Jeffrey M. Bienstock, MD, FAAP, PediatriCare Associates 

 Let’s shift to the other stuff coming in the future. There are other mechanisms being investigated in therapeutics in atopic dermatitis. I’ll start with topicals.

There’s a new topical JAK inhibitor that has been studied in ages 12 and older. It’s probably as strong or a little stronger than triamcinolone 0.1% as a steroid, but it’s a nonsteroid. There’s no atrophy. It may have more potency than our other nonsteroidals without a lot of irritancy, burning, or stinging at all. We’re really excited about that.

Tapinarof is a drug in a totally different class of medicines. It’s an aryl hydrocarbon receptor modulator. This is being developed both for psoriasis and atopic dermatitis. 

Another PDE4 inhibitor is under study as well. Another topical JAK inhibitor, delgocitinib, is being studied in both chronic hand eczema and atopic dermatitis. They’re not ready to be written yet, but these are other medicines that will give us different topical options.

Peter, do you want to talk about biologics?

Absolutely. We have some new biologic agents that are in development. In particular, we have 2 new IL-13 inhibitors that are in late-stage development, so that’s going to be exciting. It seems they’ll be similar to dupilumab but a different molecule. It may be for patients who have had an adverse event with dupilumab or if it didn’t work fully. This may be another option. This is going to be nice. It seems like they’re going to have a similar safety profile and lack of lab monitoring. That’s exciting.

We have an IL-31 inhibitor that’s also in development. That’s interesting because some people call IL-31 the master itch cytokine. That would be neat because that could answer our question we asked at the beginning. Is this the itch that rashes? If so, how much? Of course, nothing is quite that pure. IL-31 is doing other things too, but the early data seem very promising, so that’s exciting to me as well.

 There are some oral JAK inhibitors coming down the pike as well. They are well along the way. Baricitinib and upadacitinib have been approved for other indications and are being studied in phase 3 trials for atopic dermatitis. There’s also a new molecule, abrocitinib. These will be different. They’ll be oral. There are some more issues with monitoring blood work, but that will give another potential approach to some of our patients. Two of the 3 JAKs have been studied in ages 12 and older, and the other is being studied in adults but going younger. There’s lots of new stuff happening. 

This has been an incredible discussion and very practical, reflecting on all the changes that are happening in the field. Let’s get final thoughts from each of our participants. Jeffrey? 

I’ll go back to education. Educate the pediatrician and make sure the pediatrician educates the family and takes the time. This is not an easy process. This is not an easy disease state. If we do a good job outlining to the families what they need to do, we can see much better outcomes. That goes without saying for everything that primary care doctors do. This forum is going to be great for people to take a look and hear what’s coming on and where we should be.

We all have to work together in a therapeutic alliance. We need to get the patients on board. We need all of the specialists and primary care practitioners to work together because we’re all together for the same concept. We want the patient and their family to be better. When we bring all our forces together, it’s so much more powerful. There’s great synergy.

These are exciting times in the world of atopic dermatitis. The world is going to be a better place with all these new therapies on the way and with the advent of Dupixent 4 years ago. It’s a good time to have atopic dermatitis. We can do many more things to help.

Thank you. Great contributions from everyone today. Thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your in-box. Thank you.

Videos

Lawrence F. Eichenfield, MD; Jeffrey M. Bienstock, MD, FAAP; Peter A. Lio, MD; and Elizabeth A. Swanson, MD, review additional mechanisms being investigated in the pipeline for the treatment of atopic dermatitis. 

Emerging Agents for the Treatment of Atopic Dermatitis 

 What’s the deal with getting this drug approved? Does it require preauthorization? Is it more difficult with younger children than with adults or adolescents? Lisa, do you want to take that?

 Yes. The process for approval is designed to have a dermatologist, pediatric dermatologist, or allergist be the prescriber. It does definitely require prior authorization. Most of our offices and staff are used to that. It’s a well-oiled machine.

I find that coverage is getting much easier over time, especially as the label has been expanded younger and younger and it’s been available for longer and longer. Dupixent will turn 4 in March. It is getting easier. Even when I have to fight for it, it’s worth it. I’m happy to fight that fight.

Sometimes we get comments back from payers who deny it and say they need to go through a systemic immunosuppressant. The 1 that’s approved for kids? There isn’t 1 because there aren’t any even approved for adults. That’s when I get the name of the medical director so we can write this down and talk to them about it.

I had a recent 1 where they sent me a denial saying that they wanted the patient on adalimumab first, which is a drug used for psoriasis and has no utility for atopic dermatitis. I was like, “No, they picked the wrong disease state letter to deny this.”

Jeff, you’re knowledgeable in atopic dermatitis. I know you’ve been involved in the community. Do you think pediatricians are sufficiently aware about dupilumab? Do they need to get more educated so they’re supportive of patients considering systemic therapy? What’s your sense of where they’re at?

 I hate to keep coming back to education, but obviously this is 1 for us. Many of my colleagues can’t even spell the drug. I’ve made the analogy that we had a revolutionary drug for acne with Accutane many years ago, and all those kids do well. We’re seeing how well dupilumab works in asthma, as you mentioned. We’ve seen it with polyposis. We know about the adverse effects. I have not had to write for it, nor have I had to fight for it, but I know that the system in place is pretty easy. I know there’s a whole cheat sheet of what needs to be followed because I had seen that early on.

The big thing is that people in the trenches, primary care doctors, need to be educated. That’s like any new therapy for anything. This is 1 form to say, “This works.” We need to get on board. It took awhile to get a black box around 2 other drugs. We had crisaborole come out after that. You don’t have to spend hours—1 to 2 hours a day with topicals—when a child could potentially get 1 shot every 2 to 4 weeks. 

The topical exhaustion thing is something you can work around. 

I like your analogy to the Accutane situation. One obstacle I sometimes encounter in daily practice is a patient who really needs Accutane, but maybe the primary care doctor said something that wasn’t supportive of Accutane. It can be hard for me to turn that ship around and gain their trust while feeling like I’m not going against the wishes of the pediatrician.

It would be helpful to spread the word among primary care doctors, pediatricians, internists, and family medicine doctors to know enough about Dupixent to be supportive of their patients and encouraging of their patients to consider a treatment modality when they have this horrible atopic dermatitis. In much the same way, I would appreciate that support when it comes to a patient who needs Accutane. That’s a very good analogy.

 It’s real. Fortunately, in the coming months, there will be forums for all of us to join together to explain to pediatricians with webinars—because we’re not meeting face to face—and say, “Open your eyes, listen to what we’re saying, and fight for your patient. Because this works.”

A discussion on ease of access for dupilumab for the treatment of atopic dermatitis including the process for approval and coverage. 

Accessing Dupilumab for Treatment of AD 

 I’ll start with the advantages and the background. We have dupilumab. I explain to patients that we’re trying to dampen inflammation in atopic dermatitis. That inflammation is in the skin, but you can also find it in the blood. With topicals, we’re treating outside in, but sometimes the inflammation is so bad that it’s nice to treat from the inside out. That desire was to be able to dampen stuff down without a lot of other effects.

I go on. I have a variety of analogies. My favorite is that I’m trying to turn off a lamp in a living room that’s next to a kitchen. I want to turn off just that lamp. Using oral corticosteroids as the analogy, I’m turning off electricity for a few houses in the cul-de-sac. The lamp does go off, but I’m turning off a lot of other stuff as well. What we really want is a much more selective switch that’s not going to take out a lot of the immune system with it.

Dupilumab is an IL-4 receptor blocker. It blocks the IL-4 and IL-13 cytokines. What’s nice is that it’s not like a systemic immunosuppressant agent that has a very narrow set of adverse effects. It has a major advantage in that it can bring long-term disease control to a great percentage of children. It started as first being approved in adults, then approved for 12 years of age and older, and now it’s down to 6 years of age and older. It’s being studied in active trials right now for patients 2 to 6 years of age. In the 6- to 12-year-old group, 75% of patients get 75% better after 4 months. Depending on the individual, they’ll be clear or almost clear. Within a few months, 40% of those patients become clear or almost clear. 

It’s a different kind of therapy that I don’t like to use. It’s an injection that’s given every 2 weeks or every 4 weeks depending on the patient’s age, dose, and weight. It’s not a drug that we like to stop and start because it’s a synthetic antibody. As I tell my patients, when you give a synthetic antibody the first time, the body sees it and it goes, “Look, there’s an antibody there.” And it’s cool with it. The antibody blocks the inflammation from happening and cools down the eczema.

But if you stop it for a while, like a few months, and then do the antibody injections again, there’s a chance that the body is going to go, “I’m not sure this thing is really part of us; let’s attack it.” Then you can get antiantibodies. You get this antibody response neutralizing antibodies, which can make the drug not work. 

For this drug, I like people who are willing to change their lives, generally for a year or 2, with a plan to get injections every 2 weeks or 4 weeks after the loading dose, depending on their particular weight tier. It’s been absolutely revolutionary.

Let’s look at the adverse-effect profile. You can see conjunctivitis in about 10% of individuals over time. That’s something to keep an eye out for. We’ve been much more conscious about periocular disease and conjunctivitis from this. You have to be careful about avoiding live vaccines. There are some rare adverse effects that we’re seeing in some patients: psoriasiform dermatitis, a persistent facial dermatitis. But it’s been going for years in adults, and they haven’t had to change the safety labeling, which is incredible given the numbers of patients treated with it. It’s been quite revolutionary for our more severe kids, adolescents, and adults.

Lisa, do you want to weigh in with your thoughts?

 Yes, I would like to chime in with 2 quick thoughts. First, when I’m talking with patients and their families about dupilumab, I describe it as a life changer for the patient, their family, and their doctor. It makes me grateful to be practicing medicine at a time when we can offer these therapies to our patients.

My other comment is about duration of therapy. One of the most common questions I’m asked at that initial conversation about starting dupilumab is: How long will my child need to be on this? Once they’re on it, I never hear that question again because it is so life changing. People realize they don’t want to go back to the days before Dupixent. I address that question at the initial visit by saying, “We’ll think about that later, but this is ongoing therapy.” Once they’re on it, they realize the value in it, and everybody feels better.

 I should mention that the drug is also approved for eosinophilic asthma for patients age 12 and older. It’s also approved for nasal polyposis associated with rhinosinusitis. That’s 1 of the issues you have to deal with, because if you have a patient with asthma and atopic dermatitis, it can really improve their asthma. You don’t necessarily want them stopping their asthma medications. That’s part of the counseling that we need to do. Whoever is prescribing those medications should be aware of it.

It also means that more than 1 disease that patients have can be treated. It’s a tremendous benefit for many of the patients who do have these recurrent allergies. Other atopic phenomena are being studied with dupilumab as well.

Peter, you have extensive experience with adults as well. How do you consider dupilumab? Do you think it’s disease modifying? How do you assess its place in therapy?

The longer it’s been out and the more experience I have with it, I’m shifting to trying to use it earlier in the disease course. It’s interesting, because there is this feedback loop within the understanding of the disease so we can treat to target something similar to what’s been going on with psoriasis for quite some time.

In the old days, my teachers used to talk about an old commercial on television about psoriasis that would say “the heartbreak of psoriasis,” because you didn’t have much you could do for it. Now if you look at the National Psoriasis Foundation treat-to-target goals, it’s clear or less than 1% of the time. 

For atopic dermatitis, that has simply not been the case because we haven’t had the tools. But now we’re starting to say, “Why should somebody be struggling with topical steroids over 30%, 40%, 50%, 60% of their body, which becomes incredibly challenging?” You’re slathering yourself in all this ointment all the time to try to maintain control. You’re walking that fine line between safety and efficacy when we could potentially, for at least the appropriate patient, use a systemic agent that can get better control, including of the invisible or nonclinical areas that we know still have inflammation.

I’ve increasingly lowered my threshold for starting it with really good results. I suspect there may be a disease-modifying aspect to this drug. I’ll even say a little more broadly that getting good control, no matter what the means, can lead to a disease-modifying aspect. This is just another tool in our toolbox to do it. 

We put together a paper a few years ago in which we had a number of patients, generally with quite severe atopic dermatitis, who did very well on dupilumab and stayed on it anywhere from 3 months to a year. When they were doing well, for varying reasons, they came off. Sometimes it was because of eye issues. Sometimes it was because of travel, trying to get pregnant, or many other things. So we stopped them from the medicine. 

I followed those patients. What we found in this very small anecdotal series was that not a single patient in that group had a rebound. With prednisone or something, you’ll sometimes see them get worse than they previously were when they come off. Nobody rebounded. Nobody even got back to their baseline. We called it a relative remitted effect. By no means were they cured, but it was much better. It was in a remission state.

I really think dupilumab, among other treatments, can do this for the right patient, particularly 1 who’s doing well. I use that information because, as Lisa said, a lot of patients will say to me, “Is this forever? Is this going to be like insulin and I can never come off?” I say, “Not necessarily. Let’s get you better for a long time. I want to get everything back in a virtuous cycle instead of this vicious cycle.” Then it may be possible to space out or even take a break, with the caveat that we potentially could run a risk of developing drug-neutralizing antibodies, as Larry said, or becoming sensitized to the medicine. 

We clearly don’t know how many go into sustained remission if we start it early and we do so many years of treatment, but we believe that’s going to happen. We just need data.

I want to mention something about the safety profile. We don’t expect primary care doctors or pediatricians to be writing dupilumab or other biologic or oral JAKs in the future, which are other systemic agents.

One of the big issues is blood testing before you get started and the frequency of blood monitoring. The really nice about this drug is that none is required. As it went through its approval process, both adults and down to young kids as well, now for 6 years of age and older, there is no need for any baseline blood work. It doesn’t affect cell line significantly enough to need to do any particular blood work. There were recent data presented of longer-term laboratory data in the younger kids as well. That’s incredibly nice.

With our other systemic immunosuppressants that we use—some are oral—you need blood work all the time because you’re worried that methotrexate could wipe out your bone marrow, could cause liver disease, etc. There’s no need. That’s something patients get when you mention that to them. The drug appears to be safe enough that we don’t need to do any blood work monitoring. 

I know some specialists who will do general health blood work in patients prior to starting dupilumab. They may assess to make sure they don’t have steatotic liver disease if they’re heavy, etc. But for the drug itself, there’s no need for blood testing. That’s something that’s quite nice.

Examining the potential role for biologic, dupilumab, in the treatment of moderate to severe atopic dermatitis. 

Role of Disease-Modifying Therapy in Atopic Dermatitis 

Let’s move on to the bigger stuff. The next step historically if you can’t control with topicals is either phototherapy, although not necessarily easy to access, or traditional systemic therapies. Methotrexate, azathioprine, and cyclosporine are the traditional agents. They aren’t used that much in either adults or kids. Any comments on those? I’m not sure if Lisa or Peter wants to take the lead on that.

I’ll chime in. I will commonly say that picking a systemic agent to treat bad atopic dermatitis before we had dupilumab was like picking a port-a-potty out of a row of port-a-potties. You know they’re all going to suck, but you’ve got to pick 1 when you have to go.

I was never excited to put a patient on any of these therapies. It was out of desperation. I didn’t know how else to help them. I was like, “OK, let’s try a cyclosporine,” or, “Let’s try methotrexate.” Their adverse-effect profiles are not great. They’re immunosuppressing agents. There are frequent labs. Thank God we’re at the horizon of better options for people.

Lisa, I’ve heard you use that port-a-potty analysis before, and it makes me chuckle inside. With what we’re going to talk about next as an agent, we’re probably not going to have to be turning to those drugs anymore. While topical steroids frighten parents and some clinicians, using regimens like that frighten everybody.

 Some pediatric specialists still use these agents, especially methotrexate and cyclosporine in certain situations. We know from the data that there was never a large number of cases; either kids or adults in the United States. We didn’t have approval for cyclosporine for atopic dermatitis. Methotrexate can be effective in some patients, but we may want to shift to what has been a revolutionary therapy with the introduction of the first prospectively designed biologic for atopic dermatitis with dupilumab. 

A review of the safety and efficacy of systemic agents such as methotrexate, azathioprine, and cyclosporine in patients with severe, persistent atopic dermatitis.

Jeffrey M. Bienstock, MD, FAAP, PediatriCare Associates

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