Biotech Analyst and Managing Director at Piper Sandler. And before I begin, I am required to point out certain disclosures regarding the relationship between Piper Sandler and X4, which are posted at the back of the room and also down at the registration desk. Since we last sat here, X4 has gained FDA approval of Xolremdy, previously known as mavorixafor for WHIM syndrome. X4 also just recently updated phase II data, positive phase II data on mavorixafor in chronic neutropenia, and is conducting the phase III 4WARD trial. Here with us today is X4's President and CEO, Paula Ragan, PhD. Thank you for being with us.
Thanks, Ted. Great to see you.
Paula, congrats on Xolremdy approval. I mean, really a great product and really an important product for these patients. Perhaps you can start off by describing WHIM syndrome and how Xolremdy or mavorixafor works in this disease.
Absolutely. We were, as you highlighted, thrilled with our great success on a first approval for a drug for these patients in history, so we are pleased with the approval of Xolremdy, and what the drug is aiming to do is to really treat infection burden, and we were very successful with our phase III study, both seeing some biomarker data, but we also saw severity in rate, duration, and severity of infections, so it's a phenomenal step forward clinically for these patients, and that's absolutely what they need. WHIM syndrome is a combined immunodeficiency. It means their cells across their immune system are suppressed in that functioning because they're stuck in the bone marrow. Xolremdy is a targeted treatment to help mobilize those cells out of the bone marrow and then enable the clinical benefit that we saw very nicely in our phase III.
Yeah, so let's talk about the phase III. Remind us what you showed in the 4WHIM trial.
Yeah. So first of all, just to highlight the robustness of this study. I think in rare diseases, there's lots of opportunity to take different panels. We actually had the highest level of evidence that you can sort of establish with a randomized placebo-controlled double-blinded study looking at both neutrophil counts, and the primary endpoint was time above threshold. It's how many hours a day are your neutrophils more normalized than what they were versus baseline. And then we also looked at that same type of paradigm for lymphocytes and other cell types. But then importantly, what we also looked at was the infection burden around these patients. And what we learned was these patients are getting four to five significant infections a year. They were sick 49 days a year. That, to me, is unbelievable just from a human perspective.
I think all of us, I'm sure, there's stuff going around. You know, we all have had our own experiences with COVID even. Like their entire lives are fear of life-threatening infections, which is almost a day a week out of their lives, and then finally, of course, the severity. Some of them are hospitalized. We've even had, unfortunately, some losses of patients, so our phase III reduced all of those components. We saw a 60% reduction in infection rate. We saw about a 70% reduction in the days of infection. It went from 49 days to two weeks a year, and then on severity, we saw a 70% reduction in Grade 3 or beyond infections, so we are so pleased, you know, as a reminder too. This was during COVID where there were sheltering in place. Just kind of the normal infectious milieu was quite suppressed.
To see such a robust study during such a pan-suppressed state in our history just goes to show how effective the drug is and how much need there are in these patients.
That's interesting. Are patients seeing, as they kind of get back out in the real world, a higher infection rate? WHIM syndrome patients as well?
Yeah. Absolutely. So I mean, we can't, now that there's real-world evidence, we're not yet having enough data. But certainly from our physicians, we've actually known some patients from the phase II study that wanted to take a break that came back on from their own history. So we know from our studies and also from the anecdotes that this is well-placed for the community to help them.
How is Xolremdy tolerated?
It's extremely well-tolerated. It's safe and durable for lifelong use so far that we've seen. We've not really seen any issues other than what was already disclosed in the label, which is really that Grade 1, Grade 2 GI tolerability, which resolves over a few weeks as long as you kind of give those patients a little bit of a heads-up. Once in a while, they can use over-the-counter meds to help quiet that. But really no discontinuations and no evidence to support anything different at this point.
So tell us a little bit about your marketing effort. You know, how do you reach out to these patients who haven't had a therapy for so long? How do you build this market?
It's a great question. I'm glad you said that because building the market is what we need to do, right? This is an ultra-rare space, and there's been nothing ever for these patients. So they're a bit fragmented. So what we've done very purposely is we have a target group of physicians. These were the 3,400 physicians that we have either known of in the past or are certainly aware of through our data analytics methods that are likely to house WHIM patients. And we've actually hit all of those targets. So the first layer is the mind sees only what the mind knows. So we're educating physicians on the approval of Xolremdy and on the interest in WHIM patients. And we have seen a nice uptick both in the diagnostic testing rates as well as physician engagement.
Like there are more physicians who know about WHIM from our pre and post-marketing surveys. So we're very successful doing exactly what we need to do, which is drive education and awareness and then ultimately genetic testing and diagnosis.
You guys recently reported 3rd quarter, and it was sold about $1.1 million in Xolremdy since the launch. Beyond diagnostic testing and physician engagement, what are some of the important launch dynamics that you're tracking and focused on?
Yeah. And we'll be able to share more of this next year. But of course, we're looking forward to increased enrollment. Enrollment forms are always a metric. But I think what we really want to first get in is 2024 was our story of just building that infrastructure, developing those relationships. And then 2025 is the hopefully fruit of that investment. It does take a while for these patients to just get back into their physicians. These are specialists. I'm sure anyone in this room has had their own experiences with cycle times and getting in when you need to. But we certainly think that what we've planted today in terms of education and awareness and see the diagnosis, then of course the Xolremdy hopefully conversion rates will come in 2025 and beyond.
Excellent. And what are your plans for Xolremdy overseas?
So we're very excited about. There's lots of opportunities for Xolremdy overseas. First of all, sort of the lowest hanging fruit is there are certain regions that can actually accept the FDA filing and acceptance. So we're working on some smaller regional opportunities that can help unlock that value. Most importantly, we're very well positioned to file our marketing authorization application in Europe at the very start of 2025. So we're in great shape to anchor on our European strategy, which is likely ideally through an ex-U.S. partner or distributors. But the MAA filing is certainly the nice cornerstone to enable 2025 success in that category of, again, leveraging other people's rare diseases expertise. We certainly have enough to do in the U.S. and make sure we stay focused on the eye and the prize here.
But there are a number of great rare disease companies to be working with across all levels that we hope to fill you in more on when it happens.
And they're all looking for products.
They are.
I have to imagine that would be a good opportunity.
Yes.
Now, your second indication is chronic neutropenia. And this is obviously a much larger indication than WHIM. What is the clinical need here? And walk us through the recent phase II data that you've reported.
That's great. So chronic neutropenia has some similarities to WHIM where these patients are immunocompromised. They have life-threatening infections similar to COVID, that fear of not they can't socialize normally. Actually, we're learning about kids being withdrawn from schools. So their unmet need is really tremendous risk of infections, and low neutrophil counts correlate with that. There is one approved therapy, and actually it kind of lines up with their unmet need. And to the benefit, G-CSF is an injectable drug. Maybe people have heard of Neupogen. It was originally designed for short-term use and kind of bridging studies for patients who had bone marrow challenges on chemo. The drug is approved to support chronic neutropenia. And the positive it is, it nicely shows when you increase neutrophils, patients have decreased infections. There's a lot of challenges with G-CSF, and frankly, there should be something better.
They have injection pain when they're receiving it. They get flu-like symptoms, muscle cramping. Some of our patients report that they're taking it with a hot shower in bed so that they can actually try to tolerate their dose through the night. And basically, everybody is underdosed or can't tolerate it. They're not achieving the full benefit of the drug. So we're excited about our phase II data, which we believe, with an oral once daily fixed dose, it really can revolutionize the opportunity for these patients. There's been a number of very successful historic examples where you go from like the tough injectables to daily orals if you think about MS, right? Was a field that changed dramatically from interferons to now the safe oral once dailies.
You know, we certainly hope to kind of create that massive shift right in the beginning for these patients going from a tough drug with long-term sequelae to a well-tolerated oral once daily.
And remind us what you showed in the phase II?
Yeah. Great. Sorry. Great data. So the phase II was as a monotherapy, we saw normalized neutrophil counts. We even saw in the most severe population, these are patients who are walking around with Grade 4 neutropenia. Anyone in the cancer setting knows how severe that is, and they have it every day. We've shifted them up to almost above 1,000, which is what clinicians would view as a clinical win. So even in the most severe patients and across all patients, we were improving neutrophil counts, which correlates with decreased infection rates. And this was over six months. It was a very durable study. The drug is working, doing what we expect it would do.
We also saw in a population on G-CSF, the question was, well, okay, patients who have standard of care and can tolerate it to some degree, can you remove it and still maintain their neutrophil counts? And the answer is yes. And actually, we had a range of anywhere from 50% - 100% reduction in G-CSF. About a third of patients who could reduce got off completely, and the other two-thirds had about a 50% - 70% reduction. So that is a huge win compared to what we've heard from patients. They were even saying if you could just get 25%, that would be great. So the drug is doing what we know it does, which is increasing neutrophil counts. And now we know that it'll enable future G-CSF reduction in those that can tolerate it.
What are some of the long-term complications from G-CSF for these patients? Because the thing on it is, you mentioned the short-term stuff, but there's long-term risk too.
No, that's a great point, Ted. So certain patients have increased risk of malignancy. If you think about it, it's a repeated dose of a growth factor. So there has been evidence of malignant transformations, myelodysplastic syndrome. Physicians are constantly trying to use the minimum effective dose. Like they're metering it out over the course of the lives of these patients because they do recognize they're increasing risk in other areas as well.
So tell us about the phase III 4WARD trial design, and when can we get data from that?
Yes. So in X4 fashion, we are continuing to generate very robust studies and evidence to support commercial launch. So it's a randomized placebo-controlled double-blinded study enrolling 150 patients. And the endpoint on this study is infection rate, changes in infection rates, and an ANC response metric. And those have already been discussed and aligned with from the FDA. So we're very pleased with, again, almost rinse and repeating the success that we've seen in WHIM syndrome. We've designed the same type of study with a more robust number of patients. And we expect to see that data in the 2nd half of 2026. I think the meaningful milestone for us will certainly be full enrollment, which is on track for mid-2025. We gave some great updates just recently on the Herculean effort that's needed to do these large global studies and make sure you're hitting your timelines.
It's certainly around the number of sites and countries, so we've opened up, I believe, 80% or 90% of the targeted countries and then we are already at 40% of the site targets, so the team is amazing. It's a big lift. We have some real experts on board, and we're nicely on track.
Paula, in CN, there's different types of CN. I know idiopathic, congenital, and maybe acquired. Is this for all of those patients? Are there differences in response to mavorixafor or depending on these or because of the mechanism, does it really work to treat all of these patients?
That's a great question. So at this point, it looks like it would be working well to treat all patients. Now, the challenge is neutrophil counts are variable depending on the etiology of the neutropenia. So the idiopathics and acquired, they are a little bit easier to treat. And even in real-world settings, they can get by with slightly lower doses of G-CSF. Our physicians are really pleased about this because they're like, that's the layup for mavorixafor. These are sick patients, but they seem to have a healthier bone marrow reserve. So the physicians that have shared their views are like, this is where we can go to mavorixafor once a day and really have that be the staple of their therapy. The congenital neutropenia population is very diverse. There are different genetic origins to the types of causes of CN.
But for those that have reserve problems, we should be equally as effective as what we've seen. WHIM, for example, is one of those. So certainly, we expect to provide benefit. The question is, will they need a little bit more of G-CSF from time to time or in acute situations? We still don't know that yet.
Interesting. Very cool. And you talk about the steroid taper. Maybe describe that a little bit more in the phase III trial. And what would that ultimately mean as you potentially launch or for the label? Again, it's early to talk about that, but how could that be reflected as a benefit?
Yeah, so the phase III, we're specifically not tapering the G-CSF because, again, imbalanced arms. So we've had very clear conversations where folks will come into this study on a stable dose and need to be maintained. Your question is very important. Commercially, of course, we want to enable physicians to have some view of what is safe to step down, how quickly then can they step down. So we first provided that evidence with our phase II. It was a six-month study. So it's actually a robust piece of information on how they can adjust dose appropriately. And they're used to doing that. I mean, G-CSF is a tough drug to figure out to begin with. They often it takes patients six to 12 months to even find their dose. So I do think that physicians have experience.
Beyond our phase III, we're certainly looking at what's the right level of additional evidence that we can use. For example, an open-label extension, we might be able to look at different ways of providing guidance on step-down for G-CSF. But all of those will be coming in the future.
That makes so much sense. Yeah, that's helpful.
Yeah.
Excuse me. As I mentioned, this is a larger market. Maybe you can lay it out. How big of an opportunity is CN? And do you anticipate marketing mavorixafor for yourself in this indication since you've already been building out the commercial infrastructure for WHIM?
Yeah. So that's a great question. So first of all, in the U.S., there's about 50,000 patients today already diagnosed via ICD-10 codes with some form of chronic neutropenia. The highest unmet need and the way we've designed our trial, because we really want to make sure the label is aligned with the value proposition, is about 15,000 patients today in the U.S. are diagnosed with CN and have recurrent severe infections regardless of their standard of care. So it's really a sick group of people who are undertreated and need something more. And certainly, we hope to enable success with the phase III. When we think about X4, this is right in the same sweet spot that we're already in. The relationships that we're developing by commercializing WHIM are the same physicians. About 70% of the call points are actually overlapping with the treaters with neutropenia.
That's actually helped some of our education awareness on the phase III trial as it enrolls in the U.S. So there's a lot of leverage and synergies from commercial infrastructure relationships and even helping our ongoing studies.
And I guess the same question I asked earlier, but maybe it even makes more sense now, so maybe overseas, it would be a package. It wouldn't be indication-specific WHIMs versus CN, so probably the chronic neutropenia data helps with a potential overseas or even drives the overseas partnering opportunity.
Yeah. So I think, I mean, so there's different types of WHIM ways to partner, whether they're distributors or more of what I would call a more strategic partnership would absolutely be, I think, linked to the value proposition of the drug. It's very hard to indication split, as I'm sure everybody remembers. So yes, an ex-U.S. deal like the recipe for success. There are certainly the positive CN phase II data that we just had, our MAA filing, and then kind of the nice roadmap ahead for us that we know in WHIM in the U.S.
Very cool and you guys ended the fourth quarter with $135 million in cash. How long does this fund the company and what does it enable X4 to accomplish?
Yes. So today's cash on hand would get us into Q4 of 2025, and that's excluding any revenue from Xolremdy on the conservative side. And what that enables us to do is to hit several milestones next year. Of course, our MAA submission. We are looking forward to continuing to deliver on Xolremdy sales. And of course, full enrollment on the WHIM, or excuse me, on the CN phase III is a huge milestone because then it'll just set the clock for what we believe will be a very successful study. So that's our current trajectory.
Great. Well, Paula, thank you so much for being with us. I really appreciate it.
Thank you so much.
Looking forward to an exciting 2025.
Absolutely. Thanks for the opportunity.
Thank you.
Appreciate it. Thank you.