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spk06: Greetings and welcome to X4 Pharmaceuticals First Quarter 2022 Financial and Operating Results Conference Call. At this time, our 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, Dr. Glenn Shulman, Head of Investor Relations. Please begin.
spk03: Thank you, Operator, and good morning, everyone. Presenting on today's call will be X4's Chief Executive Officer, Dr. Paula Regan, and the company's Chief Financial Officer, Adam Mostafa. Following prepared marks by each of them, we'll open up the call to your questions, during which we'll be joined by our Chief Scientific Officer, Art Tavares, Chief Medical Officer, Diego Kadavid, and our Chief Operating Officer, Mary DiBiase. As a reminder on today's call, X4 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 arbitrarily from those forecasted. A description of these risks can be found in X4's most recent filings with the SEC. With that, I now would like to turn the call over to X4's President and CEO, Dr. Paula Reagan. Paula?
spk04: Thanks, Glenn, and thank you, everyone, for joining us on this call this morning. On this morning's call, I will provide a brief update on recent accomplishments, highlight a few of our important upcoming catalysts, including the readout from our Phase III-IV WIM trial, and, of course, open up the call to any questions you may have for the team. As a reminder, our lead candidate, Maverick Zafour, a CXCR4 antagonist, is being evaluated as an oral, once-daily treatment for people with rare disorders of the immune system, including people diagnosed with WIMP syndrome and chronic neutropenia, and also for those diagnosed with certain lymphomas. WIMP syndrome is a rare immunodeficiency disorder caused by genetic mutations to the CXCR4 receptor. The disease is characterized by HPV-associated warts, hypogamyloglobulinemia, multiple types of infections, and myelocortexis, a pathologic bone marrow finding associated with the reduced ability of white blood cells to move from the bone marrow to the periphery. We believe that the results from the open-label extension of our Phase II clinical trial with Maverick, Sephora, and WIM patients continue to support the significant potential of our lead drug candidate in this indication. with data showing durable TATs, or time above threshold, for blood levels of neutrophils, lymphocytes, and monocytes, decreased frequency of infections, and robust and sustained improvement in wards. Patient quality of life, including reductions in doctor or hospital visits, was meaningfully improved based on our Phase II patient narrative. Importantly, these include the primary and secondary endpoints of our ongoing Phase III WHIM trial, And just as importantly, Mavericks 4 continues to be well-tolerated over a median treatment duration of now more than 160 weeks. We continue to anticipate that top-line results from our global placebo-controlled, double-blinded, four-WIM Phase III trial, which enrolled a total of 31 adolescents and adult patients, will be available in the fourth quarter of this year. We intend to report on the primary endpoint which consists of time above threshold for absolute neutrophil count, and which was powered based on our findings in the Phase II trial, along with available secondary endpoints. The trial design and primary endpoint have been agreed upon with the FDA. Additionally, secondary endpoints evaluating sections and warp burden, among others, have been also discussed extensively with the FDA, and their guidance has been diligently followed. We look forward to preparing and submitting the new drug application or NDA for submission to the agency in the second half of next year. We also continue to conduct and publish research on the underlying genetics of WHIM as we work to further characterize and expand the definition of the disease. We have built strong in-house research programs that leverage world-class collaborators to advance bench-to-bed sign research. By continuing to establish correlations between clinical presentation and novel genetic variants associated with WHIM, we can enhance our ability to identify undiagnosed patients, including those who may potentially benefit from Mavericks IV treatment. At the upcoming European Hematology Association, or EHA, meeting this June, we plan to present more of this novel research. We will have a press release with more details this afternoon after the abstract embargo lift and we hope to see you at the Congress in Vienna. As I mentioned earlier, we believe there are additional disease areas harboring patients in need who could also potentially benefit from treatment with maverixifor. With WHIM as our B-tide indication well on its way, we are also assessing the potential of maverixifor as a therapy for other causes of chronic utropenia, given the drug candidate's potential for meaningful advantages over the only existing therapy. Chronic neutropenia, or CN, includes a number of subtypes, such as congenital, idiopathic, and cyclic neutropenia, all of which we believe could benefit from treatment with Maverick before. In our ongoing Phase 1B study, we are actively enrolling patients diagnosed with these types of CN to establish biologic activity and support future regulatory discussions. We look forward to providing both updated clinical data along with regulatory feedback during the third quarter of this year. We also announced this morning that we have completed enrollment in our ongoing Phase 1B clinical trial studying patients diagnosed with Waldenstrom's macroglobulinemia, a rare B-cell lymphoma. This Phase 1B trial is designed to demonstrate safety, dose, and elucidate proof of concept of maverick spore in combination with the BTK inhibitor ibrutinib in patients with Waldenstrom, resulting from mutations in both their MYD88 and CXDR4 genes. This patient population continues to have reduced treatment responses due to their cancers harboring these two mutations. Doses of 200, 400, and 600 milligrams per day were evaluated, and once cleared, eligible patients were dose escalated to receive 600 milligrams once daily. Data that we presented last December at ASH showed a 100% overall response rate, or ORR, and sustained decreases in serum IgM. a blood marker that corresponds with cancer burden in 10 evaluable patients whose cancers had confirmed MYD8 and CXCR4 mutations. Further to that, we also presented additional preclinical results in a poster presentation at the 2022 American Association of Cancer Research, or AACR, annual meeting. This poster reported that combinations of Mavericks before with a broad array of BTK inhibitors overcame bone marrow-induced treatment resistance, and enhanced cancer cell death in in vitro assays of Waldenstrom. We expect to report results from the Phase 1b clinical study, which we anticipate would include at least six months of treatment data for patients on the 600 milligram dose during the second half of this year. With three readouts on the horizon, including data and chronic utropenia from our Phase 1b study next quarter, results from Wallenstrom's Phase 1B study in the second half, and our four WHIM Phase 3 results in the fourth quarter, we are extremely excited for what's to come. With that brief update, I'll now turn it over to Adam to discuss our financial results for the quarter before we open up the call for questions. Adam?
spk02: Thanks, Paula, and thanks to all of you on the call today. As presented in our press release this morning, I'll summarize our financial activities and results. for the first quarter ended March 31, 2022. As of the end of the quarter, X4 had $67.7 million in cash, cash equivalents, and restricted cash. We continue to expect that our cash and cash equivalents will fund our operations into the fourth quarter of 2022. Research and development expenses were $14.1 million for the first quarter ended March 31, 2022, as compared to $12.1 million for the comparable period in 2021. Selling, general, and administrative expenses were $7.7 million for the first quarter ended March 31, 2022, as compared to $5.8 million for the comparable period in 2021. Finally, X4 reported a net loss of $22 million for the first quarter of 2022. which includes approximately $1.5 million in non-cash expenses, as compared to a net loss of $18.7 million for the comparable period in 2021. We'll now open up the call for your questions. Operator?
spk06: Thank you. At this time, to ask any questions, please press star 1 on your telephones. To withdraw your questions, just press the pound key. Once again, that's star 1 for questions, 1 moment for questions. Our first question comes from the line of Mark Fromm from . You may begin.
spk11: Hi, thanks for taking my questions. Just to start off with the SCN update, Paul, you laid out that there are a couple different subtypes. Can you maybe describe the types of patients you've been able to enroll so far and therefore kind of across those different subtypes, you know, which ones might you be able to update us on? in Q3, both from a clinical perspective, but then at least as importantly, you know, from a regulatory perspective.
spk04: Sure. I'll start, and then I'll invite Diego to chime in. But, you know, what we're aiming to do is to show the breadth of Maverick Sephora's potential benefit in patients with chronic atropinia. Those buckets, as you mentioned, are the idiopathic, cyclic, and then congenital. And I think at this point what we can share is we're certainly feeling confident that we'll be able to share data across each of those three buckets in Q3. Again, the patient flow of the numbers is always a bit ad hoc because some of these patients are, you know, sick with neutropenia, for example, it's a bit challenging just to catch the right window to explore the drug in those patients. But we're really encouraged about what we're already seeing, and maybe I'll turn it over to Diego to add.
spk07: Yes, I would just add that we are... We are sure by the strong interest at all the sites, the number of potential patients, the number of patients who have consented, as well as patients lost. And, you know, the change in the conditions of the pandemic is making this study move forward. So we look forward to being able to present data in Q3, as Paula said, that will give us a good sense about the potential across all these diverse indications within chronic neutropenia.
spk11: Okay, thanks. That's helpful. And then maybe for Adam, I appreciate the cash guidance last thing in Q4. Can you remind us the kind of status of the covenants on your debt and just kind of where that is?
spk02: Sure. Thanks, Mark. So we have a minimum cash covenant. That test kicks in on September 1st. We have a recent amendment where if we raise at this point another $27 million by June 30th, that minimum cash number will be fixed at $30 million until we get to WIM data where with positive WIM data it will be $20 million. If we do not raise that capital before June 30th in that test, it will simply be a six-month cash burn test. So it will be our prior one-month burn times six that we would need to keep in terms of cash on the balance sheet at that point in time to cover the test. So that's a little bit around the company. Yep.
spk11: Very helpful. Thank you.
spk06: And our next question will be from . You may begin.
spk01: Hi. Good morning, everybody. This is William Wood on from . Really appreciate you taking our calls and congratulations on all the the advancements that you've made. A couple questions from us. I was wondering if you could first, could you talk to how you view the WM landscape in light of the experience of our targeted therapies, and where you may think that the third quarter readout has an opportunity to improve perception as it relates to both safety and efficacy?
spk04: Sure, I'll start. And again, I think it was Waldenstrom that you're asking about, just to confirm.
spk01: Yes, correct.
spk04: Yeah. So, guidance is that we'll be sharing data second half of this year. And in terms of the competitive landscape, of course, there's a lot of, a number of BTK inhibitors given the validation of the target that are moving forward in the pipeline. Certainly, there's two approved, two or three approved. I think, again, we continue to see the importance of adding a CXCR4 antagonist across any of those BTK inhibitors with respect to patients with the CXCR4 mutations. Initially, and certainly we see broader applicability beyond that, we just presented some really exciting data at AACR, which shows the breadth of activity of our drug, not only in double mutants, but of course the single, the non-mutant Waldstrom cells as well. And then in terms of safety, you know, our drug has got a very positive or benign safety profile, which makes it more amenable to partner with some of these tougher treatments. So the overall therapeutic window in combination seems to say reasonably wide when we add drugs in combination, again, favoring our approach versus what we're seeing with other combinations. But Diego, would you like to chime in, and then Art as well?
spk07: Yeah, I would add also that we believe Mavodix-A4 is quite differentiated from some of the other drugs being combined in the sense that, for example, Venetoclax has a lot of neutropenia Xanobrutinib also showed a lot of neutropenia. You see it with ibrutinib. We actually have a drug that treats neutropenia. So in the context of having risk of infection in these combination treatments, ultimately, the safety of the combination will become very important for a chronic treatment on indolent lymphomas. So we are quite excited about the potential of Maborixifor to be a competitive drug candidate in that space.
spk10: Maybe I can add a little bit starting from the neutropenia side. There's reports already in the literature that talks about ibrutinib, zanubrutinib, acalabrutinib actually showing neutropenia and lymphocytopenia and then the corresponding increase in infections. It's grade three through five SAEs. and AEs. And so, we certainly are drawing and we've measured Maverick's A4 in combination with the Brunib in our Waldenstrom's Phase 1B trial across the patients. And we can actually see increases in all of these leukocytes. So, we actually do believe that this is going to be a benefit with respect to safety and particularly the infection safety related to neutropenia and lymphocytopenia. And then second, it's related to the data that we presented at AECR. And as Paula mentioned, there what we were working with was a single-mute and wild type of CX-04, and these are MITE-88 L265P mutation cells. And there what we found is that all of the agents that we looked at, these are the BTK antagonists that are out there, so Abrutinib and Zanubrutinib, two commercial ones, and then Loxo-305 from Lilly, and the Merck Arcul-531. And what we found is that these agents, while they work on their own, once you start to involve bone marrow, which is really where CX04 double mutation really starts to play, then you see that they become a bit resistant to the therapy. The tumor cells become resistant to the therapy. And Mavericks was able to overcome that. So a lot of opportunities here. It broadens, obviously, the combinations that could be used, so it's not just a brute could be any of these other agents, whether they're commercial currently or potentially the ones that are in clinical development, it broadens the opportunity across single mutants, which now have up-regulated CXCR4. So it's not just about the double mutants. And then the work that we're doing right now is broadening out even further to other lymphomas. So I think we have some good breadth of opportunities with Mevrix4, and the combinations actually could be quite a few, not just the with the Brutonin.
spk01: Thank you so much. We really appreciate the extra information there. And also, I mean, as you've presented, you've got a number of clinical trials providing data and the second half. I was just curious where we might be able to expect to see those data coming out throughout the year.
spk04: Yeah, I think we'll provide greater clarity on the different venues that we'll be sharing data. Certainly with the three different milestones, so the chronic utropenia milestone and then the WIM Phase III as well as the Waldenstroms, we have sort of a nice drumbeat of information, and that we'll try to optimize to make sure the community is kind of educated and understanding the data when they roll out. So stay tuned. We'll be able to provide some more clarity in the coming months.
spk01: Awesome. Thank you so much. Congratulations again. I'll leave it there. Thanks.
spk08: Thank you.
spk06: Our next question will come from the line of Swayampakula Ramakhan from HC Wainwright. You may begin.
spk05: Thank you. This is RK from HC Wainwright. Good morning, Paula and Adam. So talking about the three buckets of patients under chronic neutropenia, Is the biology the same or similar among the three buckets? And you stated that you would have data among the three buckets. So assuming that the data is similar, is there a preference to go after one of them? Or what is the decision point there?
spk04: Yeah, so I think our rationale is certainly there's other, GCSF is the only approved treatment. It has been shown to offer some benefit to those patients with significant tolerability issues. And then TXCR4's antagonism, TXCR4 antagonism is a broad mechanism as well. We've seen it to elevate white blood cell counts in any subject or patient population, so it has this tremendously broad opportunity to increase neutrophils in any form of neutropenia. You saw that in our ASH data with our idiopathic patients. Those folks have unknown cause of neutropenia. We found very robust effects. So we've kind of already checked one of the three boxes, and we'll look forward to sharing more data. But I think maybe I'll invite Arden a little bit more to talk about the mechanistic rationale for Mavericks 4 across these different buckets.
spk10: Yeah. Hi, RK. How are you? So maybe I'll just talk a little bit about the overall chronic entropenia landscape, if you will, and maybe start from WHIM and then also the connection back to Wallenstrom's. So there, you know, we were focused really on mutated CX0-4, but the work that we had done in Wallenstrom's in particular showed us that actually it's more than just mutated to even wild-type CX0-4 and how that gets upregulated under various scenarios. And then certainly across, and this is work that Diego had presented at ASH in December, that across all the different clinical programs that we've been doing, we see leukocyte mobilization when in patients treated with maverixifor, and we see baseline elevations of these leukocytes across the board. All right, so this is actually pretty promising because it actually says it's more than just mutated CXCR4. And it's more than just the specific two diseases that we've been talking about. So now it's a broader market expansion and opportunity across other patients now with chronic neutropenia. And what we're focused on is the potential of Mavericks for it to raise the neutrophil levels in those patients. And the simplest way is just take the patient, give them Mavericks before and see if they respond, or us in vitro to be able to assess pathogenic measures. And so from the data that Diego presented we're seeing that these patients do respond. So clearly there's a CX04 component, and what we've always talked about is that CX04 and its natural ligand CX012 at the heart, their master regulator in terms of granulopoiesis and hematopoiesis in general. So that's a nice connection, and it's really all about CX04 for us.
spk05: Fantastic. Thank you very much for that. And then on the VIMS syndrome, with the data coming out in fourth quarter, so at the same time, you know, you folks were identifying new mutations within the CXCO4. So when you present the data or when you start to analyze the data from fourth quarter onwards, Are you going to go back and look at individual, individually you're going to be looking at the mutations just to understand how broad Maverick SO4 can be working on? And do you think there would be any mutations where Maverick SO4 will not be able to interact with or not able to, you know, get the benefit, you know, some of these patients? I'm just trying to understand how broad you can use Maverick SO4. in the VIMS syndrome.
spk10: Okay, that's a great question. Maybe I could just share the work that we've been doing in what we call the BUSs, which are really a number of CXCR4 mutations. So at this point, we've analyzed probably close to about 70 mutations, and they really cover expanded different parts of the CXCR4 receptor. And what we find is that most of them are pathogenic. And then we know that Mavericks 4 binds to all of the CX0-4 mutants that we've tested so far. And so, or at least blocks the binding of CX0-12 to all mutants that we've tested so far. So we believe that it's going to be effective in any one of the CX0-4 mutations, and that should be irrespective of the mutation.
spk07: Yeah, and I would simply add that we already tested in the context of the Phase 2 trial different mutations, and they all respond. So we're very confident between the in vitro data and our own in vivo data. And in fact, we have enrolled a breadth of mutations in the phase three trial. The bottom line is we believe it will work across all mutations. And in fact, because of our chronic neutropenia, we know that it also works on the wild type. So it's a big promise to have for the first time a nodal well-tolerated therapy to treat people who are at risk of serious infections from chronic neutropenia.
spk05: Fantastic. That's great. So one last question on the Waldenstrom's indication. When data comes out in the second half, what are the next steps in the sense, you know,
spk00: Do you want to listen to another Encore conference? Press 1 for yes or 2 for no.
spk03: Hello? Can you repeat that? I'm not sure what that was.
spk05: On the Waldenstrom syndication, what's the next step in the sense once the data is presented in the second half? would you be able to go straight into a registrational study or do you need to do an additional study before you go into registration?
spk04: So, you know, obviously we're waiting for the data to mature and then have regulatory discussions. The, you know, there's really only been two drugs approved in Waldenstrom historically. So I think that the answer is stay tuned. Obviously data plus regulatory input then would enable us to plan for the future. And, um, So that's our milestone for the second half is to provide that guidance. So looking forward to sharing more, RK.
spk05: Thank you. Thank you very much for taking all my questions. I appreciate it. Thank you.
spk06: And once again, as a reminder, that's star one for questions, star one. I know Trevor Allred from Alpenheimer. You may begin.
spk09: Hey, good morning. Just wanted to ask if you had any conversations with Lily or Merck about combination potential and if you have any expectations for how you might advance that combo. Also wanted to ask if you see any potential role for MAV in activated PI3K delta syndrome.
spk04: So Adam will take the DD question.
spk02: Yeah, thanks for the question. We won't comment on specific names of folks who we've been talking to, but certainly we're exploring different alternatives and discussions as it relates to getting the most value from our pursuits and strengthening our balance sheet in both in oncology and in general. But we'll circle back when appropriate with any specifics in the future.
spk04: Yeah, and then with respect to PI3K Delta, certainly the pathway, signaling pathway, overlaps with CXR4, so there's a mechanistic rationale to support the use of Mavericks 4 in those patients as well. We've not yet tested specifically any patients, but it's something that we're considering for future studies.
spk11: Okay, great. Thanks.
spk06: And our next question will come from Zach Bejela from Roth Capital. You may begin.
spk08: Good morning. Thanks for taking our questions. I just have three quick ones here. The first is about the Waldenstrom data. I know at the time of the last update, you had really strong responses in the relapsed refractory patients, but a little less in the frontline setting. So we're just wondering with enrollment now complete, would you expect more patients or more relapsed refractory patients versus frontline patients? And then also regarding the 600 milligram dose, that have started to be used, you know, how should we think about the potential for that dose to kind of change the efficacy profile that we've seen for the program? And I have a couple of follow-ups.
spk07: Yeah, no, thank you for the question. We believe the potential for Maborix A4 in combination with the VTK inhibitors is broad. We chose to focus first on double mutants. because they have the highest unmet needs. We believe that the drug can actually be a really good add-on for either frontline or relapsed refractory, and we have enrolled both in our trial, and we will report on that later in the year. I mean, as I mentioned earlier, in vitro, we are really happy with the cellular models that show efficacy even in wild-type CXER4 in the context of modeling a bone marrow niche. So this speaks to the broad potential of CXER4 inhibition across tumors that are based in the bone marrow. So what will come next, Paul already mentioned, will focus on Walden's from double-Newtons, but we believe the potential is much broader.
spk08: Thanks, Diego. And then the follow-up here is just about the WIM program. You're on track to have your NDA submitted, which is a big deal. So looking at the way the stock is performing, wondering if you could just kind of, again, highlight the commercial potential, talk about, you know, some of the steps that you've taken. I know you have someone heading commercial, so just kind of wondering if you can just kind of speak to that for a little bit, and I have the last one here as well.
spk04: Sure. So in terms of the potential for Mavericks 4 and WHIM, you know, we continue to guide that there's at least about 1,000 genetically confirmed or confirmed WHIM patients in the U.S., and possibly much more than that in terms of the underdiagnosed or undiagnosed. And we're making exceptional progress towards, you know, building that patient-based education awareness and getting ready for supporting a positive launch should a Mavericks 4 be approved. Our new VP of U.S. Commercial is exceptionally strong and experienced in this area. We've got a great team on the ground already, and I think we're really revving up for a successful, you know, an ideal launch post our Phase III milestone this year. So stay tuned to more details, but we're excited about already the breadth of diversity of patients, as Art mentioned, over 70 genetic mutants, and then also the diversity of the products potentially even in chronic neutropenia beyond whim.
spk08: Thanks, Paula. And I don't know if you can say much about this, but this kind of segues based on what you just ended with regarding the broad commercial potential. I think you guys have highlighted about 60,000 patients across the different diseases that you're looking at. You're also going to have pretty much strong proof of concept data across all three indications by the end of the year. And we've seen you kind of pushing to even broaden this out some more. So And clearly, I think that there should be, you know, some partnership interest. And so is that something that you guys are exploring, you know, perhaps not just for one dedication, but across the board as it relates to Maverick so far? And then you can maybe comment on how you're thinking about maybe, you know, reaching X U.S. opportunities.
spk04: Sure. I mean, the world is a big place. We obviously have home fuel advantage in the U.S., and we have a drug that appears to work in WIM, and it's got some amazing sort of momentum behind it with these other indications, so there's a lot of opportunity for patients and for sort of commercial investment and return on that investment. We won't be able to share more of how we're thinking, but we're certainly believing that in the U.S. we can handle the commercial setting given the build that we're already investing in and the fruits of that build. But ex-U.S. is still a part of our strategy that's evolving, and certainly there's a lot of companies that create the right structure to support the most patients globally and also benefit the overall investment and return on that that's needed.
spk08: Thanks. And then, again, go back to the progress.
spk06: Thank you. And once again, let's start one for any questions. One more for questions. And I'm not showing any further questions in the queue. I'd like to turn the call back over to Dr. Paula Regan for any closing remarks.
spk04: We'd just like to say thank you for everyone for participating in our investor call today, and thanks for the excellent questions. If you have any further follow-up, please reach out to Glenn, and we'd be happy to dialogue offline. Thank you again, and have a great day.
spk06: This concludes today's conference call. Thank you for participating. You may now disconnect. Everyone have a great day.
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