JAK Inhibitors: An Overview

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EP: 1.JAK Inhibitors: An Overview

EP: 2.Topical JAK Inhibitors for Atopic Dermatitis

EP: 3.Oral JAK Inhibitors for Atopic Dermatitis

EP: 4.JAK Inhibitors: Non-Responders and Safety Considerations

James Q. Del Rosso, DO: Hello, my name is Dr Jim Del Rosso, and I’m a dermatologist practicing in Las Vegas, Nevada. I’m the research director at JDR Dermatology Research in Las Vegas and a senior vice president of clinical research and strategic development at Advanced Dermatology and Cosmetic Surgery in Maitland, Florida. I’m quite involved with clinical research and the development of new agents in dermatology.

Today I have with me Dr Neal Bhatia, who we’ll get to in a moment, from San Diego. We’re going to be discussing Janus kinase [JAK]–STAT pathway and some therapeutic agents that we have. We have a new topical that has been FDA approved, topical ruxolitinib [Jakafi], for mild to moderate atopic dermatitis, which we’ll be talking about. Then we’ll also be discussing the oral Janus kinase inhibitors, 2 of which have recently been approved for moderate to severe atopic dermatitis, abrocitinib [Cibinqo] and upadacitinib [Rinvoq]. We’ll be talking more about that and some other concepts related to this particular area because it’s obviously a very hot topic.

We recognize that the Janus kinase enzymes are different enzymes that dimerize and interact with different receptors. There’s not just 1 Janus kinase enzyme or 1 or 2 cytokines that we’re trying to block. There’s a variety of effects that can be had depending on which Janus kinase enzymes are being inhibited. It does seem somewhat complicated, but as you study it more, it starts to make sense when you put the time into understanding it. When we look at a disease state like atopic dermatitis, there are certain cytokines we want to modulate, like interleukin-4; TSLP, thymic stromal lymphopoietin; interleukin-13; interleukin-31; and interferon gamma. When we look at inhibiting certain Janus kinases that can affect those different cytokines, that has a broader spectrum in terms of modulating the disease state, but it can also have more downsides because you’re inhibiting more downstream signaling. When we look at Janus kinase 1, for example, it’s involved with all those cytokines. Inhibiting Janus kinase 1 can certainly have an effect; Janus kinase 2, the majority of them; and interleukin-4, Janus kinase 3. But the agents that we’re going to be talking about and focusing on today are primarily Janus kinase 1 and in some cases Janus kinase 2.

Neal, introduce yourself. I know most people know you, but say a little about yourself. Can you expound on what I just mentioned?

Neal Bhatia, MD: That’s flattering, Jim. Thank you. I’m Neal Bhatia. I’m in San Diego [California]. I’m the director of clinical dermatology at therapeutics clinical research. Our practice is primarily clinical trials, but we also see regular patients. My background is in immunology, which makes talking about JAK inhibitors a lot of fun. You’re correct in your starting lineup. There are 4 major JAK proteins we talk about: 1, 2, 3, and tyrosine kinase 2. There’s also a splenic version that we don’t talk much about in dermatology. There are 7 STAT proteins that, with the right pairings and the right distribution, all lead to different signaling messages as well as the way that cytokine information is processed.

If you remember back to basic science, kinase is an enzyme that brings phosphorus into play. Basically, the simplest way of talking about the pathway is the donation of phosphorus that covers the 3 important steps: the dimerization of the receptor, the docking of the STAT protein to that dimerized receptor to receive cytokine information, and the passage of that JAK-STAT–bound protein to the nucleus for transcription. Those are 3 important spots for phosphorylation. But with that comes the pairings of everything else. As Jim referred to, JAK1 and JAK2 are playing some strong roles in the messages that go along with the atopic side, the Th2 side, and a lot of those important itch-mediating cytokines. Whereas we’re seeing some pairings between JAK1, and tyrosine kinase 2, or even a third pairing of JAK1, JAK2, and tyrosine kinase 2 in the psoriasis pathways for the affinity of interleukin-12 and interleukin-23.

The main combination of pathways we don’t deal with in dermatology are JAK2 paired with itself, which tends to be more involved in oncology and hematology disorders, including myelodysplastic disorders, myeloproliferation, and some other conditions. But the reason I bring this up is we have a lot of patients who will hear these stories and they’ll say, “JAK2 and JAK2 shouldn’t belong.” These are the things we want to make sure are part of the equation.

James Q. Del Rosso, DO: They talk about selectivity, and there are some selectivity issues, but these statements that something is JAK1 or an agent is a JAK2 inhibitor, or whatever the case may be, or Janus kinases are selective but not perfectly selective. There can be some crossover depending on which pathway you’re talking about.

Transcript edited for clarity.