In part 3 of this Frontline Forum, Raj Chovatiya, MD, PhD; Neal D. Bhatia, MD; Alexandra K. Golant, MD; and Brett King, MD, PhD, discuss the rapidly changing use for JAK inhibitors and other agents for atopic dermatitis.
Chovatiya: There’s lots to unpack in what you said. I would highlight a couple of points. In the case of the orals, remember the indication, as written—even though this wasn’t how they were studied in the trials—was for individuals who didn’t have an adequate response to systemic therapies. So this includes biologics, and includes oral immunosuppressives, people on chronic prednisone, sure. So those are all people, theoretically, based on the actual indication statement, who would all be appropriate for an oral JAK inhibitor. I feel like in my practice, yes, [there are patients who]… have had biologic therapy with … dupilumab or tralokinumab who eventually went to a JAK inhibitor. … I really love this idea of redefining of what failure of any medication means, really, as opposed to just not [being] at the point that you want to be at in terms of response. I’ve had patients [who] we’ve transitioned from just standard oral therapies. I’ve had ones [who] have come in with chronic steroid use, every few years someone giving them the shot, someone giving them the oral, and they really didn’t want to do injections. They travel. Refrigeration is an issue and so the oral option for JAK inhibitors has been a good choice for them as well. In the case of some of those special populations, this gets into the really nitty-gritty as far as the labels go. At least in the United States, you’ve had axitinib approved for 12 [years] and older, abrocitinib approved for 18 [years] and older. In terms of guidance on individuals who are older, just because this is usually a small segment of any study group, they usually contain not warnings, but guidance, on the label, [saying] that we don’t have enough data to really make a conclusion. Often in older individuals, general comorbidities and thus general AEs tend to be higher. That’s not necessarily related to the drug itself, but that’s often…commented on the label. As far as pregnancy goes, we don’t always know because we don’t study things in pregnant patients. So the kind of guidance that’s usually given inside of these labels…cite murine studies to say what happened in mouse models; therefore, [that gives] guidance of whether or not this is something you want to use. In the case of the topicals, very similar wording is contained in these labels as well. Topical ruxolitinib, on the market right now, [is] approved for 12 [years] and older. In general…, the same kind of guidance across some of those special populations, and usually on label, because this is very narrowly the way that it was studied. Sometimes it’s a head scratcher what the FDA decides to do as far as indication statements go. Three percent to 20%, a reasonable area of topical treatment. I’m not always necessarily thinking about that, but I’m thinking about what’s practical for topical treatment, as mentioned. And then as far as the noncontinuous chronic use, this has everything to do with how, again, the drug was studied in the long run, where people used it as needed to control their disease.
Bhatia: This whole thing with the topicals having a warning is madness. You look at the data. You look at the absorption. You look at all of it. None of it gets to end organs. None of it causes any of the ruckus that we used to think about. But even more so, we used to give out prednisone like it was Halloween candy and we didn’t think twice about it.
Chovatiya: Used to?
Bhatia: And still do. And we talk about patients coming in just with steroids, bucketloads. It’s like, how is it possible that we’re worried about these other drugs which actually do something to the process of the disease vs all of this other stuff that’s been in the jargon and yet has all this consequence which we don’t think twice about. That’s what I don’t understand about our practice habits, which I think is crazy.
Chovatiya: Some thoughts, Allie?
Goland: When I think about the topicals, it feels almost commonplace....We’ve always had to acknowledge a boxed warning on our nonsteroidal agents, which were the topical calcineurin inhibitors before the topical JAK [inhibitors]. I find that [it] feels less new to patients, and it’s easier to contextualize, when you say, “This came from studies when this was ingested orally. It has nothing to do with topical use.” I am quite dismissive of it, just as I was with the topical calcineurin inhibitors. The oral agents, I think, require a little bit more of a nuanced dialogue to explain some of these things, but when done right, I think the conversation can be delivered effectively. And when the patient feels well informed, I have not found it to be a major roadblock.
Chovatiya: It’s good to hear the group’s thoughts, because when you actually dive deeper into the topical ruxolitinib data, about 6% of it was bioavailable in terms of the studies. Then the maximum-use studies [were looking]…at individuals who use crazy amounts for their 25% to 99% BSA. Then, you just take a look at somebody who’s been using that for a month vs…oral ruxolitinib. You don’t find any accumulation systemically and you also find that the levels that you can detect [are small]. The one thing I will say, boys and girls at home, is that with topicals, some [of the drug] is always absorbed, no matter the medication. If you think your topical steroids are not getting absorbed over time, you’re kidding yourself. That’s just generally how topicals work but—
Bhatia: I think what Alexandra said is when it’s done right. Getting into the blood should not make the headlines. This should not be a deterrent, doing what’s right for people. But we’re going to check blood at 4 weeks, [and] at 12 weeks, and then it’s off to the races… [I]t doesn’t have to be something that says, “Oh, this is so scary. We’re not going to do this.” And my laughing point to dermatologists is, “Well, if you’re not comfortable, somebody else will get comfortable and they’ll take your patients away,” and our scope of practice will continue to diminish. We’ll just end up being the pimple poppers and not actually treating patients with real disease. So we have to understand, this is not an obstacle of doing what’s right for people.
Chovatiya: And for those of you out there, acne is a real disease, but your point is well taken.
Chovatiya: To finish that last thought, even just taking a look at setting a baseline for what JAK to mean, an inhibition of bone marrow genesis would be, ruxolitinib after topical treatment for a month didn’t even get there in the maximum use study. So I think that’s the reason why we all feel pretty comfortable for its use in our populations. And …you’re hearing a lot of experience from clinicians here. Maybe we can start with you, Neal. What’s been your experience with the couple of oral JAK inhibitors we have in the United States, [and] the one topical, with your patients?
Bhatia: Well, first we got to see it come to fruition in research, which is great. Ruxolitinib was an oncology drug, which we’re fortunate to have in a topical form. And it does so much for AD but also vitiligo and everything else in between that’s coming. Where [we fit] axitinib and abrocitinib into practice should be where prednisone was. We shouldn’t have to even think about writing prednisone anymore, because the itch data for these patients getting better within days, what it does to the sprint of the process, what it does to, again, the next couple of months for patients. Even if with once a day pill for a lot of [patients] it may be a little bit of labor but to see how much better these patients get quickly is really a joy….We can take pride in [this] and say, “Look, this will be what gets you out of your own jail. This will stop you from staying up all night scratching, and get you out of the way of your own hands.” What we’ve seen now with the JAK inhibitors as a family gives us real potential for, again, not just treating the sprint but treating the marathon….We may deal with the paradigm one day where we say, “OK, put out the fire with JAK inhibitors and then switch them to shots,” and that will be OK. No one will say this is heresy. Let’s do this for 6 to 8 weeks while we’re transitioning over to shots for the next couple of years.
Chovatiya: You raise a lot of [points]. We don’t really know what we know until time comes into play, but there’s a lot of nodding around the table [right now]… I think that we all sort of agree that this has, in many ways, made dermatology fun for us…because you get to see amazing outcomes for individuals who otherwise would not have necessarily had what you were looking for after therapeutic intervention.
Bhatia: It’s the difference between providers and doctors, right?
Chovatiya: Yes, very much…We could all step our game up by just experiencing this in clinical practice…I encourage anyone…[to] try it out in your patients,...and you’ll find very quickly that the data that we’ve seen in trials mirror very well what you see in real practice. This could be a real game-changer for your patients.
[A couple of further] questions: How do you determine optimal dosing? Do you start with a package insert? Or do you do whatever the heck you please?
King: I’m a big fan of getting [a patient’s] disease under control as quickly as possible. I like the idea of following the package insert and starting with the lowest dose, and if an adequate response is not achieved, then escalating the dose. For me, watching patients not do well—watching them scratch, have a hard time going to sleep, or waking up from sleep at night—just doesn’t make sense. And so I prefer to move to the highest dose and rate, We’ve seen across the data sets that [within] 4 weeks, the majority of patients who are going to succeed will succeed, so you’ll learn quickly if you have somebody who will do well. I would much rather spend my time, or the patient’s time, figuring out what dose they need to continue to succeed, as opposed to watching them fail while I identify the people who need a higher dose.
Chovatiya: I think that’s a really good way to think about it. For those who may not be super-familiar with the way the indication statement is written, particularly for the oral JAK inhibitors, this is not how they were studied. This [can be] another one of those sort of head-scratchers, sometimes, the way this comes out. In the case of upadacitinib, the recommended starting dose is 15 mg once daily, and if an adequate response is not achieved, at the clinician’s discretion, moving up to 30 mg. In the case of abrocitinib, [the] starting [dose is] 100 mg, and if an adequate response is not achieved at 3 months, then moving up to 200 mg. I’ve actually been very pleasantly surprised in my practice that with the lower dose of the drug, it’s actually done a lot of the heavy lifting for my patients. It’s one of those circumstances where we all [assume] a lower [dose] must be bad, higher must be good. But it’s another one of those things that just comes with the experience of trying it and using it, like we talked about.
[Y]ou’ll understand and get comfortable in your population. But by and large, the number of folks who have really needed to maintain on the higher-level dosing for their AD continuously [is low],…and most of my folks do just fine the lower end of both of those oral medications…Can I ask Allie to stick her stamp on this, that when it comes to thinking about the individual patient and making an individualized plan, we know that it’s not a zero-sum game, that there are a lot of options, and there will be even more options over the course of the next decade for patients with AD? It’s about trying to [link] the patient with the right plan and the right medication. Can you can take me through your thoughts on the importance of really trying to individualize your care now that we have all of these options, both topical JAK and oral JAK, but just in general, other options?
Golant: Sure. As we do for any disease state, it’s important to understand who your patient is. And by that, I [include]: What are their comorbidities? Are they on any other significant medications that might pose an issue? Also, what motivates them, what are their major treatment goals? Do they have a life event, a wedding, a graduation, important photos [coming up, such] that they need to be clear in 4 weeks? Has their sleeping [been] destroyed and we need to give them something that’s very, very fast-acting? All of these things influence what you, I think, pull for first. What the JAKs do, or what the oral JAKs do, is really provide a level of itch relief. If we know there are data [showing that] just a couple of days after starting these drugs, [there can be] significant improvement, that is really unparalleled. So it’s important to know what motivates them. The ability to tell a patient, we’ll do this for a month or two and we’re going to know pretty quickly whether this is working for you, is very well received by patients. It feels very tangible. And all of those things, I think, come into play in terms of helping you decide what you start with. I always like to make it kind of a map for patients: These are our options, this is where I think we should start, but this is where we can go if we need to pivot.
Chovatiya: This is really where the doctoring in our job comes from: understanding everything we just talked about in terms of true data, understanding your safety, and then putting that in [a] package that not only will your patients understand, but then really allow you to select the right thing for them.
Bhatia: We cheerlead a lot when we’re trying to get patients on whatever therapy we think is best. But then they come in thinking, oh, no, this can’t happen, because I saw this on the internet. And again, the balancing act between Google and your medical degree is always going to be a paradigm. But at the same time, we have to sit there and understand the experience that they’ve been through, what they’ve heard, what they’ve seen, but also what they’ve tried and failed. Then [we have to] get them into the mindset of thinking, OK, this is an approach that’s going to take away what you think you know and get you to a place where you haven’t been yet. And that is maybe, for some, actually a little scary—and that’s OK.
[Edited for space and clarity]