Incyte Corporation (INCY) Earnings Call Transcript & Summary

Hello, and welcome to the AAD 2024 Incyte Investor Event. [Operator Instructions] It's now my pleasure to turn the call over to Pablo Cagnoni with Incyte. Please go ahead.

Good morning, and thank you for attending the Incyte Investor Event at the American Academy of Dermatology at the 2024 Annual Meeting. For those of you online, I'm Pablo Cagnoni, I am Head of R&D at Incyte. We have a wonderful agenda for you today. After a very brief introductory remarks, I will hand it over to Jim Lee, who heads our dermatology and inflammation franchise at Incyte. He will give an overview of the pipeline that we have, which we think is very exciting. And after that, we have 2 very important speakers that will share with us different aspects of some of the studies that we've conducted and that will be presented at this meeting that have been present at this meeting actually yesterday. The first one is Dr. Martina Porter, who is an Assistant Professor of Dermatology at Harvard Medical School and serves us attending dermatologist at Beth-Israel Deaconess Medical Center. She's also the Co-Director of the Clinical Laboratory for epidemiology and applied research in skin or CLEARS, and she is an expert in hidradenitis suppurativa with areas of research in women's health, quality improvement, psoriasis, HS and alopecia. Dr. Porter will talk about hidradenitis suppurativa, and then she will review the results of the study that we conducted and was presented yesterday for ruxolitinib cream in patients with mild to moderate HS. This was followed by Dr. Shawn Kwatra. Dr. Kwatra is an Associate Professor of Dermatology at the Johns Hopkins University School of Medicine and also serves as Director for the Johns Hopkins Itch Center. He is as well the incoming Chair of the University of Maryland Department of Dermatology and he specializes in medical dermatology. His areas of clinical expertise include general dermatology, chronic pruritus, prurigo nodularis, atopic dermatitis. Dr. Kwatra will talk about prurigo nodularis as well as will review the results of the study that was presented yesterday with povorcitinib in patients with prurigo nodularis that we think show very exciting results. Before I hand it over to Jim to give an overview of our pipeline, I want to highlight a few key points for you of how exciting the next 5, 6 years will be for Incyte. If you look at the number of potential launches that we have between now and 2030, starting from the top part of the slide here, for ruxolitinib cream, obviously, we have, first, the potential launch next year of pediatric atopic dermatitis. We're preparing that submission, which will be sent to the FDA this year. When we look at the rest of the new indications for rux cream, the prurigo nodularis, obviously, that it's ongoing, the mild to moderate HS that we will review today for you, and we are in the process of having -- setting up an interaction with FDA as well as lichen planus and lichen sclerosus. Povorcitinib, which we also will review some of the results today, will have potentially 3 different launches in hidradenitis suppurativa, patients with moderate to severe disease, followed by vitiligo and prurigo nodularis in the next 2 years, as you can see there. Importantly, while I move down to our next vertical in myeloproliferative neoplasms and graft versus host disease, we announced recently that we have priority review for axatilimab for patients with third line chronic graft versus host disease. That application has been reviewed by FDA, and we look forward to making that medicine available to patients as soon as possible. Importantly, we are moving axatilimab to early lines of therapy in combination with corticosteroids as well as in combination with ruxolitinib. If we move down the list, we will have later this year additional data with our BET inhibitor to continue to try to improve the outcomes that ruxolitinib produces in patients with myelofibrosis and other myeloproliferative neoplasms. That data should guide us into how to proceed with the potential pivotal trial for the BET inhibitor. For the ALK2 inhibitor, we will have data, hopefully showcasing the ability of that molecule to prevent or improve anemia in patients with myelofibrosis. And we're obviously very excited we've discussed over the past few months, our mutant CALR antibody program is now in the clinic and a 617F inhibitor is going to enter the clinic very soon. We're very excited about the potential of these 2 medicines to completely transform the way MPNs are treated. Closing on this list with oncology, our all PD-L1 program continues to advance. We're very excited about the emerging data from our CDK2 inhibitor, particularly in patients with ovarian cancer. As we recently announced, we will be disclosing the data later this year as well as the potential development plan for this really interesting program. And now while we fully have control of tafasitamab after the acquisition of the rights from our partners at MorphoSys, I just want to highlight that we will have the data from the follicular lymphoma trial this year and the first-line diffuse large B-cell lymphoma next year. Importantly, and not on this list, is our KRAS G12D program, which entered the clinic very recently, and we think we have the potential there for a best-in-class G12 inhibitor. So this was an important meeting for us, the AAD meeting in 2024. We have 2 important other presentations that took place yesterday, and we're going to hear from the speakers today as well as a number of posters that we believe continue to set the foundation forward that's emerging as a very important franchise with an insight in dermatology and inflammation. With that, I'm going to now turn it over to Jim Lee, our Head of Inflammation Autoimmunity, to give you an overview of our pipeline. Jim?

Thank you, Pablo. It's my pleasure to go into more in-depth the pipeline that we have in the immunology and dermatology space. I think I'm going to go into more detail in subsequent slides, but we believe we have one of the best pipelines in dermatology, especially in conditions that are not well served. And so we're very excited. I'm going to talk about ruxolitinib cream, our JAK1 specific oral povorcitinib and finish with our IL-15 receptor beta monoclonal antibody. An additional component of why we're so excited to be in the dermatology space is we're uniquely positioned to be able to provide patients on the full disease spectrum, meaning so both mild, moderate and moderate to severe patients can be treated with topical ruxolitinib or and hopefully, potentially povorcitinib. And you can imagine that if a patient is on a systemic therapy, a systemic JAK like povorcitinib, they have a good response and they can come off of it. Some of the patients might be able to come off of it and the disease comes back in limited areas that the physicians could treat that patient with a topical JAK inhibitor like ruxolitinib cream. So uniquely positioned and obviously trying to help all of the patients that suffer with these terrible diseases. So let's turn to Opzelura. Obviously approved for atopic dermatitis and vitiligo. We do have the approval in the EU for vitiligo. And since launch, there have been over 350,000 patients that have been treated with Opzelura. But that's not the end of the story, so to speak. We have a lot of additional development programs ongoing. We have the pediatric AV program, which I'll talk about in a little bit more detail, but we have a number of Phase II studies. We shared the hidradenitis data yesterday. Dr. Porter will go into more detail today. And we have 2 ongoing additional Phase II studies in lichen planus and lichen sclerosus. And we have an ongoing Phase III study in prurigo nodularis. Let me remind folks of the pediatric data that we shared late last year which is very exciting for children with atopic dermatitis. What we saw was basically a repeat of the efficacy and safety that we saw in our pivotal studies that is approved for adolescents and adults. And as you can see, we have great efficacy, IGA up in the mid-50s with the EASI75 in the 60s with the 1.5% cream. And as you can see from the pictures, many of these children had a really significant and great response. And from a safety perspective, we really didn't see any additional safety findings. And in fact, we saw a lower rate of adverse events in children, which is not surprising, given that they're children. And we recently shared a poster at this meeting that I wanted to remind folks, and this was the maximum use study data, specifically in 2 to 11 year old. So we've shared the maximum use study data in adolescents and adults previously, and we wanted to update folks on the safety and efficacy that we saw in the maximum use study in the younger patient population. As you can see from the safety perspective, the drug was very well tolerated. I didn't see really any changes in the safety profile. And from a PK perspective, we basically saw a similar PK that we saw in the adults and adolescents. And so really, really well tolerated. And from an efficacy, which was a bit surprising to us, this more severe patient population responded actually better than the patients that we saw in the pivotal study. So very reassuring from a safety perspective. The PK is similar to what we saw in older patients. And again, from an efficacy perspective, ruxolitinib cream worked very well for this patient population. In terms of the ongoing program, so the one program we have in Phase III right now is in prurigo nodularis, the mild to moderate patients. And this is a schematic of the study design, where we're testing Opzelura, the 1.5% ruxolitinib cream against vehicle. And we'll have that data sometime early next year, maybe in the middle of next year sometime. Let's switch to povorcitinib, our oral JAK1 specific molecule. Just wanted to highlight some of the reasons why we believe povorcitinib has the potential to be best-in-class oral JAK inhibitor. If you take a look at the bottom, this has a very long half-life. So it's really truly a once-a-day drug. It has a high volume of distribution, and this allows the drug to get into tissue, basically get high tissue penetration. And that's a good thing. That's a very good thing for skin diseases, which you want as much of the drug to end up into the skin as possible. And povorcitinib is very JAK1 selective. So we can push the dose to get maximize efficacy and avoid JAK2 off-target effects that we want to avoid. And so we believe this is a great molecule, especially in dermatology conditions, but also other conditions and why we're so excited to be able to share the data today. So this is a high-level summary of where we are in the development for povorcitinib. You'll hear today about the Phase II prurigo nodularis data from Dr. Kwatra. We have an ongoing Phase III program in hidradenitis as well as an ongoing Phase III program in vitiligo. We have additional Phase II studies in chronic spontaneous urticaria and in asthma, and we'll hopefully be sharing that data sometime in the near future. So in terms of the hidradenitis, we have the ongoing Phase III program. I just wanted to share, again, remind folks of the very exciting data that we saw in the Phase II program. Again, it's not just at the week 12 and the week 16 primary endpoints. But over time, so the sort of the durable response that we were able to achieve with povorcitinib treatment and in week 52, we saw 60% to 67% of the patients achieve HiSCR of 50, 41 to 52, HiSCR75 and almost 30% of the patients achieving HiSCR100 at week 52. So again, a deep response. Just a reminder that this isn't just -- this is the objective endpoints, but we saw a really significant effect on itch reduction and pain reduction. And I think this -- obviously, Dr. Porter will be able to share what that means for patients with HS. And again, the caveat here is this is a comparison of some of the data of povorcitinib against another JAK1 specific molecule, upadacitinib that was shared recently. And if you take a look at the data at week 12 for HiSCR50 for HiSCR90, and for pain, you see that what we believe the reason for the high volume of distribution, the high tissue penetration has the potential to provide best-in-class efficacy for this disease. And again, the caveat being that these studies weren't done together, that the drugs weren't compared together. But based on the published data, we think that povorcitinib could definitely be best-in-class for HS. So in terms of the vitiligo, this is a summary of what we saw in the Phase II vitiligo study. Again, looking at not just week 24, but with continued therapy, the continued repigmentation that you see. As you know, vitiligo takes time, the repigmentation takes time in vitiligo patients and as you can see with continued therapy, we're able to see a very significant repigmentation in all of the doses that we tested in our Phase II study. And pictures, obviously, are worth a thousand words, and as you can see in the bottom, this patient had significant repigmentation over time as she continued with povorcitinib therapy. So very exciting. And we have started the Phase II program, as I mentioned earlier, and we're very excited to be able to complete the study and evaluate povorcitinib for vitiligo patients. So as I mentioned, we have 2 additional Phase II programs ongoing. One is in asthma. And the rationale there is, is the scientific rationale there is highlighted in that schematic. Lots of cytokines that mediate its effects to JAK1 have been shown to play a roll in the pathogenesis of asthma. And so that's the scientific rationale. We know from allergists and immunologists and what pulmonologists have shared with us that there is a significant number of patients who break through standard of care therapy and that needs something else. And so we're hoping that povorcitinib can help this population of asthmatics. In addition to asthma, we're testing povorcitinib in chronic spontaneous urticaria. And again, very similar, it's a mass cell-driven disease, many of the cytokines that have been implicated in the pathogenesis of CSU also mediated effects through JAK1. So very strong scientific rationale. The Phase II studies have -- are enrolling. And again, we expect data sometime in 2025. So finally, I'd like to share with you an update with our -- or about our IL-15 monoclonal antibody. We have started or gone into the clinic last year. The study is enrolling well, and we should hope to have some data for you sometime next year. But just as a reminder of why we were so excited, so interested in this target. As we know, tissue resident memory cells have been implicated in many autoimmune inflammatory conditions. That's highlighted in the right there. And specific to dermatology in vitiligo, tissue resident memory cells have been shown to play a major role in driving inflammation and knocking out melanocytes. And so the rationale is that if you can block them through stopping the IL-15 stimulation of those T lymphocytes, we can provide a durable response to vitiligo patients. So that's a very quick overview of our dermatology pipeline. I'd like to turn the stage over to Dr. Martina Porter, who will share with you our Phase II study with ruxolitinib cream in hidradenitis.

Thank you. Yes. So I'm Martina Porter. I'm a dermatologist at Beth-Israel Deaconess Medical Center, and I'm our Vice Chair of Research and I run our clinical trials unit. And I've been doing HS, I think, for my whole career now, and it's really something I think that we made some with progress on. But just for background for anyone who doesn't know, HS is a chronic recurring inflammatory skin disease. It's associated with painful inflammatory nodules and abscess. And you can see them here in the top left corner. This is a patient who's probably in the moderate category. But over time, some patients can progress to a very severe disease, and they have more tunnels, which are those tracks under the skin and then also ulcerations as a sign of severe inflammation, foul smelling discharge and then eventually permanent scarring if they get this track formation. There is currently no approved therapy for milder HS and the standard treatments are often inadequate. We use various topical therapies, we use oral antibiotics, oral hormonal therapies and then various systemic immunosuppressive therapies as well. The prevalence of HS is someone seems to be around 0.3% to 4.1%, with the actual prevalence being probably 0.5% to 1% of the total population. And the reason that it looks so varied is that what we've been doing are claims database studies and others have done registry studies. And so because there's this huge diagnostic delay where patients usually take 7 to 10 years from the time of first symptoms to actually getting a diagnosis, there's quite a few people who are miscoded or not coded as having the disease. And so this was thought to be a rare orphan disease for a long time, and no one was interested in doing research on it. But now that we have more patients getting diagnosed correctly and seeking care, they really think the prevalence is going to land probably around 1%. And the typical onset of age for these patients is around puberty. So for women, we see it a little bit early, usually in the early teens, so the early 20s. And for men, it's probably shifted back a few years, so around like 18 to 25 is the peak age of onset. Although we do have patients who present a little bit later around menopause or middle age and they're primarily women. In terms of our gender breakdown in the U.S. and in North America as well as in Europe, we tend to see more females approximately 3x more. But in Asia, they actually have a reverse. And so they tend to see mostly males and fewer females. And people aren't sure if that's also cultural because women aren't seeking care due to the locations of the lesions or if there's truly more men who are affected. But one of the things that we have definitely originally postulated but now has been proved is that this is a disease that affects more blacker African-American than biracial people than white people in the U S. And so this disease also has many comorbidities. A lot of them are in line with what we see for patients who have psoriasis as well. So all of the metabolic syndrome, obesity, hypertension, diabetes, but also these patients have a very high level of anxiety, depression and probably the highest rate of suicidality of any dermatologic condition. And I think this just speaks to how terrible this disease is and how impactful it is on quality of life. And then because this is a disease of hair follicles in the follicular unit, we also see things like acne and then polycystic ovarian syndrome because there's the thought that hormonal component can really drive the changes in the hair follicle. And so we see a higher rate of PCOS here in women. And then also, we see more inflammatory disorders that coexist with it like spondyloarthritis, inflammatory bowel disease. And so what is mild HS. I think the most important thing, and I was talking about this with a bunch of my colleagues last night is that we have to be very careful when we talk about this trial and who we were treating because it's not correct to say topical ruxolitinib in this study was only used for a mild population because the patients in this population are probably -- could have been anywhere for mild to severe if you look at their actual inflammation because they allow patients to have up to 10 lesions. But traditionally, when we think of mild HS, we think of it either by disease or extensive scarring. And so the top pictures here are what we call Hurley staging. And this has been the traditional approach to grading the severity of disease that does not take into account inflammation, it's really looking at just scarring. And so patients who are Hurley stage 1, which is the left picture where it says mild, they have these single lesions, but they haven't interconnected yet either by track or scarring or all the hair follicle side of coalescing. And then when we get to moderate disease, which we've always designed for moderate to severe clinical trials, patients would be Hurley stage 2 or 3, and they started to have lesions that interconnected. And the only difference between 2 and 3 is the extent of involvement of an anatomic area. So in 3, they have almost the entire anatomic area defined. And I just want to point out one other thing is that by inflammatory burden, we've historically said that patients who have less than 4 abscess and nodules combined are considered mild. And those who have 4 or more were moderate to severe. And this was because when they did the pioneer studies, those are the inclusion criteria. And that's what the insurance companies have used over time to define moderate from inflammatory burden. And what happened after that in clinical trials is that they've actually increased the lesion cap requirement to get into a moderate-to-severe trial to usually 5 or more. And the reason for that is not because we thought the patients we're too mild to get in. It's because patients who have fewer than 5 lesions have much higher disease variability. And when you look at something like HiSCR in your bar for efficacy is 50% improvement, the placebo rates can be quite high because patients naturally fluctuate in disease. And so pharmaceutical companies shifted the bar to the right to try to decrease the placebo rates. And so what we call moderate to severe in a clinical trial may not be a true moderate to severe population in a clinical setting. So for the North American clinical management guidelines, these are the last published guidelines for HS, and this came out in 2019. And if you look at any of the trials, 2019 is when Novartis started the secukinumab studies in Phase III. And since then, the amount of research has been crazy. And I would say that a lot of things have kind of changed here in terms of what we do now. But all again, most of the development was in what we call moderate to severe or Hurley 2 or 3. And so everything you see here for milder patients is pretty much the same. And so most mild patients will get topical washes, benzoyl peroxide, chlorhexidine. We use zinc pyrithione, which is in things like anti-dandruff shampoos. A lot of people will get antibiotics. We use doxycycline in our practice for a few months and then escalate therapy. But there are other groups around the country and world who use a lot of antibiotic combinations for these patients of all disease severity. And then for women, we use a lot of hormonal therapies to spironolactone, oral contraceptive, finasteride and then oral retinoid, things like isotretinoin or acitretin. But if you look down here, none of these have very good strength of recommendations in terms of level of evidence. And part of this is the disease is very hydrogenous, and part of it is that probably none of these treatments work very well and so you're just always kind of shifting from one thing to the other. And then the other thing to note is that we do, do surgical management, so unroofing, laser procedures for these lesions as well. But most patients who are candidates for this have only a few lesions or they have very severe disease, and they have no options left. So this is my own when do we consider giving someone biologic or JAK inhibitors. And so I always say anyone who is moderate to severe by clinical trials criteria should be considered for a biologic or JAK inhibitor. But there's all these other types of patients who may not look like that at the outset who could also qualify for this and people have higher inflammatory border and more diffuse scarring, longer sustained flares, have significant pain or severely impact quality of life regardless of the number of lesions should be probably treated more aggressively. And then if they've tried all these other published treatments for milder patients, antibiotics, hormonal therapy and they're not responding, then we'll usually advance therapy as well. And anyone who presents a very large ulcerations, that's a sign of high inflammatory burden, they may not have the classic modules and draining and abscesses, those patients should go directly to immunosuppressive therapy. And then I always say for systemic therapy, many patients are very hesitant and some patients are very eager, and it's really the relationship that you have with patients over time that help them make these treatment decisions. So I'll go now into the data for the efficacy and safety of the rux cream in patients who had hidradenitis suppurativa. And again, these are Hurley Stage 1 and 2 patients, and this was the randomized double-blind vehicle-controlled Phase II study. So in terms of the actual study design, the first 16 weeks was a double-blind vehicle-controlled period, and people will randomize one-to-one to rux cream twice daily or vehicle cream twice daily. And then the extension period, which we haven't -- which we're not going to cover here, the patients all actually were allowed to get the ruxolitinib cream and then we changed the criteria for how we treated them. But the primary endpoint for the first 16 weeks was the change from baseline in abscess and nodule count. And then the most important thing, I think, is you have to look at the eligibility criteria. And so these are adult patients only. They had to have HS for at least 3 months. They could only be Hurley stage 1 or 2 and they had to have abscess and nodule combined count for 3 to 10. So if they were 3, all 3 had to be in the same anatomic area, but if they were 4 or more, they had to have 2 anatomic areas involved. Any patient who had draining tunnel were not eligible for the study. So they could have tunnels that they could not be driving or active. And if they were to develop a draining tunnel, they were considered a treatment nonresponder and they were removed or withdrawn from the study. They had to apply the cream to less than 20% affected body surface area and honestly, it's very rare to have a patient with any HS have more than 20% of a body surface area. And then there really were very limited, I would say, criteria for entrance for skin pain and itch. So patients only had to have a score of 1 for either itch or pain to get into the study, and that's pretty much every patient. So it's not really a limiting factor for the study if they have HS. And then the patients when we looked at the data, although we don't have it shown in the presentation, we did stratify them between people who had more mild disease, 3 to 4 as their entry, and count versus 5 to 10. And the last thing I do want to note is that this was not a field therapy. So in some topical trials, you just apply the cream to wherever the patients reported they have disease or had disease. But in this study, the cream is only applied to the abscesses in nodules that were identified at baseline plus about 1 centimeter in the surrounding skin. And then those patients would treat those lesions for the duration of the study even if they went away. But if a new lesion were to pop up, let's say they only had treated their buttocks and they got something in the axilla, that area would have never been treated before and they would start treating them once they came back in and were assessed by a physician. And so here is the demographic and the baseline clinical characteristics. You can see the age is about 29 years in both groups. This is a trial that is predominantly female, which is not really surprising because it was done in North America. And in general, when we think of female entering in trials, they really like things that are potentially low risk, which is why I think this trial was so popular and enrolled so many women so quickly. There is a very good -- yes, it's a known thing. There's a very good breakdown in terms of racial demographics here, and you can see there is a very diverse patient population. In terms of the patients themselves, they're kind of classic HS patients. They have high BMIs, they have high anxiety and depression levels. The disease duration, although they only needed to have 3 months, it's very typical where they had 4 to 6 years. And there's a little difference here, but really after patients have had disease for 2 years, it kind of evens out in terms of the severity so I wouldn't really think too much about that. And then we had about 15% of patients in Hurley 1 and 2 for both groups. And then the most notable thing was the mean AN count. So it was about 5%. And you can see this is predominantly nodules and not that many abscesses. And so this is more of what we call this kind of modular patients that don't have a lot of these tracks and don't have huge absences. But I always like to point out that the average number of the AN count here would have qualified patients for a moderate to severe systemic trial. And then the itching pain scores are slightly lower than what we typically see in moderate to severe populations where they're 6, but the score here is still moderate. They're 4. And then you can see many patients have had prior therapy, very few biologics and then about and then about a quarter with surgery, which is pretty normal. So this is the primary endpoint. It was a change in baseline in the AN count through week 16. And you can see as early as we gate, there was a significant difference between the 2 groups. And you can also see, which is the main questions they were asking me about during the presentation is the dropout rate. And so there is a difference in the dropout rate between patients who are in the vehicle and patients who are in the ruxolitinib cream group. And the way that we did the analysis is a prespecified mix model for repeated measures. And the validity of this -- of the analysis is based on the assumption that the dropout is random. And the question that I received during the late breaker was obviously -- it was framed that obviously the patients dropped out because it was not working, so it's not random. But actually, when you stratify by disease severity in this group, so the patients who had 3 to 4 lesions in the 5 to 10, the patients in the 5 to 10 group actually didn't drop out at all of the study. It was only the milder group. And you would actually expect that if it was the more severe patients dropping out, that it's probably not working. But there was still a much larger delta in the larger group for the ruxolitinib cream compared to the vehicle. And so I found that reassuring and the apparently, the panel also did. But -- and the other thing to note is that in terms of the demographic, there are about 5 patients who are last to follow up in the ruxolitinib cream group and they are all racially different -- the demographics are very different than patients that continued. So -- and this is the AN50, AN75, AN90, AN100. So it's the percentage improvement in the AN count. And you can see here that there's a difference at all of the levels and AN50 has a high placebo rate, which is what we always see as we have a 50% bar. But still, there is a differentiation from the rux cream in the vehicle. And then AN75, which is probably the best outcome measure just like HiSCR75, we still see a differentiation. AN90 and AN100, I always like to point this out because essentially, if you are enrolling a milder population, let's say a patient only has an AN count of 3, the only levels that they can truly achieve for percentage improvement are AN50 or clearance because they just don't have enough levels. And between AN90 and AN100, you have to have 10 lesions to start to actually have -- to achieve 90 and not achieve 100. And so we have had long discussions about this as like an expert HS group, like what is the acceptable primary endpoint for milder patients because we are starting to exclude them from trials, not because they don't think they need to be treated, but because they can't get efficacy measures that will demonstrate improvement. And so this, I think, will be one of the key features to define as we go forward for any milder population. And then here, you can see, these are the secondary endpoints, HiSCR patients achieving HiSCRs. So the 50% improvement at least in the AN count, plus they cannot have any increases in abscesses or draining tunnels since baseline. And then changes in IHS4. And again, I'd just like to point out that because this group has no draining tunnel, the HiSCR is almost identical to the AN50, with the exception of there are 2 patients actually in the placebo group who developed one abscess throughout the study that didn't have them at baseline. In that slide, there's actually the -- placebo rate is even lower for HiSCR. And then IHS4 heavily waived draining tunnels, so they get 4x the score of a nodule. And so I think it's much harder to demonstrate a difference when you've eliminated the factor that has -- carries the highest weight. And then in terms of the patient reported outcomes, the scores are moderate for both HS pain and they improved similarly in both groups during the study. And I didn't talk about this yesterday because they gave me very little time and were chasing me off the stage, but vehicle-controlled trials are not the same as placebo-controlled trials. So vehicles have actually been demonstrated to improve patient-reported outcomes because there is an effect of the vehicle where taking an oral or systemic placebo does not have that same effect. And so that may account for some of these differences, along with the fact that you can see there's kind of this waxing and waning in terms of how patients actually complete the diaries. And also, the other thing is that we did not have criteria at baseline, really for high pain scores because they had to have itch or pain of one. And most of the pain analyses that you see for moderate to severe have preselected for patients whose scores are at least 3 and then they look at improvement. So it's just a different mindset that you have to look at when you look at this data and you can't compare it to what you've done in other studies. And then in terms of the safety, ruxolitinib cream was generally well tolerated over the 16 weeks. There were no serious treatment emergent adverse events reported among patients. There are a couple of patients in each group who had application site reactions. And then in the vehicle group, there's a patient who developed diabetic ketoacidosis, which was the serious AE. So in conclusion, twice daily, 1.5% rux cream in the patients with milder HS. Patients who applied rux cream achieved a significantly greater primary reduction, a reduction in the AN came from baseline at week -- versus week 15, which was the primary endpoint. And then we did see changes, I showed you in AN count, HiSCR in IHS4 and the rux cream was well tolerated in these patients. And like I've been talking about, we may need to reevaluate the clinical endpoints. And then the very last point I will make before I run away here is this is a therapy -- a monotherapy trial. So everybody in this trial couldn't have other treatments for HS. And in real life practice, when we have systemic therapies that are not achieving clearance like we see in psoriasis, for example, for some of the biologics, the likelihood that patients are on combination therapy in HS is going to be very high. And I would anticipate ruxolitinib cream may be used as monotherapy for milder patients, but I would be not surprised and we'll probably see this quite frequently in patients using it in combination with other therapies.

Thank you, Dr. Porter. It's my pleasure to introduce Dr. Shawn Kwatra who will talk about prurigo nodularis as well as share the most recent Phase II data on povorcitinib with prurigo nodularis -- or excuse me, in prurigo nodularis.

Thank you, Jim. Nice to be talking with all of you today. Okay. So let's start just high-level prurigo nodularis. Two things you have to think about in this disease are itch and the skin lesions that you can see depicted here in these pictures, these are my patients, the top patient is mine. And these patients have intensely itchy nodules but then also the area around the nodules is also very itchy. The pathogenesis for this disease, until recently, had been entirely unclear. So this has been one of the underrecognized diseases in dermatology. And I actually myself, got the first NIH grant, and I'm still the only funded investigator in the United States studying PN. So a lot of the -- so of the pathophysiology is -- that I'm going to share is directly from my work in my laboratory. So we did the first immunophenotyping studies in skin. And what we found is that there is up-regulation of multiple immune axis. So starting out, we looked at the skin and the blood. In the skin, we found increased type 2 cytokines, like IL-4 receptor alpha and IL-13, elements of IL-31. But we also saw other immune axis like IL-22 and its receptor, interferon gamma as well. IL-6, there was a big signature. So there was multiple immune axis. And when we correlated this to itch intensity, actually all the immune axis are correlating with itch intensity, so we were very, very puzzled. And we looked in the blood. So we isolated peripheral blood mononuclear cells. What we found was that from CD4 and CD8 T cells, IL-22 was being released. And so we had that picture in mind that there's type 2 inflammation. There's a big role for IL-22 here, and that's kind of where we were jumping off subsequent studies. We found that there is elevated IL-13 in the bloodstream but there's endotypes of patients. Some have high IL-13. Those patients tend to respond a little bit better to dupilumab. Some patients don't and they don't respond as well and they're slower. And we're doing precision medicine phenotyping as we go and we found that we've also done cluster cytokine analysis showing their subsets with IL-6, IL-22, IL-31, interferon gamma. So it's actually the pathophysiology is honestly more like hidradenitis suppurativa. So let's move on a little bit and talk about this disease because we've also done a lot of the prevalence estimates. Again, we were the first people to start studying this. And then pharma came on, and we're so excited about it because it's going to help patients. But all the data, the prevalence data is under -- the total underestimates, and I'll give you context because there wasn't an ACD10 code for prurigo nodularis until year 2015. So you couldn't even code it, you couldn't track it, you didn't know. So we actually started studying the prevalence, we put the first estimate out which is 72 per 100,000 in patients aged 18 to 100. You see a variety of estimates. We keep looking every year and it keeps increasing every year. So the last estimate was between 300,000 and 400,000. The next estimate is going to be even higher. So my true impression is this is millions of patients. And this is followed multiple other diseases where you have development, you have greater disease awareness. These patients are not only seeing dermatologists, they're seeing infectious disease doctors, primary care doctors and there's that gap in referring these patients. So we've worked really hard increasing disease awareness, but the true prevalence in my opinion is millions of patients. So the prevalence is underestimated. The biology of the disease and the natural history is that it emerges more in middle age. So 40s, 50s, 60s, this is when the disease emerges. Men age around age 50. Slightly more common in females. We also know it affects skin of color patients. So African-American patients. Asian patients also are disproportionately affected. We also did the first whole exome genetic sequencing study and found there's a polygenic risk score that actually replicates across 3 intercontinental cohorts that predisposes you to PN, but there's many environmental factors as well and that African and Asian ancestry predicts a greater likelihood of developing PN as well. So it's associated with a variety of different diseases, such as type 2 diabetes. One hypothesis we're entertaining is that type 2 diabetes and increased blood glucose can actually have similar to peripheral neuropathy action on the cutaneous nerves, which can trigger this inflammatory condition. Itch is the #1 complaint in these patients. They come into the office and what they say is, I need my itch cured. So all these patients reach out to me. I get e-mails every single day from PN patients around the world. And the words they use with me are, I am considering committing suicide unless you reduce my itch. And it's a lot of pressure because I don't know how to respond on the e-mail, but it's all about the itch. And we actually -- I just cochaired a conference in Hawaii and one of the dermatologists came up to me and told me they actually had a patient that was so itchy they committed suicide recently. So this is different from anything we've seen, even atopic dermatitis. The itch here is the most severe of any disease on earth. This is the endpoint. That's the #1 thing. But in addition to itch, these patients have the dual affliction that they have these very disfiguring nodules. So patients' social lives are disrupted. They can't have relationships as easily. They have embarrassment, so it can affect many different domains. Heavy quality of life disruption. You also see pain, psychological effects, sleep disturbance. This all comes along with the disease. So the landscape of this disease is shifting. For a while, the dermatologists thought, oh, it's just only in those lesions, let's only do topicals and these patients continue to suffer. So we're still giving topicals to these patients, but also lowering the barrier for systemic therapy also because you can have permanent scarring as well in this condition, and we want to prevent that. So a dual strategy, load patients up and try to give them early treatment. DUPIXENT is the first approved agent for prurigo nodularis. And what I've observed in my real-world experience is that there's great heterogeneity. It's actually a mystery of precision medicine that we're trying to uncork right now is that some patients respond within a few weeks. And other patients had a patient who started responding a little bit, only at month 12. At all. And so what we've actually found, and I presented data at this conference, my fellow at the Skin of Color Society Scientific Symposium that actually elevated blood eosinophils are a predictor of response to dupilumab. And that's actually more common in Caucasian patients and Asian patients, which were enriched in the dupilumab PRIME and PRIME II study is actually heavy number of Asian patients in that study as well. And this data that we're presenting was also found in a recent Chinese study of 123 patients that found elevated blood eosinophils are predicting a response to dupilumab as well. So we talked about the mechanisms and cytokines involved with JAKs Jack. Also in my hands and others, there have been emerging reports of JAKs for PN, similar to what has happened for other agents, we're finding increasing numbers of cases and reports. And there remains a big significant unmet need. Many of my patients right now are in dupilumab and methotrexate. They're on dupilumab and phototherapy. I hate using this drug, it shouldn't even be available, but some of my patients are on [ polidomide ] right now. And these patients want relief and they want it fast. So that leads us to our study of oral povorcitinib in prurigo nodularis, the Phase II study. I'm really excited about this study because I feel like we actually contributed to a lot of the basic pathophysiology that provided some of the rationale for pursuing povorcitinib. You can see the study design here, very consistent with other similar studies in PN, adults 18 to 75, diagnosis for 3 months or longer with inadequate response and tolerance to previous therapies. Greater than 20 of these lesions, some patients had many more. An IGA score of 3 or greater. So for context, an IGA 0 is 0 nodules, an IGA 1 would be less than 6 nodules, 2 would be 6 to 20. A 3, 20 to 100. And a 4 is over 100 of these lesions. And then these lesions had to be in multiple body regions, an itch score of 5 or greater, and these patients were randomized. You can see the different arms, povorcitinib 15, 45 milligrams, 75 milligrams and placebo. So we're going to be looking at this primary endpoint here at week 16. But you can also see there's an extension period where patients are getting either 45 or 75 milligrams daily. So primary endpoint here was proportion of patients who are achieving this 4-point or greater improvement from baseline in itch at week 16. So you have to think about it. These patients are living actually very high with their itch. So we're using a 4-point response here because that's what the FDA has labeled but what the patients are interested in is am I getting down to more of an itch free state. That's their #1 concern. Additional endpoints, proportions of patients achieving the IGA treatment response, which we talked about and a 2-point improvement. This is very ambitious if you can go from 20 to 100 or over 100 lesions down to less than 6 by 16 weeks, I mean, that's asking a lot. So I was a little bit concerned we were setting the benchmark too high. And then the proportion of patients achieving both the itch-NRS 4 and the IGA and then frequency and severity of adverse events. So you can see the stats analysis there. So let's look at the baseline demographics of the study. Overall population, 146 patients. This mirrors the epidemiology of PN broadly. The age is in the 50s, more female preponderance. All studies have a little bit -- are more biased towards Caucasian patients, so that's nothing novel by the study. The patients are a little bit more overweight and you can see a variety of comorbidities. Actually, the prevalence of atopic dermatitis, 14.4% mirrors what we see. So we've done lots of studies now, and it's around 10% to 15% of PN patients that have concomitant atopic dermatitis. So I believe that's very accurate. For IGA score, 80% of patients had an IGA score of 3, which means 20 to 100 of these nodules skin lesions. And then IGA 4, actually, that's a big number, 20% that had over 100 of these lesions. The itch score here is very high, so in 8 out of the 10. That's a big number in terms of the etch that these patients have. Also significant skin pain, 7 out of 10, and the DLQI of 15.6% is very severe impairments these patients are having in their overall quality of life. You can see the prior therapy that patients have been on, many also with systemic therapy, oral steroids in a good small subset of these patients. So let's flip through the data. First, the primary endpoint. You can see a perfect dose response here between the 15 milligrams, 45 milligrams and 75-milligram arms of povorcitinib. And there, at week 16, that is 54% of patients are having that 4-point response, which is very significant. Let's look a little bit backwards there and start at the beginning, 2 weeks, that 2-week metric. We have already 30% of patients in the 75 milligrams arm that's reaching the 4-point response. The week 4 data, I think, is very telling here because at week 4, especially in that 75-milligram arm, you already have over 50% of patients that are reaching that 4-point response at a very early metric. And that's the best itch data that's ever been recorded in a clinical trial for prurigo nodularis. And when you look at that number throughout, what's happening is that it's not just the 4-point response. I'm sure in the secondary cuts, what we'll see is that these patients are actually entering what we call an itch free state, which we've actually seen with topical ruxolitinib. We published on that together as well. So that's IGA 0-1 -- I mean itch NRS less 0 to 1 or less than 2 that you're having. So very, very fast, very, very deep itch response, which is what these patients need with the different arms here in the study. Let's look at the time. Perfectly follows dose response like we'd expect. If you are on the 15-milligram dose, it'd take on average 58 days to have a 4-point improvement in your itch. If you're in the 45 milligrams, 35 days. In the 75 milligrams, very fast, 17 days to get that 4-point improvement in itch. This number very much so surprised me, like I said it up, I wasn't expecting this number. So if you look at week 16, at the 75-milligram dose there, you're already having nearly 50% of patients are down to IGA 0-1. So some of these patients have had hundreds of lesions, many 20 to 100 that are now less than 6. So when I say like -- the itch data is incredible, but I'm actually not sure which one is more impressive here because this is a number we've never seen also, that number in that 75-milligram arm. When Jim was talking about povorcitinib, me and [ Brett King ] did a session on all the JAK inhibitors just the other day, and I think there's something about povorcitinib that it's very, very selective, and it seems to be even above 30 in terms of how potent it is without hitting JAK 2, in my opinion. So that number speaks for itself. That's been represented right there. And then you can see at the other time points it's having early relief with the nodule as well. So very impressive improvement. And then you can see the percentage of patients with both the itch improvement and the nodule relief, already 35% of patients there at week 16 in the 75-milligram arm is very impressive. Safety was very well tolerated and all those side effects were just what's consistent with known oral JAK inhibitors, no surprises here. Actually, there wasn't much more in the 75-milligram arm. I was looking at that closely to see if there was any signals and there wasn't. So that also, I think, in my mind, helps solidify some of the JAK1 selectivity that, that data is pretty good, headache, fatigue, nasopharyngitis. There was one patient that had a death in the study but deemed not related to study drug. This was day 9 in a 70-year old woman who had a very high BMI. A 49, a smoker also, COPD, high blood pressure. So very excellent safety data, look at the 75 milligrams, 0 discontinuation of patients. So that speaks for itself on safety. So in conclusion, once daily povorcitinib had a very meaningful 4-point improvement in itch and early impact on it. Actually, I'm very much looking forward to the data cut where we look at itch-free state because I think that's going to be pretty impressive. And then you can see many patients achieving that IGA endpoint combined skin lesions and itch endpoint. Well-tolerated safety profile, consistent with what we know about this molecule. I was impressed with the 75-milligram dosage where you had high efficacy that you didn't see a dramatic increase in safety signals. And so these Phase II study results really paved the way for the Phase III studies, a new treatment option. I'm really ready to go for the Phase III. So very excited about this. This is a huge thing for our field and also the gap in the field is that many of our skin of color patients have broader immune access involvement in HS and in PN. So I think -- I have to thank the company because that's -- I'm the Treasurer of the Skin of Color Society, so we have to thank companies publicly when they're investing in therapeutic targets and disease areas that affect skin of color patients with mechanisms tailored for those patients. So that just goes beyond the presentation. That's just gratitude to you guys.

Thank you, Dr. Kwatra and Dr. Porter, Jim. We have now time for questions. So if there are questions in the room, please go ahead and I'll repeat it for those online. [ Ben ] and [ Greg ] will tell me whether we have questions online.

So we had a couple for Dr. Porter, maybe about milder HS. So one of them is when designing to treat milder HS patients, assuming there are different therapies available targeting JAK inhibitors or IL-17 TNF alphas, how would you decide which pathway to go about treating?

To be honest, if you look at the data for patients who accept or take biologic therapies, and this pre secukinumab, it's only 2% of HS patients. And that's far less than any other disease state that we see where biologics are available, and it's likely because of a combination of reasons. One is that there's more women and as I alluded to, they're more risk averse. And so I would say most of my patients who come in who have not had a biologic even if it's been recommended to them want to start with a "safer" therapy first, like a topical. Or they want to -- and a lot of patients don't even take antibiotics. And so that's why, I think, this trial just enrolled so quickly is that this is what patients want are like the safest topical therapy. And in truth, we usually prescribe multiple things to patients. I never just give patients like who need a biologic only biologic therapy and that's it. And so for milder patients like in this study, the patients who would probably not get a biologic are ones who have mostly nodules and don't have that many lesions and they're just intermittently popping up here and there, which is probably over half of the patients total that we see with HS. Did that answer your question?

Actually, add one thing. I actually had a lot of HS patients here. Itch is really underappreciated in HS. Whenever I lecture, people ask about that. And if you think about it, there's a recent paper and [ sell ] that show that [ staff areas ] directly activates itch and staff areas is colonizing HS, a topic in prurigo nodularis. So itch is a big component. That's actually one of the commonalities between the different studies of JAK in addition that you're hitting that aspect as well.

And then maybe to follow up on that. In milder HS patients, itch or pain relief is the most important or...

I think for all patients, pain relief is the most important thing. And I don't think patients -- and this is why the pain studies are -- the pain numbers that we see for all HS trials, they tend to improve significantly at first and then they just plateau, and this is a very complicated disease. There is, I think, chronic pain that people have from having the lesions, and then there's acute pain that they have from having flares. And I also see patients who have a lot of itch and some of it is with the activity -- the active disease. And a lot of it is as the disease heals and they develop scarring, they can also have itch associated there. And these are things that we're still trying to tease out and understand because flares in HS have been defined by trialists just to put into presentations, but they don't actually match what a patient describes a flare as. And to every patient, a flare can be slightly different.

I guess just one last one on Phase III design, given the vehicle response. Is there anything you're thinking about doing for Phase III to kind of [indiscernible]?

I don't work for Incyte. So...

Maybe I can address that.

We can address that one.

That's an important question. And obviously, we're still finalizing and considering all of the inclusion and exclusion criteria, especially around the target patient. And so we'll share more of those details as we finalize our Phase III study design. Thank you.

We'll now be taking questions from people over the phone. [Operator Instructions] Our first question is coming from Michael Schmidt from Guggenheim.

This is Paul on for Michael. Mine is for Dr. Kwatra on PN. Just in a future scenario where povorcitinib is approved, how do you expect the therapy to fit into the treatment landscape where Dupixent and possibly some of the investigational IL-31 antibodies are also on the market? And then maybe you could comment on how the mechanism of JAK inhibition and PN might compare with some earlier investigational approaches such as kit end volume as well?

Did you get that?

Yes.

It was a little bit hard to -- okay, go ahead.

I think it's povorcitinib in comparison to dupi and nemo.

Yes, how -- yes, if approved, how would you use it in comparison with dupi and nemo.

Yes, it's a great question. So this is actually evolving because there's very few of us that are experts in this area, and we're actually going to be discussing this in our prurigo nodular symposium later today at 4:30 in person, where we will review all the trial data. So it looks like if you look objectively at the data, the dupilumab data, the improvement in itch is delayed and more so in PN than in atopic dermatitis. And in some patients, it can take a very long time. Looking at nemolizumab's data, the itch response appears to be much faster. But in both trials, if you look at the percentage of patients that's hitting response, it's still a significant subset of patients. They're early on that are not meeting the metrics. So 40% to 50% of patients are not meeting that 4-point improvement. And when you factor in that patients don't want a 4-point improvement, they want it all gone, then what I predict is -- and I'm leading other experts to help define what are our treatment goals with patients. We're doing this right now. But I think you're going to have to have a shared decision-making with patients and ask them what is most important to them and then let them decide. But if you ask patients, they will likely be prioritizing depth and speed of itch response, in this condition more than any other condition on earth. Patients, I've never had a patient refuse thalidomide for PN. And I tell them they could have a thromboembolism then die. And I haven't had a patient refuse it because living with this disease is almost not worth living. So I think if you actually factor that in, there will be very high uptake of this drug if we actually count some patients the correct way and let them make the decision, which is what I always do.

Do you want to address the contrast with nemolizumab or capture there?

Yes. Yes. So contrast with nemolizumab. Nemolizumab also looks fast, in a few days and good response. But if you look at the early data as well, especially at that week 16 metric, you still have 40%, 50% that are not meeting it. My suspicion here is that it's not necessarily overlapping. So I spoke in the JAK inhibitor section and showed that a patient who doesn't respond to dupilumab might respond to a lower dose of a JAK inhibitor. And I suspect the same thing would be happening here, where a patient who doesn't respond to nemolizumab and dupilumab, which are primarily type 2 cytokines would have a great chance of responding to povorcitinib. And our lab, in particular, has shown a very strong role in issuing the 4, 13 and 31 for IL-22, and the other one is interferon gamma. And we actually did one study published in Frontiers in medicine, you can look it up. And we decided to take out race, ethnicity, gender as covariables, so we took PN patients and atopic derm patients, black females in both groups, and we compared their transcriptomics. And the signals were for JAK1, in particular, interferon gamma as well. And the third thing is that there's a big signal in our data that we have for matrix metalloproteinases. We also did a for single cell -- one of the -- for single cell RNA-Seq studies here and found -- and in the bloodstream and in the skin a role for matrix metalloproteinases. And we believe that JAK1 is able to modulate those MMPs, and that could probably explain the nodule resolution because this is very significant nodule resolution that we're seeing here as well. That number was 50% at week 16 is almost unfathomable. When I saw the data the first time, I didn't -- I wanted to double-check it to make sure that there was not a statistical error, and there wasn't. But I had to double-check it. It was that good.

Good to know. Thank you.

The next question today is coming from Vikram Purohit from Morgan Stanley.

This is Gospel on for Vikram. We have 2 questions for the Incyte team. How many tubes per year would you expect the average HS patient to walk through? And how would you compare and contrast this -- first, the duration you are currently observing for Opzelura in AD and vitiligo? And the second question is, how would you expect rux cream to be used by HS patient clinically or episodically?

Did you get the first one? The second one is about how will we use rux cream in HS, whether it's acutely or chronically? Can we get the first one?

Actually turn to Dr. Porter and have her provide her clinical judgment.

Yes. So for -- one of the effective topical creams that is compounded is something called resorcinol. They actually use it daily. And then when they have a flare, they increase the application to twice daily. And this is what I would anticipate something used chronically for suppression because I actually think that's probably what maintains clearance. But what -- but for areas that are unlikely to be affected, like the patient may only have 1 lesion in the [indiscernible] every 4 months because patients have had the disease for years. So they kind of know which sites are always the ones prone to be active. Those would probably be treated chronically. And then for some sites that are only active like intermittently that they know of, they'd probably treat them actively at the time tapered down to like a more chronic treatment and then taper off and then wait again to use it so they have intermittent breaks.

[indiscernible].

No, I think that covers both parts.

Okay, great.

The next question is coming from Brian Abrahams from RBC Capital Markets.

This is Nevin on for Brian. Just a couple of questions from us as well on prurigo nodularis. So with the PN study, we're kind of seeing these itch improvements quite quickly at week 4 at the highest dose. And then we kind of see this deepening of response with the IGA as kind of time -- as time goes on. Is there any potential -- the improvement in itch potentially driving some of the reduction that we're seeing in the nodule size? Or do you think that, that might be something that's more due to a chronic use of JAK over time? And then my second question is when you use dupilumab in practice, how long do you typically use that before kind of considering utilizing it separate or different therapy?

That's it? Okay.

Yes. I think I got those questions. So the first question is about the tremendous itch response and also the IGA response. I believe the activity of the JAK1 inhibitor is obviously directly on itch. But also, I think there's a direct effect on fibroblast biology. We have a paper that just published. You can look at that, that will give you more information about single-cell RNA sequencing in prurigo nodularis. But the fibroblasts are very dysregulated subpopulation that we've been studying, and there's a lot of JAK1-related cytokines that we believe are propagating these abnormal species. So I actually think it's through the itch, you're having less nodules and you see that also with other agents, nemolizumab and dupilumab, but there's also cytokines, JAK1-specific cytokines I also believe that are propagating this fibrosis. And there's a story that's waiting to be told with the matrix, the MMPs, the matrix metalloproteinases and the connection with the JAK1s. So our labs are studying that. I know that's something we're going to look at with this data cut too, but I believe there's independent effects on the nodules.

The second one was how long do you use dupi before you decide whether it works.

Yes. So I'll -- right now, dupi is the only FDA-approved agent. So I started immediately and give topicals also, and I personally have had so many patients had a little bit of a slower response that I look at the percentage of circulating blood eosinophils and IgE. And what I found in my personal experience is that those are both high, that's a rough biomarker for type 2 inflammation. And actually, in our lab, we found correlates well to TARC and other circulating blood markers. So if those are both high, my personal experience then there, disease gets better a little bit quicker. But if they're not, which is not in a good subset of patients, then they really suffer. So I sometimes will prescribe it alone, but I've got in the habit now of actually sometimes doing methotrexate along with dupilumab first line together right now and then having them come back and then trying to taper the methotrexate. And sometimes, to be honest, I'm doing dupilumab, methotrexate and phototherapy to start. And I still struggle, so then I do dupilumab, methotrexate, phototherapy and I do intramuscular steroids. That's kind of where we really are. Yes. Unless they are like very rich for type 2 inflammation, that's the truth of what we're doing.

Our next question is coming from David Lebowitz from Citi.

I had a question on the HiSCR, which has traditionally been the registrational endpoint for HS. Given that you're pursuing a milder overall disease, what type of adaptations might be made to the score? And has there been any dialogue with the agency on what the score might look like?

Yes. Before I give it to Dr. Porter to address that, we will have a conversation with FDA on the results of the mild to moderate study. And we will make a decision on those endpoints after consultation with them, but it will be interesting to get your perspective, Dr. Porter.

Yes. I think -- let me go back and explain HiSCR. So when HiSCR first came in, it was validated through the pioneer studies. And actually, it was the regulatory body to require the addition of the abscess and the draining tunnel criteria. So originally, they were planning to just do a 50% reduction in AN count, but -- or lesion count overall. But the regulatory bodies told them that they needed to account for essentially switching. So in the sense that a patient could have started with 5 abscesses and nodules and then transform to like 2 draining tunnels, which they perceive to be worse. And so they wanted to make sure that there was no ability to kind of hide these patients who had similar or fewer lesions, but the lesion types are now worse. In actual practice, if you look at the -- I think it was the lutikizumab trial, just that came out. They use something called simplified HiSCR where they took away, I can't remember now off the top of my head if it was at no increase in abscesses or been no increase in draining tunnel criteria. And the data was identical between the HiSCR and the simplified HiSCR. So the other thing is that for patients who need to demonstrate 50% improvement for HiSCR, there's more and more studies that suggest you have to have 5 or more lesions. And in this dataset, too, I think if you have 5 or more, it's possible to achieve 50% improvement. It's just those patients that have fewer than 5 that you're really -- if you use 50% as a benchmark, the placebo rate for them is quite high. And the bar for improvement is also quite high because if you go any higher than 50, you have to achieve clearance and we're really not seeing patients get clear and remain clear for all times or any drugs at this point in time. So it's something that I think we'll still be discussing.

Indeed. Thank you.

The next question is coming from Tazeen Ahmad from Bank of America.

I guess based on the physician's comments about faster onset of action observed relative to, let's say, Dupixent, do you think -- and this is a question for Incyte, do you think it makes sense to run a trial head-to-head versus dupi? And then secondly, as you think about both Opzelura and povorcitinib, how are you thinking about which indications you would want to pursue within dermatology and whether you might want to pursue both in the same indication as well?

So first, let me comment. I think what we're seeing in prurigo nodularis I was presented with Dr. Porter is consistent with what we've seen in other indications with povo and with rux cream, which is very fast onset of action, a lot of relief when it comes to itch and pain. And so we've seen that across the board, which I think it's ultimately going to be really important. Aside from registrational endpoint, it's going to be really important for patients for adoption, for use, the fast relief that patients get from these medicines. When it comes to future indications for both, I think we'll continue to discuss internally and with key opinion leaders such as those we have here today what additional indications we can pursue. I mean we're very excited about the data that we have with povo and rux cream. As you know, we have 3 pivotal readouts potentially in the next 3, 4 years with povo. So will we continue to add indications? Absolutely. We'll continue to take that into consideration. When it comes to specific comparator arms, I think those are always difficult decisions. We believe that when you put the data side by side at these randomized Phase II data with the Phase III data, we have a superior profile to dupi and prurigo nodularis. Whether we decide to go head-to-head will be a decision we'll make in the future.

The next question is coming from Kripa Devarakonda from Truist Securities.

I have a question for Dr. Porter. Thank you so much for talking about the mild to moderate disease and how you classify it. Just wondering if you can talk about the progression in patients from the mild reversion towards severe. What percentage of patients do you think progress? And do you think treatment with the appropriate medication at the earlier stages could actually help control or manage the progression of the disease? And you also talked about potential for combo therapies with topical rux. Given the comorbidities that some of these patients have, do you see any kind of restrictions because of that?

Thank you so much. So the question was first to ask you about...

So first was asking, I think Dr. Porter, about the mild HS patients and the use of Opzelura in rux cream in those patients and potentially with some of the comorbidities whether you have any concerns.

Yes. I mean I use combination therapy for the most severe patients where I use oral JAK inhibitors plus oral biologic agents. So from a safety profile, I actually -- obviously, topical ruxolitinib versus oral JAK inhibitors in general, the safety profiles are phenomenally different. We've seen that just -- I don't think there's going to be any problem with combining topical ruxolitinib other than from a payer who may not want to pay for 2 creams. But from a safety perspective, there's really none. And we're already doing -- I mean patients who use topical clindamycin, they use oral antibiotics, along with biologics and small molecules. This is just a fact of the matter for the disease itself. I can't remember what the first question was about.

It's really hard to hear. Can you repeat the first part of the question, please?

Yes, of course. I was wondering your treatment in the milder form of the disease earlier, stages of the disease can help control or prevent progression to more severe.

Yes. Sorry, you were very clear. It was just many questions came at once. This is actually, I think, one of the things that every single person that studies HS, invest in HS or treats HS wants to know is like which patients are going to progress and which ones are not and which factors determine progression, and what might actually prevent progression. And unfortunately, the answer is that nobody really knows at this time. There are a handful of patients who never progress despite having disease for years. So people don't start off at Hurley stage 1 and always go to Hurley stage 3. Probably half the patients with HS always start off with Hurley 1 and stay in the 1 to 2 category for their whole lives. And then there are some patients who slowly progress and others who chronic like just over 4 years progressed slowly. And others who explode like they have nothing and then 6 months later, there's stage 3. In terms of treatment that could actually modify or prevent progression, that's why a lot of the biologic companies are telling you right now that if you treat early and they have said that maybe IL-17 is active earlier in the disease and some of these other like B-cell components and targets are later on in the disease, but that's never been proved. And the fact of the matter is we don't know clinically or from any sort of biomarker, any sort of histology, like there's no data right now that's really well studied for progression.

Just to add one point about that from a different disease state, but I think it highlights what might be the future. So there was recently a study in atopic dermatitis that was done by Larry Eichenfield with crisaborole. And what they did in this study is they actually put it on just a few times a week as a preventative therapy. Yes, topical. Yes. No, no. But this study was with topical crisaborole. But what it showed is that if you use it on even normal appearing skin, there's subclinical inflammation and that actually prevented subsequent disease flares pretty significantly. And we know that crisaborole is not very potent. So my personal thing that I do with all patients is get them clear and then I instruct everyone to do twice a week because now we have a little bit of data across diseases. That's where I've moved, and I think that's where the field is moving.

And we don't have any studies like that in HS, but there are some ultrasound studies that I've looked at patients who have reported these intermittent like they have a "cyst" or they have a lesion that could be HS. And they use these very high-frequency ultrasounds, and they ultrasound over the area that clinically appears to be normal skin. And when they look, they actually see all of the hair follicles are already dilated, suggesting that these hair follicles are diseased, but they haven't clinically manifested the symptoms yet. And whether or not it's -- there's another like insinuating event that causes them to get inflamed separate from the swelling or the kind of like hyperkeratosis that causes this follicular dilation is not known because there's kind of a -- people don't know what comes first. But I definitely think that there's probably something underlying there that patients have this subclinical disease and can we detect it and can be treated at that point. And hopefully, we'll find something.

Our next question is coming from Jessica Fye from JPMorgan.

A few on povorcitinib and then a couple on Opzelura, please? First, for Dr. Kwatra on povorcitinib. How do you think about the safety profile here, specifically the serious treatment-emergent adverse events and the grade 3 plus treatment-emergent AEs? What were those? And I guess, overall, is the safety profile acceptable to you? And then while we're on povorcitinib, I think you mentioned that elevated blood eonosinophils predict response to dupi. Is that the case for other therapies too or thought to be the case? And with that in mind, I noticed that baseline demographics weren't broken out by treatment arm. Were the racial demographics balanced in this trial? And what about the other baseline demographics?

All right. Just I think the first one was for Dr. Kwatra about the safety profile and the prurigo nodularis with povo. So do you want to comment on this?

Sure. Yes. So the safety profile was good in this study. If you look at the AEs, headache, fatigue, nasopharyngitis, those are all consistent with what we'd expect. There was not a significant activity that we found in platelets, which is very significant. It actually highlights the JAK1 selectivity in my opinion as well. And to me, the most important thing, and I mentioned this earlier, is that 0 patients in the 75-milligram arm discontinued treatment. So to me, the safety profile here is very strong. And I would also comment that more broadly, we did a session on JAK inhibitors, Brett King and I, and we went deeply in depth on the Pfizer study with all dermatologists. And we talked about how in that study, you were over the age of 50 with rheumatoid arthritis on trexate in addition to a JAK inhibitor with a cardiovascular disease risk factor to have like 1 in 113 patients lead to an event. And so we're trying to put that in context better so our patients don't suffer. So I think people are getting that a little bit more versus just saying that there's a warning. We're going into it, the field is. And we're understanding and giving patients the context for that risk.

Jess, can you -- do you mind repeating the second question? I think there was second and third. it's hard to hear in the room.

Yes. It was on the elevated eosinophils, predicting response to dupi and whether we think that's the case for other therapies, given that I think you said that those are elevated more so in Caucasian and Asian patients. And so with that in mind, were the racial demographics balanced in the povorcitinib trial? And what about the other baseline demographics? Because it looks like the data is provided on a pooled basis.

Yes, that's a great question. So the -- all clinical trials right now have more Caucasian patients and less skin-of-color patients. So that's not unique to this trial, that's every trial. The HS trial had very high numbers of African-Americans actually higher than the population prevalence. So we're.

We're going crazy trying to get...

Yes. But there was no imbalances, but that's consistent with the dupilumab and nemo arms. For the elevated eosinophils, I mean, we just found it and this group in China just found it. So now we're trying to look at it. We have no idea with nemolizumab. But I will say, if you look at some of the AEs, you have -- you can see how the cookie is crumbling. So nemo, you have some AEs for eczematous events, either eczematous or eczema, it's a small percentage, it's managed by. But for dupi and [indiscernible] too, what we're seeing is there's an immune switching phenomena where then you're getting -- I have a few patients who have a [ story as a forum ] phenomena. We know about head and face neck dermatitis in our lab studying this. So what we think is IL-4 receptor alpha actually upregulates Th117 responses, which may actually harden some of those different pathways in PN patients. And then with nemo there may be very mild, but there may be some effect in subsets of patients with the eczematous derm as well. So we have some kind of insights into it. I would expect that you have very good efficacy in both groups with this molecule because we know it's IL-22 interferon gamma IL-6, and JAK1 hits all those. So that would be my hypothesis, but we'll look at it in the translational data.

Thank you.

Just to add, we will be sharing more details around the demographics, the full safety. Remember, this was the late-breaker session, limited in terms of time. But yes, we will be definitely sharing all of -- a lot more of the detail from the study in subsequent meetings.

And can I ask a couple on Opzelura?

Yes. Go ahead.

On the explanation of the different rates of dropout in the Opzelura arm not being explained by those with more nodules at baseline, is that to say that there were disproportionately high dropouts from the Opzelura arm versus placebo in the milder patients? And then what might explain that? And then secondly, for Opzelura and HS, it looks like the HiSCR didn't separate until week 16, and I'm curious about the time course of the AN50, 75, 90, et cetera, response criteria. Did those also not separate until week 16?

Well, sort of a heads like you were saying, we haven't cut all the data that way yet to -- so I don't know the answer about the separation for the AN50, 75, 90 by week. I can tell you for the dropout, let me just see, wait a sec here. Oh, there it is. Thanks. Yes. So the dropout was the same between the vehicle and the rux cream for the moderate patients, which we define in the 5 to 10 arm, and the delta there was different and it had a very similar pattern that we saw at week 8 where they were separating. The milder patients is where all of the dropout essentially occurred almost. And of those patients, some of them -- well, there was a big portion of them, 5 that were lost to follow-up, and all 5 of those patients were of the same racial demographic. And it wasn't clear why those patients dropped out. And it could be that they were not experiencing much improvement because they started out with only 3 or 4 lesions and their expectation was to be clear. And so I think it's a little bit difficult to really tease out with such a small dataset if these trends will carry forward to a larger trial. But also, I would say the other thing is, in this study, if you started as mild and you're only treating one area where you had those lesions and something pops up elsewhere, then you're artificially also seeing fewer changes because there's no way or, in my opinion, no expectation that treating an area at a distant site would have prevented those lesions from popping up elsewhere.

I think we have time for 1 or 2 more questions. Next question, please?

Our final question today is coming from Eva Privitera from TD Cowen.

Congrats on the data. So for Dr. Kwatra, looking at dupi and nemo Phase II, it looks like the placebo rate in povo's trial seems to be lower. What do you think could account for that? Anything about the patient characteristics?

The question is the placebo rates compared with the placebo rate in the dupi trial, the dupi Phase III trial.

Yes. No, I don't have a great explanation for that. I think there may be differences biologic versus oral as well. I think that might be. Do you guys have any other thoughts on that, Jim?

Yes. So you're always going to get some placebo response in every clinical trial. I mean it's amazing that Dupixent had such or [indiscernible] has such a high placebo rate, right, in their pivotal study. So in this study, you're right. We saw a lower response. But I think part of it is that we had very good clinical studies, good investigators who select their patients.

And I would also say that what's probably happening here is you have to look at the study population between studies very carefully. And for the dupi PRIME and PRIME2 study, there is a huge Asian component with 35% or so. And what we found is that the biology is very much so shifted towards type 2 inflammation in those patients. There's sky-high IgE and blood eosinophils as well, and that's a little bit different. And so many of the patients have already been treated, and the ones that are left and ready to go into a trial are also selecting for a more rigorous population. I can say that as being a trial site, the patients that are enrolling in this study are usually a hardened patient population that's less likely to respond to therapy. So that's why if you put these results in that context, in the real world, if you stack them up with some of the therapies, it may be even better because this is a hardened population that's had access to some of the therapeutics. That could explain it as well.

Yes. In terms of placebo rates in HS trials, we've done a lot of research in this because it's really been hampering, but the disease -- but the other things that we noticed are if you have a more severe patient at baseline population, it will always will be lower because it's less likely they're going to improve. The other thing is that if you have a more effective drug, the placebo rates also tend to be lower because you can -- as an investigator, they identify that one thing is working much better. And there's this expectation by us and it goes -- yes, because they're like now I can tell this patient is on the drug and this patient is on the placebo. And these are things that we see in HS and the drugs do not work. The placebo rates are much higher, and they should be the same. And this is part of it and then they see them in Phase III and the placebo rate.

Yes. And the best I'll say is startlingly obvious immediately, that patient was on drug.

We reached the end of our question-and-answer session. I'd like to turn the floor back over to management for any further or closing comments.

I just want to thank everyone for attending here and online. I hope we had time for all the questions that you had. We continue to be very excited about how the pipeline in dermatology is progressing, and we'll continue to update over the course of the year. Have a great week, everybody. Thank you.

Thank you. That does conclude today's teleconference and webcast. You may disconnect your line at this time, and have a wonderful day. We thank you for your participation today.

Thank you.