You’re listening to CME on ReachMD. This activity, titled “Late-Breaking Data in Moderate-to-Severe Atopic Dermatitis,” is part of the Conference to Clinic series and is provided by Med-IQ and supported by an educational grant from Pfizer.
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The presenter in this activity may reference unlabeled/unapproved off-label drug uses or products.
Disclosures for Dr. Eichenfield are as follows: Dr. Eichenfield serves as a consultant or is on advisory boards for: Almirall, Asana, Cutanea, Dermavant, DS Biopharma, Forte, Galderma Laboratories, L.P., Glenmark, Incyte Corporation, LEO Pharma, Inc., Lilly USA, LLC, L'Oreal, MatriSys Bioscience, Medimetriks/Otsuka America Pharmaceutical, Inc., MorphoSys, Novan, Novartis Pharmaceuticals Corporation, Ortho Dermatologics/Valeant Pharmaceuticals International, Inc., Pfizer, Inc., Regeneron Pharmaceuticals, Inc., Sanofi Genzyme
Dr. Eichenfield serves as an investigator for: AbbVie Inc., LEO Pharma, Inc., Regeneron Pharmaceuticals, Inc., Sanofi Genzyme
Since atopic dermatitis affects millions of adults and children alike, this chronic inflammatory skin condition has been the focus of much research. And now that new clinical trial data has been published, how will these findings impact the way we manage our patients with moderate-to-severe atopic dermatitis?
This is CME on ReachMD, and I’m your host, Dr. Jennifer Caudle. Here with me to review late-breaking data in the field of moderate-to-severe atopic dermatitis is Dr. Lawrence Eichenfield. Dr. Eichenfield is a Professor of Dermatology and Pediatrics, Vice Chair of the Department of Dermatology, and Chief of Pediatric and Adolescent Dermatology at the University of California, San Diego School of Medicine. Dr. Eichenfield, welcome to the program.
Thank you so much. My pleasure to be here.
To start us off, Dr. Eichenfield, what are the current challenges in moderate-to-severe atopic dermatitis? And why is there a need for novel targeted treatments, specifically systemic therapies?
First of all, moderate-to-severe atopic dermatitis is very common because atopic dermatitis is very common. We have a higher prevalence than we did decades ago. And while a lot of people project because atopic dermatitis is a disease that starts in young children and traditionally people are told that their child would outgrow it, they don’t recognize that there’s just more atopic dermatitis that persists and more atopic dermatitis that’s moderate-to-severe, so one of the first challenges is recognizing that there’s this big set of patients who could use better therapy. The other thing is that we’re in this relatively early stage in revolution and therapy for systemic therapy, so while there are some exciting new topical agents, the focus today is on newer systemic therapies. The reason why we call this a revolution is first to take a step back and where were we before we had newer agents.
So we do have the first targeted therapy that was approved in 2017—that’s dupilumab, an IL-4/13 blocker—but before 2017, there wasn’t a lot of use of systemic therapy for atopic dermatitis. The only approved drugs in the United States were corticosteroids, which were used systemically, either orally or by IM injections, but were not really advised by expert panels to be used. It was sort of rescue therapy but with lots of side effects and potential toxicities. Methotrexate and cyclosporin were also used but not used a lot. They weren’t approved, and there were significant side effects and toxicities. We then had the introduction of dupilumab, initially in adults only, then in adolescents, recently in children as well, and now we’re excited as well that we’re getting expansion of both newer biologics but also non-biologic and small molecule agents, including JAK inhibitors, giving us another set of agents that can really help us to control the disease.
Our consideration now from a patient perspective and a practitioner perspective is that we have a need for these systemic therapies because the disease can have such significant impact on the individual. The quality of life impact on atopic dermatitis is really tremendous. Patients have many comorbidities, the traditional atopic comorbidities which can include food allergy, allergic rhinoconjunctivitis, asthma. There are higher rates of depression and anxiety. There’s the physical aspect of rashes and itch and itch causing a lot of sleep disturbance. All of this tremendously impacts the individual. It impacts on school performance and work performance across the ages.
So we have this set of individuals who could use better therapy to minimize the impact of their disease, and I’m excited that we have these new drugs that are being developed that could help them to control them better.
So, what are the inflammatory pathways that are informing the clinical development of the new agents that are currently in late-stage development?
Really good question. There’s a variety of inflammatory mediators that are important in atopic dermatitis, and this is partially our perspective—I have to say, I think an empiric approach. We sort of figure we know which inflammatory mediators are important, but you really know when someone develops a drug that blocks them and then the drug works. We know that IL-4 and IL-13 are important Th2 cytokines, and we also know that IL-4 and IL-13 are pathways that could be targeted for therapy. I already mentioned dupilumab, an IL-4 and 13 blocker, but we also have 2 agents that are specific IL-13 blockers without blocking the IL-4 pathway that are also well on the way of study for atopic dermatitis. IL-22 is also a cytokine pathway that can be important, and IL-31 is an important pathway as well. IL-31 is considered the itch cytokine, and we have a biologic agent that targets that as well.
Another part of the inflammatory cascade that appears very important in atopic dermatitis is the JAK/STAT pathway. These pathways are very important in mediating inflammatory diseases, and these are definitely pathways that are being explored. There is a set of JAK inhibitors, some of them selectively different in terms of how they impact on that JAK/STAT pathway. There’s JAK1, 2, 3 and a TYK2 that mediate these inflammations. Then we have these different drugs that are being developed. But all these together are specific targets that people are looking at to try to mediate the inflammation of atopic dermatitis.
So, Dr. Eichenfield, earlier you spoke a bit about the challenges in managing moderate-to-severe atopic dermatitis and the inflammatory pathways that are informing the clinical development of new agents. So now let’s take a look at those new agents. What are the recent clinical trial data for targeted agents in late-stage development?
Okay, so a lot of data has come out in the last few months, so I’m going to try to emphasize the main points but go through a lot of data really quickly. First of all, dupilumab, big clinical update for that is that it’s now approved from 6–11 years of age based upon data sets that have been presented and now published by Amy Paller, et al. in a recent publication in the JAAD. These patients did very well. They were on 2 different dosing regimens—1 on a q4-week; 1 on a q2-week regimen. Their results looked quite good, if anything a little better, getting almost 70% of patients getting 75% better—that we call the EASI-75—a little better than the adults and way better than the adolescents in these clinical studies. The safety in these younger kids seems to be the same—conjunctivitis injection site reactions, no other worrisome abnormalities—so with this drug there’s no laboratory baseline work that needs to be done and no laboratory monitoring that’s necessary. Do be aware that if you’re prescribing, though, in the 6–11 age group, you have to be more careful that patients are up-to-date with their live vaccines because live vaccines aren’t supposed to be used. They haven’t been studied specifically, but they’re not supposed to be used with dupilumab. There’s also been some longer-term data sets in terms of the adults, so with extra years of experience, we look to see if there are emergent new safety signals. None so far, which is great information.
Let’s move over to new phase 3 data on JAK inhibitors. Abrocitinib, Phase 3 trials have been completed and published in JAMA by Silverberg, et al. This is a drug that’s specifically designed for atopic dermatitis. They had really robust outcome measures. The EASI-75 was 61% with a dose of 200 mg, only 10% in the placebo group. There was a rapid decrease in itch within 24 hours of treatment initiation. Now, there were some emergent adverse events—nausea, nasopharyngitis and headache at some of the higher doses, but impressive clinical results.
Baricitinib, we’ve also seen data on that published in the British Journal of Dermatology and presented recently. This is a drug that’s approved for rheumatoid arthritis. Their clear-ish rates were a little bit lower than some of the other JAKs. There’s 4 mg and 2 mg dosing that’s been studied elsewhere than in the U.S. The higher dose will probably not be approved in the U.S.—at least that’s my sense because they were not allowed to study it. A little nasopharyngitis and headaches seen in the population. In Europe, again, they were allowed to study the 4 mg dose for atopic dermatitis and in the U.S. 1–2 mg dose. But this is a drug that has experience. It’s approved in rheumatoid arthritis, and had some very nice data also presented on impact on work performance in some of the patient-reported outcomes. The patients were definitely sensing that it was very helpful for their disease state.
Upadacitinib is another JAK inhibitor that showed very potent results in Emma Guttman-Yassky’s data sets that have been presented. This is a drug that’s dosed 7.5, 15, and 30 mg, and they had efficacy endpoints of being clear and almost clear up into the 60 to almost 75% of the population treated in these clinical studies. Side effect profile: upper respiratory tract infections in some individuals, an unusual acne that may be seen with some JAK inhibitors as well.
Really, these 3 drugs are well on the way in their studies. We will see what happens with how the FDA approaches them and see what the label will be, but these are drugs that almost certainly will require blood monitoring, but they’re also oral agents and show some very nice efficacy, so we’re really excited to take a look at them.
Wow. That’s great, Dr. Eichenfield. Are there any other agents in late-stage development?
Certainly. I’d mentioned before that there are IL-13 agents which are different than IL-4 and 13. One of them is tralokinumab, which is a specific IL-13 agent. They just presented their phase 3 studies and what we call the ECZTRA studies, ECZTRA 1, 2, and 3. One and 2, which were placebo-controlled, showed about 16–22% of patients making it to clear or almost clear versus 7% in the placebo group. They did better concurrent with their topical corticosteroids as well and very nice safety data—some nasopharyngitis but nothing that stood out. Lebrikizumab is another IL-13 drug just starting their phase 3 studies now. In their phase 2s, they showed very nice itch relief as well as an impressive clinical response, also seeing lower rates of treatment-emergent adverse events.
There was a question early on about whether these IL-13 agents wouldn’t have conjunctivitis associated with them, something that’s occasionally seen with dupilumab. I think they both have had conjunctivitis rates that are higher than in the placebo, maybe a little lower rate than dupilumab. We’ll see.
Nemolizumab is the IL-31 blocker which, again, is targeting the itch cytokine—just had a New England Journal of Medicine paper with Kabashima, et al., really nice clinical data. So again, this is targeting itch with a secondary target for inflammation, and we’ll look forward to more data on these other biologics as we move forward.
Now, we’re almost out of time, but before we close, Dr. Eichenfield, what are some key takeaways that you’d like to share with our listeners?
I think the biggest takeaway is that there is a tremendous evolution, and I’d say revolution, in treatment. Our job as we get the new data is to say, “Where does this data fit for my patients? Who are the patients who can benefit for these different drugs? How do I choose one drug as compared to the other?” Right now there’s a huge amount of data coming. This will probably translate into approvals of multiple drugs, so I think people have to keep their ear to the ground or listen and read as new material comes out. And then I think the biggest thing is, right now we should bring forward to our patients the promise that we can do a lot better than what we could have done a few years ago before we had this real revolution in systemic therapy for our patients with moderate-to-severe disease.
With those great takeaways in mind, I’d like to thank my guest, Dr. Lawrence Eichenfield, for joining me to review the latest data on moderate-to-severe atopic dermatitis. Dr. Eichenfield, it was great having you with us.
Thank you so much. Happy to be part of this.
This activity was part of the Conference to Clinic series and was provided by Med-IQ. To receive your free CME credit, or to download this activity, go to ReachMD.com/CME. This is CME on ReachMD. Be Part of the Knowledge.