Episode 47: New nonsteroidal eczema cream approved for kids
New treatment alert! The FDA recently approved Tapinarof, applied as a cream, for kids 2 years and up. We ask Dr. Leon Kircik from Icahn School of Medicine, NY, who led the clinical trials about the safety, efficacy and side effects of Tapinarof. And because we are parents too, we ask: How quickly does it work? Can you start/stop it as needed? How easy will it be to access? And more. If you like our podcast, please consider supporting it with a tax deductible donation. Read the transcript.
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Lynita: Hello and welcome to the podcast. Tapinarof was recently approved by the FDA down to two years of age. It's a game changer for young kids because there are so few options for kids this age. It is a cream applied to the skin, it is not a steroid. It has a good safety profile and really impressive efficacy. And joining me today to explain what this means is Dr. Leon Kircik. from the Icahn School of Medicine at Mount Sinai, New York. He's the lead investigator of the phase three trial that the FDA's approval is based on. He is a clinical professor of dermatology and has over two decades of experience. He has published extensively on developing new therapies to address skin conditions, including eczema.
[00:01:14] Lynita: Dr. Kircik, welcome to the podcast.
[00:01:17] Dr. Kircik: Good morning and thank you for inviting me to your podcast.
[00:01:21] Lynita: Before we get into the questions, for full transparency, can you tell us what your relationship is with Dermavant, who makes the cream?
[00:01:28] Dr. Kircik: So, today we'll discuss tapinarof, which recently got approved for atopic dermatitis. However, the drug has been around for quite a few years before for psoriasis indication. And I have been an investigator, a speaker, and advisory board member in Dermavant, as well as actually companies that have their competition medications such as Insight and Arcutis.
[00:01:54] Lynita: Thank you. Tell us about the origins of tapinarof?
[00:01:58] Dr. Kircik: Tapinarov was first discovered in a worm that's known as nematode. And in that worm, there is a bacteria called P. luminescens in the worm's intestine, And the metabolite of that bacteria has properties to preserve the host tissue. And tapinarof being part of that metabolite of that bacteria, has anti inflammatory properties, which basically led to the discovery of this drug.
It's very ironic that usually we don't talk about dead bacteria, but in this case it was actually useful. And then we started the development program for psoriasis. And then atopic dermatitis, and I was involved with the original development program, for psoriasis, quite a few years ago, it goes much before the pandemic, actually.
[00:02:56] Lynita: So this has been tested previously for psoriasis for safety.
[00:03:00] Dr. Kircik: Well, you know, the FDA is not going to approve anything. You have to prove to them that not only you're efficacious, but you're also safe.
[00:03:08] Lynita: Very encouraging, especially for parents with little kids. Let's get into the study that you did. What did your study show?
[00:03:15] Dr. Kircik: Okay, so first let me explain you a little bit how we do studies for the drugs to get approved. You need to show that you're better than the placebo. So, we had more than 800 people in this study, for 8 weeks. and we started at two years of age and older, which is very important by the way. And then the primary endpoint is the IGA, which is clear, almost clear. We started moderate to severe, and our goal is to become clear or almost clear.
So let's take a look at the results. The people who got treated 46% of them got better, clear / almost clear, and the placebo was about only 14 to 18%
[00:03:58] Lynita: That's quite good. And that's your end point, which is to be clear or almost clear, but there could have been a greater percentage that had their eczema improved dramatically, but not reached that clear or almost clear margin.
[00:04:11] Dr. Kircik: 100% you're correct. So let me give you an example. If you take somebody who's severe, right? They can have two grade improvement, they can become mild, but that is still a study failure in the eyes of the FDA. That patient in real life in my office will be a very happy camper and they're gonna give me a big hug. So, you're absolutely correct. Yes, we're not calculating those people. I'm just giving you the raw numbers, the important numbers that got the drug approved.
[00:04:44] Lynita: So, the numbers look like almost half of people reached clear or almost clear, but it's still life changing for probably a great percentage of people.
Dr. Kircik: Yes, 100% you're correct.
Lynita: It's so exciting that it's for kids down to two years old, because there's not much available for kids at that age, you know, before they look at things like moving on to injectables. Which is a big decision.
[00:05:06] Dr. Kircik: Absolutely. We are lucky that we have biologics. They're great drugs and they have come a long way, but it's not for everyone.
[00:05:15] Lynita: Sure. Biologics like dupilumab, lebrikizumab, and tralokinumab are an option when other treatments have failed, but at the end of the day, they are second line therapies.
How long does it take if you start using tapinarof to see an improvement in symptoms?
[00:05:30] Dr. Kircik: I'm going to give you an example by using the itch, right? You start seeing actually results, from day one. And remember itch is the yeah. Most horrible symptom of the disease, because kids cannot sleep, they scratch themselves to death, and here really in matter of days, you see improvement in the itch. And then about, even around week one, you see statistically significant results in the itch, but starting day one, you see some results, which is, I think, very important,
[00:06:08] Lynita: For the kid who's suffering, for them to have an immediate improvement, that's fantastic. But I know as a parent, the minute I see my kid have some relief suddenly my anxiety and my stress goes down.
[00:06:19] Dr. Kircik: You know, ironically, both my kids had eczema atopic dermatitis and my nephews. And so I understand what you're saying and the fact that, not for eczema only for anything in life, when you see some results early on, people get hopeful and they are more enthusiastic and they use the drug. If they don't see results early on, they're gonna say, ‘Well, this is not working. Let me go to the next one.’ Which may not be correct, right? Because some drugs work later. But that's human nature: If we don't see results early on, we think, okay, time to move on.
[00:06:59] Lynita: Yeah, I do want to ask you a bit about the safety of it, because we're talking about little kids. Is it absorbed into the body at all when it's put on the skin?
[00:07:08] Dr. Kircik: Everything does get absorbed to a degree, but sometimes it's even less than amounts that you can measure. So let me tell you a little bit of the maximum dose study, right? Before drugs topicals get approved, FDA wants to know exactly the question that you ask. Do they get absorbed? How much of it? And what happens if they get absorbed, right? So this is very important. And this is actually called maximum use study.
They take the drug and they apply it as much as they can up to 35% of body surface area. Basically, you're looking at one third and then they look at what kind of side effects. So what we know that the mean Cmax, basically maximum in medical terms was 2.4 nanogram per ml with minimal to no systemic exposure when they use this highly sensitive assay. And more or less, there was no correlation between the tapinarof cream exposure and the baseline body surface area, and that's an important statement, let me explain to you why.
So, you expect that if somebody has 35% body surface area, it's gonna have more absorption than somebody that has, let's say, 3% body surface area. But there was not that correlation between the tapinarof cream Cmax exposure, versus baseline body surface area. And overall, 75% of the blood samples that you collected on day 28, which was the end of the study, had concentrations that were below the quantifiable limit. And the quantifiable limit was 50 Picogram per ml. So the bottom line is, of course, there is absorption, but it was not even quite enough to be able to measure as
Lynita: So, systemic absorption is minimal. Good to know.
[00:09:06] Dr. Kircik: Long as your kid is not eating it. Don't make a sandwich out of it.
[00:09:11] Lynita: That's a very good point. Well, it's just not unheard of with little kids. So you can put it up to 35% body surface area and it's not going to be detectable in the blood. What if you've got a kid that's severe and they're covered with eczema, maybe more than 35% of their body? Is it okay to put, tapinarof on?
[00:09:29] Dr. Kircik: We don't know, but let me answer that from the practical perspective. I think it is very difficult to use a topical cream on more than 30% body surface area, So this is the time when you go systemic treatments,
Lynita: Sure. So that might be when you move to a biologic like Dupilumab, lebrikizumab, or Tralokinumab. What about any other side effects? Are there any serious or not serious side effects that came out of the study?
[00:09:57] Dr. Kircik: Again, that's FDA requirement, once you finish the placebo controlled period, you move on to a whole year of a study period that everybody gets the real drug. And that's called open label period and that's totally for safety. What happens if you get the drug every day for a year, okay? So when you look at that, and we know most of those things from the psoriasis study as well, right? The drug has been studied for psoriasis. It has some contact dermatitis. It has some folliculitis.
Lynita: What is folliculitis?
Dr. Kircik: Folliculitis is inflammation of the hair follicles.
[00:10:41] Lynita: Okay.
[00:10:42] Dr. Kircik: Ironically, some people get a headache, we really don't know why. But those are the things you see during the placebo controlled period. And then when you look at the open label period, it's very, very similar.
Lynita: Okay. I am just going to list all the reported side effects because I know parents will want to know. From the study about 10% experienced folliculitis, as you mentioned, of which 80% was mild and non-severe. Headaches, again, about 10%. Then less than 5% of patients reported upper or lower respiratory tract infection. Asthma, vomiting, ear infection, pain in extremities or abdominal pain. Is there anything else parents should be concerned about?
[00:11:27] Dr. Kircik: Not really, but even though I was joking with as long as they don't make a sandwich and eat it. But, a couple of things are always important, and this has nothing to do with tapinarof. But with using topicals in kids, you learn this by experience, right? You apply it on the hands, then the kid puts his fingers in his mouth. Well, you don't want that. That's just one example, very practical things, but we don't think about it.
[00:11:55] Lynita: No, that's very true. So if they have eczema on their hands, maybe it's better to do it at night time when they can have mittens or gloves put on.
[00:12:02] Dr. Kircik: Correct. The other thing is, the application process is very important. Again, this has nothing to do with tapinarof, but overall creams, right? A lot of people think that if you put a thick layer and you leave that on the skin, it's better and that's just the opposite.
The application of any topicals is very important. You don't want the drug to sit on the skin. You want the drug to penetrate the skin and you only get that by rubbing it into the skin really well. And make sure it goes through the skin. So that's just one practical advice that most people don't think about. It's the same thing even with moisturizers.
[00:12:47] Lynita: That's great practical advice for any parent who's new to this journey, that don't know what to do next. Which many parents are. They don't know anything about eczema when they get a diagnosis. So they're on a big learning curve. And I know, I've been there.
[00:13:03] Dr. Kircik: You know, When it comes to atopic derm, you need a gentle cleanser and a moisturizing program. And that moisturizing program helps the epidermal barrier dysfunction and may keep you clear for a while. So that's important. Anybody who has atopic dermatitis, they really have to follow a very simple regimen of gentle cleanser, no soap and a good moisturizing system.
[00:13:32] Lynita: Yeah, that's good advice for every parent that's got a kid with eczema. If they're using tapinarof, can they use other treatments?
[00:13:40] Dr. Kircik: So, first I should say this, Tapinarov study has been done as monotherapy and that's usually the norm to get a drug approved.
Lynita: Monotherapy just means it's been studied alone without any other treatment. Right?
[00:13:51] Dr. Kircik: Correct. So we don't know what happens if you use it in combination. But believe it or not, in dermatology, we always use things in combination. But I don't see any benefit, for example, using topical calcineurin inhibitors with tapinarof together, right? If anything, maybe using it with a topical steroid in the beginning for a couple of days, and then use the tapinarof may be a good idea. But, not in the long term, in the short term, to take the fire away.
Lynita: Okay. I guess that brings me to the question, how does tapinarof work and how is it different from topical steroids?
[00:14:32] Dr. Kircik: Tapinarof is a naturally derived AHR ligand. Organs, not only in the skin, but in the nervous system, in the eye, in the lungs, in the gut, can bind to a diverse range of ligands. And the AHR binding can cause induction or repression of different genes, facilitating diverse biologic responses in many different types of tissues. So in this case AHR activation binds to the ligand, and it ends up, gene expression modulation.
[00:15:06] Lynita: And I just wanted a quick explanation, if you don't mind, but AHR receptor, What does that mean? And ligand, those two words you just used.
[00:15:16] Dr. Kircik: So, let's go back in very simple terms. Usually things work on the cellular level, with a receptor on the cell, and then you have a ligand that binds to the receptor to activate the process in the cell.
Lynita: And just for our listeners, an AHR is a receptor. It stands for aryl hydrocarbon receptor.
[00:15:38] Dr. Kircik: Most of the drugs actually work by binding to the receptor or the ligand itself and inhibiting the process. In this case, AHR is very unique. The ligand binding to the receptor sometimes inhibits or represses the process or sometimes activates. So that's where tapinarof is unique as being an AHR ligand. Rather than an inhibitor. It's very interesting, because AHR is quite ubiquitous in the body, ironically.
Lynita: So what I'm hearing is that tapinarof binds to a receptor AHR, on a cell and activates that receptor, which then sends a message to reduce inflammation in the skin. Thank you. It's a lot to understand.
It's different from topical steroids because it's made up of this AHR ligand. How does that compare to other treatments out there like crisaborole and tacrolimus?
[00:16:41] Dr. Kircik: It's very different. Crisaborole is a PD4 inhibitor, it's an intracellular process as well, just like tapinarof, but totally a different mechanism of action. The other Tacrolimus or Pimacrolimus, they've been around for a long time and they are topical calcineurin inhibitors, which is also a different process. So they are all different mechanism of actions.
[00:17:12] Lynita: Okay, so they're completely different ways of working in our body and affecting the itch and the redness that we get from eczema.
I know parents will be curious about the comparative efficacy of tapinarof with topical, other topical creams, and I did find a recent paper, I'll share it in the links, a meta-analysis on the comparison between Ruxolitinib. Crisaborole and Tapinarof in adults. That study found that Ruxolitinib was the most effective, but it's only available for older kids. Do you know how tapinarof compares in efficacy to other topicals available for younger kids?
[00:17:51] Dr. Kircik: Unfortunately, we don't have answers yet.
Lynita: Okay. that's fair enough. just covering my bases, I guess, really. Um. Now this is a question, it's a little bit left field, but we're really interested in prevention. If we use tapinarof early in the life course, before the eczema gets really severe, do you think it could stop us developing severe eczema?
[00:18:13] Dr. Kircik: So, really, that's a million dollar question, and in order to have that answer, you need prospective studies of years and years and years, right? And honestly, we do not have an answer for that. In the case of topical steroids, they work wonderfully well, but then when you stop it, your effect is gone and the disease comes back, sometimes even with a revenge.
In the case of tapinarof, going back to the psoriasis studies, we had people who remained clear after stopping the treatment for five, six months. And we see some parallels with atopic dermatitis - that people are clear quite a few months after stopping the drug. But is it because of the drug or was it going to happen anyway? Right? Because atopic derm is a very unstable, volatile disease. It does come back and forth quite fast. So, unfortunately, we don't have answers yet.
[00:19:21] Lynita: On that note, is there anything that we don't know yet that we should be looking out for, or concerned about?
[00:19:26] Dr. Kircik: In medicine we say what we don't know, we don't know yet. So, hopefully, we don't have any surprises in the future. But I think so far, we have great data, both efficacy... And I just want to mention one thing that, you know, FDA is very, very stringent and conservative in what they do in their decision making process. And when they approve a drug all the way down to two years of age, it's very saying just in itself .
[00:19:56] Lynita: I think that's why we were so excited because to approve all the way down to two straight out of the bat, really demonstrates that there's a very good safety profile on this drug,
Is it safe to go on and off it or is that going to be.. confusing?
[00:20:10] Dr. Kircik: Absolutely. That's how we did the open label study and the beauty is that people off the drug do remain clear / almost clear for a while.
[00:20:19] Lynita: That's fantastic. This is another question because I know with um, Dupilumab people have had to demonstrate that nothing else works for them. Do you think it'll be just easy for parents to go to their dermatologist and say, can we please try tapinarof?
[00:20:34] Dr. Kircik: In the ideal world, they can. But unfortunately, in the real world we deal with this issue every day with the payers, insurance companies. Is it covered or not? How can you get this particular drug to the patient? Access has become a very big problem in this country, unfortunately, and this is not only for tapinarof. Any new product, we have to give up such a fight every day, hundreds of times a day to get drugs to our patients.
[00:21:06] Lynita: We also need to acknowledge that companies have spent a lot of time and effort and research producing these.
[00:21:12] Dr. Kircik: Yes, I mean it's humongous. I’m in the clinical study business, right? And if you look around in the R&D, research and development world, it's quite expensive, it's quite difficult. It takes years and years, and if you study five drugs over several years, one comes to the market. It's a very difficult business, but it's very satisfactory.
[00:21:36] Lynita: Yes. And, we as parents, are so grateful that the researchers are doing this work because it does give us other options, even if there are hurdles. So, that's appreciated.
Thank you so much for your time, Dr. Kircik. I appreciate it.
[00:21:49] Dr. Kircik: Thank you so much.
Research discussed
