or any prescriptions that we asked them to do this. With regard to the choice, it is a balance between the level of ANC, as Paula just mentioned. They were very comfortable with the level of ANC and the clinical manifestations that these patients were experiencing. Therefore, we could not identify a specific pattern, but this is really what drives most of those decisions.

Okay. Thanks. And then any early anecdotes or is it a little too early to make that assessment?

I think it's early to make that assessment. And of course, what we're most pleased with is the broad applicability, the broad reduction in G-CSF across the 75% of patients and even some of them completely coming off. Certainly, a lot more study to be done, Kristen, but thanks for the highlights.

Yeah. And if I may ask one more question then. Can you talk a little bit more in terms of what lower G-CSF usage actually means? Is it that physicians are assessing it every other day for usage? Is it the amount of G-CSF that is administered that is lowered? Do we have a general sense to give us whether what correlation of G-CSF reduction could ultimately lead to alleviating some of the dangerous side effects and the inconvenient ones?

So we'll address the second part first. Our initial research findings from patients and physicians indicate that a reduction of around 25% in either dose or frequency appears to be a significant threshold for clinical relevance. Generally, a lower dose is preferable as it minimizes both short- and long-term toxicities associated with treatment. Percent reductions are always calculated based on the patient's initial criteria. The complexity with G-CSF arises from the variability in each patient's condition, which we have considered in our approach, similar to how clinicians operate. Consequently, that reduction reflects changes from their initial baseline levels.

Thanks again and congratulations.

Thank you.

Thank you. Our next question comes from Ted Tenthoff with Piper Sandler. Please go ahead. Your line is open.

Great. Thank you very much. Good morning, everyone, and congrats on the Phase II data. I had a one quick follow-up question. When it comes to the Phase III trial, is there a way or are you looking at benefits, kind of following up on the last question, from G-CSF reduction? Is there any way to capture those in terms of improved tolerability, improved safety? And I have a quick one on XOLREMDI. Thanks.

Sure. I'll turn that over to Christophe.

Yes. The Phase III trial is designed as a registration approval trial as per the FDA requirements. We will look at those aspects as a follow-on study to that Phase III trial.

Great. Yes, that makes a lot of sense. I imagine it might take some time for some of those to emerge, but yes, that's great. And then regarding XOLREMDI, you announced a new initiative. Can you provide a little bit more detail around that in terms of reaching out to patients?

Sure. Ted, just to clarify, a little bit more color on our sort of patient ambassador efforts?

Yeah. Thanks, Ted. You’re right, we’re laser-focused right now on raising disease awareness and driving screening for WHIM and presenting XOLREMDI as a treatment that has proven to work in WHIM. We’ve just launched a new patient-directed campaign. This is a combination of digital campaigns with websites as well as hard copy material that we can provide to patients. We believe this will help to educate patients and encourage them to discuss WHIM syndrome with their physician.

Great. Excellent. Well, thank you very much. Appreciate the time.

Thanks so much, Ted.

Thank you. Our next question comes from RK with HCW. Please go ahead. Your line is open.

Thank you, and good morning, Paula and team. I just want to focus a little bit on XOLREMDI and the uptake in the market. Can you educate us on how many patients are on the drug? What is the commercialization setup right now? I'm trying to understand how long you think it would take for the drug to be adopted in a significant way.

Thanks, RK. I'll turn it over to Mark.

Yeah. Thanks, RK. As I mentioned, we are currently focused on raising disease awareness and driving that screening for WHIM, encouraging physicians to look for WHIM patients in their practice, helping them recognize these patients. Up to now, there has been no approved treatment for this disease. Everything starts with raising disease awareness and encouraging physicians to identify the patients and then have a discussion with them about XOLREMDI. We share the data that demonstrates XOLREMDI works. This is really where we are now, building the foundation for our ramping up into 2025, and we’ll be able to share more details with you then.

Thank you. Thanks for taking my question.

Thank you. Our next question comes from Stephen Willey with Stifel. Please go ahead. Your line is open.

Yeah. Good morning. Thanks for taking the questions. Maybe one on the data and one on XOLREMDI. On the data side, was there any correlation between CN subtype and the rapidity and magnitude of G-CSF dose reduction? Also, was there any correlation between the G-CSF dose these patients were receiving at baseline and the magnitude of the dose reduction they were able to achieve?

Sure. I'll start, then Christophe will provide more color. But regarding the CN subtype, the good news is the drug seems to be robustly and consistently working. We did break out the severity of those patients because they are the toughest to treat, and we saw a robust response there. In terms of congenital or other CN types, we're seeing a very consistent effect. For G-CSF percent reduction from baseline, again, we aren't seeing variability in response based on their G-CSF profiles. However, Christophe has had a lot of data analysis and can provide further color.

Yes. Thank you. In the CN Phase II, the sample size and number of patients in that study is too small to draw any conclusions about the different patient types. We know that across all patient types included in the Phase II study, any type of those patients decreased G-CSF and chose to decrease G-CSF voluntarily. That, we know for sure. The Phase III trial will help us have a bigger picture of how those different subtypes, the congenital variations, etc., will all be analyzed in detail with much more data.

Okay. And then on XOLREMDI, you've hit 100% of your target accounts. I think you also mentioned that 60% of healthcare professionals have increased their screening. Do you have a sense of how many of these HCPs that you're targeting are indeed actively screening? Just wondering how low of a base you're starting at, and what kind of runway you might have?

The way we identify physicians that we believe have a WHIM patient in their practice is through claims analysis and our market research. These are the physicians we are targeting to raise awareness of WHIM syndrome and encourage them to screen for potential patients. This is where we're getting the most engagement right now. Additionally, we've really doubled down on our conference presence this year, focusing on hematology and immunology and meeting those physicians where they are.

All right. Thanks for taking the questions.

Thank you. Our next question comes from David Bautz with Zacks. Please go ahead. Your line is open.

Hey. Good morning, everyone. For XOLREMDI, I'm curious if you will be able to provide any type of sales guidance numbers moving into 2025. And for the new Phase II data this morning, I realize the numbers are small, but was there any data collected on infections, number of infections or types for those patients where G-CSF was reduced?

Sure. For sales guidance in 2025, we're not yet providing that. As Mark mentioned, we will provide some more robust insights into our commercial launch as we head into the year. Regarding infection data, as you can appreciate, this is a Phase II study, and it was not designed to assess infection rates, with no randomized comparator or arm, and thus no history collected. Importantly though, we would like to remind everybody that in this population, ANC is proven to correlate with infection risk based on G-CSF clinical trials and everyday use. We’re extremely pleased that our ANCs are robustly increasing and the neutrophils are functional, thus we are confident about our data and are prepared for the Phase III.

Okay. Great. Thanks for taking the questions.

Thank you. This concludes our Q&A session. I will now turn the call over to Paula Ragan for closing comments.

Well, thank you so much for joining us on the call today. As you can appreciate, we are very excited about these data, and we are on track to deliver value. From all of us at X4, stay classy, and have a great day.

And this does conclude today's program. Thank you for your participation. You may disconnect at any time.