Evommune, Inc. ($EVMN)

Welcome to the Evommune's Role of MRGPRX2 in Migraine conference call. [Operator Instructions] As a reminder, this conference call is being recorded. If you have any objections, please disconnect at this time. I would now like to turn the call over to Kyle Carver, Chief Financial Officer.

Hello, everyone, and thank you for joining us for today's webinar highlighting the role of MRGPRX2 in migraine. My name is Kyle Carver, Chief Financial Officer at Evommune. Over the course of this presentation, we will walk you through the scientific rationale, the unmet need in migraine prevention and why we believe this program represents a compelling new pipeline expansion opportunity for EVO756, our MRGPRX2 antagonist. We will then open the line for questions. Before we begin, I need to remind everyone that today's discussion includes forward-looking statements. These statements reflect our current expectations and are subject to risks and uncertainties that could cause actual results to differ materially. Please refer to the language on this slide and to our SEC filings for additional detail. Let me briefly outline how we will spend our time today. Luis Peña, our President and CEO, will begin by overviewing the broad pipeline and opportunity at Evommune and specifically the EVO756 program in migraine. We are thrilled to be joined by 2 guest speakers who are leaders in the field today, Dr. Stewart Tepper, Vice President of the New England Institute for Neurology and Headache in Stamford, Connecticut, and Professor of Neurology at the Geisel School of Medicine at Dartmouth, who will discuss the migraine treatment landscape and the current unmet need. Dr. Greg Dussor, the James Bartlett Chair in Behavioral and Brain Sciences, and Professor and Department Head of Neuroscience at The University of Texas at Dallas will also join us to review the pathophysiology of migraine and the role of MRGPRX2. Dr. Jeegar Patel will then review Evommune's migraine program and planned development path. Luis will close by providing some brief closing remarks before we move into Q&A. With that, I will turn the call over to Luis.

Thank you so much, Kyle. Hi, everyone. We are really looking forward today to introduce the migraine indication to the X2 program. As you have seen, we have now 2 programs that are in Phase II development. The evolution of Evommune has been founded on the premise that we are going after novel targets and molecules in chronic inflammation. And the goal for us is to make inroads into many of the autoimmune diseases that now are growing in prevalence and are the #1 health care problem for the world. As I mentioned, 2 programs that we have in mid-stage II. We have shown positive data in our MRGPRX2 program, both in urticaria challenge that we did in Phase Ib as well as in CIndU patients. We have 2 trials ongoing, one in chronic spontaneous urticaria that's finished with enrollment and one well into the enrollment in atopic dermatitis. And as we'll talk about today, we are about to initiate a trial in migraine, which we're pretty excited about along with the other 2. Also importantly is that we have an IL-18 program that we will be advancing into Phase IIb. In February, we announced data from a Phase IIa program. The data was very compelling. This promises to be a great new target in atopic dermatitis, but IL-18 is elevated in a number of disease states, and we think it could have broad applicability much like our MRGPRX2 inhibitor. MRGPRX2 is a really exciting target in that the receptor itself is expressed both in mast cells as well as sensory neurons. We know and there's mounting evidence that they work in unison to really turbocharge inflammation in a number of disease states. When there's inflammation, especially chronic inflammation, we know that mast cells proliferate, that they migrate towards neurons, and neurons themselves can quadruple in size. And the neurons not only serve a sensory function, but they also are able to secrete neuropeptides that actually activate mast cells. So they really work in unison to drive inflammation. We think that the MRGPRX2 receptor is an exciting way to address this pathway or at least stimulation of mast cells and sensory neurons. It seems to be pretty well tolerated in terms of inhibiting this, for example, in knockout mice and so far from what we've seen in the clinic. And the role here is for potentially having as an oral small molecule, a very broad-acting anti-inflammatory in a number of disease states. So what are some of those indications? Well, as I already mentioned, we have a study ongoing in chronic urticaria and atopic dermatitis. Migraine is really an exciting new entry into our clinical development program. We really have been led, as we are with all of our programs, and we have a very experienced team, almost 28 NDAs now approved and BLAs amongst the team. So we really know how to navigate the discovery and clinical and regulatory pathways, but also have pretty good insights into what is needed in the field of immunology and in terms of developing new medicines for autoimmune disease. And so we really have been driven by science in choosing these indications as well as our IL-18. So what we're targeting here as a product profile for this molecule is an oral that's well tolerated and can be used broadly across various different practices, and we think we're well on our way to being there. And so with migraine, it's very interesting. There is building evidence. You'll hear about it today. We know that, first of all, X2 is expressed in human trigeminal neurons as well as meningeal mast cells. There has been pretty compelling data that you'll see across preclinical translational assays and some proof of concept now with inhibition of the ligand PACAP that really all validates that this could be a great target to go after, especially in patients with chronic migraines. And so from that perspective, we're really excited about moving the program forward and for the potential of X2 in the program itself. So this is a very broad population worldwide. While I think the prevalence of any kind of migraine worldwide is about 1 billion people, and it's really pretty massive, we're looking at a more addressable chronic migraine population, and we know that it's at least 75 million people worldwide and growing. And we've seen that, especially with preventative migraine, and we think that MRGPRX2 as an oral inhibitor would be best suited as a preventative agent. We see that the world market is growing rapidly, approximately $8 billion in 2026, and mostly with just one kind of therapy, which is the CGRPs. And so there's definitely potential for new therapies in this space. And so I mentioned the CGRPs. It's really been the main go-to in terms of preventative therapies, and there's been a number of these that have been developed. But the migraine burden still persists. And you could argue that maybe while there has been clinical benefit in these patients, it's been somewhat modest. So there's still a really pretty big opportunity here to see if we can really increase the benefit to these patients, increase the efficacy as well as broaden the number of patients that may benefit from it. So with our trial, we are going to start to see, first of all, X2, the relevance of X2 in the disease, but also hopefully help these patients have better benefits than they have with the CGRPs, which have been great, by the way, a great advance so far in the field. So with that, I would like to turn it over to Dr. Stewart Tepper, who is going to give an overview of migraine.

Thank you very much for the opportunity to talk about migraine and current clinical situation and the unmet need with respect to migraine treatment. Migraine is remarkably prevalent, and it occurs in 18% of women in the U.S. and 6% of men for an overall prevalence of 12% of the general population and has been stable across years. There are different types of migraine. And what I just showed you was migraine occurring less than 15 headache days per month. At 15 or more days per month, it's called chronic migraine, and that represents an additional 3%. And then if people do not meet all of the criteria for migraine and miss one, that's called probable migraine, but it really is just another form of migraine. So that adds another 15% of the general population. And it comes to at least 40 million people with migraine in the U.S. The prevalence unfortunately peaks during the prime working age years, and the result is a tremendous clinical and societal impact. In terms of daily functioning, it's the third leading cause of disability among all diseases. I'm going to show you some world headache organization data on this. There is a 50% reduced productivity in migraine patients and elevated rates of anxiety and distress as comorbid illnesses, and the result is missed events, reduced participation and, in the case of the workplace, presenteeism as well as absenteeism, in which people go to work but don't function properly. Migraine itself is more than just a headache, and each attack is preceded by prodrome of 1 to 3 days, in which the brain changes, and a postdrome. So the actual amount of impact is expanded beyond the headache days. The World Health Organization actually showed and did a study across 328 medical conditions in a little bit less than a decade ago and found that if one counted the years of disability with a particular illness, migraine ended up in the top 5, a leading cause of disability worldwide. And there's a disconnect between payers and regulatory authorities and what is actually happening on the ground to patients, in which there has been a mismatch of the urgent need to address this incredibly common and disabling and protracted neurologic condition. Attack frequency can be greater than 4 attacks per month, so more than 1 a week in 1/4 of people; 1 to 4 attacks in about 1/3; and less than once a month in another 1/3. But remember that it's more than just the headache days, and the result is 4 days per year of bed rest per patient and many patients reporting impaired functioning between attacks. That's the critical point is that the pervasive effect of the migraine is more than just the headache. It's the days in between, and that results in cognitive dysfunction and other areas where patients do not function adequately and need prevention. In addition to the bedridden days, there are restricted days up to 74 million annually and impaired or lost function. I want to drive home the frequency and the severity for patients of migraine across their life. Now the question arises as to what is the primary driver that sends people in to see the practitioner for treatment of their migraine. And one might think it's the number of monthly migraine days or the severity of the headache days or the disability and job aspects of migraine, but it's not. I want to draw your attention to a study called the OVERCOME study. The OVERCOME study was done in up to 100,000 people with migraine in Japan, the United States and the EU. And they asked participants, what was it that drove you in to see the practitioner with migraine. And the answer was unexpected. It was not the headache severity or duration or monthly migraine days or disability. It was the interictal burden. It was the total picture. It was the pervasive effect of the migraine in all aspects of living, both during the headache day and in between. And this was true whether it was looked at in the U.S. or in the EU, and disability in the interictal burden of migraine is the primary driver for treatment seeking. It's changed the way we talk to patients about migraine. Now the way that we used to treat migraine a decade ago was we had nonspecific preventive treatments that were invented for other disorders such as antihypertensives, antidepressants, antiepilepsy drugs, and we used these for patients to prevent migraine. They had modest effectiveness. They had significant side effects. And in a remarkable study of over 8,000 patients who were prescribed these medicines, over a year, 86% of people had discontinued them for migraine prevention. And the reasons for the discontinuation shown here in an international paper by Andy Blumenfeld was not surprisingly the lack of effectiveness and the side effects. So very poor adherence driven by lack of efficacy and poor tolerability was the standard. And what has happened since then is a targeted set of classes of medication, the anti-CGRP medications, monoclonal antibodies and gepants, have been created. These are the first migraine-specific preventive treatments and increasingly across the world, professional organizations and regulatory authorities are saying we shouldn't step the patients through the lower level nonspecific treatment first. We should go right to the migraine-specific treatment and the stepping through the older treatments delays the access to effective treatment in a high burden, low adherence disease. In early 2024, the American Headache Society took a position statement saying that we should no longer do the step-through requirements and the main 3 pharmacy benefit managers in the U.S. have accepted that. And the majority of commercial payers now in the United States align with the professional society position and no longer recommend the older treatments first, but suggest migraine-specific treatment as first line. Now in addition to the problem of discontinuation, those few patients that do take the older drugs do all sorts of things which are not good. And in a prospective study of over 200 patients who are administered the older nonspecific drugs, half of them modified their treatment without consulting with the physician that prescribed them, even though they knew they were being followed over 6 months and being followed carefully. And the modifications that they did without checking, including abruptly stopping the therapy entirely, changing the dose or frequency, including increasing the dose, delaying or skipping dosing. And the result of this can be very dangerous for patients, because an abrupt discontinuation of an antiepilepsy drug can result in a seizure, even in someone without epilepsy; the abrupt discontinuation of a beta blocker can result in a withdrawal arrhythmia. And so the majority of people who are given the older treatments don't stick with them. But those who do take them do potentially dangerous things. The unsupervised treatment changes introduce risk and reflect inadequate disease control, again, showing the need for migraine-specific treatment. These anti-CGRP drugs have been a big breakthrough, and they're the first migraine-specific prevention ever created with a target. We know that CGRP, which stands for calcitonin gene-related peptide, levels rise during migraine attacks and normalize after appropriate treatment. And in people who have migraine, who get CGRP infused, that triggers migraine. So we know CGRP is important. And as I said, the result of the understanding that CGRP was important was the creation of 2 major classes of anti-migraine prevention, monoclonal antibodies and gepants. And you can see some of the data here on what happens when these preventive migraine-specific anti-CGRP drugs are administered. This is the 50% responder rate, meaning the percentage of patients who have at least a 50% reduction in their migraine days. And you can see it's pretty good, but many patients continue to experience more than 10 migraine days per month. And you can see the average is still in the 50% range. So only about 50% of patients get a 50% reduction in their monthly migraine days. And that suggests inadequate treatment. We cannot accept that people are left with 2 or more migraine days per week because of the pervasive effect of migraine on their lives. This is a big improvement. Patients who get a 50% improvement are initially happy, but it's not adequate. It's not where we need to be for patients. And that led to setting higher standards for migraine prevention. This was a position statement of the International Headache Society published in January of 2025. And what is now the position of neurologists and headache specialists worldwide, including in the United States, is the opportunity for a more fulfilling migraine-free life with potential impact on society as a whole. The emphasis there is on migraine freedom. The goal should be migraine freedom in prevention. We want the patients to come back and say, I forget I have migraine. And even with the anti-CGRP therapies, we're not there yet. As I just showed you, half the patients have a 50% reduction. That's not where we need to be. So there is an unmet need that leads us to a search for appropriate new targets and the development of additional migraine-specific prevention. We need it clinically, and we're hoping that, that's where we're going. Just to summarize then, migraine is the most common neurologic illness, more common than epilepsy, more common than Parkinson's, more common at this point than dementia, and is a leading cause of disability in the top 5 of all medical illnesses, not just neurologic illnesses, for years lived with disability and profound impact on patients, families and societies. Interictal burden, the pervasive impact of headache days and in between headache days is the primary driver of treatment seeking. What we need to be paying attention to is the pervasive effect of migraine in people's lives. The older nonspecific preventive therapies are limited by modest efficacy, significant side effects and very low adherence. And even when they take it, they're doing potentially dangerous things. The low cost of the old therapies is irrelevant if they're not taken. I mean, it just makes no sense to be recommending low-cost drugs that people don't take. And the American Headache Society position statement now calls for migraine-specific therapy as first line rather than stepping through the nonspecific options. But there still remains a significant unmet need for new targeted therapies and for oral options. And because the anti-CGRP therapies are helpful, it's a first step toward what we're really aiming for, which is the goal of care and prevention, migraine freedom. And it's my hope that we'll get there with the new targets, and I thank you. It's now a great honor for me to introduce Dr. Greg Dussor, who's a professor in the Department of Neuroscience at University of Texas at Dallas. Dr. Dussor is one of the world experts in the basic science of migraine. And as I say, it's a tremendous honor for me to be able to turn it over to him and listen to what he has to say.

Thank you, Stu, and good afternoon, everyone. I'd like to spend the next few slides connecting what we understand about migraine with why MRGPRX2, which I'm just going to refer to as X2, has become such an interesting target. So migraine is a complex neurobiological disorder that involves multiple interacting pathways. And that complexity actually matters because it suggests that there may be important drivers beyond any single peptide or any single cell type. As we work through the data, I think what you'll see is why mast cell sensory neurons and X2 may represent a particularly important intersection in the disease. Migraine pain is closely linked to activation of the trigeminal vascular system. Migraine involves altered brain sensitivity to sensory signals, of course, but the pain itself associated with the activation of trigeminal nerves. Signals from peripheral nerve endings in the meninges and associated vasculature are perceived as pain. This framework has helped shape much of modern migraine biology. It also creates a strong rationale for looking at other contributors in the meningeal environment that may amplify or sustain those signals. That broader biology brings us to mast cells. Meningeal mast cells are in the right place. They're residing in the meninges and perivascular spaces innervated by trigeminal neurons. They're also positioned for neuroimmune communication because neuropeptides like CGRP, PACAP, VIP and Substance P can activate them. Once they get activated, they release mediators, including histamine, cytokines, proteases that can sensitize the sensory neurons. In that way, mast cells may help create a positive feedback loop that increases and sustains migraine pain. This is an area where translational support continues to build. That sets up the relevance of X2. X2 is expressed in both trigeminal neurons and meningeal mast cells, which are the disease-relevant tissues. It also mediates signaling from migraine-associated neuropeptides such as PACAP, VIP and Substance P. So X2 appears to sit at a biologically important intersection between meningeal mast cells and trigeminal sensory neurons. From a mechanistic standpoint, that is a very interesting position for a therapeutic target. Next, we can move from expression to functional evidence. In these studies, PACAP was injected directly into the meninges of wild-type and knockout mice and induced migraine phenotypes. The key finding is that knockout of the X2 homolog significantly reduced PACAP-induced migraine symptoms. That supports a functional role for X2 signaling in migraine biology. In other words, the receptor is not only present in relevant tissue, it appears to contribute to migraine relevant responses in vivo. The translational story becomes even more compelling when you look at human data. PACAP infusion induces headache in healthy subjects and migraine-like attacks in migraine patients. VIP and Substance P also induce headache in humans, including migraine-like attacks in people with migraine. So we're looking at ligands that are not just theoretically relevant, but clearly capable of producing clinically meaningful symptoms in people, and all of them are known ligands that activate X2. That is a strong bridge between mechanism and disease. A natural question is whether PACAP drives migraine symptoms through X2 as the primary receptor rather than PACAP's other receptors. So if you look at the various PACAP receptors, PAC1 has been tested clinically and did not show migraine benefit despite neuronal expression. VPAC1 and 2 are expressed on cranial vessels that have limited preclinical evidence, but the relevance hasn't been tested in humans. So the working hypothesis is that VPAC1 and VPAC2 are less likely to be the relevant receptors for PACAP in driving migraine benefit. By contrast, X2 is expressed on mast cells and sensory neurons, which are highly relevant tissues, and it has supported preclinical evidence. In addition, PACAP VIP and Substance P all trigger migraine attacks and blocking X2 has the ability to block all of these ligands while VPACs do not. As such, it seems likely that PACAP's migraine impact may be mediated primarily through X2. If that's correct, it makes X2 a particularly attractive intervention point. Importantly, we now have clinical validation of this pathway in migraine. Lundbeck's bocunebart, an antibody targeting PACAP, reduced monthly migraine days by about 2 days versus placebo in the preventative study in effect size that's in line with CGRP inhibitors. It validates the role of neuropeptides beyond CGRP, and because PACAP signals through X2, it directly reinforces the rationale for this target in migraine prevention. So with that, I'll hand this over to Dr. Jeegar Patel.

Thanks, Greg. I want to again thank Dr. Tepper and Dr. Dussor for joining us today and providing such great insights into the migraine landscape and biology. What I'd like to do now is translate that biological rationale into the way we're thinking about the development of EVO756 in migraine. From our perspective, this is where the story becomes especially actionable. We have a target with strong scientific rationale, a molecule with attractive properties and a disease area where unmet need remains very significant. One of the most important strategic advantages of targeting the X2 is breadth. If you target PACAP alone, you're addressing just one ligand. If you inhibit X2, you may be able to affect signaling from PACAP, VIP, Substance P through a single aggregating mechanism. Each of those neuropeptides has a supportive preclinical evidence and all 3 of these ligands, PACAP, VIP, Substance P are known to induce headaches in humans. So the appeal of X2 inhibition is that it may offer broader migraine benefit than a single ligand approach. That broader hypothesis is supported by the pharmacology of the molecule. EVO756 inhibits multiple migraine-relevant endogenous ligands and X2 overexpressing tumor cells. It also inhibits these ligands in primary human mast cells in vitro. Importantly, this activity is achieved with low nanomolar potency. So when we talk about broad pathway coverage, we're talking about something we can already see at the level of compound activity. We've also confirmed distribution of EVO756 to both meningeal mast cells and trigeminal neurons in vivo, which is important when considering 756's potential activity against these ligands in relevant tissues. Our view is that migraine involves a self-reinforcing neuroinflammatory cycle, trigeminal overactivation, X2 signaling, mast cell degranulation and peripheral sensitization that can all contribute to maintaining a disease state. Our hypothesis is that blocking X2 may disrupt this cycle. That is why 756 has the potential for a compelling profile of migraine with dual action biology, multiple neuropeptide coverage and mechanistic breadth that could translate across diverse patient endotypes. In our view, that creates the possibility of a true frontline therapy opportunity. We are planning a Phase IIb dose-ranging study in adults with refractory migraine of at least 6 days per month with a target enrollment of approximately 330 patients. This study is designed as a randomized, double-blind, placebo-controlled trial with two 756 dose arms and placebo. We are currently exploring daily dose ranges up to 100 milligrams across the 12-week treatment period. Based on our PK/PD modeling, we expect drug levels at these doses to be pharmacologically active and cover the receptor at the target site. The primary endpoint will be mean change from baseline in monthly migraine days. We will also measure key secondary endpoints, including threshold of response rates, changes from baseline in monthly headache and migraine days, and we also plan to explore patient subtyping, biomarker changes and migraine-specific quality of life. We believe this design gives us a strong opportunity to evaluate activity while also learning how to best position this program going forward. We look forward to starting this trial midyear and generating top line data in 2027. I'll now turn over the call back to Luis.

So hopefully, this has given you a broad background into why we're excited about moving into migraine, both from the perspective of the opportunity in general, the clinical pathway, the exciting data that has compelled us to move forward and the substantial opportunity for these patients. So we're excited to move forward. As we get closer to initiating the trial, we will give further guidance in terms of when the trial is going to start, how long it's going to take. and so forth. So thank you for your time today. Hopefully, you found this compelling and to be useful time. And we will now turn the call over to questions.

[Operator Instructions] Our first question comes from Thomas Smith with Leerink Partners.

One, if I could, for Dr. Dussor and Dr. Tepper. I was wondering if we could get their thoughts around the Phase II trial design and what they would consider to be clinically meaningful change on that primary endpoint of monthly migraine days. And then I have a quick follow-up.

Why don't I start? In the Phase II dose-ranging study for prophylaxis, you want to see a signal. And what I'm most interested in is drop from baseline. And in the migraine-specific treatments, drop from baseline is anywhere from 2 to 4 monthly migraine days. And that's kind of the magnitude that we see. Sometimes we see up to 6, sometimes we even see up to 8. Those kinds of changes really move people clinically. So those would be the kinds of changes I would expect versus placebo. Bigger than that would be really remarkable and dose ranging is obviously appropriate in Phase II.

I don't have anything to add to that. Stu is a clinical expert.

Great. Awesome. Yes, I appreciate the color there. And then maybe one for the Evommune team. It sounds like you're evaluating doses here up to 100 milligrams daily versus I think we're looking at up to 150 milligrams daily in the CSU and AD studies. Can you just talk about dose selection here for migraine? And I guess, what went into that sort of top up to 100-milligram dose?

Jeegar, do you want to go, then I'll go?

Yes, absolutely. So it's a good question. I think when we looked at all the data, including our PK/PD assessments of target coverage and where we want to be in terms of IC50s and IC90s, and our desire to limit this to 2 dosing arms versus placebo, we felt that up to 100 milligrams was more than adequate to sufficiently cover the target and give us that dose range that we want to evaluate in this specific indication.

I echo that. You can see how this trial design can increase in number significantly with each additional arm, and we wanted to be judicious but also cover the target where we would get the efficacy. And based on what we see from our internal programs and external feedback, these appear to be right in line with where we need to be with the 2 doses selected.

Our next question comes from Judah Frommer with MS.

Maybe first, just for the doctors. How are you thinking about learnings from anti-PACAP antibodies and how those might read through to X2? And then maybe if we fast forward the clock, in an ideal scenario where patients have 2 additional drugs available to them, how could you see both of these approaches being utilized in clinic if you did have kind of both of these types of drugs approved?

I'll start on this one. The efficacy of the PACAP monoclonal antibodies, I think obviously, there's multiple receptors that PACAP could be using. The X2 is one of them. The PAC1 is another major receptor. And we know that targeting the PAC1 receptor failed in humans with a receptor-targeted monoclonal antibody. So I think we can reasonably eliminate that category of receptor for PACAP. So what does that leave? That leaves the X2 as a great option for what PACAP might be working through. The efficacy of a ligand-targeted antibody doesn't necessarily tell you what the receptor is. It just tells you that the ligand is important. What I don't really know, what is the population, what are the numbers of people that are going to respond across the population to a PACAP-targeted therapeutic. We don't really know. I don't think there's any way to identify which peptide is relevant in any given person. So that still remains a big question, but the ability to go after a receptor that is targeted by multiple peptides, PACAP, VIP, and Substance P, I think you don't necessarily have to go through -- if there were a PACAP antibody that existed and then a VIP antibody that existed and a Substance P antibody, and sort of trial them separately, you can just essentially take out all 3 by targeting a single receptor. And I think that will be an interesting way to go targeting people when you don't really know what their mechanism is, you don't know which of these peptides is important.

And there may be an additive benefit. We don't know this yet. At the American Academy of Neurology meeting next week, there's going to be a presentation of a study of using an anti-CGRP plus an anti-PACAP. And our goal, as I said in my talk, is migraine freedom. So there's no reason why, once we get additional targets, we can't layer them, as long as it's safe, and get even greater degrees of reducing migraine and try to get to migraine freedom. So I think what Greg said about being able to incorporate multiple peptides into one receptor and then thinking about where you're going to go from that is very, very exciting and potentially shows our way forward.

Great. And then maybe just a quick follow-up for the company. Can you guys remind us, have there been any learnings, I guess, from the derm conditions? Have there been comorbid migraine patients there that maybe give you some directional learnings on what impact could be here? And then just on background meds for enrollees into the migraine trial, what are you going to allow for there?

Thanks, Judah. We're tracking that. We're actually looking at that for all potential comorbid conditions with CSU, AD and migraine. And not just for migraine or CSU and AD, but also the other potential conditions that people who have mast cell mediated diseases might have. So we can track their background meds and things like that accordingly.

Our next question comes from Prakhar Agrawal with Cantor. Please unmute your line and ask your question.

Hopefully, you can hear me.

We heard you for a second Prakhar, we lost you now.

Prakhar, we will come back to you. Our next question is Matthew Phipps with William Blair.

Thanks for putting this together, and thanks to the physicians for their perspectives here. I guess maybe for the company, can you just remind us on some of the differences between the B2 expression in rodents versus X2 in humans and how you think you can kind of control for that and look at some of your preclinical data here. And then I guess -- sorry, would you only look for patients who had CGRP prior in your Phase II? Or would you kind of include all comers?

So Greg, maybe you can follow up on the B2 mice. But I mean, I'll just say that the expression of the B2 mice is a little bit differentiated from what occurs in humans with the X2 receptor cell, primarily focused at least the way these B2 mice are created on the mast cell component of the X2 expression.

And I don't think one should limit the clinical trial to people who have had a lack of success with CGRP. I think one should test this on the widest collection of people with migraine. You can do a prespecified analysis of those who have had CGRP exposure, both successful and unsuccessful, but I don't think you should limit it in terms of testing it.

Our next question comes from Prakhar Agrawal with Cantor.

Hopefully, you can hear me now. Maybe one question for the KOLs. Just like how will the X2 drugs differentiate from the CGRPs? Are there other endpoints apart from just looking at migraine days reduction where the extra mechanism could have differentiation? And maybe for the company, could you see this as a combination therapy with CGRP drugs as well? Or will there be some redundancy in the pathways?

Well, we're very interested in additional endpoints beyond monthly migraine day reduction. We particularly want endpoints that evaluate what I talked about, the pervasive effects of the migraine. And interictal burden scale is one, Patient Global Impression of Change is another. And Richard Lipton is working with the NIH and the FDA to create a cognitive endpoint that can be used for evaluating patients who have brain fog as a result of their migraine, which is a very unfortunate and common symptom. So a variety of additional endpoints beyond monthly migraine days are in process. Some are actively being used, work productivity, the amount of acute medicines used, there's a long list. And we are attempting to include these in as many preventive trials as possible.

If I could just piggyback on that. There are these studies that you can do where you infuse humans with these peptides and then you look at the symptoms that develop. And of course, headache is a big one. There's a variety of other things that come along with a migraine. Migraine, obviously, is not just a headache. But when you compare the ability of CGRP to cause a broad list of sort of side effects or the effects that you see in a migraine and you compare that with the ability of PACAP to do the same thing, you actually see a broader list of physiological effects that happen with PACAP versus with CGRP. So that's an interesting observation. It doesn't necessarily mean that a PACAP targeted therapeutic approach would hit more of the sort of effects -- the non-headache effects that come along with migraine, but it's an interesting observation.

Our next question comes from Martin Auster with Raymond James.

Sorry, there was a question about the combination of agents that was asked that we didn't...

Pardon me.

That's okay. And I'll give a comment, and then I think it would be best to have Dr. Dussor on the MOA and Dr. Tepper being a specialist in migraine. There's nothing that precludes its use as a combination agent based on what we've seen that that's not part of our study plan to date. We will be capturing patients that have had exposure to CGRPs and the results of that, but there's nothing that we are not going forward with that. However, it's not something that we see would be something that you couldn't do. I'll let the others comment.

Yes, I would say mechanistically, we don't really know exactly how CGRP is working in migraine yet. This is still kind of an unresolved question in the field. And I think the company has data, they can address this better than I can on whether and how well CGRP actually binds to and activates the X2 receptor. I don't think it's a major activator of the receptor. And so you'd have to conclude from something like that, that CGRP is working through a different mechanistic pathway than PACAP, VIP, and Substance P are. And so I think the combination actually would be really interesting. I mean I can't wait to see this. I hope we get to the point where we can do this, because I think you're talking about mechanistically distinct pathways. And to be able to target 3 peptides with an X2 antagonist and another peptide with a CGRP blocker, I mean I'd love to see what that does to people. That would be interesting.

Yes. And Greg, your understanding of the X2 and CGRP is absolutely on point. And I think there is potential as we understand the monotherapy profile of the X2 antagonist in migraine and then look at also the breadth that you can cover with combo, I think that's something to consider as we go forward. Obviously, Lundbeck's data combining the PACAP antibody with their CGRP oral will also be interesting.

Our next question comes from Martin Auster with Raymond James.

Can you hear me?

Yes.

Excellent. A couple of questions for the company, I guess. You've shown nice proof of mechanism, proof of concept from the Phase I icatibant challenge data and the CIndU Phase II data. Obviously, a couple of Phase IIb placebo-controlled readouts coming up. Curious how you think about the read-through from the CSU data coming up in the atopic derm data later in the year, and how to think about the derisking or how influential you think that is in terms of thinking about the migraine opportunity? And then the second part of the question would be, possibly very different price points for markets like CSU and atopic derm compared to chronic migraine prevention. Are you thinking about long-term pushing this all through with the same molecule? Are you looking at maybe sister-brother compounds, things like that? Just curious if there's a long-term sort of thinking about that going on.

Yes, Marty, I can take the first one. I think as the TPPs evolve, we'll take the pricing considerations at that point in time. I think there's -- if we deliver efficacy and safety across these indications, we think that will drive value and allow us to be reasonable on pricing. That's for our future TPP evolution conversation as the story evolves. Mark, do you want to talk about CSU and AD?

Sure. Martin, it's an excellent question that we're trying to give you the answer to. But I think what we see at this point is we know we have an active molecule that impacts patients who have X2-mediated disease. As you noted, we demonstrated efficacy by reducing the icatibant wheal size, which means we hit the target in the skin in a meaningful way. We also demonstrated that in CIndU. We've seen that CIndU translates nicely to efficacy in CSU. Our patients with CIndU had symptomatic dermographism, all of them, and that translates nicely to CSU as well. The read-through from CSU to AD, I think, is a little harder. I think we feel like that X2 plays a significant role in patients with atopic dermatitis. Jeegar and the team have done a nice job at demonstrating upregulated X2 ligands in patients with AD. We know we have the X2 receptor on the sensory neuron, and it's upregulated in patients with AD as well as the mast cell. And so we're hopeful that if we impact it in the way we saw in the skin, it will also impact AD. And then the read-through to CSU, I think if we see it work in AD or CSU -- excuse me, in migraine, I think -- again, we know we have an active molecule. It's just what role does it play in migraine like it did in the others. So our hope is that it works in all 3. We do know we have an active molecule. We're excited to see where it's going to have its most impact or hopefully all 3 of them. Jeegar, do you want to add?

No, I think you covered it well.

Our next question comes from Brian Abrahams of RBC Capital Markets.

Maybe just for Dr. Dussor and Dr. Tepper. Just wondering in this proof-of-concept study, what are the key biomarkers that you might be looking for here to validate the mode of action? And then, I guess, how much do we know about the degree to which anti-CGRP therapies might modulate mast cells or neutrophils and how that might impact the population that might be optimal for X2 going forward?

Stu, do you want to start with the clinical part and then I'll do the mechanistic one or...

I actually think it all fits into you. Why don't you go forward?

Yes. Yes. I mean, it's a good question, how do you validate the mechanism. We don't -- in the case of CGRP, how do we know that -- the CGRP drugs are very specific, right? Of course, the monoclonal antibodies are extremely specific. But we don't actually know what CGRP is doing in the context of migraine, right? And so how do we really know ultimately that the CGRP drugs -- I mean, we know that they're working through a CGRP mechanism, but we don't know what that mechanism actually is, right? So the target engagement studies that were done with those drugs early on were studies where you inject capsaicin into the skin and you look for a redness response, which has a CGRP component to it. And you can dose humans with the drug and you can block the redness response, but we don't actually know that the redness response that you see in the skin has anything to do with what the mechanism of CGRP is for migraine. And yet these drugs are actually -- you saw the data from Dr. Tepper's part of the talk, if they're working. So there can be studies like this that can be done. You can inject PACAP in the skin. You can dose with an X2 antagonist and you can look for a similar kind of redness response. But the mechanism of migraine is so poorly understood at this point that I really wouldn't know what we would be looking for in terms of a mechanism to validate that the X2 antagonist was working through a very specific mechanism. So it's a good question. I like it. I just don't know how to best answer that. For the other types of immune cells, CGRP receptors aren't -- it's somewhat controversial as to whether or not they're highly expressed on mast cells in humans. Many people say that they're not, but they are expressed on macrophages. So there's plenty of other types of immune cells that I think CGRP is more likely to be driving than the mast cell. And so neutrophils are a completely different category of immune cells, right? I don't think we know yet which of these immune cells are really contributing what in the context of migraine and meningeal inflammation. It's still an open question in the field. But I think the more of these different kinds of immune cells that you can target with different kinds of selective therapeutics, the more we're going to learn about what type of immune cell actually is relevant in the context of the disease. We're just -- it's really -- it's shocking to me given the numbers that you saw at the beginning of Dr. Tepper's part of this talk and in the beginning, how many people have migraine, it's really still shocking to me how little we know about the actual disease and its mechanisms. Every time I say that, I'm surprised that I have to actually say that, but it is what it is.

Our last question comes from Konstantinos Biliouris with Oppenheimer.

Can you hear me?

Yes.

Thanks for the helpful information here. Maybe a question on target occupancy from us. Do you need full receptor occupancy to achieve a preventive effect here? Would that be different from a therapeutic effect? And are there any safety risks related to chronic receptor occupancy?

Yes. Just I'll take the safety one first. I mean, there hasn't been anything identified that points to an on-target chronic safety risk of target engagement at the fullest context. We know that there are knockout animals. Obviously, we've had some very good data early clinical development. As far as the kind of target engagement necessary to show clinical activity, I think that's still to be determined. We're taking the approach that we want to cover target as completely as possible for the longest part of the duration of the day that we can. We know these diseases kind of ebb and flow throughout the day and there's different triggers. And so from a conservative standpoint, that's the approach we're taking with the dose levels that we're carrying forward.

And maybe a follow-up, if I may. What percentage of patients is still using the nonspecific migraine drugs today?

It really depends on the country and the region. And all I can really tell you is that the frequency with which migraine-specific prevention is being used is escalating very rapidly. And the big result was after the American Headache Society position statement was as each of the 3 largest pharmacy benefit -- PBMs decided to allow migraine-specific treatment first line. And across the world, what is happening is in country after country, the step edits of using the nonspecific treatments are gradually going away and the number of obstacles to getting to migraine-specific treatment are falling. So it's a very encouraging gradual change. In the U.S., it's really a sea change. And in certain countries in the rest of the world, it is as well. Others are taking more time in getting -- but I think it's a matter of when migraine-specific treatment will be first line rather than a matter of whether migraine-specific treatment will be first line across the world.

This concludes the question-and-answer session. I will now turn the call back over to management for closing remarks.

Thank you, everyone, for joining. I hope this is insightful and look forward to chatting with everyone about this in the near future. Appreciate the time.