A panel of experts discuss JAK inhibitors and their potential impact on the management of atopic dermatitis.
Peter Lio, MD: Let’s move to 1 of the exciting new categories of treatment for atopic dermatitis that’s in development. Some of the agents are hopefully getting ready for launch. These are the JAK inhibitors, or Janus kinase inhibitors. Kristen, can you talk to us about these agents?
Kristen Demundo, PharmD: Absolutely. JAKs, as you said, stands for Janus kinases which are a family of protein tyrosine kinases that interact with cytokine receptors and are responsible for driving abnormal immune responses and are key components in many immune-mediated diseases, such as atopic dermatitis. JAK inhibitors are a promising new class of drugs, and their mechanism of action is unique in that they act to block off this overactive pathway of enzymes, which in turn leads to limited cytokine production, which reduces eczema symptoms, such as itch and inflammation.
The JAK family consists of 4 components: JAK1, JAK2, JAK3, and tyrosine kinase 2. The JAK inhibitors can target 1 or more of these components, which in turn improve symptoms and signs of atopic dermatitis. They work quickly to block nerve-itch signals, and they also have anti-inflammatory properties. The JAK inhibitors work at an immune system level and are able to broadly target several symptoms of this disease. They also target different combinations of kinases and have various mechanisms of action and safety profiles.
Peter Lio, MD: Excellent. It’s fascinating because while these are all in the same class, we know that there are probably some differences with each molecule, and that’s going to make it a little tricky. Not only do we have these 3 oral agents—abrocitinib, baricitinib, upadacitinib that are in late stage—but we also have a topical version, and this is ruxolitinib. Jamie, can you talk to us a little about how these compare in terms of safety, route of administration, and frequency of administration?
Jamie L. McConaha, PharmD, NCTTP, BCACP, CDE: Yes. One of the biggest differences, as you mentioned, is how they are applied or taken orally. Ruxolitinib, as you mentioned, is the topical 1; the other 3 are oral agents. All of these, although they’re not FDA approved for use, are showing very promising results in clinical trials. I’ll start with our topical agent, ruxolitinib. This 1 is a Janus kinase 1 and 2 inhibitor. In phase 3 trials, it was studied in adolescents and adults with mild to moderate atopic dermatitis. For the dosing, 1.5% cream, and that was applied twice daily.
In the study they were looking at scores on the Investigator Global Assessment, so looking at the skin to see how well the inflammation and things like that cleared up. We found significant statistic results that were better than placebo.
The next 1 we have abrocitinib. This 1 is a Janus kinase 1 inhibitor, also many phase 3 trials. The few that come to mind are the JADE Mono trials: JADE Mono-1, JADE Mono-2, and then JADE REGIMEN. All these were studied in adolescents and adults with moderate to severe atopic dermatitis. The interventions in these studies were the medication abrocitinib at a 100- or 200-mg dose that was taken once daily compared with placebo, looking for—on that Investigator Global Assessment—clear or almost-clear skin vs placebo. This was beginning at 2 to 4 weeks, quick in the grand scheme of things, seeing statistically significant results in both intervention groups over placebo.
Then we have baricitinib, another oral Janus kinase inhibitor. This 1 inhibitors JAK1 and JAK2. This 1 was studied in adult patients with moderate to severe atopic dermatitis. The interventions here with several dosages that were studied, so we had baricitinib 1 mg, 2 mg, and 4 mg, all compared with placebo, looking at similar types of outcome, looking for results on clear skin. Some of the studies with this 1 were a trial called BREEZE. There was BREEZE-AD1, BREEZE-AD2. Once again, it seemed that the higher dosages performed a little better, but all 3 intervention groups were statistically significant over placebo.
Our last 1 is upadacitinib, our last oral Janus kinase inhibitor. This is a JAK1 inhibitor studied in adolescents and adults with moderate to severe atopic dermatitis. We’re seeing a theme in this class of medications. Some of the studies, for example, were Measure Up 1 and Measure Up 2 trials. The doses studied were upadacitinib 15 mg and 30 mg. They were also studied in another trial of this medication, with a topical corticosteroid or just patients receiving placebo with topical corticosteroid. In all these studies that I’ve mentioned, we saw better results in the upadacitinib groups, in both strengths of medications.
Peter Lio, MD: Thank you. There’s a lot there, and these are a pretty exciting new category with a lot we have to learn about them. Shannon, can you tell us about some of the features of these JAK inhibitors that make them unique in the management of atopic dermatitis?
Shannon M. Rotolo, PharmD, BCPS: There will be more as we see final results from ongoing trials and hopefully some FDA approvals. Something that both my colleagues here have touched on is that some of those studies are happening in adolescent and adult patients, so we may have some limitations in terms of our ability use them in pediatric patients, which we referenced earlier was a really large population for this specific disease state. That’s something to keep in mind. There are some other things to consider that could potentially be limitations to using these agents widely. Before I get into that, 1 of the advantages when dupilumab came out was that it was a new drug on the market for specifically atopic dermatitis. With some of the JAK inhibitors, we have experience from other disease states. We know a little more about these medications and what to expect in terms of practical considerations and in terms of safety and monitoring. You can see variation in terms of the safety profile of medicines in different patient populations. We have a couple of things that we can preemptively expect or think about with this entire drug class before these even come to market for this disease state.
Specifically, some of the things we should be thinking about are patients with gastrointestinal disorders. There may be some limitation in terms of our ability to use these medications for that group. For patients with cardiac disease or specifically thromboembolic disease, there may be some limitations in terms of our ability to use these medications in that group. Those would be some different considerations than some of the other meds that we think about in atopic dermatitis.
We have a good snapshot from other disease states of what monitoring will need to look like, though, to ensure that we’re using these medications safely when we use them in our patients. That will probably include complete blood count with differential, which is critical to be monitoring in liver function tests for these specific drugs. It will be important to be monitoring lipid panels with this set of medication.
Peter Lio, MD: That’s fantastic, and that’s a lot. It brings us to the last point, which is if—hopefully when—these JAK inhibitors are approved, how are we going to fit these into our practice? In particular, how are we going to fit the topical JAK inhibitor into our modern approach to treating atopic dermatitis? This is the big question on everybody’s mind, and I have to be honest: I don’t know yet. First, the oral JAK inhibitors, because of their slightly different profile for safety and efficacy, seem like they’re very effective and are going to work very quickly, but the safety trade-off is a little different. They may be reserved for more severe patients who’ve tried and failed other aspects, maybe even some who’ve failed some of the biologic agents that maybe are not as powerful but a little safer in general.
For topical agents, it could be exciting because even though we have 3 agents—tacrolimus, pimecrolimus, and crisaborole—it would be nice to have another agent. The early evidence for ruxolitinib looks like it might be pretty powerful. That could potentially be the next step after steroids. Depending on that accessibility and some other considerations, maybe certain patients or in certain areas of the body, it could even supplant primary use of topical steroids. There are lots of things we have to learn and explore, and I for 1 am excited to be part of this because this is all new. Even though I’ve been focused on atopic dermatitis for more than a decade, we’ve never seen anything like this.
This transcript has been edited for clarity.