Webinar: Managing Mild to Moderate Atopic Dermatitis

Explore evolving non-steroidal topical treatment options for mild-to-moderate atopic dermatitis in adult and pediatric patients. Faculty will discuss the role of topical JAK inhibition in itch relief and share considerations for identifying appropriate candidates for targeted topical therapy. 

This is a non-CME activity.

Moderator: Hello, and welcome to today's Allergy & Immunology Learning Network webinar. Today's presentation is Managing Mild to Moderate Atopic Dermatitis. This webinar is supported by Incyte. We're happy to have you join us today. The presentation will be followed by a question-and-answer session, so we encourage you to submit your questions to us throughout the webinar. At the end of the presentation, we'll try to answer as many of your questions as possible within the remaining time.

Today, we are pleased to welcome our featured speaker, Dr Greg Bensch. Dr Bensch is a board-certified specialist in allergy and immunology and internal medicine. He earned his medical degree from the University of North Carolina at Chapel Hill, where he also completed his residency, and later received advanced training in allergy and immunology at the National Jewish Medical and Research Center. Dr Bensch has been widely published in leading journals, including the Journal of Allergy and Clinical Immunology in Practice and Annals of Allergy, Asthma & Immunology. A recognized leader in his field and has held multiple leadership roles, including serving on the Board of Regents for the American College of Allergy, Asthma, and Immunology. We are very happy to have him join us today.

And with that, I will turn it over to our presenter, Dr Bensch.

Dr Bensch: Great. Thank you, Jenny. Welcome everybody. Good afternoon, good evening, depending on where you are. Thank you so much for taking the time to join us today. Today, I'm going to talk to you about the role of Opzelura in managing mild to moderate atopic dermatitis. It's really a wonderful time in atopic dermatitis after I think a long period where we really didn't have much advancement, and we really relied predominantly on topical steroids and calcineurin inhibitors. We really have a wide variety of new options available, much-needed options for our adults and children who have atopic dermatitis, a very, very common condition. This expanding treatment option includes Opzelura, a topical JAK inhibitor.

One thing I want to point out to you, big news here in the indication: you can see it has slightly changed. I'll run through it with you, but it's indicated for a topical, short-term, non-continuous, chronic treatment of mild to moderate atopic dermatitis in non-immune-compromised adult and pediatric patients. And here's the new part, now down to two years of age or older. So, we can use this now, even in our younger patients with atopic dermatitis, whose disease is not controlled with topical therapies or when those therapies are unavailable.

So that's our discussion today. This is a promotional program. Thank you to Incyte for sponsoring this. I'm speaking on their behalf and being compensated by them. I will be presenting information today that is consistent with the USA FDA rules and guidance for the FDA-approved label in Opzelura. We will have a Q&A at the end where I will answer any on-label questions. Of course, we will review important safety information. The full PI is available; usually, that's in the chat box. And we ask you to please refrain from taking any pictures. So those are a few housekeeping notes for you.

One thing I'd like to start off with, and we'll be going into further detail with you, is that I've already discussed the indication with you again. One thing I should note for you, in addition to atopic dermatitis two and up, it is also indicated for non-segmental vitiligo in patients 12 and up. We're not going to discuss vitiligo today. Other important safety information includes warnings regarding serious infections, mortality, malignancies, and major adverse cardiovascular events. We often refer to that as MACE and thrombosis. So, there's an interesting genesis to this ISI data, and I'm going to spend a little time later in the deck explaining why it's included in the label.

So Opzelura, let's first talk about just what atopic dermatitis is and how we think about its management. This is a terribly common chronic inflammatory skin disorder affecting literally millions of people in the US. If you look at the breakdown between children and adults, we have about five million children 18 and under, and you can see the vast majority of these have mild to moderate disease. 18 and up, we're looking at eight million adults. Again, most of these people have moderate to mild disease. Sadly, like many of these inflammatory conditions, the number of individuals affected by AD is continuing to grow. So, this isn't something that's getting better. It's not something we can cure. It's just more people, as type two inflammatory responses seem to become more prevalent. We continue to see even skin conditions like atopic dermatitis advancing in terms of the number of people affected.

It's a very complicated treatment regimen. It can be quite complex because it's often done in layers, and it's a huge burden for patients and their caregivers to manage complex treatment plans. That's why I personally like to try to keep the treatment plan as simple as possible and limit ... I get patients literally coming into the office with bags full of creams and it's easy to see why they're so confused about what they should be using, where they should be using it, how long you can use this one and how long you shouldn't use that one. You can see it's quite complex.

This is a chronic relapsing-remitting condition. So, patients kind of sit there waiting for, 'When am I going to have that next flare?' There's a lot of concern amongst them. When am I going to flare again? When's my child going to flare again? And they have people of all ages and ethnicities. I think we're all familiar with the presentation, typically a scaly, very pruritic. I think that's key. If a patient has a non-pruritic lesion, that would be unusual for atopic dermatitis, as it's usually quite pruritic. A lot of people will say, "This is the itch that gets a rash associated with it." It's typically erythematous, but that can look different based on skin pigmentation.

If I direct your attention to the person of color in the upper right corner, you can see that it doesn't look so much reddish; it has a more violaceous color. And you can even see pigmentary changes, dyspigmentation caused by the inflammation or possibly by some of the treatments they may have been using. And you get more chronic, longer-lasting lesions. We get what's called lichenification. And this is where these lesions become much thicker and deeper, and they can take longer to treat. All of this is more common in people with darker skin tones. It's also interesting where it is.

Typically, when we're dealing with infants and young children, the location tends to be more on the face and extensor surfaces, and as people age, they tend to find it more on the flexor surfaces or in the creases. And it's interesting: when I show you some of the pediatric trial data coming up, you'll see there's a lot more facial involvement in the pediatric patients, as you saw in the adult and adolescent trials.

So, really, treatment options are important. I think simplicity is important. I think about how long you can use it, possibly trying to find an agent that you can use anywhere, even in sensitive areas, for people of color and pediatric patients. So, all of these are important treatment options for this group of patients. So, we can really help these patients with newer treatment options such as Opzelura.

Now, when you talk to patients about atopic dermatitis and ask them about different symptoms they may have, you can see across the bottom axis here a variety of symptoms people experience with the disease. You can see that itching and scratching are by far and away the most burdensome symptoms. In fact, if you add up the dark blue and light blue, which are the most burdensome and the second most burdensome symptoms, 75% of patients are reporting itch as the top two most burdensome symptoms they're having. Dryness, scaling, inflammation, blistering, thickening, sores, pain, sleep disturbance, you can see that all are on the list, and some people find this bothersome more than others, but you can see nothing really ranks up there with itch. And I think that's why it's so important when we're thinking about treatment options that we really try to home in on options that are good at addressing itch and addressing it quickly.

Atopic dermatitis also often presents in our younger patients. I think that's why it's really nice that we can use Opzelura through age 2. And it's often the first event in the atopic march. For those allergists in the group I'm speaking to tonight, I think we're all aware that these children with atopic dermatitis, probably many of them may also have IgE-mediated food allergy. As they get older, a lot of times their atopic dermatitis and food allergy may wane, but these are our future allergic rhinitis patients, our allergic asthma patients. Some of them may even develop GI diseases such as eosinophilic esophagitis. Atopic dermatitis is often the first event we associate with the atopic march, and it's associated with a 1.5- to 3-fold greater risk of developing other atopic conditions later.

So, it's important to address this sort of barrier dysfunction early in the disease. And there's even some research being done on whether, if we do a good job of addressing this disease early on, we can change the progression of the march. We really don't know if that's true, but there is additional research looking into that barrier dysfunction, which is often initiated at the epidermis. So, we do have new and different treatment options, including JAK inhibitors. I want to talk to you a little bit about the pathophysiology of AD and how the MOA of a topical JAK inhibitor may help us in this disease.

So, when we think about the pathophysiology of AD, this cartoon I'm going to show you is sort of what we call the outside-in proposal. And that sort of means that things in the outside environment are interacting with the skin barrier. And typically, this barrier has sort of become what we call dysfunctional and almost more porous. The tight junctions between cells have become loosened. The cells themselves have become a bit more amorphous, making the barrier more permeable to external factors such as allergens and environmental stimuli. This can result in immune cell activation. So, the epidermis plays an active role in initiating immune activation. We used to think of the epidermis as purely a barrier, but it’s really an active immunologic player, and it produces epidermal-derived cytokines. One of the more predominant ones is TSLP, which can activate step two. And this is often initiated by dendritic cells, triggering a predominantly T2 inflammatory response.

Then you begin to see other familiar cytokines associated with T2 inflammation. This can include more TSLP, such as that released from the epidermis. IL-4 and IL-13 are certainly very important players in initiating this inflammatory response, resulting in feedback inflammation that further disrupts the barrier.

As we continue advancing this cartoon, we also want to highlight the role of IL-31. IL-31 is often referred to as the itch cytokine because it can activate non-histaminergic neurons and cause an itch response. What happens when you start itching? You're going to scratch, and that itch-scratch cycle further damages the skin barrier and continues to promote this feedback cycle, resulting in additional inflammation and worsening barrier dysfunction. I think the key takeaway here is I want you to recognize there's really a lot of different cytokines, TSLP, IL-4, IL-13, IL-31, that all really play an important role in the itching and the inflammation that's associated with atopic dermatitis.

So if we think about these various cytokines and what they cause as part of atopic dermatitis, we can kind of work our way across with IL-4, really promoting that type two cell differentiation, leading to more production of pro-inflammatory cytokines and also interrupting production of skin barrier proteins, resulting in worsening inflammation and worsening barrier dysfunction. IL-13 is also very, very important in promoting localized Th2 effects on the skin barrier, again driving more inflammation and more barrier dysfunction. IL-31, again, as I pointed out earlier on the prior slide, this is one of the key drivers of pruritus through those non-histaminic neurons. So important to interrupt that because these neurons tend to be insensitive to antihistamines, thus the name non-histaminergic. And so, IL-31 is important for itch.

And then there's our friend TSLP, which is really released up and down this inflammatory cascade. It's also thought to dry pruritus, and it really activates T-cells again, sort of promoting further cytokine production and more inflammation. So, really, all of these are important players. And I think that's one thing we've learned is that the better we are at really treating all these different inflammatory cytokines, the better results we'll often see in treating people with atopic dermatitis.

So how can a JAK inhibitor help this? So, if we look at the MOA of a JAK1/2 inhibitor such as ruxolitinib (Opzelura), we see that it inhibits the JAK-STAT intercellular signaling pathway. So, when these cytokines, again, IL-4, 13, 31, and TSLP, interact with their receptors, they often initiate an intercellular response through the JAK-STAT system. Opzelura competes with STAT for binding to JAK1 or JAK2, thus interrupting downstream signaling and, really, short-circuiting the inflammation that would be caused by any of these cytokines.

So again, you really have a broad anti-inflammatory response because we're not just targeting one or maybe two of these cytokines. We're really disrupting signaling for all four of these cytokines, which are thought to be very, very important and to contribute to itch and inflammation, which is, again, inherent to atopic dermatitis. So again, you can really think about the interruption of these JAK-STAT1/2 signaling pathways, which have broad downstream anti-inflammatory effects and reduce downstream itching.

So, this was tested in three trials now. I'm going to discuss TRuE-AD1 and 2, and TRuE-AD3, go through the design of these trials, and the results we've had in them. Go through some other phase two study data, and then, as we go through this, show you some real-world outcomes because I always believe pictures are worth a thousand words. So, we have a very similar design of TRuE-AD1, 2, and 3. As a matter of fact, TRuE-AD1 and TRuE-AD2 were the adult and adolescent trials. These were completely identical. So, if you look at the enrollment, there were approximately 1,249 patients in these trials, 12 and older. They had to have had atopic dermatitis for two years or longer, and they had to come in with an IGA score of either mild, so that'd be two or moderate at three. BSA had to be between three to 20%.

When you look at TRuE-AD3, very similar trial design, but they were looking at two- to 12-year-olds here. Because we're dealing with younger children, they only had to have a diagnosis of atopic dermatitis for three months or longer. The rest of it's really the same IGA of two or three, BSA between three and 20. They had to have an NRS score of four or higher if they were between six and 11. They did not look at that between two and five because it's really hard for a two to five-year-old to establish what an NRS score is at that very immature age.

The design was the same. So, they had an eight-week, double-blind period. So, there were two doses of ruxolitinib. There were 0.75% ruxolitinib cream BID, 1.5% ruxolitinib cream BID, vehicle, or placebo. At the end of the eight-week run-in, the vehicle group was randomized 1:1 to either the 0.75 ruxolitinib or Opzelura active treatment arm. And then, over the next 52 weeks, they entered a long-term, double-blind safety period. And here they rotated off and on treatment. So basically, when they were cleared, they did not use any treatment; they stopped it. When they had symptom recurrence, they re-initiated therapy with one of the two doses of ruxolitinib until they achieved clearance again, and then they stopped treatment.

So, this was real-world, just like what patients would do when they begin to have a flare-up, they initiate therapy. Once the flare-ups are controlled, they withdraw therapy. And what they were looking for as primary endpoints in all the trials were patients who achieved what we called treatment success, or IGA-TS. To be considered a treatment success, they had to achieve an IGA score of 0 (completely clear skin) or 1 (almost clear), and show at least a 2-point improvement from baseline. So, if they came in at an IGA of 2 or mild, they had to reach zero to be considered a treatment success. If they came in at a three, they had to reach either a zero or a one to be considered a treatment success.

Other key secondary endpoints included the proportion of patients who had an improvement in their daily itchy NRS score of 4 or more points. That's considered clinically significant by the FDA. And then they also examined the proportion of patients who achieved 75% or greater improvement in their EASI score. In TRuE-AD3, they again looked at the six-to-11-year-old age group who had a four-point or greater improvement in their daily itch score at week eight, day seven, and day three. Again, they did not look at that in the age range of two to five for the reasons I mentioned earlier. So again, similar design across TRuE-AD1, 2, and 3, a few caveats for the pediatric groups.

If you look at the patient demographics and characteristics, just to point out a huge difference, obviously, the age differences are inherent to these trials. You can see on the right that the mean BSA involvement for the call-out is very similar across the adult-adolescent trials and the pediatric trial, right around 10%. As I mentioned earlier, facial involvement is more common in children. That’s just a location. We see more facial involvement of AD in kids. So, you can see it was 64% in the pediatric trials versus 39% in the adult adolescent trials. Another call-out here is what their IGA was when they entered the trials. You can see that about three-quarters of these patients had an IGA score of 3, indicating moderate disease. Pretty much the same in all three trials. The remainder were moderate at two. So, sort of calling out the important differences here, itch scores were also similar at five and 6.7, as you can see on the bottom line.

Those were our baseline characteristics of these patients. Look at the primary endpoint results here. So, here's the adult adolescent data on the left, TRuE-AD1 and 2. This is pooled data from both trials, and you can see that, as early as week two, over a quarter of these patients are achieving treatment success by week four; that's up to 45%, and over 50% by week eight. So substantially better than the placebo group. And I think it's impressive what we saw at TRuE-AD3. Even in these younger patients, a very similar pattern. We saw as early as week two that 35% of patients were treatment successes, getting close to 50% by week four, and by week eight, we're over 50% at 56.5. By the end of these eight weeks, over half of the patients across all age groups had achieved treatment success. So, I think this is impressive data here.

What about EASI-75? So again, here on the left we have adults and adolescents. This is the proportion of patients who had an improvement in their EASI score of 75% or greater. And you can see that's broken out in TRuE-AD1, 62% of the active treatment group versus 24% of the vehicle group. And in TRuE-AD2, that was 61.8% greater than the 14.4 in the vehicle group. Pediatrics looks a little bit better. The active treatment group (67.2%) achieved a 75% improvement in their EASI score, while 15.4% of the placebo group did. So again, consistency across all trials and all age groups, with all patients on Opzelura, achieving a greater than 60% probability of reaching the EASI-75 threshold.

Now that's EASI-75. What if we even raise the bar a little bit higher and look for the proportion of patients at an EASI-90, so a 90% or greater improvement from baseline in this score? And you can see it's greater than 40% in all the treatment groups. TRuE-AD1 was 44.3, TRuE-AD2 was 43.4, and the TRuE-AD3 group was 43.5. That's amazing consistency. I mean, all within literally a fraction of a percent of each other. And when I see consistency in trials like that, that really means a lot to me. So again, more than 40% of people are hitting the EASI-90 score. Again, that's impressive because that's a really high bar.

Finally, what does all this look like, where, as I said, we're talking about a lot of numbers here? What about our patients? What do our patients see? So, this is an example of a patient from an actual clinical trial participant in the 3 trials. And you can see it's a two-year-old male. They're showing some pictures of some very bright highlighted exhibitus patches in the popliteal fossa here, and you can see they're an IGA of three at baseline. By week two, they're down to an IGA of zero. You can see quite quickly that the skin is completely cleared up, and then they continue out to week eight. And again, that skin remains quite clear. So, really, a very rapid, dramatic improvement of their skin, achieving an IGA of zero in this individual by as early as week two.

Here's another example. So, a very different patient here. Here we have a 33-year-old Black female. You can see these areas of hypopigmented, very pruritic exhibitus patches here on her arm. And so, this is a picture of her left arm. Her BSA was about 14%. She entered this trial with an IGA of 3. Here's a picture from week six. Not only do you see that these exhibitus patches have really cleared, but you can also see impressive improvement with these pigmentary changes, where the skin is much more even in color. So, I think that's also something, particularly in our patients with skin of color, that they are looking for is improvement in their pigmentary changes. So again, very nice improvement here as early as week six in this individual.

So finally, what about itch? I think this is important because what did I tell you at the beginning of the talk? I showed you that data from patients who had AD, and they said, "The thing that bothers me the most is itch. This is what I really want to get to. I want my skin to look nice. I want to look pretty, but I want to stop itching." So again, we consider a four-point or greater improvement in the itch score (NRS). And again, that's a score of zero, meaning I don't itch at all, one, which really means I'm barely itching at all, to 10, which really means I almost just want to rip my skin off, I'm so itchy. So, we think four represents clinically meaningful itch relief.

And if we look at TRuE-AD1 and TRuE-AD2, we can see 52.2% of people achieved improvement of NRS 4 or higher. And in TRuE-AD2, that was 50.7%, much greater than what you're seeing in either of the vehicle groups. Now, in a post-hoc analysis, they answered, I think a very important question was how many people got down to an NRS of either zero or one? Again, this is either no itching at all or a barely perceptible itch. And if you look at the Opzelura group here at study day one, they're at about 8.7%, by day two they're 19%, over 20 by day three, and you can continue that line continues to go up, and you hit 36% of patients were having almost zero to barely perceptible itch by the end of day seven. Pretty rapid, impressive relief of itching. Again, patients will be very, very, very pleased with these kinds of results. What's also, I think, probably the most impressive and I think the real standout thing with Opzelura is how fast we achieve itch relief.

SCRATCH-AD was a phase two open-label single-arm trial, 46 patients who looked at the effects of Opzelura on itch in adult patients with mild to moderate AD. So, these people came in, and they're looking at a mean change from their baseline mPP-NRS at day two. So, this is sort of the primary endpoint, but they did look at a secondary endpoint, and that was how much itch relief did you see almost immediately after use, within 15 minutes of application? And if you look here, you can see that blue line at 15 minutes. They're always seeing a greater than 2-point improvement in their mPP-NRS, with improvement sustained at 30 minutes out to 3 and out to an hour at 3.8. And you can see it continues to improve by hour 2 or 3.8, and then we're over the four-point threshold at hours 4 and 6 at 4.2.

So, this is really amazing. I mean, people can literally put Opzelura on and, within a matter of minutes, start to feel itch relief. I've even tried this in the office with samples with patients where I've asked them to put it on, come back, and checked in on them 15 to 30 minutes later, and it really confirms what I'm seeing in my office, with what I'm seeing here in this study, is that people's itch relief is extremely rapid. They really find it quite amazing. I think this is an interesting, very cool phase two trial that was performed.

Now, what about that long-term safety data? So again, these people then all went on open-label treatment, even if they were previously on just vehicle, or if they were already on Opzelura, they were kept on Opzelura. So that's the blue line, the people who are on Opzelura the whole time. The purple line shows the people who were switched from the placebo or vehicle to Opzelura. So, if we look at the left chart, the TRuE-AD1 and TRuE-AD2 pooled trial, you can see really in those first four weeks, there's a marked catch-up once the people in the vehicle group are moved over to Opzelura. They're pretty much completely caught up by week 24, and then you can follow those lines out to the end of the 52 weeks, and you can see that 74.1 of the vehicles in the Opzelura group and 77.8% of the on Opzelura to Opzelura achieved an IGA of zero or one. So again, over 70% by the end of the year.

Very similar picture here on the graph to the right. So TRuE-AD3, here we go. Again, most of that catch-up all occurs just in those first four weeks. You can see considerable overlap between the Opzelura and vehicle-to-Opzelura groups. And again, at the end of the 52 weeks, both treatment groups have over 72% of patients achieving an IGA score of 0 or 3. So over 70% of these patients in this trial had clear or almost clear skin, even with that intermittent or as-needed use of Opzelura about week 52. So again, very impressive results with skin clearance.

And what about time off therapy? This is important because people spend a lot of time caring for their skin, or, if they're a caregiver, their child's skin. So these people have intermittent flares. What did that 44-week period look like when they're intermittently off therapy? And when you look at the TruE-AD1 and tube pool data, they had 4.5 months when they were not doing any active treatment. That represented 44% of the 44-week period. If you look at the kids and what maybe they or their caregivers were going through, they saw five months off treatment.

So that means about half of that 44-week long-term treatment period, they were not on therapy. That's a big relief for our patients. It's also a big relief for their caregivers. One study conducted here found that a third of caregivers report spending 11 or more hours per week managing their patients' atopic dermatitis. Imagine if you got 11 hours of your work week back. That's almost like going from full-time to part-time. I mean, what a relief for these caregivers to get that time back. And not only are they relieved, but I’m also sure their children are much happier, too. So, kind of a win-win there.

Finally, here are some more pictures. So, another young male, an old male. Here are some eczematous patches in the left antecubital fossa. So, this patient came in with an IGA at three. You can see that at the baseline picture here, that thick red erythematous, some violaceous changes there in that left antecubital fossa, that sort of flexural area. And two weeks later, you can see they've improved to an IGA of 1, and pictorially, the skin is much, much less inflamed and much less crusted. Here they are at week eight. There's still an IGA of one. I look at pictures like this, and I go, "God, that looks like zero to me." But you must remember that the IGA is a global score, and we're only looking at pictures of the left antecubital fossa here. So, there might have been some very mildly perceptible diseases in other parts of the body. But again, I think it's impressive how quickly we saw this flexural eczema clear up in this young child.

Now, what about body surface area? So again, most of these people entered the trial at about 10% body surface involvement. And again, we have three groups here. We have continuous use for the first eight weeks, and here you see Opzelura in blue in the vehicle group. And then we enter the long-term treatment cycle, and that's where we have the gray bar. So, these are the people who move from vehicle to Opzelura. So again, you can see pretty rapid improvement in the left graft, TRuE-AD1 and 2, where again, they start off close to 10. By week two, it's down to 5.7, and BSA at the end of the eight weeks was down to 2.9, where you can see the vehicle group here is still 7.4.

Then they enter the open-label treatment section, and all are transferred to the vehicle for Opzelura. And again, you can see fairly rapid catch-up in the first four weeks, and you follow both of those lines out, both the dark blue and the gray line. And by the end of the trial, they have less than 2% BSA involvement. Very similar pattern and consistent in TRuE-AD3. Again, you see the Opzelura group down to 6% at week two, down to 2.9 at week eight, not much change in the vehicle group, but once they're switched over to Opzelura, they catch up quite quickly, and you can follow those lines out to the end of 52 weeks, and again, they are below 2% in both groups. This represented a 70% reduction in the mean BSA just after eight weeks of continuous use in patients to and older. So again, nice improvement in that, even in our younger patient groups. So, another win.

Now what about TEAEs? If we look at the 12+ group, here's the data through week 8 for all populations. So, we have both Opzelura and the vehicle group here. And this is the percent of patients reporting TEAEs and nasopharyngitis at the top of the list, with 3% of Opzelura versus vehicle at 1%. And then you go down the rest of the list, and you can see that 1% of the Opzelura patients had either bronchitis, an ear infection, increased EOs, urticaria, diarrhea, folliculitis, tonsillitis, or rhinorrhea. There were very low rates of any sort of application reaction, such as burning, at 0.8% with Opzelura. It's 4.4% with the vehicle. Pruritus was 0% with Opzelura and 2.4% with vehicle. This is also nice. It's not a steroid. There's no atrophy, no stria in either group, or discontinuation due to any of these AEs was very low compared with Opzelura. 8% of the Opzelura group had a discontinuation rate of 3.2%, compared with the vehicle group. So again, you can see that most of these TEAEs resulted in very few, very, very few cases of treatment discontinuation. And most people found the Opzelura to be more comfortable to use in the placebo.

If you look at the open-label treatment area, again, these are predominantly done for safety reasons. So, there is no comparator group, but again, you see a very similar list here. URI, nasopharyngitis, headache, bronchitis, influenza, rhinitis. So again, a lot of typical infectious-type processes that we see intermittently in the human population. Atopic dermatitis and asthma are also on this list. And again, even after they were continued out to 44 weeks, no atrophy or stress was noted. So, this is a really nice, I think very good safety data in our 12 and up population. What about our pediatric population?

So again, during the eight-week double-blinded period, you can see that upper respiratory tract infection rates are 15% with Opzelura versus 11% with the vehicle. These trials were conducted during the pandemic, so there were COVID reports in 5% of Opzelura 3% of the vehicle. And then you can see application site reactions: 5% and 2% pyrexia, and WBC decreased at both 2% and 0% due to the vehicle. Again, no atrophy or striata were reported in either group, and discontinued weights were also very low: 0.8% and 0% for Opzelura and vehicle, respectively. So again, very well tolerated in the pediatric population.

You look at the open-label section here out to week 52. Again, you see predominantly infectious processes at the top here: URI, nasopharyngitis, COVID-19, viral gastroenteritis, media, diarrhea, ear infections, pyrexia, and vomiting. Again, things you commonly see in the pediatric population. And then you can see a 2.6% or 4 of the rest of the list: application, site pain, asthma, headache, hypokalemia, impetigo, influenza, lymphopenia, molluscum, and neutropenia. So again, low rates of these other. Again, no atrophic stria reported at the end of the week, 44-week extension. So again, very, very well tolerated with these patients.

Now, remember, at the beginning of this, I did say, remember that sort of scary list of adverse events. Why does it say all that? Well, that comes from a post-marketing trial called ORAL, which is the oral rheumatoid arthritis surveillance trial. This was about Xeljanz (tofacitinib). This is an oral JAK inhibitor, and it was established that it did increase the risk of death, malignancy, MACE, and venous thromboembolism in rheumatoid arthritis patients 50 and older with increased cardiovascular risk. So, for those people who received Xeljanz plus methotrexate compared to those who received a TNF inhibitor with methotrexate.

So, I just want you to note this was with an oral agent. It was a different agent. It was not the same medicine that's in Opzelura, and it was in a much different patient group. These were patients with rheumatoid arthritis, 50 and older, who were also on methotrexate. Despite the differences, the FDA concluded that some JAK inhibitors indicated for the treatment of inflammatory conditions may have similar risks, which is why the US prescribing indication includes a boxed warning that should be considered when you're considering treatment with Opzelura. So, when we look at the Opzelura data, and we sort out the specific TEAEs that were noted in these trials, and we look at the Opzelura versus vehicle in TRuE-AD1, 2, and 3, you can see that across the top, and you see the event rates listed in 100 patient years. So, this would be the number of events that would occur in a hundred patient years, and you go down the list.

So, they would see 0.2 events in 100 patient years. So that's basically 1 in 2,000, opportunistic infections, TB, 0.0. Herpes zoster 1.1 and mortality at zero. So again, very low rates there. Malignancies and lymphoproliferative disorders, non-melanomatous skin cancers at 0.4, were really the only thing that showed up. In the vehicle group, you can see that other malignancies were 2.9. There were no major adverse cardiovascular events, attributable cardiovascular death, or MI. I'm sorry, there was 0.2 non-fatal CVA versus 0. And then if you look at pulmonary embolism, DVT also 0.2.

Of note in the pediatric trials, kind of zeros across the board, except for 0.9 events per 100 patient-years under serious infection. So again, very, very low rates. Really, of the things that were observed in the ORAL trial, you don't really see these sorts of same things when you evaluate the specific TAEs and compare them to the Opzelura TRuE-AD1, 2, and 3 data.

Okay. One more trial I want to show you, because I think this is an interesting way to look at efficacy. We always compared a vehicle, but what if we have an active comparator? So, this is a phase two double-blind trial looking at patients with adult AD. It was a dose-ranging trial predominantly for Opzelura. So, you can see various doses of ruxolitinib cream given either BID or QD. You can also see a placebo arm, and there was an arm here with one of the more commonly used topical corticosteroids. And that was 0.1% triamcinolone applied BID. So again, these were adult patients with a history of AD for two or more years, IGAs of two or three, and a BSA of three to 20. And they looked at a variety of primary and secondary endpoints here.

But I want to show you a couple of predominant primary endpoint results on this graph. And the first one looks at the EASI score. So, this was the mean improvement in their EASI score. And if you look at Opzelura, it was 71.6%, much higher than the vehicle, but compare it to triamcinolone. It was even better than triamcinolone at 59.8%. But what I think is impressive is the proportion of patients who saw an improvement in their NRS score of 4 or more. That was 62.5 of the Opzelura group, much higher than the vehicle group and almost double that of the triamcinolone group.

And that really comes back to what I was trying to impress upon you earlier is how effective Opzelura is at reducing itch in patients. You can see considerably greater than vehicle, but even considerably greater than triamcinolone, which many people consider the topical corticosteroid workhorse for atopic dermatitis. So again, no statistical comparison was made, but numerically, you can see a clear difference between these two treatments.

Okay. Another picture here, this is hand dermatitis. So, classically, a very difficult area to treat is a 20-year-old female. You can see these exhibitus plaques on her right dorsal area. She had about 2% BSA, and here's this patient at week four. So just in a month of therapy, that hand has really cleared up. I mean, it pretty much looks normal. And again, I think this is a nice picture to look at because hand dermatitis is notoriously difficult to treat.

Okay. Dosing and administration are quite easy. So, you apply a thin layer to the affected area up to 20% of BSA. You should not use more than 60 grams a week in adult adolescence. And for our smaller patients, ages 2 to 11, no more than 60 grams every two weeks. Patients and caregivers should wash their hands after applying, unless, of course, that’s the area you're treating. You want to apply it directly to mild to moderate AD lesions, and you would like to stop this once the AD has resolved. I always think it's a good idea to consider reexamining them if they're not improving with therapy. Maybe they even need a biopsy, making sure they don't have a cutaneous T-cell lymphoma that's mimicking their atopic dermatitis or something like that. So again, lack of response is kind of a red flag to me for further evaluation.

This is for topical use only. But again, this is what we're looking for. You can use this one product anywhere. So, it leads to treatment, even in sensitive and non-sensitive areas, so your patient doesn't need a bag of different creams. They can just count on one cream that they can safely use anywhere except in the eye, the mouth, or intravenously. It's very cosmetically comfortable. It's not greasy. Patients, particularly caregivers, appreciate that it's steroid-free. We do not want to use this or use an occlusive dressing over it. So, when patients do recur or have their next flare, you would want to restart therapy at BID or twice a day.

90% of commercial lines are covered. So key information when you're doing PAs, now two and older, mild to moderate AD, here's the ICD-10 code. Depending on your plan, you almost always must step through a topical corticosteroid. Some plans also require stepping through a topical calcineurin inhibitor. And remember, BSA is up to 20%. There is copay coverage for commercial insurance up to $0 per tube. And then there is also the Opzelura On Trac patient support program to help with PAs, PA denials, appeal processes, and all the support you would need to work. These are the network services provided.

Okay. Just to wrap up again, I want to go through the rest of the ISI data and point out some things as we go. As you'll see under serious infections, it refers to the ORAL trial. So, it says patients treated with oral JAK kinase inhibitors were at risk, and again, for the list of things reported earlier, including various infections. But again, it does specifically point out that it was from a different trial. Although it does say you should avoid using Opzelura in someone with a serious active infection.

Mortality, again, refers to the ORAL trial. The post-marketing ORAL trial observed a higher mortality rate. Malignancies have been reported in patients with Opzelura. They've been observed in other patients with JAK inhibitors in the ORAL trial. And so again, there are the warnings here, particularly for those who are past smokers.

MACE events, again, a reference here to RA trials, patients 50 and older. So again, that reference is noted in here, but it does say to discontinue Opzelura in patients who have had an MI or a stroke. Thromboembolic events were noted in trials with Opzelura. Again, another reference back to the ORAL trial. Cytopenias have been reported in clinical trials with Opzelura, although you don't need to monitor CBC. We would want to consider doing it if lipid treatment is clinically indicated. Lipid elevations have been noted with oral ruxolitinib. Other AEs, we've gone through a relist here for atopic dermatitis. In non-segmental vitiligo, you can see the AEs listed here as well.

And then finally, there is a pregnancy registry for any pregnant woman who is exposed to Opzelura. You can see the phone number listed here and the website, and it is advised for under-lactation for women not to breastfeed during use with Opzelura, and approximately four weeks after the last dose, that'd be five to six elimination half-lives.

All right. So just to wrap up here, this is a path relief and a fast relief. It's the first and only topical JAK we have for AD. It's indicated for short-term non-continuous treatment of mild to moderate AD adult patients two and older now. We saw phase three data showing powerful inflammation relief. Over 50% of patients achieved an IGS treatment success in week eight. We have the long-term treatment showing over 70% of patients with intermittent use of Opzelura at an IGA of 01 at week 52. We offer rapid, effective itch relief, with results as quick as 15 minutes. Again, truly impressive here. And then the most common AEs are seen at 1% or higher, listed here for age 12; a very similar list here at age 2.

So, with four years on the market now, we have 700,000 patients who have already been treated with Opzelura, so it’s really tried and true. A lot of patients have experience with this, and thank God, a lot of providers have experienced it out there. It's wonderful to have this as a treatment option for our patients with AD. And with that, think about this: where people who are desperate for rapid itch relief use it anywhere, even in sensitive areas, you may not want to use a topical steroid. People who are looking for extensive AD for control, but they're not interested in pursuing systemic therapy. And again, now available for even our youngsters, up to children and adolescents can use this product. All right. Well, thank you, everybody. I see it's 10 minutes to the hour, and I’m ready to take any questions from the audience.

Moderator: Well, that's perfect, Dr Bensch. Thank you so much for that wonderful presentation. If you do have a question for our speaker, this is a reminder that you can send it in via the question box on your screen, and we'll try to get to as many as we can in the remaining 9 or 10 minutes we have available.

With that, I think we can turn to our first question, Dr Bensch, in the long-term extension study, what does as-needed use mean?

Dr Bensch: So, what does " needed use " mean in the very real world? As long as the patient's symptoms remain clear, they continue to remain off therapy. When they came in for a follow-up and began developing new lesions, they would reinstitute Opzelura until lesion clearance. Once there was lesion clearance, they would discontinue Opzelura and remain on it until a lesion recurrence. So, as needed, I think the way they designed this trial would be very, very similar to what we would recommend for our patients in real life.

Moderator: And that's great to hear, that was reflective of that real-world use. So, thank you for explaining that definition.

Dr Bensch: Sure.

Moderator: The next question I have for you here, Dr Bensch, is how patients are directed to treat during the long-term extension?

Dr Bensch: I think that's similar to the first question, though. Is there a difference between the two? BID dosing.

Moderator: Yep. I think that makes sense. I think they're similar in terms of need and how patients were directed to treat. So that makes sense.

Dr Bensch: Yeah, it would be BID.

Moderator: You answered it with your first response.

Dr Bensch: Yeah, but I think the rest of its similar to my first response. I don't think I would change much, but again, I guess I didn't include BID dosing.

Moderator: Thank you for clarifying.

Dr Bensch: Sure.

Moderator: Moving on to a slightly different question. Of the data you presented, which do you feel is most compelling to your clinical practice?

Dr Bensch: The itch data, hands down. I mean, again, I think if you look at any atopic dermatitis quality of life studies, they consistently show people are desperate for rapid and effective itch relief. And I think that is also an area where Opzelura really, really shines, is that rapid ... It's the only medication out there that I've seen that has data up in 15 minutes, you're beginning to see reduction of itch. You can see a very, very effective number of patients achieve good itch relief. Again, I showed you that data. Just within that first week, over a third of patients reached an NRS of 0 or 1. That's no itch or barely perceptible itch. So, hands down, I think that's an easy question. Itch relief is what they're looking for, and Opzelura really delivers at a very high level.

Moderator: Wonderful. Thank you for that. Maybe a related patient-facing question for you. How do you review the boxed warning with your patients?

Dr Bensch: Exactly. Because I think it is a pretty scary label, and I think predominantly in the pediatric population, I think our caregivers are very, very careful, and that's why a lot of them are so steroid phobic. So, I think the first thing I do is I introduce them to the ORAL trial. I said, "Look, this data was ... " I described to them what the ORAL trial was. I described the patient population to them, how it's very different from who they are, and that it was treated with an oral agent for a different indication.

I also like to explain many things to them, including their topical corticosteroids. There are a lot of things in the label that are sort of blanket indications. I think there are a lot of things that if they read the label on their topical corticosteroid or their topical calcineurin inhibitor, they would also find very concerning. And I think for the TCSs, many people realize this is data derived from oral corticosteroids. And I'd say, look, we need to be aware of this warning data, but it was derived from a different patient population with a different drug administered systemically.

So, I don't want them to think that I just brush it aside and it's not important. I want them to understand where this came from and what kind of patients it came from. And then I go into the data, saying, when we looked at Opzelura and the events seen in these trials, they're very, very low rates. And I showed you that data as part of the talk, showing these sorts of adverse events in the clinical data with Opzelura.

And then I like to close my conversation by saying, "We've had this drug on the market for four years now. We literally have hundreds and hundreds and hundreds of thousands of people who have experienced use of this drug, and we're not seeing any of these sorts of things show up even years after this drug's been available and widely used." So, I know it's a little long-winded, but for those patients with that concern, I think you really need to kind of walk them through where it comes from. Did you see these sorts of things in the trial, and have they seen these things post-marketing?

Moderator: That's great. Thank you. And it's great to hear that you keep your patients so well-informed and up to date with all the information they need. Speaking of counseling patients, do you counsel them to apply a moisturizer over the Opzelura?

Dr Bensch: I do not. I do think moisturizer is important, but I don't moisturize on top of the Opzelura; I like to moisturize untreated skin.

Moderator: Excellent. Thank you. I think we have a couple more minutes remaining. So, if there are any other questions, don't hesitate to throw them in the box on your screen, and I can maybe ask you one more. Which patients are most appropriate for treatment with Opzelura?

Dr Bensch: Honestly, I think that's a great question. I'm going to give you a very open-ended answer. I mean, any of them. I think anybody two and up would find this a great treatment. Our young and older kids are all looking for rapid itch relief. Our adults want rapid itch relief. They want to be able to sleep at night. They want to perform well at school. They want to perform at work. That's what I love about this new indication, down to age two: we really have something you can use. You can make a simple treatment regimen for these patients. You can use it in sensitive areas, in patients with skin of color, and across a very wide age range. I like the flexibility we can really use this across the board with a wide variety of patients, of different ages and skin color, and regardless of where their lesions are located.

Moderator: That's great. Thank you.

Dr Bensch: I think it's particularly important in kids because so many kids have facial disease, where we really like to avoid topical steroids.

Moderator: Yeah, that makes a lot of sense. Since you mentioned the approval is now down to 2 years of age, maybe one more question with the time we have available is: are there any areas of the body where we cannot use Opzelura, even in children down to 2 years of age?

Dr Bensch: Right. So again, as I noted earlier, not in your eye, not in your mouth, and not intravaginally. But otherwise, anywhere else is fine.

Moderator: Excellent. Thank you.

Dr Bensch: Sure.

Moderator: Well, we're just about out of time, so we'll go ahead and wrap up for today. Again, we'd like to thank Incyte for sponsoring today's presentation, and I'd like to thank Dr Bensch again for that wonderful session. This webinar will be archived and available for online viewing soon at the Allergy & Immunology Learning Network under Webinars. Thanks again to all our attendees and our speaker, and we hope you have a great rest of your evening.

Dr Bensch: Thanks, everybody. Goodnight.