Updates in AD: Janus Kinase Inhibitors

Dr Bowers is a resident at Wake Forest School of Medicine in Winston-Salem, North Carolina.

Transcript

Melissa: Hello, everyone. I am Melissa, associate editor of The Dermatologist. In our Updates in Atopic Dermatitis podcast series, we will be covering the latest advances in the management of atopic dermatitis.

Today, I’ll be speaking with Dr Nathan Bowers about the latest research on the use of Janus kinase inhibitors for the treatment of AD. Dr Bowers is a resident at Wake Forest School of Medicine in Winston-Salem, North Carolina. Thank you for joining us today, Dr Bowers.

Dr Nathan Bowers: Thank you for having me.

Melissa: JAK inhibitors are an exciting new development for AD. Could you briefly discuss the JAK-STAT pathway and how it works in atopic dermatitis?

Dr Bowers: Yeah, absolutely. As we all know, atopic dermatitis is a complex inflammatory skin disease involving really multiple cytokines and signaling cascades. Many of these cytokines -- IL-4, IL-13, which drive type 2 inflammation, IL-31 and TSLP, which promote pruritus, and IL-22, which plays a role in skin barrier dysfunction and atopic dermatitis -- actually signal through the JAK-STAT pathway.

While all of these signal through different JAK pairs, they share a common one, which is JAK1. Thus, by targeting specifically JAK1, it’s possible to decrease signaling of key cytokines that drive, as I discussed, inflammation, itch, and skin barrier disruption in atopic dermatitis, making this an attractive pathway to target.

Melissa: What oral options have been investigated for treating atopic dermatitis?

Dr Bowers: There’s a couple that are going through various clinical trials, and I’ll discuss two of those in brief today. Baricitinib, which is a JAK1/2 inhibitor, and it’s Eli Lilly and Incyte’s inhibitor, is one of the oral options as far as JAK inhibitors.

In randomized, multicentered, double-blind, placebo-controlled phase III clinical trial, or the BREEZE-AD5 trial, they looked at the efficacy and safety of one milligram versus two milligram doses of this medication as monotherapy for moderate to severe atopic dermatitis in adult patients in North America.

The primary and secondary endpoints were reached by participants who received the two-milligram dose. As these patients an EZ75, they experienced clear or almost clear skin and achieved a minimum two-point improvement on the validated Investigator’s Global Assessment scale by week 16.

Overall, treatment was pretty well-tolerated, with the most common adverse events in this study being diarrhea, nasopharyngitis, and upper respiratory tract infections. Abrocitinab is another oral options. This is Pfizer’s medication.

It’s a second-generation JAK1 inhibitor. In the phase III trials, JADE-Mono1 and JADE-Mono2, they were able to meet the study’s primary endpoints, which was an Investigator’s Global Assessment score of clear or almost clear, and two-point greater improvement from baseline. Then also, a 75% or greater change in baseline of the EZ score.

Treatment was also pretty well-tolerated with this group, diarrhea being one of the more common side effects, as well as upper respiratory tract infections, headaches, and dermatitis. Importantly, GI upset was really the only side effect that was substantially reported, compared to the placebo group.

Melissa: Are there any topical options being developed for atopic dermatitis?

Dr Bowers: Yeah. When we talk about JAK inhibitors, that are a few that are under investigation as far as topical medications. Ruxolitinib, which is Incyte and Pfizer’s second-generation JAK1/2 inhibitor in a topical formulation.

There’s actually been a couple phase III studies, the TRuE AD1 and TRuE AD2 study, that were both randomized, double-blind, dose-ranging, vehicle-controlled phase III studies to evaluate the safety and efficacy of this topical medication, compared to placebo in patients with adult atopic dermatitis.

Both of these studies enrolled more than 600 patients, age greater than 12 years or equal to 12 years. Both of these trials actually met their primary endpoint of an IGA, or Investigator’s Global Assessment, treatment score of zero or one.

Zero being clear, or one being almost clear, with at least a two-point improvement from the baseline after eight weeks of treatment. They also reached some of the secondary endpoints, which included achieving an EZ score of greater than 75% at week eight, and then also a greater than four-point improvement in their H numerical rating score at week eight as well.

Then another topical that’s in phase II-III clinical trials is delgocitinib, which is Tory’s novel inhibitor. This one’s a little bit different in that it’s a pan-JAK inhibitor. In some of the initial randomized trials, one of which was a double-blind, vehicle-control study comparing the safety and efficacy of a topical 0.5% ointment to vehicle in patients with moderate to severe atopic dermatitis.

Patients receiving this had a significant effect and improvement on their baseline EZ score, compared to patients receiving only vehicle, with an improvement of 44% for the medication, versus 1.75% for placebo. Really, overall, these topical JAK inhibitors are tolerated fairly well.

Melissa: How will JAK inhibitors add to the arsenal for treating atopic dermatitis?

Dr Bowers: That’s a great question. I think for patients that have either failed therapy with topical steroids or tacrolimus or are concerned about some of the side effects associated with these medications, topical JAK inhibitors would be a great option.

In patients who need systemic therapy, I think JAK inhibitors will be a key component of our treatment algorithm, especially with those who have failed some of the more conventional therapies. I think, over time, we’re going to see it become one of the more first-line options, just like we have seen with Dupixent.

Melissa: What key takeaways about this new therapeutic option would you like to leave with our audience?

Dr Bowers: JAK inhibitors have really emerged as an effect therapeutic option to treat atopic dermatitis. As an upstream regulator for cytokines’ secretion and immune activation, these inhibitors inhibit really multiple immune pathways simultaneously, which makes them pretty attractive for the treatment of atopic dermatitis.

The JAK inhibitors discussed today, both the topic and systemic, demonstrate the ability to significantly reduce objective disease measures, so the EZ score and the IGA score, as well as subjective symptoms of itch.

Overall, they’re pretty well-tolerated. We talked about the most common side effects. I think it’s also important to note that there can be a dose-dependent neutropenia and thrombocytopenia, possible side effect due to the role of the JAK-STAT pathway in hematopoiesis.

Really, nevertheless, the JAK inhibitors, both topically and systemically, are exciting novel therapies for the treatment of moderate to severe atopic dermatitis.

Melissa: Do you have anything else you want to add?

Dr Bowers: I would just say there’s been a couple of studies when I’ve looked within the past few years looking at the public health burden of atopic dermatitis. They found that atopic dermatitis affects approximately 12% of children and 7.2% of adults in the US, and has a pretty significant economic burden of roughly $5 billion annually in both direct and indirect costs.

Really, a key component to reducing disease burden is the development of novel therapies such as these JAK inhibitors. I think it’s really a very exciting time to be in dermatology, as we continue to see the development of more targeted therapies.

I think it’s really changing the landscape, and in many ways, how we view disease pathogenesis as well as management. Really, most importantly, easing the burden of disease on our patients.

Melissa: Thank you for joining us.

Dr Bowers: Yeah, it was my pleasure. Thank you for having me.