Good morning. My name is Rob, and I will be your conference operator today. I would like to welcome everyone to the call. At this time, all lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question-and-answer session.
If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question again, press the star one. Thank you. I'd like to introduce Beth DelGiacco, Vice President, Global Head of Corporate Communications and Investor Relations. You may now begin your conference.
Thank you, Rob, and to everyone for joining us today. A press release was issued this morning with the top-line results from the ADVANCE sub-Q study of VYVGART Hytrulo in primary immune thrombocytopenia. We have a short slide deck to accompany our remarks this morning. We will not guide you through the slides in the script, but they are available on the investor section of our website for your reference.
Before we begin, I'd like to remind you that forward-looking statements may be presented during this call. These may include statements about our future expectations, clinical developments, regulatory timelines, the potential success of our product candidates, financial projections, and upcoming milestones.
Actual results may differ materially from those indicated by these statements. argenx is not under any obligation to update statements regarding the future or to conform these statements in relation to actual results unless required by law. I'm joined on the call today by Tim Van Hauwermeiren, Chief Executive Officer, and Luc Truyen, Chief Medical Officer. We also have Karen Massey, Peter Ulrichts, and Karl Gubitz, who will be available during the Q&A. I'll now turn the call over to Tim.
Thank you, Beth, and thank you to everyone for joining us today. By now, you've seen our press release from this morning and have been able to read and digest the results from the ADVANCE sub-Q study. As you can imagine, we were disappointed that the study did not meet the primary endpoint of a sustained platelet count response in chronic ITP patients.
Luc will share more details on these top-line data in a few minutes. They're still very fresh to us, but it is important to be here today to communicate what we know and where we stand, recognizing that many analyses remain ongoing. I want to start with gratitude, first to our internal ITP team, who worked so hard to manage and enroll the study.
I also want to thank the patients who participated in the study and their families and the trial investigators. We know they share in our disappointment today. We have heard firsthand from patients and physicians the need for a new treatment option that are both safe and effective, and we remain committed to the ITP community to continue to advance the understanding of this complex disease.
When we initiated the ADVANCE trials in ITP, we did so based on a strong biology rationale. The role of IgGs in ITP is well documented in the literature and by plex and even absorption data, as well as the outcome of our first ITP trial, which was successful. The question we have from our second study is why the efficacy results did not match those of the first. We don't have a full understanding yet, but I want to share what we know today. This was a well-designed trial.
There is now a standardized way to run an ITP study, and we stayed true to it with validated endpoints and consistent inclusion/exclusion criteria. We had a very refractory patient population once again. We knew it would be a challenge to enroll two large ITP studies in an overlapping fashion, so we were not surprised to get a heavily pretreated population, which is more difficult to drive into response.
We saw a smaller treatment effect in the second study, which we can't fully rationalize, but does align with the high intrinsic variability that is often seen with refractory patients. We also saw a significantly higher placebo response, much higher than the first study and historic trials. We used a primary endpoint that is meant to knock placebo down close to zero, but this simply did not happen.
We are learning that ITP is a very complex disease to study and to treat, but both successes and setbacks contribute to our deeper understanding of FcRn biology. We have been fortunate to have four out of four wins in proof of concept studies and four out of four in phase 3, but we know the path will not always be linear when it comes to building an exceptional drug like VYVGART.
We will face attrition, and this is part of pioneering a new class of medicines. This also underscores our approach to launch multiple indications in parallel so that we can follow the data and invest where we will have the most patient benefit. We want to transform outcomes for patients globally in as many diseases as possible, as quickly as we can.
This type of optionality positions us well for success, and we believe that we have it in place across VYVGART and our broader immunology pipeline. I'll now turn the call over to Luc to walk through the trial design and results. Luc?
Thank you, Tim. I also want to share my gratitude to the ITP patient community and our investigators for their support with this trial. Before I get to the results, I will remind everybody of the trial design, which was the same between the two ITP studies. ADVANCE-SC was a double-blind, placebo-controlled global trial evaluating the efficacy and safety of VYVGART Hytrulo in adult patients with primary ITP.
... We randomized 207 patients into the study, including 192 chronic and 16 persistent ITP patients. In order to enroll, patients had to have a platelet count of less than 30,000 at least twice during the screening period. They could be on stable concomitant therapy or a watch-and-wait approach of therapy.
The baseline demographics between the two ADVANCE trials were generally consistent, and our second trial included a very refractory patient population, with 75% of patients having been on three or more prior ITP treatments. All patients received a fixed weekly subcutaneous injection for the first four weeks, after which they had the option to switch to biweekly dosing, depending on platelet counts.
The primary endpoint was measured in the chronic population starting at week 19, and patients were classified as sustained responders if they achieved a platelet count of 50,000 in four out of the last six visits. We did not see a significant result on the primary endpoints. 13.7% or 17 out of 124 Hytrulo treated patients were sustained platelet count responders at week 24, compared to 16.2% or 11 of 68 placebo patients.
The patients who did respond on Hytrulo were typically earlier in their diagnosis and not on concomitant medication. However, this was not the patient type who comprised the majority of the study. But even more notable, and what primarily drove the negative results, was a placebo effect that was three times larger than the first study.
To better understand our high placebo response, particularly on an endpoint that's proven effective in managing placebo in the past, we looked at sustained platelet count response by subgroups to see if we could identify any learnings.
There were notable regional differences in placebo response, including in regions and countries which were not part of the first study. We did not achieve significance in the secondary endpoints either, including the additional endpoints which performed well in the first study, like the International Working Group score, the onset of response, and the mean platelet count change from baseline.
Importantly, we looked at the available pharmacodynamic data in ADVANCE-SC, and these results look consistent with the first ITP study and all prior clinical trials. The HYTRULO-treated patients achieved mean IgG reductions of the same magnitude as prior trials, and mean placebo patient levels remained unchanged.
Safety intolerability data also look consistent with previous clinical trials and with the confirmed safety profile of VYVGART and VYVGART Hytrulo. Our safety data baseline includes more than 1,400 patients from clinical trials and more than 6,000 patients on commercial drugs globally.
Now, a full data analysis ADVANCE-SC will be important for us as we determine next steps. We are currently seeking approval for VYVGART in ITP in Japan, but we'll also assess its positioning in other markets where the regulatory path and access makes sense.
We know there's a real unmet need for ITP patients who face high relapse rates and significant side effects from current treatments as they seek better management of their disease. I thank you for your time today, and I will now turn the call back to Tim for closing remarks.
Thanks, Luc. You can see that we still have a lot of questions to answer, which will require time, but we look forward to presenting full results at a future medical meeting, including data from the open-label extension. Before we get to Q&A, I want to close with a few final sentiments.
First, these are times when we really embrace who we are as a company, one that is grounded in both innovation but also humility. We have a significant opportunity before us in pioneering the FcRn space, and it is important we learn from each data set as we navigate this new field of medicine.
We take our responsibility seriously on behalf of patients and the broader autoimmune community to continue to unravel new biology with VYVGART, based on its potential relevance in more than one hundred serious autoimmune diseases. We are fortunate that we are well positioned for success and have launched a strategy for VYVGART that is focused on the value creation and transforming outcomes for patients.
We expect to be active in at least 15 indications by 2025, running trials in parallel with multiple product presentations, because we recognize that optionality is crucial to maximize the potential of this opportunity. Last, we have a lot of exciting milestones ahead of us, including data points from pemphigus and bullous pemphigoid in the next few weeks.
You can be confident as a shareholder that we don't celebrate long in our successes or dwell for long on our setbacks. It is right back to work, because that is what is required to execute on our ambitious strategy. I want to thank you all for the time and for the support on this innovation mission. We will now take your questions.
At this time, I would like to remind everyone, in order to ask a question, press star, then 1 on your telephone keypad. We ask you please limit yourself to one question and then rejoin the queue for further questions. Your first question today comes from the line of Derek Archila from Wells Fargo. Your line is open.
Hey, good morning, and thanks for taking the questions. So maybe just two brief ones, actually. So first, I just want to know, in terms of, like, how you think this data today impacts the Japanese filing in ITP. And I guess looking forward, is there actually a scenario where you don't pursue ITP in the U.S. and the EU at all?
I guess if I look at the range of indications that you're pursuing now, not many, but maybe only ITP or in hematology, and, you know, with FcRn being so de-risked now, you know, is that an option on the table as well? Thanks.
Yeah. Thank you, Derek. Thank you for being with us today. I will give your first question to Luc in a minute when it comes to, you know, how we proceed with the Japan filing for ITP. In general terms, I would like to make the following comments on your second question. First of all, we're still in full data analysis, but it's a ton of data, and we're still completely trying to understand the totality of the data.
But what you should know is that we will be responsible stewards of capital and that we will make data-based decisions. So if you have this level of optionality in front of you, you can take the position that the data should guide resource allocation. Luc, do you want to comment on anything we can say today about our ongoing Japan submission?
Yes, absolutely, Tim, and thanks for the question. Yeah, as you know, the PMDA is in active review of our IV submission, and we took the step this early today to reach out to PMDA and alert them to the press release and the top-line findings of the sub-Q study. And we will continue to provide them with data as they become available to us that would help them in their closing the review on the IV.
Got it. Thank you.
Your next question comes from the line of Tazeen Ahmad from Bank of America. Your line is open.
Hi, good morning. Thanks for taking my questions. Tim, could you just elaborate on how big you think the Japan market is in terms of number of patients relative to, continental Europe or US? And then can you just clarify what Europe has said for needing to run two studies? Is it the same feedback that you got from US, or do you think that there could be a different path in Europe? Thanks.
Yeah, thank you for these excellent questions, Tazeen, and thanks for spending the time with us today. In terms of market size in Japan, I think the incidence and prevalence of ITP, primary ITP in Japan is comparable to, you know, Western Europe and the United States. So I think you can extrapolate from the U.S. data, which you have on file, to triangulate what the potential opportunity could be.
And then when it comes to EMA, they have given similar guidance, unlike the PMDA, similar guidance to the FDA, that actually they want to see two independent registrational trials executed for ITP. So that's the same story as for the FDA. Thank you for the questions.
Your next question comes from the line of Yatin Suneja from Guggenheim Securities. Your line is open.
Hi, good morning. This is Eddie on for Yatin. Thanks for taking our questions. Just one from us. Can you provide any other color on how the drug performed in the U.S. versus international sites? Is this driven by placebo responses only, or did the active arm perform differently? And were there any specific countries or sites that were out of sync? Thanks.
Thanks for the question. Luc, Luc, do you want to talk about some of the early regional differences, which we seem to distill from the data sets?
Yes. Yes. So, while the response on active was also somewhat lower than expected, so but still in the range, like observed with fostamatinib, for example, what really stood out to us was the high placebo response. And, that makes you think about many things, but one of this is looking at all the subgroups.
And we indeed found that certain regions had a highly variable response on placebo, on the platelet counts and ultimately also on reaching sustained responder status. In that sense, there's a, if you ask about the US, that doesn't show that picture, but the sample size is rather low. But we will dig in every patient profile to figure out what's at the basis of this.
Your next question comes from the line of James Gordon from JP Morgan. Your line is open.
Hello, James Gordon, JP Morgan. Thanks for taking the question. My question is about the read from this ITP result today to the ongoing PV trial and latest confidence in PV success. So do you see a risk that we see a strong placebo on performance in PV, or the reasons that we might have a placebo arm that is more predictable in PV in the PV trial?
So how do you expect placebo to perform there at any read or not? That would be the question, please.
Yeah, thank you, James. I would like to hand over the question to Peter Ulrichts, our CSO.
Yeah, thanks for the question. I think there's a fundamental, fundamental difference between the pemphigus study and the ITP study, not only on the protocol, where there is indeed a fourth taper involved in the pemphigus trial, but also in terms of patient population, where there's an ITP, ITP trial, there was a high refractory population with a profile.
Well, a lot of patients having received three or more previous treatments. This is not the case in pemphigus, where there is a substantial proportion of patients which will be newly diagnosed. In terms of concomitant medication, there's only one variable, which is the-
So I would say, James, it's a distinctly different biology. It's a distinctly different clinical trial, so we don't see any lead through. Just like success didn't lead through, this failure will also not lead through.
Your next question comes from the line of Danielle Brill from Raymond James. Your line is open.
Hi, guys. Good morning. Thanks for the questions. I guess, Tim, I'm curious, do you think this is primarily a conduct issue, or do you think the biology of the disease evolved and was no longer primarily IgG driven in the enrolled population in this study? And then as a follow-up to that, did those that were less heavily pretreated perform better? Thank you.
Yeah, we have been diving deep into that question, Danielle. It is true that the patient population you study today is a totally different patient population than, for example, you would have studied in the days of the TPO receptor agonists. I mean, this is basically now the patient population, which is reflective to splenectomy, watch and wait, steroids, rituximab, one or two or three TPOs, and sometimes fostamatinib.
So you just wonder to what extent the biology is still representative of the biology which we picked up in the literature. I think that is one. There is another element which we pick up in the data, but it's probably too early to really draw firm conclusions.
It is true that if you respond on efgartigimod, and actually we have some real clear, nice responders with a robust and a sustainable response. They're typically early in their disease, and they're typically also on fewer concomitant medications. So this is a data point which we need to double-click on and further unpack.
Your next question comes from the line of Yaron Werber from TD Cowen. Your line is open. Yaron Werber, your line is open.
Yeah. Hi, can you hear me?
Yes, Yaron, we can hear you now.
Great. Thanks for taking my question. So I just-- we're getting a lot of questions. When you look across studies, and even in your data in the phase 1 healthy volunteer, you looked at the max mean IgG reduction, and I believe in the ADAPT phase 3 gMG study, you looked at total IgG reduction.
What can you just give us a sense, how are those two different from each other, kind of mean maximal versus total IgG reduction? And also, if you recall, did you ever release the 6-8-week data on mean max IgG reduction in the healthy volunteers? I'm just comparing across drugs. This is not about ITP, obviously. Thank you.
Yeah, Yaron, from a PD point of view, there is not really anything there. But when we compare the data across studies, you basically see consistent PD effects for VYVGART IV or VYVGART Hytrulo. So that's not really the corner where you have to go and look. I would refer to the phase 1 publication for all the details on the PD effect in healthy volunteers.
And then, of course, we have plenty of work in phase 2s and phase 3s to go back to, but that's not exactly where I think we should look. When we looked at the data, this was a nice, clean, robust PD effect. So, we think it's something which must have to do with disease biology and of the specific experiment we have been running.
Thank you for the question.
Your next question comes from the line of Joon Lee from Truist. Your line is open.
Thanks for taking our question. Tim, you mentioned several times that ITP is a complex disease. In the ADVANCE IV trial, was there a correlation between the magnitude of IgG reduction and response? In other words, would greater IgG reduction be able to overcome this complexity of ITP? Thank you.
Yeah, this is an excellent question, and we need to look into that. So I think what we have been able to do so far is look at the data on a population level. Now is the time to go into the data on a patient-by-patient level, but we felt that we had to disclose this top-line data now. There's, of course, a ton of analysis going on in the background, and we will talk about this data in the not-too-distant future. Thank you.
Your next question comes from the line of Matt Phipps from William Blair. Your line is open.
Thanks for taking my question. Was there any difference in the speed, the onset of platelet response, as you saw on the SC versus the IV trial, or percentage of patients who switched to Q2-week dosing?
Yeah. Matt, thanks for the question. It's, again, early days. I think it's fair to say we see - we still see patients switching to every other week dosing, but because the response rate is somewhat lower, you also see that reflected in the switch to every other week dosing. In terms of, you know, speed to place the response, we're still looking into that, to be honest. So stay tuned. There's a ton of data to unpack here. Thank you.
Your next question comes from the line of Sam Semenkow from Citi. Your line is open.
Good morning. This is Eric on for Sam. Thanks for taking our question. How does this impact your thinking about the role IgG plays in disease pathology across your pipeline? Are there any other indications where our understanding of biology could be overemphasizing the role IgG plays?
It's an excellent question. So I think we're learning here about ITP while we digest the data. Every disease, of course, is different. I mean, here in the case of ITP, we do know that pathogenic IgG antibodies drive disease in terms of, you know, opsonizing platelets and mediating the clearance of platelets and also attacking the megakaryocytes.
We do have a ton of patients in this study which actually stopped responding to anything. And so even rescue medication doesn't work in these patients. So then the question is, what is that remaining disease biology, and what are the pathways which are really in play? And you know that we're building a biology rationale for each and every indication.
So if you look at MG and CIDP, I think we have been very clear about how we triangulate from the IgG biology, you know, plasma exchange data, immunoadsorption data, also passive transfer models, which, by the way, work beautifully well in ITP. So I think we're looking at something which must be disease-specific, and once you're very advanced in disease, the question is, you know, what pathways are actually in place? It's a key question we have.
Your next question comes from the line of Joel Beatty from Baird. Your line is open.
Hi, thanks for taking the question. Do... For any future trials in ITP, do you see a potential to kind of pre-identify or pre-select which patients may be likely to respond to VYVGART?
We're still going through all the lessons learned, Joel. I think it's a very fair question. I asked the same question to the team: If you were to lead a clinical trial in ITP, just conceptually, what would you change? It's not an easy question. I think from inclusion, exclusion criteria point of view, we were state-of-the-art.
When you look at the endpoint, this is a well-accepted endpoint. The reality in an ITP space is that patients actually have been on multiple lines of therapy and are actually on quite a few concomitant medications. I think that ITP space has evolved, and it is something to take into account when you design your clinical trial, clearly.
Your next question comes from a line of Alex Thompson from Stifel. Your line is open.
Hey, great. Thanks for taking my question. And, Tim, maybe as a follow-up to your last point there, would it be feasible to run a trial where you were to cap, you know, patients on more than or equal to three prior therapies? Is that something that you would think about in the future? Thanks.
Yeah. You're balancing a few forces that, you know, there's a regulatory question, and there's an enrollability question. Maybe, Luc, you want to briefly comment on that without speculating?
Yeah. I think based on what we've seen, based also what the requirements are, it would be very hard to run a trial tailored more towards where we find the ADAPT responders at first blush. That would take an inordinate amount of time and engagement from patients to run. It's, it's very tough. We, we got some external views on this, too, and it's basically the perfect trial may not be possible to be run anymore, given the background, the availability of background treatments.
Your next question comes from a line of Douglas Tsao from H.C. Wainwright. Your line is open.
Hi, good morning. Thanks for taking the questions. Just, just as a follow-up on that last point, will you, when you go through the additional data, be able to sort of identify, you know, sort of which treatments or number of treatments that placebo versus active patients were on? To just get a better understanding of how much noise that may have contributed to this trial result. Thank you.
Yeah, we thank you for the question. We have exactly the same question. It's a matter now of going through the patient profiles one by one and really try to understand at an individual patient level what happens. Is there an impact of concomitant medication? If yes, which one? And how long did patients already stay on that, on that type of therapy?
We already touched on, you know, time from, time since diagnosis, which clearly is a factor. We see that. So there's a number of questions we share here, and that's actually the task of the team, which is currently working through the data in detail. So stay tuned, we will communicate about it.
Your next question comes from a line of Rajan Sharma from Goldman Sachs. Your line is open.
Hi, thanks for taking the question. Just, are you able to kind of provide any initial thoughts on what drove the difference in efficacy for the subcut relative to the IV formulation? You know, could there potentially be any difference as a result of the route of administration or the formulation? I'm just wondering if you think there's potential to run another IV study to support a filing here.
Yeah, it's, it's hard to imagine it because what we know is that the PD effects actually behave perfectly in line with expectations. The subcu formulation has shown, you know, non-inferiority in the MG trial and spectacular data in CIDP. So that, that, that, I think is speculation. I think we will take a deep dive into the data. I think our current thinking is going in the direction of disease biology, but it's too early to be firm on it because we like to be data-based. Okay?
Your next question comes from a line of Xian Deng from UBS. Your line is open.
Hi, thank you for taking my questions. Two, please. The first one is just sort of a confirmatory one. Apologies if I missed it earlier. So did you mention the subcu population is more refractory than the IV trial population? And the second one is, on the IV trial, you have shown the data on the average changes in platelet count over time, where we sort of see a very nice separation between the VYVGART arm and the placebo arm.
So just wondering, you know, what does that curve actually look like for your subcu trial? Just wondering, do you still see the nice separation of curves, but with very large error bars on top of overlap, or you don't see the separation at all?
I'm just trying to understand, you know, where that p-value comes from, whether it's sort of just a small difference or exactly comes from some very large variance from the subcu trials, potentially from the difference, as you alluded to, the difference in regional differences? Thank you very much.
Yeah, thank you for these two excellent questions. Luc, do you want to comment on how comparable both patient populations are from-
Mm-hmm
You know, the degree of refractory disease, and secondly, you know, regional differences in the placebo? Thank you.
Yep. Thanks, thanks for the question. So there is a slightly higher proportion of refractory patients in the subQ trial. As we said, 75%, in the IV trial, it was around 68%. I'm not sure if that would fully explain the difference, but clearly the placebo response, which is the main difference and the main reason for non-separation, shows that we have regions where the profile is as expected. And then we have regions where due to high placebo variability, platelet counts and making it through the end gate, where placebo response seems inordinately high.
And we have to unpack that. What are the difference in practices, et cetera, in these different regions? So again, something to be done and talked about for the future. But to us, that placebo response differential across regions is one of the main differences between the trials.
And again, if you would like to ask a question, press star, then the number one on your telephone keypad. Your next question comes from the line of David Seynnaeve from Degroof Petercam. Your line is open.
Hey, good afternoon. Thank you for taking my question. I was wondering, can you comment perhaps on what the implications are of today's news on the regulatory filing strategy and commercial timeline in China? And then perhaps also secondly, you know, with this setback in hand, will this make you reprioritize in any way future indication selection for subQ? Thanks.
Yeah, thank you, David, for the two questions. So for China specifically, we work in partnership with Zai Lab. So the first thing we need to do is, you know, bring Zai Lab on board, share the data, and then discuss, you know, potential implications for a potential regulatory path in China. We are in control of the Japan tracks, and that's where we're going to double down with our internal team.
So stay tuned on the China question. And in terms of, you know, biologics rationale for future indications, that's not changing. I mean, we will each time be very transparent about, you know, what are the published scientific data which we think have value in underpinning the IgG-mediated nature of these diseases, and explain, you know, what we think are the risks in the clinical experiments and how we think we can mitigate these risks in the clinical trial.
Clearly, we knew from the phase 2 and the first phase 3 that an unexpected placebo response could be in the cards. That's also why we borrowed that validated phase 3 primary endpoint. And in this specific experiment, it did not do the job. And that is one of the questions to the team: Why do we have the placebo activity which we have in this study? Thank you for the two questions.
There are no further questions at this time. This does conclude today's conference call. We thank you for your participation.