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

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

Thank you, operator, and good morning, everyone. Thanks for joining us. Presenting on today's call will be X4's Chief Executive Officer, Dr. Paula Ragan; and the company's Chief Financial Officer, Adam Mostafa. Following prepared remarks by each, we will open up the call to your questions. And we'll be joined by Dr. Diego Cadavid, Chief Medical Officer; Art Tavares, Chief Scientific Officer; and Mary DiBiase, Senior Vice President, Technical Operations and Quality. As a reminder, on today's call, the company will be making forward-looking statements regarding regulatory and product development plans, as well as research activities. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A discussion of these risks can be found in X4's most recent filing with the SEC. I'd now like to turn the call over to Paula Ragan. Paula?

Thanks, Dan, and thank you, everyone, for joining us on the call this morning. We hope that you are all safe and healthy. As with many companies, 2020 threw some unexpected and significant challenges our way. Certainly, the COVID pandemic was chief among them. And working within a community, where many patients are immunocompromised, that resulted in challenges for the enrollment of our clinical trials. However, I'm extremely proud of the work done by our team in mitigating these obstacles. We made significant progress in the clinical development of our lead candidate mavorixafor and have an experienced leadership team in place to execute on our 2021 goals and beyond. As a reminder, mavorixafor is our first-in-class small molecule antagonist of the chemokine receptor, CXCR4, being developed as a once-daily oral therapy to treat a number of conditions caused by excessive signaling in the CXCR4, CXCL12 pathway. Our most advanced mavorixafor program is in WHIM syndrome. As you may recall, WHIM is a rare inherited primary immunodeficiency disease caused by Gain-of-Function CXCR4 mutations, that prevents the healthy trafficking of the immune cells and effective immuno-surveillance. We believe mavorixafor has the potential to be the first disease-modifying therapy for the more than 3,500 estimated diagnosed and undiagnosed WHIM patients in the U.S. We are currently conducting a global Phase III clinical trial in WHIM syndrome. The 4 WHIM trial is a randomized, double-blinded, placebo-controlled, multicenter study, designed to evaluate the safety and efficacy of mavorixafor in genetically confirmed WHIM patients. The primary efficacy endpoint for the trial will compare the level of circulating neutrophils relative to a clinically meaningful threshold in response to treatment with mavorixafor versus placebo, measured over the course of 52 weeks. Secondary endpoints include infection rates, work burden and assessments of immune system function and quality of life. Given the current pace of enrollment and the fact that this is a 52-week study, we continue to anticipate top line data from this Phase III trial in 2022. Notably, during the fourth quarter of 2020, we received both fast track and rare pediatric designations from the FDA for mavorixafor for the treatment of WHIM syndrome. These FDA designations further recognize WHIM as a serious condition, with a clear unmet need in both adult and pediatric populations, and underscore the importance of our efforts to advance this program as rapidly as possible. Through this fast track program, we will be eligible for more frequent meetings with the FDA to discuss the drug development plan, protocols and the clinical data that would support mavorixafor's potential approval for WHIM. As you may recall, mavorixafor was previously granted breakthrough therapy designation by the FDA as well as orphan drug status by the FDA and the European Commission for the treatment of WHIM syndrome. With the rare pediatric designation, we may qualify in the future for a priority review voucher, which, if awarded, could potentially be monetized. In the meantime, we expect additional data this year to further support our confidence in the outcome of the 4 WHIM trial. Notably, the open-label extension of our Phase II clinical trial in WHIM has continued to dose patients. We anticipate presenting detailed, updated results from the study within the next year. Since we expect that mavorixafor will be used as a chronic therapy, if approved, these long-term data are quite meaningful to the patient and physician communities. We are also continuing our research into WHIM prevalence, characterizations of specific WHIM mutations and compelling patient case studies, all for the potential presentation at upcoming medical conferences and other venues in 2021 and beyond, again, with a goal of a better understanding of the WHIM market for future commercialization and also increasing our visibility in the WHIM patient, physician and KOL communities. Turning now to our other ongoing mavorixafor clinical programs, enrollment is progressing in our Phase Ib trial, investigating the safety and efficacy of mavorixafor in combination with ibrutinib for the treatment of a subset of CXCR4 mutant patients with Waldenström's macroglobulinemia, a rare form of non-Hodgkin's lymphoma. We look forward to presenting initial data from the study in the first half of 2021 with a more robust data set expected to be presented later this year. As previously discussed, Waldenström's results from a thematic mutation in the MYD88 gene that is present in more than 90% of patients. Approximately 30% to 40% of these patients have a second mutation in the CXCR4 gene. These double mutant patients, with both the MYD88 and CXCR4 mutations, typically present with a more severe disease profile and do not achieve the same depths and robustness in responses as in patients with a single MYD88 mutation, treated with the current standard of care. We are targeting this high need, double mutant subset of Waldenström's patients as we assess the potential of mavorixafor treatments in combination with ibrutinib in our ongoing Phase Ib trial. The Phase Ib multi-center, open-label, dose-escalation clinical trial is expected to enroll approximately 12 to 18 patients. In addition to safety, dose and pharmacodynamic markers, the study is designed to evaluate changes in serum immunoglobulin M and hemoglobin from baseline, both key biomarkers of clinical response in Waldenström's patients. And lastly, regarding our Phase Ib trial in severe congenital neutropenia, we continue to anticipate initial Phase Ib data from the study later in 2021. As you can see, we expect that 2021 will be a year of key value-driving catalysts for X4 across clinical data readouts, enrollment completions and breadth of opportunity initiatives. On our last call, we briefly introduced you to Dr. Art Taveras, who had just joined as our new Chief Scientific Officer. As we mentioned, he has a wealth of experience in discovering and developing novel, next-generation CXCR4 antagonists. Art is an ideal fit to lead our R&D initiatives and has already had significant positive impacts on our research activities and on our earlier-stage pipeline initiatives. Following Art's joining in November, we also welcomed Dr. Diego Cadavid as our new Chief Medical Officer. Having previously served in key senior medical leadership goals at Fulcrum Therapeutics and Biogen, Diego has brought us broad and deep clinical experience in the rare disease space. He is also proven invaluable to us already as we continue to advance our multiple clinical programs in parallel and further advance our preclinical pipeline towards the clinic. With that summary, I'll now turn the call over to Adam to discuss our financial results for the quarter. Adam?

Thanks, Paula, and thanks to all of you on the call today. As presented in our press release this morning, I will summarize our financial activities and results for the fourth quarter and full year ended December 31, 2020. As of the end of the year, X4 had $80.7 million in cash, cash equivalents and restricted cash. We continue to expect that our cash and cash equivalents will fund our operations into 2022. Research and development expenses were $12.3 million and $41.9 million for the fourth quarter and full year ended December 31, 2020, respectively, as compared to $7.1 million and $30.2 million for the comparable periods in 2019, respectively. General and administrative expenses were $5.4 million and $20.9 million for the fourth quarter and full year ended December 31, 2020, respectively, as compared to $3.9 million and $17.6 million for the comparable periods in 2019, respectively. Finally, X4 reported net losses of $18.4 million and $62.1 million for the fourth quarter and full year 2020 as compared to net losses of $10.8 million and $52.8 million for the comparable periods in 2019, respectively. Let's now open up the call for questions. Operator?

[Operator Instructions] Our first question comes from Stephen Willey with Stifel.

I guess, Paula, maybe you can just kind of frame up expectations for us in terms of what this first WHIM or Waldenström's disclosure might look like, just in terms of, I guess, maybe timing? I know that there's a couple of potential venues on the medical conference front in the first half of the year. What we might be able to expect in terms of just patient numbers? And then also what a median duration of follow-up in those patients might look like?

Sure. Thanks, Steve. So the plan is to present the data at a medical conference. Of course, that's not always in our control, but we are likely to aim for one of the more visible conferences, like EHA. And there's some other conferences around that same time frame that could be a good fit as well. And in terms of the data, it's an open-label, Phase Ib, as you know, with 3 different cohorts. So we'll present e-presenting data, which will support a demonstration of obviously, safety and dose escalation. And then patients have joined the trial at various time points. So we will be providing a range of treatment times for that initial cohort of patients, and also be providing IGM changes as well as hemoglobin changes, which are indicative of activity. I think the most important thing for people to recognize is we'll aim to provide some relevant benchmarks so people can put our data in context with standard of care. And so I think that's the plan at this point.

Okay. That's helpful. And I guess, as you continue to characterize some of these additional CXCR4 mutations, have you gained any insight as to whether or not certain mutations within Waldenstrom's are more oncogenic just in terms of the pathogenicity?

Yes. So there are -- there's 1 reference in the literature that talks about sort of 2 different buckets of mutations in Waldenstrom's, some possibly a little bit more impactful than others. And we certainly reflect on that and think that's an important sort of information to be tracking. At this point, we're tracking that within our patients, but we'll use our own data set to better inform us on how to think about variant mutations and how they may or may not impact clinical outcomes. I think just overall, the data are still early across the board. And so we look forward to contributing that -- to that total data set with our own study.

Okay. And then just lastly, can you maybe just talk about some of the pediatric work that you may have planned for WHIM, I guess, specifically in the context of having the voucher now potentially available? And I think the age cutoff in 4 WHIM is 12 years, if I remember correctly?

Yes. That's right. So the ongoing study does capture the adolescent population. In terms of expanding our studies beyond the age of 12, we're currently evaluating that. Certainly, our goal is to always move forward in a safe way for patients and then expand as appropriate. So we're learning. That is certainly on our sort of near-term list of priorities, and we'll be glad to update you when we have better clarity on how we'll be initiating studies in younger populations.

Our next question comes from Joel Beatty with Citi.

First one, thanks for the -- in the previous question, you talked about what to expect from this Phase I Waldenstrom's data coming, around later in the first half. Could you compare that with what to expect in the data set that's expected towards the end of 2021?

Sure. So most Phase Ib studies in Waldenstrom's obviously are focused on safety and dose, but predictably, they also are assessing changes in IGM, as well as hemoglobin as a measure of activity against the disease. So the early part of this year, we'll be looking at changes in those 2 metrics, in addition to safety and dose over time. The longer-term outcomes enable us to measure response rates, which are more robust in terms of their requirements. So typically, that includes imaging for patients who have systemic disease as well as bone marrow assessments. So the end of the year will include response rate information, because the study will be much more mature across a broad number of our patients. The earlier data will be the leading indicators that are certainly highly correlative with response rates. For example, IGM is one of the major components of response rates, so it's a nice correlation for the long-term outcomes.

Okay. Great. And then for WHIM syndrome, could you help us think about the enrollment speed? And it seems to be a little bit slower than first expected. And how to think of that in light of what that may mean for patient interest? And I ask because you've done a lot of work characterizing the size of the patient population out there, and it seems like it's more than 3,500 patients in the U.S. alone and there's no approved targeted therapies like this. So it seems like, perhaps, the need for interest enrollment might be a little bit faster than what we've been seeing. So could you help us kind of reconcile those 2 thoughts?

Sure. No, it's a great question. I wish enrollment, as I think most of us in the industry wished enrollment would correlate with patient numbers. Unfortunately, that's not the case. Patients and sites need to be lined up. The lead time for opening sites in a geographic region that supports patients and minimizes their travel requirements, especially during the COVID pandemic was set before COVID hit us. So really, this is a story of matching patients to open sites, supporting their travel and risk profiles for COVID. We identified patients well in advance of opening our sites to make sure we could optimize across the globe in terms of how we would logistically open these trials. So I don't have anything to offer other than to suggest that the connectivity is not there for the industry, and unfortunately, it's not there for us as well. The good news is, we've known our patients now for quite a period of time. They're ready. They're there. And 2021 will be the year we successfully enroll this trial and communicate that to the Street.

Our next question comes from Leland Gershell with Oppenheim.

Just wanted to ask in terms of the open-label update in the Phase II and WHIM. Would we also be targeting EHA? Or will it be later in the year? Just wanted to add some color around the timing of that. And also I wanted to ask, just in terms of the earlier pipeline. Just wanted to check in and see how -- any progress may be going with some of the earlier candidates you have in the pipeline?

Sure. Diego, would you like to comment on the open label extension? And then, Art, would you like to comment on the pipeline? Go ahead, Diego.

Yes. Thank you, Paula. Yes, we are planning for a later disclosure of the Phase II WHIM open-label extension and not at EHA, but most likely later in the year or early next year. And Art, would you like to comment on the pipeline?

Sure. Thank you, Diego. Thank you, Paula. Yes, the pipeline, actually I'm pretty excited about where we're going with them. We've been looking at some of the profiles of various molecules. We have a very deep target series, and we're looking for opportunities. And so, this year, I think we're going to be able to push something towards -- into the IND-enabling studies with the hope of getting something into the clinic next year. So that's the goal. We got some pretty good profiles we're able to penetrate in. I think that leaves us with opportunities for some brain-related diseases that are associated with CXCR4 regulation. And then we have compounds that look like they target various lymphocyte populations. So there are opportunities for lymphocytopenia type diseases. So more to come, and I'll disclose a lot more information as we get it.

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

A couple of quick questions. The first one on Waldenstrom's. I think since ibrutinib got approved as the combination therapy as well, along with rituximab in 2018, the combination has been kind of moving more into the first line therapy. But you are doing your studies just as a combination with ibrutinib. So how do you see your combination working within the therapeutic paradigm for this disease?

Thanks, RK. I appreciate the question. I think there are some geographic differences. So what we've been hearing is certainly ibrutinib is still used, single agent, sometimes in the frontline setting and certainly in the second-line setting in the U.S. and has some shifts to do that as well as in Europe. We recognize the ibrutinib plus rituximab sort of frontline paradigm. If you look at the data, and also we hear some input from our ex U.S. clinicians, I think most people experience rituximab offering very little to the combination and effectively are prioritizing ibrutinib in the frontline setting. So I think that could actually bode well for us. It is still early, and you mentioned 2018. It's really only about 2 years into it, and it does take some time for the paradigm to settle in. But I think we're actually in very good shape with -- initially partnering with ibrutinib, even in the event that the paradigm shifts, I think CXCR4 antagonism partners more broadly with other types of mechanisms and agents in Waldenstrom's and even more broadly lymphoma. So in either regard, I think we're well positioned with this early data set, to just show the power of CXCR4 antagonism and move forward from there.

Great. And then the second question is on SCN. So just as you discussed a little bit more in terms of data expectations from data indication in the middle of the year for Waldenstrom's. So here, in SCN, I know you're not telling us specifically when in 2021. But what sort of -- what sort of -- will we see any efficacy area at all? Or would it just be some safety and dose escalation that you'll see?

Sure. So let me just remind you of the strategic importance of SCN. So severe congenital neutropenia is ideally what we hope. Assuming WHIM is approved, we'd certainly like to explore the application of mavorixafor in other patients with these profound neutropenias and lymphopenias, and SCN is a natural first pick -- place to explore. So strategically, that the timing on the data still continues to fit well with the overall timing of our global efforts around mavorixafor. So as we think about the data this year, the SCN trial has probably been the most complicated due to COVID because of the duration of the trial. It is a 2-week dosing period, which offers little opportunity to provide clinical benefit for patients, and we respect that. It is really a translational study that will correlate a patient's genetic profile with a response after 2 weeks of dosing. So at the end of the day, we need to be respectful of the patient dynamics, given the global and once-in-100-year pandemic that we're all experiencing. So we will have some initial data towards the end of the year. And we'll provide more color on that as we gain better clarity.

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

This is Sohail Kazmi on for Mayank. Congrats on all the progress. Couple of brief questions from us. Could you discuss a little bit about the IGM response kinetics and kind of how you see the levels or how you think about the levels potentially evolving over time from -- in this initial readout relative to kind of what we can expect to see at the end of the year? And then briefly on WHIM, if you could just give us a little bit of color on the enrollment dynamics in terms of U.S. versus ex U.S., any considerations for the pandemic that you alluded to in the SCN program as it relates to maybe missed doses?

Sure. So I think the first question was around sort of IgM level kinetics and benchmarks to help you appreciate ibrutinib. Is that -- did I catch that correctly?

Yes, exactly.

Okay. So I'll begin, and then I'll ask Diego to also chime in, but there are actually some very good references. Ibrutinib has been well studied in the Waldenström's population. Dr. Steve Treon is considered one of the global experts in this area. And thankfully, he is one of the key investigators on our trial. Dr. Treon's translational work has shown that patients with the CXCR4 mutations have IGM drops that are dramatically different than those patients without CXCR4. And just a few references for those folks on the phone. There's a great publication by Dr. Treon in Blood of 2017 that actually splits out the kinetics of IGM versus time for the 2 different types of populations. So it will be -- it's a great benchmark for us because we understand what patients do on ibrutinib, with the CXCR4 mutation and without and ideally, our treatment with mavorixafor could correct for that, and change the patients from double mutants to look more like the kinetics of single mutants, and that's some of the efforts that were going on now to measure and benchmark. So I hope that was helpful. I think the second question was a little bit around the pandemic's impact on our WHIM trial. So I do think there are differences there. Certainly, the WHIM trial provides the potential for clinical benefit. If we reflect on our Phase II data that's been published, it has certainly strong suggestions or reductions in infection rates and some of the sequelae of having WHIM syndrome. So there is reason to be motivated and committed to this trial, which we've certainly seen our great patients step forward with and because we certainly had these broad relationships with KOLs over the years and their patients, we feel like that relationship is certainly one of the key things that we continue to respect and appreciate and support, hitting our enrollment targets, which are nicely on track for this year.

Our next question comes from Zegbeh Jallah with ROTH Capital Partners.

Just wanted to quickly confirm, Paula, if we're going to see any kind of highlights from the Waldenstrom data before a presentation at a medical meeting? And then also, would you expect any updates or data progress for your partnership with Abbisko this year?

So why don't I invite Diego in to comment about our plans around the Waldenstrom's data given his connection with our investigators. And then I'll take the other question.

Yes. Thank you, Paula. So we are looking to do an initial public disclosure of the Waldenström Phase Ib data towards the end of H1, most likely at EHA, that will report on initial safety, PK/PD. We have a very good pharmacodynamic marker and some initial data on the serum IgM and hemoglobin, which are really helpful biomarkers. Later in the year, most likely at ASH, we plan to have a second presentation. It should include more patients and longer follow-up, including an assessment of responses, including bone marrow and whole-body CTs. And both of these presentations will be able to be compared with the benchmarks from ibrutinib monotherapy in double mutant population. So we believe that will help us assess the emerging efficacy of mavorixafor in this type of lymphoma, which has, obviously, a high unmet need as they are the, really the sickest. And we'll use that information to decide our next steps. Regarding the partnership with Abbisko, Paula, could you take that one?

Thank you, Diego. Yes. So the Abbisko partnership is advancing. I would bet that we'll be able to provide a more clear update towards the end of 2021, but it's launching nicely, and as we gain clarity, we'll look forward to sharing more details at a future point.

I am not showing any further questions at this time. I would now like to turn the call back over to Paula Ragan for closing remarks.

Thank you so much for joining, everyone, this morning. I hope you all continue to remain safe and healthy. And if you have any follow-up questions, we'd be happy to answer those offline. Thank you again, and I hope you enjoy the rest of your day. Goodbye.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.