JAK Inhibitor Therapies for Atopic Dermatitis

Linda Stein Gold, MD: Eric, I'm going to turn to you because this has been such an incredibly busy time for FDA [United States Food and Drug Administration] approvals for new therapy—especially JAK [Janus kinase] inhibitors for atopic dermatitis. We've had 3 of them recently. We have 2 oral agents. We have abrocitinib and upadacitinib, and we also have ruxolitinib, which is a topical JAK inhibitor. There's a lot of data. For those people who are looking at this and saying, help me to understand what this data means, what am I supposed to do with these? I want to just start talking about efficacy first, and we'll talk later about the box warnings that go along, but let's first have a conversation. Eric, talk to us about what the data shows us in terms of the efficacy of these agents. Are they different? Do you think about different ones for different patients? When would you pick a topical as opposed to an oral, and are there limitations? What are we making of the efficacy data?

Eric Simpson, MD, MCR: I'd make a global statement for all of them. The beauty is that you can push efficacy higher than we've ever seen both with a nonsteroidal topical and a systemic agent in this disease state. I want us to walk away with the understanding that these are powerful, effective therapies, and I'll give you some numbers here in a second, but that's like kind of a global perspective. Then in terms of, let's start with topical since we're kind of separating these patients to a certain degree between a topical patient versus systemic patient. I think it's easier to think about it that way. In the topical space, ruxolitinib is approved for patients aged 12 and older with mild to moderate atopic dermatitis. The FDA left the indication relatively open for us as clinicians. As long as they have failed kind of 1 topical therapy, it seems like from the indication they're eligible for this type of therapy. I lump it in the topical group, in the topical nonsteroidal. So I use it like I would tacrolimus, but what I think this brings to the table is a cream formulation, so a nonsteroidal cream. When you look at the phase 2 data, it's probably equal or better than a medium-potency topical steroid. Triamcinolone 0.1% cream—not ointment—was used in a phase 2 trial, and it showed numerically higher results in clearance rates at 4 and 8 weeks. We haven't seen that in our current nonsteroidal armamentarium. I think on the efficacy side, it's been a real godsend for patients who are failed by these other nonsteroidals or need relief from too much topical steroid use. I'd love to hear from my colleagues how they use it because this is all new, just like Ale said. That's why I'm really going to enjoy this conversation.

Linda Stein Gold, MD: In terms of having a nonsteroidal that actually works potentially as monotherapy, 1 of the things and 1 of the key benefits I see here is it’s almost like 1-stop shopping. Because as opposed to saying, OK, you have it on your face, you have it on your eyelid, you have it on your hands, you have it in some sensitive areas, you also have it on the tops of your hands and more difficult areas. You can potentially give a patient 1 agent as monotherapy and use it and just help to simplify that regimen....We want to be so good for our patients, but sometimes you end up with a list of things to do that can be so daunting for a patient. The older I get, the more I've been out, the more I realize, simplify it down. If you give somebody 1 thing to do, and you say, yeah, it's fine. Go ahead and use it there. The chance that they'll actually use it is a lot higher. Just you guys, in terms of topical ruxolitinib for atopic dermatitis, any thoughts here before we have Eric move on to the systemics?

Raj Chovatiya, MD, PhD: I think that what Eric said largely fits my clinical experience as well....You're talking about something that is at least medium to even high in terms of potency, in terms of comparison. In the phase 3 trials, we were looking at at least 40% of people with some type of head and neck involvement as well, so it's been tested in that population. I think that for my patients, it's a great, great choice, particularly since the indication includes up to 20% body surface area for people with a lot of site-specific disease. Individuals do have involvement of the genitals, body folds, even the hands in particular—obviously areas of the head, neck, and face—and so it’s great all across the board in those places. Additionally, it can't be overstated that sometimes patients just get turned off by the feel of a particular topical therapy. We've had disappointments in the past with nonsteroidals having issues with cutaneous side effects related to burning, stinging, and itching. The good news is if you follow the data from phase 2 and phase 3, largely patients tolerate it really well. If anything, the vehicle actually had more of a signal than the actual medication itself of any cutaneous side effects.

Linda Stein Gold, MD: That's such an important point because we think nonsteroidal irritation means it's going to burn; that it means that it's going to be a problem and you have to talk the patient through it. We don't see that local irritation. Ale, what about the itch? Do you notice that even with the topical, the itch really turns off?

Alexandra Golant, MD: Yes. A hallmark of our inhibitors seems to be speed of onset, and the same has applied to the topical use. If you look at the data from their phase 2 and phase 3 clinical trials, the itch improvement even with the topical happens within a matter of days. We've been using this now for almost 6 months, and that has really been what patients have been reporting. It is within days of when I've started using it. I felt less itchy or I felt less uncomfortable. I think Raj mentioned the tolerability, which is I think the game changer for so many of these patients who had tried the other nonsteroidals and associated them with the thought, oh, but I can't use them because I'm putting it on something that burns and stings and it made it worse. That has also been something that the feedback has been consistently positive about.

Linda Stein Gold, MD: Eric, we have 2 new orals.

Eric Simpson, MD, MCR: I'll just round out Raj and Ale....To the company's credit—looking at daily itch scores—you can see statistical differences as early as the first day, meaning within 12 hours of application. It goes back to some of the mechanism of action in that it probably at the beginning stops the signaling of itch in neurons directly, which uses a JAK protein to do that. That is a nice benefit. Then, in terms of clearance, it's about 50% or so who get almost clear within 4 to 8 weeks. Just to round out that efficacy data.

Raj Chovatiya, MD, PhD: I'd say that itch data actually fits exactly what I say to my patients. The first few times I prescribed that, patients messaged me saying within like a day or 2, I'm like the best I've ever felt. I was like, I don't believe it. Fine; whatever. That's wonderful. Then it started happening more than once so I was like, OK, I need to listen to these folks. Largely it's 1 of those situations where trial data has largely mirrored what I've seen in my patients as well.

Linda Stein Gold, MD: Raj, that's such an interesting point, because I run clinical trials, and it's always disappointing when you see clinical trial data and then you try it in your practice and you're, huh; I didn't see that, but it is true. The patients we saw in the clinical trials that, when you run a study, if you can tell the difference between those who are on the vehicle and those who are on the active, you know it's going to be a good drug. We saw pretty instantly, they were seeing a decrease in itch, which was for them just as delightful as seeing an improvement in the rash. Let's go back then and talk a little bit about how we make sense of the orals.

Eric Simpson, MD, MCR: In your patients who are systemic eligible, these are new FDA-approved oral therapy options for you. In terms of efficacy, I'll give you some rough numbers because they have like 8 trials each drug. I'll just try to set your expectations, but the percentages of patients who are getting almost clear are higher than we've ever seen, especially at the high dose. It's important to know that there is a dose-response relationship. If you use higher doses, you're getting almost clear at either week 12 or week 16—somewhere in the ballpark with abrocitinib of around 44%. With upadacitinib, there are studies of monotherapy—­meaning without topical steroids—getting up to 62% of people clear at week 16. These are not numbers we've seen before, and it makes you wonder as a clinician, is this something that's going to be better than, let's say, a biologic approach, dupilumab or methotrexate? We have head-to-head studies now, and we know that at the higher doses, depending on what point you look at, both systemic JAK inhibitors can beat dupilumab in efficacy at certain time points for certain domains. It's extremely helpful for us as clinicians to have that direct head-to-head data. Now, there may be some slight efficacy differences between the 2 with upadacitinib on paper and numerically looking a little bit higher on some of those end points than abrocitinib, but it's hard to tell the difference between those 2 drugs. We'll talk about some cosmetic, superficial, and some indication differences that are helpful. It's important for us to know as dermatologists that you have the power for higher efficacy if you need to go there for these patients.

Linda Stein Gold, MD: With each of these drugs, as you mentioned, there are 2 different doses. With upadacitinib, there's not a timeframe for going from the lower dose to the higher dose. Do you have a recommendation as to how long you should wait? We know that with abrocitinib, they recommend waiting the 12 weeks before we advance to the higher dose. What's your thought with upadacitinib? Do you have a thought there?

Eric Simpson, MD, MCR: It's important to note that the FDA states, at least in the US, that you start low and move high if needed for both. I would prefer the other way around, but that's the indication. Then, the question is: When can you move forward? For me, looking at both drugs, I don't see any reason why I would wait beyond a month. I know it's an indication so this is an off-label discussion, but when you look at the curves of people's improvement, it's 4 to 8 weeks when you really know maximum effect for 1 of the doses, so I don't see any medical reason why you would have to wait for 3 months for abrocitinib unless you're a conservative prescriber and you want to stick to indication no matter what. I would reevaluate patients either at 1 month or 3 months, whatever makes sense for their clinical situation, and then decide together if this is the time to move forward with a higher dose for a particular drug.

Linda Stein Gold, MD: Either of the other guys, thoughts on do you give the lower dose a longer period of time? You might start and say 3 months isn't a big enough trial. Maybe I want to go 4 months; maybe I want to go longer. Or do you feel comfortable with advancing to the higher dose because we might see better efficacy, but maybe an increase in the side effects as well? Raj, I'll start with you.

Raj Chovatiya, MD, PhD: Eric couldn't have put it better. The data around that 4-week time point between 4 and 8 is largely where you can make the best conclusions about that sort of exponential improvement that patients are going to experience. It’s not a topic we're talking about yet, but that's a good time point to have people back to talk about some of the lab monitoring and safety, in terms of when you'd expect to see that as well. It all fits around that sort of first month, and so that's largely what I would do in my practice. Much like Eric, for a while I was a little disappointed because I was thinking on-label and I was hoping we'd start high and go low. If we're going to be talking about how trials have now reflected the real world, my patients have done remarkably well on the lower dose—better than I probably thought they were going to do on the lower dose. This has been 1 of those circumstances where I've been pleasantly surprised about the fact that I haven't needed top-level dosing as much as I thought I would have in the very short time these have been on the market.

Linda Stein Gold, MD: Ale, do you have a thought there as to managing dosage for each patient?

Alexandra Golant, MD: I've been doing the exact same thing. I see these patients between week 4 and week 6, so it's corresponded nicely with just touching base, checking labs, and making sure that everybody is on track. The conversation that we were having around the topical JAK inhibitors bears out even more strongly when you're talking to patients on systemic JAK inhibitors in terms of speed of improvement just after the first dose or 2. Hearing about those very early stories and having the opportunity to touch base with you as their health care provider so early on is very reassuring and a good level set for patients and their providers.

Transcript Edited for Clarity