Video
Emerging Treatment in Plaque Psoriasis
Author(s):
Experts in dermatology discuss recent advances in the plaque psoriasis treatment toolbox, highlighting the mechanism of action and data of tapinarof.
Brad Glick, DO, MPH: Now that you’ve talked about the beautiful, elegant, ideal topical therapy, Mona, what are the advances in topical therapies? What do we have in our toolbox? There are a couple of nonsteroidal agents that we have. Tell us what these agents are. Tell us a little about that, and we’ll dig in to the specifics as well. What’s approved?
Mona Shahriari, MD, FAAD: We haven’t had a lot happening in the topical space in the past 20 years when it comes to novel molecules to treat psoriasis. We had some reformulations or combinations of our old stuff, but truly novel mechanisms of action are what we’ve been privileged to have in our toolbox as of last year. Last summer we saw the approval of tapinarof, which is an aryl hydrocarbon receptor agonist. Basically, the aryl hydrocarbon receptor is a ligand-dependent transcription factor. Based on whatever binds to it, it modulates the transcription of certain genes. This is FDA approved for the treatment of mild, moderate, and severe plaque psoriasis. It makes it easy for our patients with all ranges on the spectrum of disease. It’s FDA approved for adults 18 and above. The other agent approved last year is roflumilast, and that’s a next-generation PDE4 inhibitor. It’s not your grandma’s PDE4 inhibitor. That’s FDA approved for the treatment of both adolescents and adults, ages 12 and above, with mild, moderate, or severe plaque psoriasis.
Brad Glick, DO, MPH: Tell me a little about the mechanism of action [MOA] of tapinarof.
Michael Cameron, MD, FAAD: It’s compelling. It’s an interesting story. Dermavant doesn’t have a patent on the novel chemical entity because you can’t patent something that was discovered in nature. It’s an interesting discovery story that involves 3 species. A scientist discovered that these insects weren’t undergoing normal desiccation in the rainforest, but I’m not sure where it was happening. There were tapeworms. The insects had a tapeworm in them. There were bacteria inside the tapeworm, and these insects were not decomposing. They isolated these bacteria inside the nematode, and they realized that the bacteria were producing these aryl hydrocarbon receptor agonist molecules. This is an agonist, not an antagonist. They did in vitro analyses on aryl hydrocarbon receptor agonists and found that they had compelling pharmacodynamic effects on the IL-17 pathway as well as the type 2 inflammatory pathway.
We’ve seen recently phase 3 data in eczema for tapinarof. It also affects structural proteins. Also, an aryl hydrocarbon receptor agonist, like tapinarof, depending on which cell it’s working in, has very different pharmacodynamic effects. What’s also quite compelling about tapinarof is that orally it’s not bioavailable. They’ve tried to make a pill, but they can’t. So when I’m using it around the mouth, I don’t have to worry about them ingesting it. Pharmacokinetically, it’s not systemically available. If you read the label, which is only 3 pages—which is crazy, I’ve never seen a 3-page label—the absorption data are measured in picograms. We’re used to seeing nanogram absorption data. They’re going to end up a few years from now having an eczema indication down to age 2 with the exact same 1% tapinarof cream because there’s no systemic absorption. It’s a compelling MOA, in addition to the pharmacokinetic aspects to the therapy.
Brad Glick, DO, MPH: In the psoriasis trials they had the subjects use the topical tapinarof on as much as like 50% of their body surface area. It’s a significant amount.
Linda, dig in a little deeper into the mechanism of action of tapinarof. You know a lot about this agent. From there we can talk about some of the clinical trial data. Tell us a little more about tapinarof and what it does.
Linda Stein Gold, MD: This is a new mechanism of action for us in terms of thinking about topical treatments of psoriasis. Traditionally, individuals would think, how is this drug going to work? This drug has been shown to downregulate Th17 cytokines, and that’s important for psoriasis. It has some barrier repair effects and some antioxygen effects, and it also downregulates Th2 cytokines. This is also being studied for atopic dermatitis, but it hits the key pathways that are central to the pathogenesis of psoriasis. The truth is in the pudding. What do the clinical trial data show us? This drug works as monotherapy for plaque psoriasis.
Brad Glick, DO, MPH: Go into a little more detail with that. You know this drug very well. You did the clinical trials. Tell us a little about PSOARING 1 and PSOARING 2. Then we’ll move on and talk a little more about long-term data.
Linda Stein Gold, MD: This drug was studied the way we study topical therapy. It’s a cream formulation. It’s tapinarof in a 1% formulation, and it was studied head-to-head with the vehicle cream. Vehicle isn’t placebo. We expect that any good cream formulation or vehicle formulation should have at least minimal effect on the skin. This was studied once a day for 12 weeks for every 2 patients on active drug. One patient was treated with the vehicle. We found that up to 40% of patients got to clear or almost clear using this as monotherapy once a day over 12 weeks. It was highly statistically significant compared with the vehicle alone.
Brad Glick, DO, MPH: Mona, what’s your perspective and optics on PSOARING 1 and PSOARING 2? Share your experience. We’ve had this product on the market for a year. Tell us your perspective as it relates to the clinical trial data.
Mona Shahriari, MD, FAAD: I was lucky to be 1 of the investigators on the PSOARING 1 and PSOARING 2 trials. This was 1 of the first times in my career where I could tell you who was on drug and who was on vehicle. The effect of this medication in the clinical trial was incredible. After using this drug in the real world over the last year, it’s held up to what we saw in the clinical trials when it comes to the speed of efficacy and the remittive effect. The interesting thing is that we saw patients achieve that primary end point—that clear, almost-clear benchmark—as early as the 4-week mark. We also had patients achieve improvements in itch that were meaningful as early as 2 weeks after they started the cream. Don’t forget, psoriasis is itchy. We don’t typically ask about that. But that offers additional burden to our patients, and if a cream can alleviate it in as little as 2 weeks, that’s promising for our patients.
Brad Glick, DO, MPH: I was fortunate to be an investigator in these trials too. I saw exactly what you both described. But from the clinical trial data itself, we expect a significant vehicle response a lot of the time. We didn’t see it here, so I liked that separation. I liked that it happened early within that first month.
Linda, let’s talk a little about long-term extension data. These individuals were able to move on and go into a long-term extension known as PSOARING 3. Tell us a little about PSOARING 3, what the makeup was of those subjects, and how they were directed in the clinical trial. It was a little different from what we’re used to for topical trials for psoriasis and other inflammatory skin diseases.
Linda Stein Gold, DO, MPH: This was an interesting long-term study. The 3 of us all do clinical trials, and sometimes we have to hold a patient’s hand and say, “I need you to finish the phase 3 clinical trial. Hang in there with me, please.” We’ve got to finish the 8 weeks, 12 weeks, or 4 weeks—whatever gets that primary end point. What was fascinating with this study was that almost 92% of patients volunteered to continue on the open-label long-term study. That means they were either happy with the drug they were using or they were on vehicle and excited to try this new drug. To get that many patients to go into the long-term trial is extraordinary. We structured this long-term study a little differently from the way we had looked at long-term studies in the past. First, the long-term studies are always safety studies. The question that’s asked is, if our patients are using this medication for a longer period of time, beyond that initial 12 weeks, are we going to see any new safety signals that weren’t identified in the phase 3 clinical trial? At its heart, it’s a safety study, but we also look at efficacy.
The way we designed the treatment regimen for the long-term study was different from other studies. Normally, we treat patients. When they get to clear or almost clear, we take away their drug and wait to see how long it takes for the disease to come back. If they get mild disease or worse, they’re allowed to restart their drug. In this study we said, “Why don’t we take a different approach? Why don’t we allow patients to continue to treat their skin until they get to completely clear skin?” In real life, if I still have a little pink or a little scaling, don’t take my drug away. I want to continue treating until I’m completely clear. We also thought if you get to completely clear skin, there’s a possibility of a more durable treatment response. We designed the study that way. After the initial 12 weeks, if you came into the long-term study with completely clear skin, we didn’t give you any medication in the long-term study. If you came into the long-term study with mild disease or worse, you stayed on medication until you got completely clear skin. Those initial patients who came in with completely clear skin had 40 weeks or the longest runway to see how long it’s going to take for that disease to come back.
We found about a 4-month durable remission. In patients who initially came in with clear skin, it took 4 months on average. That means half the patients went longer than 4 months, and half the patients went less than 4 months. We also found that for patients who came into the long-term study with mild disease or worse, when they got to completely clear skin, they had a 4-month durable remission. This was exciting because this is truly a remittive effect. This means you give patients the possibility of a drug holiday. If you’re going away for the summer, maybe you don’t have to take your medication if you’re completely clear. If you’re going on a cruise, maybe you can leave your medication at home and not have to worry about TSA [Transportation Security Administration]. This is exciting for patients. It’s exciting for physicians as well.
Brad Glick, DO, MPH: I’m going to ask Mona some questions about the long-term extension PSOARING 3 in a second. But Linda, comment a little about some of the adverse effects. Then we can talk about the perspective in not only the short-term PSOARING 1 and PSOARING 2 but also the long-term extension. I’m going to ask both of you to comment on what you’ve seen postapproval.
Linda Stein Gold, MD: The first thing I want to mention is that I talked about nonsteroidal options for psoriasis, both on-label and off-label, to treat psoriasis. One of the No. 1 issues with nonsteroidals is that they sting and burn. With tapinarof we found that the local tolerability was exceptional. Stinging and burning were very minimal. When we look at the adverse effect profile, the most frequently reported adverse events were folliculitis, which occurred in just over 20% of patients, generally mild to moderate, and contact dermatitis, which occurred in just over 5% of patients. Upper respiratory tract infection was in a little over 4%. Most of the adverse effects were mild to moderate. One way to understand how important the adverse effect is, is to look at how many patients decided they were going to stop therapy because of a particular adverse effect. The number of patients who discontinued due to adverse events was quite low.
Transcript edited for clarity
