Systemic JAK Inhibition in Atopic Dermatitis Care Strategies

EP: 1.The Pathophysiology of Atopic Dermatitis

EP: 2.Understanding Patient Presentations With Atopic Dermatitis

EP: 3.Persistent Atopic Dermatitis and Flare-ups

EP: 4.What is the Burden of Atopic Dermatitis?

EP: 5.Identifying Comorbidities Associated With Atopic Dermatitis

EP: 6.An Overview of JAK Inhibition in Atopic Dermatitis

EP: 7.Atopic Dermatitis: Clinical Trials With Topical Ruxolitinib

EP: 8.Topical JAK Inhibition in Atopic Dermatitis Care Strategies

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EP: 9.Systemic JAK Inhibition in Atopic Dermatitis Care Strategies

EP: 10.Concomitant Use of JAK Inhibitors in Atopic Dermatitis

EP: 11.Nonpharmacological Approaches to Managing Atopic Dermatitis

EP: 12.Atopic Dermatitis: Patient Factors in Selecting Therapy

EP: 13.Topical Calcineurin and PDE-4 Inhibitors in the Treatment of AD

EP: 14.Atopic Dermatitis: Systemic Therapy Armamentarium

EP: 15.When to Change Therapy for Atopic Dermatitis

EP: 16.Atopic Dermatitis: An Evolving Treatment Landscape

Transcript:

Lawrence Eichenfield, MD: Let’s move to systemic JAK inhibitors. I’ll do the honors on that. I’m going to do it moderately because you could go into great detail. Basically, there are 3 oral JAKs that are well developed and up for FDA review at the time we’re taping this. One is already approved in Europe. I’ll do it in order. I’m discuss baricitinib first and then abrocitinib and upadacitinib.

Baricitinib is a relatively selective JAK1/2 with moderate activity against type 2 and significantly less against type 3. Probably the important thing to know about baricitinib is that it’s 1 of the drugs, like upadacitinib, that’s already approved for another indication. Abrocitinib is the oral JAK inhibitor that’s being developed first for atopic dermatitis. The breadth of experience with the medicines are different depending on what their other uses have been.

Baricitinib does pretty well in terms of its clear or almost-clear rate, but probably not at the same efficacy level as we see with the other 2, abrocitinib and upadacitinib. That’s especially so in the US data, because there were variable doses studied. There were 1-, 2-, and 4-mg doses. Because of safety concerns with the 4-mg dose, the FDA didn’t want it developed in the United States. The development program was looking at the 2- and 1-mg doses, compared with Europe, where the EMA [European Medicines Agency] approved 4 mg. It’s a little different. I’m going to go through efficacy data together and then some of the adverse-effect profiles with the drugs as compounded.

Basically, the clear or almost-clear rate in baricitinib was around 14% to 17% at the higher dose and more like 11% with the lower dose that would be available in the United States. The clear or almost-clear rate isn’t quite as strong as it’s going to be with the oral JAK. It’s potentially head-to-head with dupilumab, but there hasn’t been a head-to-head report of baricitinib compared with dupilumab. There are also a lot of secondary data sets showing incredibly positive impact on quality of life and occupational issues with individuals, and it’s already being used in the hands of atopic dermatitis experts in Europe.

Abrocitinib is a new medication. It’s also being developed at higher and lower doses. It’s very quick. I’d say all the oral JAKs are quick in terms of impacting the subset of patients who respond well to it. At their 12-week data points, they basically had 2 parallel phase 3 studies. It was 38% and 44% of patients who made it to clear or almost clear. Upadacitinib, a drug that’s previously been approved for rheumatoid arthritis, like baricitinib, had even higher values of clear or almost clear. Different populations were studied, but in those studies, it was 52% and 62% at the higher dose and about 40% and 48% at the lower dose.

When we look at data sets, we tend to go with higher dose to look at the efficacy, and that’s where we sit. But in real-life practice, there may be trade-offs. Basically, it’s 3 drugs with variable efficacy, and less overall primary efficacy in terms of clear or almost clear. EASI [Eczema Area and Severity Index]–75 with baricitinib as compared with abrocitinib and upadacitinib was probably a little stronger, but each has its own pros and cons in terms of the adverse-effect profile.

I’m going to briefly mention that there are 2 head-to-head studies of an oral JAK with dupilumab, our only approved biologic agent. It was abrocitinib compared with dupilumab in what’s called the JADE COMPARE study. Depending on the data points and the time course you look at, it showed pretty comparable primary outcomes measures of clear or almost clear or EASI-75, but quicker with the oral JAK inhibitors compared with dupilumab. There was also the Heads Up study, which was upadacitinib vs dupilumab. They had about a 44% clear or almost clear with upadacitinib compared with 18% with dupilumab at week 16. There were secondary outcome measures that looked stronger to a degree from an efficacy standpoint for upadacitinib.

Let’s talk about some of the differences with the oral JAKs. The 2 oral JAKs that exist already require monitoring. They require blood testing. They have established labeling issues. If you look at baricitinib and upadacitinib labeling, there are concerns for serious infections, venous thrombosis, and major adverse cardiovascular events. Some of these weren’t seen in the clinical study program for atopic dermatitis, but the labels presumably have this incorporated into them. There’s concern about malignancy with extended use. They’re contraindicated in pregnancy. They’re going to require blood monitoring because they can have an impact on hematologic parameters.

Oral JAK inhibitors seem to have a significant herpes simplex zoster signal. When some of my colleagues are lecturing about oral JAKs, they say that they’re going to push older patients to get the zoster vaccination prior to initiation. And in patients with a significant history of oral herpes, they may be giving them antivirals prophylactically. There are also tolerance issues and acneiform eruptions with some of them. The tolerance issues, particularly headache, nausea, and vomiting, are especially seen at the higher doses with several of the drugs.

Not to be a Debbie Downer, because we’re still very excited. There are going to be patients with both the choice or an oral agent, the ability to use these for a few months at a time and then switch back to topicals. We’ll discuss where they might fit in. But there’s definitely an adverse-effect and tolerance profile that will require discussions with patients and considerations as we mix and match our medicines. Leon, I’d like your thoughts regarding the oral JAK. Let me start with a general question. What’s your sense of how you think they’re going to be placed in therapy?

Leon Kircik, MD: We have to take it from the safety perspective. You gave a very good summary of what to expect. One thing I have to say is that abrocitinib is lucky to not have the baggage from rheumatoid arthritis [RA], so we don’t know. The other thing is that when you look at the atopic dermatitis studies, either with upadacitinib or baricitinib, we don’t see the same safety profile as in patients with RA. That has to be a comfort zone for us in dermatology. It reminds me of going back to TNF [tumor necrosis factor]–alpha inhibitors in psoriasis. When you look at the TNF-alpha inhibitors in psoriasis, the package insert for RA has all the horrible things: fungal infections, tuberculosis, malignancies, and lymphomas. Still, adalimumab is the most commonly used biologic in psoriasis to date.

Lawrence Eichenfield, MD: Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to the e-newsletters to receive upcoming Peer Exchanges and other great content in your in-box. Thank you.

Transcript edited for clarity.