The JAK Inhibitors Changing Dermatology

Over the last 13 years, 10 separate therapies under the Janus kinase (JAK) inhibitor drug class have received US Food and Drug Administration (FDA) approval. These agents have predominately reached dermatologic indications, ranging from the more commonly chronic diseases (atopic dermatitis and psoriasis) to the cosmetic-affecting, difficult-to-treat conditions (alopecia areata and vitiligo).

Not only have many of these agents proven historically robust in their efficacy, but their limitations in care are, in many cases, still not yet defined. The last 5 years alone have seen a handful of novel treatment indications for patient populations who previously had no targeted treatment options for their skin diseases.

In a recent interview with HCPLive, a pair of the site’s Editorial Advisory Board members provided a comprehensive review of the state of JAK inhibitor research and development within dermatology. Our featured experts include:

• Raj Chovatiya, MD, PhD, MSCI, assistant professor of dermatology at Nortwestern University Feinberg School of Medicine.
• Lawrence E. Eichenfield, MD, vice chair of the department of dermatology at the University of California, San Diego School of Medicine and chief of pediatric and adolescent dermatology at Rady Children’s Hospital.

Here are Chovatiya and Eichenfield’s perspectives on the current state—and future developments—of the most exciting drug class in dermatology.

Ruxolitinib Cream (Opzelura)

HCPLive: The first subject is on ruxolitinib cream, with which there are ongoing clinical trials assessing an open-label, one-year regimen in adolescents with atopic dermatitis, as well as another assessing the overall efficacy and safety of the agent in children ≥2 to <12 years old.

What could be the utility of ruxolitinib cream in the management of pediatric and adolescent atopic dermatitis, relative to standard care for such eligible patients?

Eichenfield: I’ll start with my just clinical experiences and then the new data. So, we have topical ruxolitinib approved for ages 12 and older for both vitiligo and atopic dermatitis. It's incredibly helpful in clinical practice. And I use those phase 2 trials that did a head-to-head with triamcinolone cream over 4 weeks that showed it was a little bit stronger in our major outcome of measures, as compared to triamcinolone cream, which is really nice for giving a sense of how strong it is. I think it performs like that in clinical practice, where it's really useful.

Now we know they've completed the core studies, for atopic dermatitis down to age 2, with very similar robust efficacy results, with good tolerance, and after some peak trials that didn't show that much systemic absorption—with the caveat of being limited to 20% body surface area, which is how they did the phase 3 trials as well. So, I think with expanded indication for age, it'll be a useful adjunct. I think expanded non-steroidals are really important.

Chovatiya: You know, especially in that younger age group, this is where we start to run into those problems with topical steroids— whether it's actual fear, chronic use, limitations in terms of potency based on where you're going to be applying it. And thus, it's one of the reasons why we've all been after non-steroidals that can work fast, effectively and mimic what we want from a topical steroid. So, the fact that you're thinking about potency in the class of a topical steroid that doesn't necessarily have some of the limitations as far as application goes repetitively in certain sites—plus with good absorption data suggesting that some of the JAK side effects we'd worry about perhaps are not going to be a major issue—is sort of a win-win-win on all accounts when thinking about a drug that could work for this population.

Eichenfield: Lastly, I'll say that I think in the general dermatology community, what happened to be the first JAK which was approved for atopic dermatitis was our topical ruxolitinib. And there was a lot of hand-wringing about the class warning label. And most of us don't really deal with that too much when we're prescribing topical JAKs on-label for atopic dermatitis, because we don't really see big risks for that in clinical practice, or really in the expanded safety data set with topical ruxolitinib.

Chovatiya: It's been a pretty easy counseling point. It's not one that's really stopped use of the topical in the real world the way that which perhaps with the oral (option), there's a bit more discussion.

Upadacitinib (Rinvoq)

HCPLive: The Level-Up trial showed promising phase 3b/4 data comparing the JAK-1 inhibitor upadacitinib to the IL-4/13 inhibitor dupilumab. Upadacitinib was associated with significantly bettered patient rates of EASI 90 and itch scores at week 16.

What does this do for our appreciation of itch and skin clearance outcomes associated with either targeting drug? What more would you want to learn from head-to-head assessments of targeted therapies in atopic dermatitis?

Chovatiya: So, one of the big questions now that we have so many treatments has been, 'Exactly how do these things stack up with one another?' And we know from topline efficacy, we're really batting in the same ballpark. So, the question is, 'If we get really stringent with our endpoints and start thinking about not only the signs of disease, but the symptoms of disease— plus setting those at a high threshold, maybe getting people to the point of being almost clear and having nearly or no itch—do we start to differentiate amongst our therapeutic options?'

And so, this is what the Level-Up study was really trying to do: taking a look at the starter dose of upadacitinib—15 mg, with built-in criteria for moving up to 30 mg if people weren't getting to where they needed to 4 weeks in—and directly comparing it to dupilumab. So essentially, treating on-label the way you would in the real world, versus dupilumab, and setting a primary combined end point looking at both itch and lesional severity.

What the data showed is that this is when you really start to see a separation, where upadacitinib even at this lower dose outperformed dupilumab in this regard. I think for those of us that have been involved either in the studies or involved in actual, real-world use, it's not entirely surprising given that when you start setting some of these thresholds, it's really when the differentiating criteria for JAK inhibition compared to biologics. And I think that overall, I sense that it's going to be helpful for the marketplace and for prescribers who are maybe confused about what therapeutic choice they might make based on what they're looking for.

So, I think it's very helpful data. We're of course going to want to know a little bit more about when dose escalation happened for some folks in the trial, knowing that 15 mg is sometimes the dose you start at, and 30 mg is the one you jump to—what happens if you continually go through on 15 mg all the way? Does that perform in the same way, and then how does this fold over in the long run as well?

Eichenfield: I agree. I think it's helpful to have the data, but it goes along with our understanding that upadacitinib—along with abrocitinib—get a higher percent of patients to some more stringent endpoints than dupliumab, which is not taking away the utility of any of those 3 drugs and the decision making that goes on in relationship to that, because we have patients who are perfectly satisfied at their level of eczema and itch and others who aren't. But having the data to understand that under more stringent criteria to make it to essentially no itch, you may get higher in a population in that comparison study with one drug versus the other.

But it comes back to the decision making of which drug you may go to with the individual based upon a variety of factors—including their age, other comorbidities, what they've been treated with before, what they're going for in terms of level of clearance, what their most often and size of symptoms are. All of that comes into the in real clinical practice discussions with our patients, and in my case, in pediatrics.

Chovatiya: I’ll add one point too that if the lasting legacy of this is people start asking about lesional severity plus itch, that's a win—because we know that getting individuals to not focus on just the signs of disease but the symptoms is where we want to take the field. The fact that this end point of the study required both of those criteria to be checked is key, and I think that hopefully will get people thinking about, 'Okay, let me think about trying to ask my patients about how good can I get them in terms of their skin, but also what I want to see in terms of the major symptoms, of their condition.'

Eichenfield: And a different issue, but I'll give a little shout-out to upadacitinib that they also got recent approval down to age 2 for arthritis. In the sense of relative applicability of the drug, that would be off-label under 12 in the US, but from but the aspect of the use in other in other disease states, amongst other specialists, is certainly a history that's coming in there that helps us in our perspective on the medicines.

HCPLive: Upadacitinib, ruxolitinib and povorcitinib are also approaching late-stage data for the treatment of hidradenitis suppurativa. Combined with the advancement of IL-17 inhibitors for this patient population, we’re about to have a boom of targeted HS therapies. What do you value in treatment outcomes for this patient population, based on the available data from these agents?

Chovatiya: When it comes to thinking about hidradenitis suppurativa (HS), if there's one thing that we value, it's a drug that works and keeps working. The bar is still very low for this disease, because we just don't have the ability to, number 1: stop progression of disease in some patients, and number 2: really get them to a point where the symptoms and signs are not bothering your day-to-day life and the drug itself can keep them under longitude control. TNF (inhibitors) are an amazing advancement, but we all sense that in general at some point, it doesn't work as well for patients. IL-17 is the next step forward in that regard, and we've seen some really good, impressive, real-world uptake of secukinumab for a lot of these patients that have been waiting for something else. And from what the data is telling us so far, if you more completely blockade IL-17, particularly in the case of bimekizumab or even sonelokimab you start to be able to actually drive efficacy outcomes higher.

And take this with a grain of salt, because I'm sure as Larry would agree, we don't even know if we have the right outcome measures for hidradenitis suppurativa, which is why there's so many hits and misses. And the data itself is a bit messy—when you look at JAK inhibitors, for instance, they seem to be performing well in phase 2 trials—maybe not the levels you might expect for a broader target, but is this simply just because we're not measuring the right things?

Eichenfield: Yeah, and I'll be an annoying expert and say that it's a complex disease. But it's a complex disease from many standpoints. It's a complex disease because of the degree of desperation that patients with severe disease have. It's a complex disease because we're not moving to clear many patients. But it's also this complex mixture of inflammation, infection, occlusion, surgical approaches plus medical approaches in a population that's much more common than it used to be. There's some really fascinating evidence that looks at etiology—you know, a correlation with ultra-processed food and HS development, and this issue of how endocrine disruptors and microplastics may be impacting its development.

But we're excited to have new, potent anti-inflammatory agents to have in the armamentarium. There's lot of work to do going forward, because it is such an incredibly impactful disease in those who are moderately and more severely involved.

Baricitinib (Olumiant)

HCPLive: Baricitinib was approved for the treatment of severe alopecia areata in June 2022, and was more recently associated with continued hair regrowth benefit in responsive patients over 76 weeks in data presented at ADA 2024.

Two years into its rollout, what are our perspectives on the long-term utility and benefit of baracitinib?

Chovatiya: Alopecia areata has been fascinating because baricitinib has shown us a couple of things about the disease that we never expected. Number 1: the more severe your patient is, the less well they're probably going to do, especially when they're very severe—95 to 100% hair loss. S,o you'll want to treat as expediently as possible to get the best outcomes. Two: the longer that they seem to have the disease, the less likely they are to get full regrowth. And the baricitinib data has shown us that as well.

Eichenfield: Yeah, the length of disease in years, but also the length of the episode of alopecia impacts on the outcome.

Chovatiya: Great point, and that's been another learning from the studies. And, the fact that sometimes you can't make predictions 3, 6, 9, even 12 months into the actual trial of medication itself, as some people just respond way slower and later. And we're not used to being so patient in dermatology. Everything is like an 8-week situation, a 4-week situation—12 if we're feeling lucky. It's a really different type of visit now to get someone on one of these medications and understand that just because you're not seeing anything, this is really a very cheerleading-type situation, where you're not going to be making that many changes, because you just don't know if this individual is going to hit what they want to at 9, 12 weeks or beyond.

Eichenfield: And like lots of our inflammatory diseases, we have a sense of what we think the key pathogenic driver is, which we then morph over time, right? Because, let's be truthful: baricitinib is a JAK 1/2, then we have a JAK-3 attack. We know there's relative specificity, and then there's biologics that are being developed as well. So, we'll see what the most important target is, as we have more experience with different things that we've blocked.

Future Indications

HCPLive: What indicated uses are you most interested in seeing more data on for specific JAK inhibitors, and why?

Eichenfield: We're commonly in a situation where we're talking to each other and asking, what are the next inflammatory diseases we want to see? It ranges from like, severe granuloma annulare—with then the question of whether can a topical JAK help with mild granuloma annulare? Both like lichenoid dermatitis and lichen planus, and then other lichen conditions are definitely up there, with an expanded literature. Actually, at (the SDPA Summer 2024 Annual Meeting), Matt Zirwas, MD, listed every disease state—even though some of them have, like, 1 paper or 2 patients—with information on what you can treat with. And it's this expanded list, so we'll have to do more careful, controlled analysis of what works with each one.

But I do think there are a lot of inflammatory conditions. Lichen sclerosus is something we see across the ages, and I think that the potential topical JAK is ruxolitinib being studied for that as well—to sort of have a replacement after our topical corticosteroids. Those are conditions I think are well along the way of study and intervention.

Chovatiya: Yeah, I think that to add to the diseases we want to know more about—how about just different ways to use these JAK inhibitors in the real world? Whether it's in combination, whether it's not in continuous but intermittent, whether it is as a part of therapy that includes other systemic agents—these are questions that we have for some of our more severe patients, some of our patients that have flaring associated with diseases at different times.

And I don't liken it to a situation of prednisone and cyclosporine, but I think that many folks have wondered, 'Can JAK inhibitors potentially offer us long-term control in some cases, but also for people that need it, short-term control for a more acute situation?' And the answer may end up being 'yes,' but we're going to need more real-term data.

Eichenfield: And also, to potentially mix and match. You know, I really look forward to vitiligo where, instead of an induction regimen of dexamethasone that some people use... oral JAKs for 3, 4, or 6 months might work as a kickstart, and then shift over to the topical for maintenance. It might be more exciting for patients to undergo than chronic JAKs that they might need forever. These are issues that we'll face over time, but there's some promise there.

References

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