Latest / The Science of Skin / Beyond Steroids: PDE4 Inhibitors & the Future of Topical Dermatology with Dr. Peter Lio

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Beyond Steroids: PDE4 Inhibitors & the Future of Topical Dermatology with Dr. Peter Lio · The Science of Skin

• 0:00
  SPEAKER_01: Thank you to our sponsor, Arcutis Biotherapeutics, for their support of the Science of Skin podcast and furthering Derm Education.
• 0:07
  SPEAKER_01: Arcutis is a medical dermatology company that champions meaningful innovation to address the urgent needs of individuals living with immune-mediated dermatological diseases and conditions.
• 0:18
  SPEAKER_01: With a commitment to solving the most persistent patient challenges in dermatology, Arcutis has a growing portfolio of advanced targeted topicals.
• 0:27
  SPEAKER_01: Arcutis's unique dermatology development platform, coupled with their dermatology expertise, allows them to develop differentiated therapies against biologically validated targets for a range of inflammatory dermatological conditions.
• 0:41
  SPEAKER_01: Arcutis strives to simplify disease management and optimize drug efficacy, safety, and tolerability.
• 0:48
  SPEAKER_01: They're determined to elevate the current standard of care, solving for the challenges others haven't.
• 1:02
  SPEAKER_02: Hello and welcome to the Science of Skin podcast.
• 1:04
  SPEAKER_02: My name is Dr.
• 1:05
  SPEAKER_02: Ted Lane.
• 1:06
  SPEAKER_02: I am a board-certified dermatologist practicing in Austin, Texas.
• 1:09
  SPEAKER_02: But I'm so excited about my guest.
• 1:11
  SPEAKER_02: It's Dr.
• 1:12
  SPEAKER_02: Peter Leo.
• 1:13
  SPEAKER_02: Dr.
• 1:13
  SPEAKER_02: Leo is the founder of the Chicago Integrative Eczema Center, and he is a world-renowned expert in atopic dermatitis, speaks all over the world, and consults for tons of companies.
• 1:26
  SPEAKER_02: And really, if there has been a new uh atopic dermatitis treatment, whether we're talking about a prescription product or available over-the-counter, Dr.
• 1:36
  SPEAKER_02: Leo has been involved.
• 1:37
  SPEAKER_02: So who better to talk about PDE4 inhibitor responsive dermatoses than Dr.
• 1:43
  SPEAKER_02: Peter Leo?
• 1:44
  SPEAKER_02: Peter, thank you so much for being here.
• 1:45
  SPEAKER_00: Thank you so much for having me, my friend.
• 1:47
  SPEAKER_00: It's always a pleasure.
• 1:48
  SPEAKER_02: Yes, great.
• 1:49
  SPEAKER_02: Well, listen, we wanted to talk about this because, and this this episode is being sponsored by Arcutis, which makes a PDE4 inhibitor topical, which I'm sure we will talk about.
• 2:00
  SPEAKER_02: Because, Peter, you you spearhead spearheaded a publication uh in JCAD, which we will link in the show notes, uh, about this very subject.
• 2:09
  SPEAKER_02: And, you know, it's so timely because all we've been talking about is steroid-responsive dermatoses, but I think we need to change the narrative, right?
• 2:18
  SPEAKER_00: Exactly.
• 2:19
  SPEAKER_00: And I love it.
• 2:20
  SPEAKER_00: That's exactly the right setup because for all these years, we've had this huge group of conditions that are only brought together by the fact that a medicine, steroids, helps them, but they're not really connected in other ways.
• 2:31
  SPEAKER_00: And finally, after many, many years of things where I think it would be much harder to argue that we have a class that is similar to corticosteroids in terms of the broad ability to treat across different indications.
• 2:43
  SPEAKER_00: But at least in my opinion, and I think this is the general consensus, they are a lot safer in general, particularly for prolonged use than corticosteroids.
• 2:50
  SPEAKER_00: So this really deserves sort of a secondary class of its own.
• 2:55
  SPEAKER_02: You know, I feel like in Durham we go through popular themes, right?
• 2:59
  SPEAKER_02: Maybe five to ten years ago it was antibiotic resistance, like we have to be stewards of antibiotics.
• 3:05
  SPEAKER_02: And I hope we're doing that.
• 3:06
  SPEAKER_02: I I feel like that that has percolated through uh pretty well in our community.
• 3:12
  SPEAKER_02: But now we're we're really focusing on on steroids, particularly topical steroids, because of all the local and systemic reactions and and adverse events that can occur.
• 3:22
  SPEAKER_02: You you go through them so beautifully in that publication, but do you mind just reviewing those quickly with us just to I think people really need to understand why we need to avoid them as much as possible?
• 3:33
  SPEAKER_00: Right.
• 3:34
  SPEAKER_00: And I I thank you for that because the first thing is we're not anti-steroid, or I'm not.
• 3:38
  SPEAKER_00: I don't think you are.
• 3:39
  SPEAKER_00: We use them all the time.
• 3:40
  SPEAKER_00: I probably use more steroids than most because most of my patients are eczema and inflammatory stuff.
• 3:44
  SPEAKER_00: So I use them all the time and I love them and I'm grateful for them.
• 3:47
  SPEAKER_00: And I love the fact that they're super accessible, that they're very reliable.
• 3:51
  SPEAKER_00: Almost everybody, if it is a steroid-responsive dermatosis, they're going to respond.
• 3:54
  SPEAKER_00: Like you can count on it.
• 3:55
  SPEAKER_00: So why do we need anything else?
• 3:57
  SPEAKER_00: Well, it's because that is a huge group of people that uses them a little bit, gets better, and moves on.
• 4:02
  SPEAKER_00: But I have this enormous group of patients where they use them, they get better.
• 4:06
  SPEAKER_00: But as soon as they stop, it flares right back up.
• 4:08
  SPEAKER_00: And then they say, Well, now what do I do?
• 4:10
  SPEAKER_00: And a lot of times the advice is, well, it's a chronic thing, use it again.
• 4:13
  SPEAKER_00: So they use it again and they stop.
• 4:14
  SPEAKER_00: And again, bam, it's right back.
• 4:16
  SPEAKER_00: Sometimes even worse.
• 4:17
  SPEAKER_00: We're getting like an escalating need.
• 4:19
  SPEAKER_00: So these are the patients where I'm starting to say, okay, before we get into trouble, we got to do something.
• 4:23
  SPEAKER_00: What kind of trouble do we see?
• 4:24
  SPEAKER_00: Well, if you read the guidelines, they'll talk about the most common things, and that's stuff like thinning of the skin, true atrophy, stria, like all that's real.
• 4:32
  SPEAKER_00: We've seen that in patients.
• 4:33
  SPEAKER_00: It's relatively rare.
• 4:34
  SPEAKER_00: I'm not saying this is all the time.
• 4:35
  SPEAKER_00: And again, we're talking about a specialized group of patients, but for those patients, it's real.
• 4:39
  SPEAKER_00: And then for especially littler kids, they can have systemic absorption.
• 4:43
  SPEAKER_00: We can see them fall off the growth curve.
• 4:44
  SPEAKER_00: We can actually see potentially permanent loss of overall height.
• 4:48
  SPEAKER_00: And this has been one of the interesting things we've seen with some of the biologic agents.
• 4:52
  SPEAKER_00: The kids actually get vertical growth compared to the control group, suggesting that not that presumably the biologic is making them grow.
• 4:59
  SPEAKER_00: We think it's just that they're not needing as much steroids.
• 5:01
  SPEAKER_00: And potentially by controlling their disease, they're able to actually put a lot more resources to growth.
• 5:06
  SPEAKER_00: So probably some combination, but that's powerful stuff.
• 5:09
  SPEAKER_00: And then we have the somewhat controversial, although I would argue increasingly less controversial, but still poorly understood, idea of topical steroid withdrawal, which when I talk about it, I take a pretty defensive posture.
• 5:21
  SPEAKER_00: I tell the story of how I started out pretty skeptical.
• 5:24
  SPEAKER_00: I was converted over time by seeing it over and over and over.
• 5:27
  SPEAKER_00: And now I have a huge patient population with this, and I don't fully understand it.
• 5:31
  SPEAKER_00: I do not have all the answers, nor do I claim to, but I'm really interested in helping these patients.
• 5:35
  SPEAKER_00: And I'm also very interested in giving them alternatives to steroids that still give them relief.
• 5:39
  SPEAKER_00: My goal is still the same to get them better.
• 5:41
  SPEAKER_00: It's just a little bit harder because I'm saying I want to get you better without relying on steroids.
• 5:45
  SPEAKER_02: Yeah.
• 5:46
  SPEAKER_02: And you know, systemically, like you said, for the small children, they can they can fall off the growth, growth curve, failure to thrive.
• 5:53
  SPEAKER_02: We talk about HPA access suppression, we talk about um osteopenia at the very least, um increased risk of diabetes as well.
• 6:02
  SPEAKER_02: I mean, we the list goes on.
• 6:03
  SPEAKER_02: And so it's really incumbent upon us, I feel like, um, Peter, that since we know about this, we have to do something about it.
• 6:12
  SPEAKER_02: And and while we may need steroids for the acute phase of certain dermatoses, and maybe that's enough, like you talked about, maybe for a poison ivy, for example, that's enough.
• 6:22
  SPEAKER_02: But for many others of these chronic rashes, we have to convert from acute phase steroids to something more long-term.
• 6:30
  SPEAKER_02: And we've had things for that, right?
• 6:32
  SPEAKER_02: We've had topical calcineurin inhibitors, for example.
• 6:36
  SPEAKER_02: But now we have these this new class of really highly active, these advanced topical therapies uh that are really exciting.
• 6:45
  SPEAKER_02: And and I guess the first, if we're gonna focus on PDE4 inhibitors, let's talk about what that means.
• 6:51
  SPEAKER_02: Like what phosphodiesterase 4.
• 6:53
  SPEAKER_02: Can we talk about that enzyme, Dr.
• 6:54
  SPEAKER_02: Leo?
• 6:55
  SPEAKER_02: And will you just let us know what that enzyme does and why inhibiting it leads to an anti-inflammatory response?
• 7:01
  SPEAKER_00: It it is such a cool enzyme.
• 7:03
  SPEAKER_00: It really is.
• 7:04
  SPEAKER_00: So as I understand the history of it, I believe Dr.
• 7:06
  SPEAKER_00: John Hanniffin at Oregon Health Sciences University back in the 80s was one of the first people to really pick up on this part of the inflammatory pathway because we know atopic dermatitis is fairly complex.
• 7:18
  SPEAKER_00: There's a lot of different mediators now.
• 7:19
  SPEAKER_00: We know all the cytokine, at least many of the cytokine names.
• 7:22
  SPEAKER_00: We know about IL4, IL-13, we know IL-31, the master itch cytokine, all these things.
• 7:27
  SPEAKER_00: But it turns out that part of that cascade after those cytokines, it is mediated by phospodiasterase 4, this enzyme that's playing a role in in driving this inflammatory cycle.
• 7:38
  SPEAKER_00: So it turns out that it's pretty focused too.
• 7:40
  SPEAKER_00: It's not playing a role, for example, in making white blood cells or something like that, right?
• 7:45
  SPEAKER_00: Because we know some things, if you tinker with them, you can have myelopenia or anemia and all this kind of stuff.
• 7:49
  SPEAKER_00: So this is the classical Goldilocks problem in medicine.
• 7:52
  SPEAKER_00: And we're we're lucky when we find them because we sure we can shut everything down.
• 7:57
  SPEAKER_00: Arguably that's what corticosteroids do.
• 7:59
  SPEAKER_00: You shut down a whole bunch of systems, and boy, you sure get better, but there's a major price to pay if you overdo it.
• 8:04
  SPEAKER_00: Even things like cyclosporin or to some degree the calcinurin inhibitors, which work similarly.
• 8:08
  SPEAKER_00: They block a little bit more broadly, although I would argue much safer, of course, than some of the alternatives.
• 8:13
  SPEAKER_00: But here, PDE4 is so targeted to this general pathway that we we find that we can block it without a whole lot of adverse effects.
• 8:21
  SPEAKER_00: It doesn't seem to bother other systems, but it does all the big pieces we want, decreases inflammation, decreases itch, and allows the skin barrier to heal, which makes it really great in atopic dermatitis, really good for psoriasis too, and even in sebreic dermatitis.
• 8:35
  SPEAKER_00: So that actually we know reflumolast, the newer agent, that actually has three independent indications, which is pretty amazing.
• 8:42
  SPEAKER_00: It's, I think, to my knowledge, it's really one of the only topicals outside of steroids that has three.
• 8:47
  SPEAKER_00: Others might have one or two, but we really see three.
• 8:50
  SPEAKER_00: But we also know in the case reports, case series and reports, it's gigantic.
• 8:54
  SPEAKER_00: There's all these other things people have used it for, everything from lichen plainness to other inflammatory conditions.
• 8:58
  SPEAKER_00: And that tells me again that this is maybe the perfect Goldilocks pathway.
• 9:02
  SPEAKER_00: And Dr.
• 9:03
  SPEAKER_00: Hanniffin was 40, 50 years ahead of his time.
• 9:06
  SPEAKER_02: Yeah, you know, the I so so when we look at PDE4 just in the inflammatory cascade, it's responsible for converting CAMP to 5AMP, if I'm if I'm correct.
• 9:16
  SPEAKER_02: And that by by blocking it, right, we're able to increase the concentration of CAMP intracellularly, which decreases pro-inflammatory pathways like NF kappa B.
• 9:26
  SPEAKER_02: We we deal with MAPK as well.
• 9:29
  SPEAKER_02: Like there, there are multiple pathways that that are pro-inflammatory that are affected by just increasing the CAMP levels, the cyclic AMP.
• 9:37
  SPEAKER_02: And that's where it's really interesting because in addition to its efficacy, and and like you said, we already have three uh disease states for which it's indicated seborrhea, psoriasis, atopic dermatitis.
• 9:49
  SPEAKER_02: Down to the age of what, are we five now, Peter?
• 9:52
  SPEAKER_02: For for actually down to age two, finally.
• 9:55
  SPEAKER_00: We got it down to age two for atopic dermatitis, which is so cool.
• 9:58
  SPEAKER_02: Thank you.
• 9:58
  SPEAKER_02: Down to age two, and we're working on the three months of the thing.
• 10:02
  SPEAKER_00: If we look at the cousin, Chrisoboral, another PDE4 inhibitor, that goes all the way down to three months.
• 10:06
  SPEAKER_00: So exactly right.
• 10:07
  SPEAKER_00: I think with reflumolas, we're hoping we'll get that down to the same level as well.
• 10:10
  SPEAKER_02: There you go.
• 10:11
  SPEAKER_02: So we're working on that.
• 10:12
  SPEAKER_02: And it's so great to tell patients and parents look, this is indicated down to the age of five, we're working on, or down to the age of three, and we're working on less than that.
• 10:21
  SPEAKER_02: And uh, you know, that just gives a halo of safety, doesn't it, when you're talking about that.
• 10:26
  SPEAKER_00: Amen.
• 10:27
  SPEAKER_00: I love that uh that same piece because even to talk to an adult, it's like actually we use this in little kids.
• 10:31
  SPEAKER_00: And I think that, and it is reassuring, and it should be because, right, it's a lot of work getting a drug approved in kids.
• 10:36
  SPEAKER_00: You do actually have to take the studies on again.
• 10:38
  SPEAKER_00: Each time you do that, weird stuff can come up.
• 10:40
  SPEAKER_00: So there is a bit of a risk.
• 10:41
  SPEAKER_00: And I and I'm grateful because especially half my practice is pediatric.
• 10:45
  SPEAKER_00: I'm used to most everything I do in kids, is off label.
• 10:48
  SPEAKER_00: It's really unfair to the kids.
• 10:49
  SPEAKER_00: They don't get the same level.
• 10:50
  SPEAKER_00: So when a company bothers to do it, it is so nice to be able to say, yes, they really did study it in little kids.
• 10:55
  SPEAKER_00: We really can have something to say about this.
• 10:57
  SPEAKER_00: And I'm grateful.
• 10:59
  SPEAKER_02: There is nothing like when you see uh a very young child in your clinic and you can see they're falling off the growth curve, they're struggling with atopic dermatitis.
• 11:08
  SPEAKER_02: I certainly don't see this as much as you, Peter, but I still see it a little bit.
• 11:11
  SPEAKER_02: And the parents are frazzled, they're doing the very best, the primary care doctor has kind of reached their limit of what they know what to do, and God bless them, they're trying their very best.
• 11:20
  SPEAKER_02: And then you're able to, you know, either with a topical that's indicated for that age group or moving into a biologic indicator for that age group, get them back on the growth curve, get them back sleeping, get them back interacting with their peers.
• 11:35
  SPEAKER_02: I don't know that there's much in my practice that makes me feel as um uh appreciated as doing something like that for a family.
• 11:45
  SPEAKER_00: I couldn't agree more.
• 11:46
  SPEAKER_00: It is the most satisfying thing because you're right, if the kid is suffering and miserable and not sleeping, as you say, the whole family tends to be sufferable, misering, miserable, you know, miserable and not sleeping.
• 11:56
  SPEAKER_00: So if we can get them better, you see this beautiful virtuous cycle.
• 11:59
  SPEAKER_00: Plus, I truly believe that when we get the skin calmed down, their sleep gets better, they're able to concentrate, they're able to grow and develop better.
• 12:07
  SPEAKER_00: How many times have we heard a family say, it's like a new kid?
• 12:10
  SPEAKER_00: I barely recognize him.
• 12:11
  SPEAKER_00: He's energetic, he's smiling, he's laughing, he's interacting.
• 12:14
  SPEAKER_00: We'll see the school interactivity and grades go up.
• 12:17
  SPEAKER_00: They're actually able to participate.
• 12:18
  SPEAKER_00: And that's our job.
• 12:20
  SPEAKER_00: Like we have to get these people back into the world.
• 12:22
  SPEAKER_00: And it's so hard to do that when we keep being stuck by the same things that they've tried.
• 12:26
  SPEAKER_00: To give a patient another jar of trium sinalone, sure, it helps in the short term.
• 12:30
  SPEAKER_00: But, you know, eventually they kind of burn out on that.
• 12:32
  SPEAKER_00: I think they're frustrated.
• 12:33
  SPEAKER_02: Yeah.
• 12:34
  SPEAKER_02: Well, so let's focus on PDE four.
• 12:36
  SPEAKER_02: As you mentioned, Chrisoboral was pre was the first, right?
• 12:39
  SPEAKER_02: The first topical that that utilized this pathway that targeted the PD4 pathway.
• 12:44
  SPEAKER_02: Boron-based molecule.
• 12:45
  SPEAKER_02: We were all so excited, and now it's indicated down to two months of age, as you mentioned.
• 12:50
  SPEAKER_02: But there's a little bit of an issue with Chrysoboral, isn't there?
• 12:54
  SPEAKER_00: There is.
• 12:54
  SPEAKER_00: That was one, honest to goodness, when it was coming out, we were both so excited.
• 12:58
  SPEAKER_00: We thought it was going to change the world, and and it did, it did something.
• 13:02
  SPEAKER_00: But yeah, the biggest setback with it, I think, was that for a decent percentage of patients, there was some stinging and burning.
• 13:07
  SPEAKER_00: Even though if you look at the trial data, it was pretty low.
• 13:10
  SPEAKER_00: It was around 4% had the cutaneous stinging or burning.
• 13:13
  SPEAKER_00: But in real life, in my own hands, it was probably closer to 10 or even 20%.
• 13:17
  SPEAKER_00: And it's not a dangerous thing, thankfully.
• 13:18
  SPEAKER_00: It's not a safety signal, but it's a big tolerability signal.
• 13:21
  SPEAKER_00: And especially in kids, when something stings and burns, not only might they say, I don't want that ever again, sometimes they really say, I don't want anything on my skin.
• 13:29
  SPEAKER_00: I don't want a moisturizer, I don't want another medicine.
• 13:31
  SPEAKER_00: So you have this real crisis for these patients and families.
• 13:33
  SPEAKER_00: So once that happened, and it doesn't have to happen much, but certainly more than 4% in my hands, then you got really nervous about it.
• 13:39
  SPEAKER_00: You thought, oh golly, what are we gonna do about this?
• 13:42
  SPEAKER_00: Not to mention the fact that, like a lot of new medicines, it was expensive.
• 13:45
  SPEAKER_00: Um, of course, it's not very powerful.
• 13:47
  SPEAKER_00: That initial one was sort of modest efficacy.
• 13:50
  SPEAKER_00: It's still around.
• 13:50
  SPEAKER_00: I'm still grateful for it.
• 13:51
  SPEAKER_00: I always say we need all the tools we can get because every patient's different and every pot has a lid.
• 13:57
  SPEAKER_00: We got to find it.
• 13:58
  SPEAKER_00: But I will say that it was a bit overall, a little bit of a disappointment for us when it came onto the market in 2016.
• 14:03
  SPEAKER_02: Yeah, it sure was.
• 14:04
  SPEAKER_02: But but thank goodness for Reflu Malastroite, because this molecule, born from the oral version, right, which is indicated for COPD, uh, has a a much stronger binding affinity.
• 14:15
  SPEAKER_02: It's it's a totally different molecule altogether.
• 14:18
  SPEAKER_02: And we just don't see that stinging and burning incidence as we did with Chris Aboral.
• 14:23
  SPEAKER_02: So we know it's it's kind of a next generation, is the way I think of it.
• 14:28
  SPEAKER_02: Um, and as you mentioned, Peter, it's being used all over the place.
• 14:32
  SPEAKER_00: It really is.
• 14:33
  SPEAKER_00: And I have to say, true confession time, when it was being developed, honestly, I wasn't that excited about it because I sort of was like, well, we already have a PDE for it's not maybe the best thing.
• 14:43
  SPEAKER_00: I had pretty low expectations.
• 14:45
  SPEAKER_00: And how rare is it in this world?
• 14:47
  SPEAKER_00: What a cause to celebrate when something you had low expectations for over-delivers, right?
• 14:52
  SPEAKER_00: It underpromised and overdelivers.
• 14:54
  SPEAKER_00: The first few patients I gave it to, another beautiful piece is that it's once daily that makes simplification of a plan.
• 15:00
  SPEAKER_00: They came back and said, Oh, this is great.
• 15:02
  SPEAKER_00: I love it.
• 15:02
  SPEAKER_00: And I was like, any stinging or burning?
• 15:04
  SPEAKER_00: You know, no.
• 15:05
  SPEAKER_00: And now I've used it in hundreds and hundreds of people.
• 15:07
  SPEAKER_00: So I feel so comfortable.
• 15:08
  SPEAKER_00: Does it ever cause stinging and burning?
• 15:09
  SPEAKER_00: Sure, once in a while, but it's super rare and it's super mild.
• 15:12
  SPEAKER_00: And even my most sensitive patients, generally speaking, have zero issues with it.
• 15:17
  SPEAKER_00: So that makes me so much more confident with it.
• 15:19
  SPEAKER_00: I feel very comfortable saying, you can use this, you don't have to worry about it.
• 15:22
  SPEAKER_00: It's great around the eyes or on the eyelid area.
• 15:24
  SPEAKER_00: It's great in those sensitive areas, neck folds.
• 15:27
  SPEAKER_00: And I feel so comfortable with it.
• 15:29
  SPEAKER_00: For some patients, it is enough by itself, which I love if they're in that milder or more mild end of moderate, where they can actually do it just that.
• 15:38
  SPEAKER_00: But for a lot of my patients, my preferred way to use it is they can use their topical steroid twice daily for a while, maybe a few days or a week or even two weeks.
• 15:46
  SPEAKER_00: When they're better, though, they can shift gears in a more maintenance type mode.
• 15:50
  SPEAKER_00: Now they can rely on the reflumolast once daily, simpler when they need it, where they need it.
• 15:55
  SPEAKER_00: And the best situations, a patient who says, you know, I barely needed it.
• 15:58
  SPEAKER_00: Once in a while, I had a little spot spot starting up.
• 16:01
  SPEAKER_00: I used it for a few days and I was better.
• 16:02
  SPEAKER_00: Now you've gotten from a patient who was out of control, overusing steroids, to essentially drug-free, needing a little bit of reflumolast from time to time.
• 16:10
  SPEAKER_00: I'm like, this is winning all around in the expense.
• 16:13
  SPEAKER_00: Yes, it is more expensive than steroids, of course, because it's a branded medicine still.
• 16:17
  SPEAKER_00: But if they're not refilling it much, if they're able to use it in a careful way and gain control, I think we've already seen other studies that show a more proactive approach and getting better control really does lower all the healthcare costs overall and of course improves the quality of life.
• 16:35
  SPEAKER_01: Thank you to our sponsor, Arcutis Biotherapeutics, for their support of the Science of Skin podcast and furthering Durham education.
• 16:43
  SPEAKER_01: Arcutist is a medical dermatology company that champions meaningful innovation to address the urgent needs of individuals living with immune-mediated dermatological diseases and conditions.
• 16:54
  SPEAKER_01: With a commitment to solving the most persistent patient challenges in dermatology, Arcutis has a growing portfolio of advanced targeted topicals.
• 17:02
  SPEAKER_01: Arcutis's unique dermatology development platform, coupled with their dermatology expertise, allows them to develop differentiated therapies against biologically validated targets for a range of inflammatory dermatological conditions.
• 17:17
  SPEAKER_01: Arcutis strives to simplify disease management and optimize drug efficacy, safety, and tolerability.
• 17:24
  SPEAKER_01: They're determined to elevate the current standard of care, solving for the challenges others haven't.
• 17:35
  SPEAKER_02: You and I are formulation geeks.
• 17:37
  SPEAKER_02: Like we really get into the science of the formulation of some of these new topicals.
• 17:42
  SPEAKER_02: And this one, uh, Zareve, Rafumolas, cream, uh, as well as the foam, really changed the game.
• 17:50
  SPEAKER_02: And I don't know that we can un under, I don't know that we can, excuse me, overappreciate how important it was for them to take some of the ingredients that are commonly used in the cosmetic industry and apply them to a medical cream.
• 18:05
  SPEAKER_02: Because I think there was a really strong appreciation early on with the founders how important the the use and the feel and the cosmetic dry-off, all of that was to the patient suffering from atopic dermatitis initially, and then spread to the psoriasis patient and the sebderum patient.
• 18:22
  SPEAKER_02: Do you do you agree?
• 18:23
  SPEAKER_00: Oh my gosh, yes.
• 18:23
  SPEAKER_00: And I have to take the opportunity to thank you and Patty, of course, for putting the Science of Skin Summit together and bringing this important concept and these ideas to life.
• 18:33
  SPEAKER_00: Because honestly, Ted, you know how I feel about this.
• 18:35
  SPEAKER_00: They are so important.
• 18:36
  SPEAKER_00: I know you do.
• 18:37
  SPEAKER_00: You built a conference, you built a movement around teaching about this, talking about this, learning.
• 18:42
  SPEAKER_00: I've learned so much from you and from the conference.
• 18:45
  SPEAKER_00: I feel like I've been able to engage in this discussion because typically you don't talk about this, but yes, amen.
• 18:50
  SPEAKER_00: This is exactly what we're saying, for especially for the eczema patients.
• 18:53
  SPEAKER_00: But if they can benefit, golly, the psoriasis patients, the sebderm patients, everybody's gonna benefit from a well-formulated product that feels good to put on.
• 19:00
  SPEAKER_00: And it's weird if we don't talk about that, because that is a huge part of the adherence and a huge part of the satisfaction of the patient.
• 19:07
  SPEAKER_00: If they're not happy, if they're miserable using it, even if they're better, why are we putting friction there?
• 19:11
  SPEAKER_00: If they like it and they say, Oh, it feels great, it's so nice to use, that's gonna help everybody.
• 19:15
  SPEAKER_00: Again, everybody wins.
• 19:18
  SPEAKER_02: Yeah, the they they realized early on, I think, Peter, that there was such a barrier issue with all of these different dermatoses that we're talking about, that they had to make sure that their cream with the penetration enhancers that everyone needs, although they didn't need much, wouldn't affect the barrier at all.
• 19:35
  SPEAKER_02: And that's what they found with Crotofoss, for example, transcutol, as well as another ingredient that they borrowed um from the cosmetic uh uh realm to apply to the formulation of Zareve uh cream.
• 19:49
  SPEAKER_02: Uh I just thought that was brilliant.
• 19:50
  SPEAKER_02: When when they started talking about that, that's when I was really hooked.
• 19:54
  SPEAKER_02: Because, like you said, we had the baggage of Chrysoborol that we were also worried about.
• 19:58
  SPEAKER_02: And they were like, no, no, no, we figured this out.
• 20:01
  SPEAKER_02: Like we understood what you were saying, and we've applied that to the ex to the ingredients in the inky list.
• 20:08
  SPEAKER_02: And man, that from then on was like, I'm your guy.
• 20:12
  SPEAKER_00: Oh my goodness, me too.
• 20:13
  SPEAKER_00: And and to hear sort of the story of its development just like that, I kind of that that's kind of my my origin story of falling in love with with the importance of formulation.
• 20:23
  SPEAKER_00: After I really took that to heart, I thought we need to understand this better as a specialty because this really matters.
• 20:28
  SPEAKER_00: And we can say that with authority.
• 20:30
  SPEAKER_00: I went in skeptical.
• 20:31
  SPEAKER_00: I'm here now as an evangelist of sorts for this medicine and for others like it.
• 20:36
  SPEAKER_00: I mean, this isn't the only thing out there, but I love that I want everyone to follow their lead.
• 20:40
  SPEAKER_00: I want this to be a beacon to say, hey, look, topical medicines are so important.
• 20:43
  SPEAKER_00: They touch everybody's life.
• 20:45
  SPEAKER_00: When they're well done and they put together, they solve a problem that literally nothing else can solve.
• 20:49
  SPEAKER_02: Yeah.
• 20:50
  SPEAKER_02: And I love the fact that you touched on the maintenance dosing, right?
• 20:53
  SPEAKER_02: Where maybe it's just twice weekly to the hot spots to prevent a flare.
• 20:57
  SPEAKER_02: Because I think our patients, like they they hate the disease, right?
• 21:00
  SPEAKER_02: But they truly hate the they they live in fear of the flare.
• 21:05
  SPEAKER_02: And if if we can alleviate that fear by saying, hey, just use this twice a week.
• 21:10
  SPEAKER_02: We've got good data to show that that it can prevent or delay flaring, that um is huge for them.
• 21:17
  SPEAKER_02: It's not every day because they hate to apply medicine every day, as would I.
• 21:21
  SPEAKER_02: Uh, but if you could say, hey, just choose Mondays and Thursdays and just put it on once a day for me, you know, I feel like we get a lot better compliance that way.
• 21:29
  SPEAKER_02: And honestly, patients are much happier as well.
• 21:32
  SPEAKER_00: Amen.
• 21:33
  SPEAKER_00: And it would I like them not to have to use anything?
• 21:36
  SPEAKER_00: Sure.
• 21:36
  SPEAKER_00: But again, this is not, we're not putting this in healthy people.
• 21:39
  SPEAKER_00: This isn't for fun.
• 21:40
  SPEAKER_00: This isn't for, you know, for beauty.
• 21:42
  SPEAKER_00: This is because they're suffering.
• 21:43
  SPEAKER_00: These are miserable patients who are unhappy and potentially exposing themselves to more dangerous treatments.
• 21:48
  SPEAKER_00: And we're trying to minimize it.
• 21:49
  SPEAKER_00: We're trying to thread that delicate needle, get people better, keep them better safely.
• 21:54
  SPEAKER_00: And we want to make sure they can keep it up.
• 21:55
  SPEAKER_00: And that is hard to do.
• 21:57
  SPEAKER_00: And this is one of those situations where I can say with a plum.
• 22:00
  SPEAKER_00: We did it.
• 22:01
  SPEAKER_02: Yeah.
• 22:01
  SPEAKER_02: You know, the 0.3% foam was first indicated for sebarrilla, which of course uh commonly occurs on the scalp as well as the mid face behind the ears and going down onto the body.
• 22:13
  SPEAKER_02: And now it's also approved for psoriasis.
• 22:15
  SPEAKER_02: But I love this formulation also, because it's got a charge that repels it from the hair shaft.
• 22:22
  SPEAKER_02: And so it stays on the scalp.
• 22:24
  SPEAKER_02: How brilliant is that?
• 22:26
  SPEAKER_00: It's unbelievable.
• 22:27
  SPEAKER_00: And it just shows you the cleverness and formulation and the care that they crafted it, right?
• 22:32
  SPEAKER_00: So many times we hear about the drug, and the drug is important, but for something like this, half the battle is what the vehicle is.
• 22:38
  SPEAKER_00: And this vehicle is doing so much.
• 22:39
  SPEAKER_00: I love that too, because if it's on your scalp or if it's in a hair-bearing area, it's repelled from the hair.
• 22:44
  SPEAKER_00: It's not going to feel greasy or gross on the hair and it's going to go to where it's needed, which is so powerful.
• 22:49
  SPEAKER_02: Yeah.
• 22:49
  SPEAKER_02: I feel like, you know, there's nothing else really indicated for Seberea, right?
• 22:53
  SPEAKER_02: And so they should just have the market for Sebria.
• 22:55
  SPEAKER_02: Although I'm not sure our peers are prescribing it as much as I think it should be prescribed.
• 23:01
  SPEAKER_02: And I say that out of my experience from the phase two and three trials when we were an investigational site.
• 23:07
  SPEAKER_02: It was one of maybe five or six trials that I've I've ever run in my clinical trial history where patients would not want to give me back the drug.
• 23:17
  SPEAKER_02: Like they really just kept it, the canisters.
• 23:20
  SPEAKER_02: They uh it was hard for us to get it back because nothing else over-the-counter or available by prescription worked in the same way.
• 23:26
  SPEAKER_02: And we saw such quick reduction in signs and symptoms, which is which is kind of reflected in the overall study.
• 23:33
  SPEAKER_02: If you if you read the um study report, it's there.
• 23:36
  SPEAKER_02: I I just um I really to those listening, really consider this for Sebria.
• 23:41
  SPEAKER_02: It is such a great option for patients.
• 23:45
  SPEAKER_00: I couldn't agree more.
• 23:46
  SPEAKER_00: And the foam base is delightful approved for both Sebria and psoriasis.
• 23:50
  SPEAKER_00: And now we have that ability to use the foam also on the body in psoriasis.
• 23:54
  SPEAKER_00: So you kind of can do multiple areas with one treatment.
• 23:57
  SPEAKER_00: It lasts a long time.
• 23:58
  SPEAKER_00: The safety, the efficacy, the speed, I feel like it is an incredibly nice addition to our treatment regimens.
• 24:05
  SPEAKER_02: When we look at the the manuscript, Peter, the the publication for the PDE for uh inhibitor responsive dermatosis, you you have a beautiful table at the end that lists so many different indications, whether it was just purely case reports or case series of just tons of different ones that that you know this drug may, or this at least this pathway, uh could be inhibited and help.
• 24:30
  SPEAKER_02: I was surprised at some of them, honestly.
• 24:32
  SPEAKER_02: I would never have thought to use um the perforating dermatoses, for example.
• 24:37
  SPEAKER_02: Didn't think of that.
• 24:38
  SPEAKER_02: Um, it's really impressive and it just makes me think how widespread this pathway is and how important it is for us to target in a targeted way.
• 24:49
  SPEAKER_00: It is so true.
• 24:50
  SPEAKER_00: And it's one of those things, whenever we talk about it, or if I'm giving a lecture about new topicals, people inevitably ask, can it be used for this?
• 24:56
  SPEAKER_00: Or they'll tell me, I used it successfully for this.
• 24:59
  SPEAKER_00: And that's part of what this paper was in response to, just this outcry of people telling us, hey, this works in a lot of different ways.
• 25:06
  SPEAKER_00: And for listen, I do understand we're not trying to say you should use things off label.
• 25:11
  SPEAKER_00: And I would never push that because that's not what we're all about.
• 25:14
  SPEAKER_00: But at the same time, in dermatology, most of the things we treat, especially used to be off-label for paragonodularis.
• 25:20
  SPEAKER_00: We got the first drugs ever in the history of the disease in the last few years.
• 25:24
  SPEAKER_00: We've got two of them.
• 25:25
  SPEAKER_00: What else are you supposed to use for perforating dermatoses?
• 25:27
  SPEAKER_00: Look it up.
• 25:28
  SPEAKER_00: What is indicated?
• 25:29
  SPEAKER_00: Zero, nothing.
• 25:30
  SPEAKER_00: So that's why we kind of felt like, well, the only thing you can put on there if insurance was going to be very strict, is I guess you could you make the argument for steroids.
• 25:36
  SPEAKER_00: Okay, this is a steroid responsive dermatosis.
• 25:38
  SPEAKER_00: So why not then broaden this concept?
• 25:40
  SPEAKER_00: Hey, this is a non-steroidal responsive dermatosis, specifically the PDE4 inhibitory pathway.
• 25:46
  SPEAKER_00: And I think that opens the door for stuff we need.
• 25:48
  SPEAKER_00: Pediatric diseases, half of them have nothing.
• 25:51
  SPEAKER_00: Like in plainness, is it real?
• 25:52
  SPEAKER_00: It's a real thing.
• 25:53
  SPEAKER_00: It's in the textbooks.
• 25:54
  SPEAKER_00: We have to treat it.
• 25:55
  SPEAKER_00: What's approved?
• 25:55
  SPEAKER_00: Nothing.
• 25:56
  unknown: Yeah.
• 25:57
  SPEAKER_02: You know, I think we just need to touch on the safety just a little bit because we really haven't, we've talked we've spoken about the efficacy and the formulation and really all the amazing attributes.
• 26:06
  SPEAKER_02: But you know, we should touch on safety.
• 26:07
  SPEAKER_02: It's also an amazing attribute.
• 26:09
  SPEAKER_02: It is a PDE4 inhibitor, right?
• 26:11
  SPEAKER_02: And we know from a Premolast, for example, that we can have some systemic side effects.
• 26:15
  SPEAKER_02: Certainly not to any extent of a systemic drug, but but we do see some people have a little bit of GI upset, maybe some diarrhea.
• 26:24
  SPEAKER_02: Um, what else do we see?
• 26:25
  SPEAKER_02: Headache in a small percentage of people.
• 26:27
  SPEAKER_02: Uh, am I missing anything, Peter?
• 26:29
  SPEAKER_02: I think those are the most common.
• 26:31
  SPEAKER_00: Those are the biggies.
• 26:32
  SPEAKER_00: You know, we saw the reaction site, you know, any of the application site, pain or stinging is is all very, very low, is like around 1% or less.
• 26:39
  SPEAKER_00: So we know that's really good.
• 26:41
  SPEAKER_00: But yeah, the one I tell my patients about is loose stools because it's once in a while and it really does seem to be part of that pathway.
• 26:47
  SPEAKER_00: This is a this is a powerful medicine, it's well absorbed.
• 26:49
  SPEAKER_00: And apparently in our distal colon, some of the water uh reuptake enzymes rely on PDE4.
• 26:56
  SPEAKER_00: So if we block that, then you retain a little bit more water in your stool distally and you'll have a little loose stool.
• 27:01
  SPEAKER_00: But what I tell my patients is if you see a little bit of that, usually it's fine.
• 27:04
  SPEAKER_00: Within a few days, your body will regulate.
• 27:06
  SPEAKER_00: If there's an issue, you call me, you let me know if it seems too much.
• 27:08
  SPEAKER_00: But generally speaking, knock on wood, I've never had to stop it because of that.
• 27:12
  SPEAKER_02: Yeah, very mild to moderate at the very most.
• 27:15
  SPEAKER_02: Usually, if it happens once, it doesn't happen again.
• 27:17
  SPEAKER_02: Um, and I think in the studies, I I don't know if anybody discontinued because of that.
• 27:23
  SPEAKER_02: Um, if it if it were, it was very, very low numbers.
• 27:26
  SPEAKER_02: So yeah, I I think, you know, I think we've got a great overview here, Peter, of of the PDE4 inhibitors, kind of the history of them, um, where we are now with this most modern PDE4 inhibitor with reflumolast, which again was born from its its uh oral systemic cousin for COPD.
• 27:43
  SPEAKER_02: So it wasn't a brand new molecule to the body.
• 27:45
  SPEAKER_02: We knew that it was well uh tolerated.
• 27:48
  SPEAKER_02: And now, as a topical, boy, the sky's the limit.
• 27:53
  SPEAKER_02: And that's just exciting.
• 27:55
  SPEAKER_00: It really is.
• 27:56
  SPEAKER_00: And I think it just it bodes well for the future of our topicals.
• 27:59
  SPEAKER_00: They mean so much to me, to both of us.
• 28:01
  SPEAKER_00: We want people to keep working on them because there are unmet needs.
• 28:05
  SPEAKER_00: I mean, I wish this worked for everything, it works for a lot of things, and now we have a new tool.
• 28:09
  SPEAKER_00: But I want to encourage people to see the success of Reflumolast in this context, and hopefully it will inspire other companies not to be afraid of making topicals, but to embrace them and say, hey, this is really important to dermatologists.
• 28:20
  SPEAKER_00: And boy, this is great for our patients.
• 28:22
  SPEAKER_00: It helps them in ways that, yes, the new fancy systemics, those are amazing for the more severe patients for sure.
• 28:28
  SPEAKER_00: But a topical can touch lives, so many more lives, because even the mildest or the most localized disease, we have to start somewhere.
• 28:35
  SPEAKER_02: Yeah, and I don't I don't think we'll ever gonna move away from topicals.
• 28:38
  SPEAKER_02: I mean, they're just like you said, the from the for that mild to moderate disease where you know the$10,000 per month biologic is probably not the right way to go.
• 28:46
  SPEAKER_02: Uh, this a really effective, safe, once daily topical with maintenance dosing that's that has been published is is important.
• 28:56
  SPEAKER_02: And and I love what you just said as a call to action for industry.
• 28:59
  SPEAKER_02: Please don't veer away from topical therapies.
• 29:02
  SPEAKER_02: I know everyone's so focused on biologics and systemics, and I appreciate that.
• 29:07
  SPEAKER_02: Uh, but we continue to need uh innovation in topical therapies, much like Reflumolast.
• 29:15
  SPEAKER_02: So um, with that, Peter, I'd like to thank you for your time, your expertise.
• 29:20
  SPEAKER_02: That's a wonderful article that you spearheaded, uh, and I think it's really informative for everyone.
• 29:25
  SPEAKER_02: Again, we'll we'll link it in the show notes so you'll have access to it.
• 29:28
  SPEAKER_02: Uh, but thank you, my friend.
• 29:30
  SPEAKER_02: We're we're recording this right before the 2026 AAD, and so we've got a full plate.
• 29:35
  SPEAKER_02: So I really appreciate your time, Peter.
• 29:37
  SPEAKER_00: My pleasure.
• 29:38
  SPEAKER_00: I can't wait to see you soon, and I wish you all the best, my friend.
• 29:41
  SPEAKER_02: Thank you, me as well.
• 29:42
  SPEAKER_02: So listen, thank you for listening, everybody.
• 29:44
  SPEAKER_02: We really appreciate your support.
• 29:46
  SPEAKER_02: If you like this episode, give it a five-star rating.
• 29:48
  SPEAKER_02: Of course, we would love it if you subscribe as well.
• 29:51
  SPEAKER_02: And you know, the the growth of the podcast we found is really due to word of mouth.
• 29:55
  SPEAKER_02: So if if you have a peer that that you'd like to refer our podcast to, please do so.
• 30:00
  SPEAKER_02: We'd really appreciate it.
• 30:01
  SPEAKER_02: We're trying to keep things at the cutting edge and and let you know what's going on within dermatology and within our dermatologic community.
• 30:08
  SPEAKER_02: Uh, thanks so much for listening.
• 30:10
  SPEAKER_02: Bye-bye.
• 30:16
  SPEAKER_01: Thank you to our sponsor, Arcutis Biotherapeutics, for their support of the Science of Skin podcast and furthering Durham education.
• 30:24
  SPEAKER_01: Arcutis is a medical dermatology company that champions meaningful innovation to address the urgent needs of individuals living with immune-mediated dermatological diseases and conditions.
• 30:35
  SPEAKER_01: With a commitment to solving the most persistent patient challenges in dermatology, Arcutis has a growing portfolio of advanced targeted topicals.
• 30:43
  SPEAKER_01: Arcutis's unique dermatology development platform, coupled with their dermatology expertise, allows them to develop differentiated therapies against biologically validated targets for a range of inflammatory dermatological conditions.
• 30:57
  SPEAKER_01: Arcutis strives to simplify disease management and optimize drug efficacy, safety, and tolerability.
• 31:05
  SPEAKER_01: They're determined to elevate the current standard of care, solving for the challenges others haven't.