JAK Inhibitor Updates: Upadacitinib and the Level-Up Trial

The state of dermatology drug development has been accelerating at an unprecedented rate for the last half-decade, with a myriad of targeted and novel therapy breakthroughs achieved in both common chronic diseases—like atopic dermatitis and psoriasis—and previously under-treated and psychosocially-affecting skin disorders—like alopecia areata and vitiligo. Drug options are becoming more robust, more versatile, and more efficacious in in dermatology, and there’s little indication the pipeline will slow any time soon.

At the center of this incredible trend is the Janus kinase (JAK) inhibitor drug class—a selection of targeted agents already in development and US Food and Drug Administration (FDA)-approved for oral and topical use in a variety of dermatologic conditions, including each of the ones mentioned above.

In a recent interview with HCPLive, Editorial Advisory Board members Raj Chovatiya, MD, PhD, MSCI, assistant professor of dermatology at Nortwestern University Feinberg School of Medicine, and 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, provided a review on a handful of JAK inhibitors at the forefront of dermatology research, development, and real-world care.

After reviewing the status of ruxolitinib cream in their first segment,¹ Chovatiya and Eichenfield discussed promising new data for 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 16.²

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 upadicitinib—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.³ 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.

References

1. ^{Kunzmann K. JAK Inhibitor Updates: Ruxolitinib Cream for Pediatric, Adolescent Eczema. HCPLive. Published June 27, 2024. https://www.hcplive.com/view/jak-inhibitor-updates-ruxolitinib-cream-pediatric-adolescent-eczema}
2. ^{Silverberg JI, Bunick C, Hong C, et al. Efficacy and Safety of Upadacitinib vs Dupilumab in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis: Results of an Open-label, Efficacy Assessor-Blinded Head-to-Head Phase 3b/4 Study (Level Up). Abstract presented at Revolutionizing Atopic Dermatitis 2024. Chicago, Il. June 08-10, 2024.}
3. ^{Pine L. Upadacitinib Expands Indication to Pediatric Patients with pJIA, PsA. HCPLive. Published June 4, 2024. https://www.hcplive.com/view/upadacitinib-expands-indication-to-pediatric-patients-with-pjia-psa}