Activity Transcript

Linda F. Stein Gold, MD: Hello, I'm Dr Linda Stein Gold, the director of Dermatology Clinical Research at Henry Ford Health in Detroit, Michigan. Welcome to this program titled, "The Changing Landscape in Topical Therapies for Psoriasis." So let's take a look at where we are for the topical treatment of psoriasis. We have a number of different agents that are commonly used yet when we look at the treatment guidelines and the treatment guidelines. Basically, we're put together by a number of psoriasis enthusiasts who scour the literature to find the best evidence-based for the topical treatment of plaque psoriasis. And what we find are there are a few agents that have the highest level of evidence. What are they? First of all, topical steroids, and topical steroids really kind of our gold standard. There are first go-to for the treatment of psoriasis. They kick in quickly. But there are some limitations. 

When we think about potent steroids, we understand that these are great for thick areas and thick plaques, yet they have to be used with caution. Super potent steroids have a limitation of use generally for 2 weeks, for some, maybe 4 weeks, but we have to use them with caution. I think of them as more of a bandaid. They're a short-term solution to a long-term problem. We can get thinning of the skin. We worry about HPA axis suppression. We worry about lightning of the skin and skin of color. So they're good agents, but they definitely have some limitations. The other agents that have the highest level of evidence are 2 nonsteroidal options. These include vitamin D analogue and tazarotene, or vitamin A analogue. 

So, when we think about these agents, what's great about them is these agents can be used on areas other than the arms, legs, and trunk. They can be used on skin folds and sensitive areas. They tend not to thin out the skin. They don't cause HPA axis suppression, so they can be used on multiple body surface areas. They're also very commonly used in combination with topical steroids. However, when we think about topical calcipotriene or vitamin D analogue, this by itself isn't the best in terms of efficacy. It kicks in kind of slowly, as monotherapy for elbows, or knees, or hands. It doesn't necessarily work quite as rapidly or as completely as we might like. We also know that calcipotriene is vehicle dependent. The ointment is superior to the cream, which is superior to the solution in terms of efficacy. Vitamin D is also inactivated by anything that has an acidic pH. So you don't want to use it with salicylic acid. It's also inactivated by light, so you want to make sure you use it at night and don't use it when you're having phototherapy. 

In addition, topical vitamin D can be irritating, so we have to warn our patients about that. Looking at tazarotene, which is the other nonsteroidal that's FDA approved for psoriasis, this is a drug that has been shown to work in monotherapy. The good thing about tazarotene is when you stop using it, generally you have about 4 weeks where the skin remains clear. So we have a durable effect with tazarotene that can last about 4 weeks. The problem with tazarotene is it can be irritating. We do have a fixed combination of halobetasol and tazarotene, which helps to calm that down. So usually we use these nonsteroidals in combination with at least a potent topical steroid in order to counteract the side effect profile. The good thing about tazarotene and vitamin D is some studies have shown that they can counteract or counterbalance the atrophy genetic effects of topical steroids. 

So we have a number of different agents that are listed here. Only 3 of them though have actually the highest level of evidence. And each of these has a side effect profile that we have to make sure we manage and explain to our patients. Good news. We actually have 2 new FDA approved nonsteroidal topical agents for the treatment of plaque psoriasis. The first one is to tapinarof. This is a small molecule. It's a new mechanism of action. It's an oral hydrocarbon receptor agonist. It actually is a small molecule that works inside the cell. It binds to the receptor and has a number of different properties. First of all, it down-regulates Th17 cytokines, and that's very important for the inflammation of psoriasis. In addition, it decreases oxidative stress. It helps to improve the barrier by improving certain barrier proteins. And finally, it downregulates Th2 cytokines, which is important for atopic dermatitis. 

When we look at the two large phase 3 clinical trials called PSOARING 1 and PSOARING 2, these were identical phase 3 studies that looked at adult patients who had plaque psoriasis. They had between 3% and 20% body surface area. They used 1% cream once a day or vehicle cream once a day for 12 weeks. We actually enrolled patients who had mild, moderate, or severe disease. We looked at an endpoint, which was getting these patients to clear, almost clear with a 2 great improvement. So what that means is if you came in with mild disease, you had to get all the way to completely clear. That means they couldn't have any residual pink skin. If they came in with severe disease, they had to jump three or 4 levels to get to a treatment success. So we treat every day, once a day, for 12 weeks. 

We had a secondary endpoint where we actually looked at the PASI75 score at week 12 as well. When we look at the demographics for this clinical trial, we see that these were patients were typical psoriasis patients. The mean age was around 50, more male than female. We see the majority of these patients had moderate disease, but we had several who had mild and several who had severe. The mean body surface area was about 8%, which is typical for a topical psoriasis study. 

So, how do these patients do? Again, they're using one medication, one cream once a day, 2 clinical trials that are sister studies. And the first thing that I notice is that the data is very reproducible. We see that up to 40% of patients got to clear, almost clear with that 2 great improvement, highly statistically significant as compared to the vehicle itself. When we look at the reduction of itch or pruritus, remember pruritus is so important for our psoriasis patients. We saw a nice onset of action and continued improvement over time with about 60% of patients getting that 4-point reduction in their worst itch by week 12, statistically better than those who were treated with vehicle alone. 

Here's an example of a patient from the clinical trials. Notice they had moderate disease at baseline. We already see a nice improvement by week 4 and by week 12, they were completely clear of their psoriasis. What I like to note in these photographs is notice by week 12, there's no shadow, no footprint. You can almost not tell where the psoriasis was at baseline. So this patient got a completely clear result. So this next example is really interesting because this is a treatment failure. This is a patient who came in with moderate disease. Notice their DLQI score is a 14. DLQI, when it's above 10, means that this has a major impact on their overall quality of life. If it gets to a 0 or 1, it means basically no impact on quality of life. And notice the itch score is an 8. Now, you can imagine that the psoriasis really impacts this particular person because every time they put their hand out to shake hands, you're greeted with somebody who has a disease on their hands. People will jump back. They're not sure if it's contagious. 

Notice by week 4, although they still have moderate disease, their DLQI score goes from a 14 to a 4, really nice improvement, the itch from an 8 to a2. And by week 12, now they went from moderate to mild disease, which by definition is a treatment failure. The DLQI score is down to a 1, which means their psoriasis no longer has any significant impact on their overall quality of life. And their itch score is down to a 1, which means minimal itching. 

So, what about patients who came in with larger body surface areas? As I mentioned, you could have up to 20% body surface area to be part of this clinical trial with a topical agent, often we think above 10% we really should be thinking about a systemic agent. But when we look at those patients who had between 10% and 20% body surface area, notice that about 35% of patients got to clear, almost clear. So this is a potential option for those patients who have a little bit more body surface area who still want to use or try a topical agent. Now, when we think about nonsteroidal options, we worry about tolerability because in the past our nonsteroidals tended to have some stinging and burning. What's interesting is when we look at the patients who used tapinarof in sensitive areas, we find that the tolerability was really quite well tolerated. No matter where they used the drug, they actually didn't seem to have stinging or burning or irritation.

So, what about the adverse event profile? Basically, what we found was that patients tolerated the drug well, the most frequent adverse events were folliculitis, which occurred in up to about 20% of patients and some contact dermatitis, which was mild to moderate. The good news is most patients continued on the drug even with the folliculitis or the contact dermatitis, and very few patients dropped out because of adverse events. Tapinarof was also studied in a long-term open-label extension study. In those patients who completed the Phase 3 clinical trials, they were eligible to enter into the open-label study. That means that everybody was on drug. 

So, what's interesting about this long-term study, which is generally a safety study, we also looked at efficacy. And this was done a little bit different from what we've seen in long-term open-label studies in the past. If patients got to completely clear skin, they were taken off drug and remained off drug until their disease got to mild or worse, then they went back on drug. So we followed these patients for the rest of the year going on and off drug depending on their physician's global assessment. 

So by nature, this is a safety study. So the first thing we're looking at is the safety study for both the short and the long-term use. And the good news is there were no new safety signals that were identified with patients having access to this drug for up to an entire year. Now, what's interesting is when we look at efficacy, we found that almost 60% of patients got to clear or almost clear in evaluation their physician's global assessment over the course of the long-term extension study. And actually about 40% of patients got to completely clear skin at some point during their long-term study. So that means no matter what percentage they came in with, at some point they got to completely clear skin. Now, the other thing that we did was we analyzed if you got to completely clear skin and we took you off drug, how long did you remain to either a clear or an almost clear without having to go back on medication with disease of mild or worse. 

And what we found was tapinarof had a remittive effect, in patients who entered the study with completely clear skin. They had on average 4 months of a durable remission where they went off drug. So that means, potentially, if you're completely clear, you might be able to go three months in the summer without having to use your medication. Or if somebody is working at a summer camp and they're going to be away for a few months, if they're clear they might not have to use their medication, or maybe they're going on a cruise and they don't want to take their medicine, there's a good chance that you will have a long-term effect. And remember, 4 months is kind of the average. Half those patients lasted longer than 4 months, half of them lasted less than 4 months, but the majority of patients, the vast majority lasted at least 1 month. 

So now, let's switch gears and look at our second drug, another nonsteroidal topical drug that's been FDA approved for mild to severe plaque psoriasis, and this is roflumilast. Roflumilast is a topical phosphodiesterase type 4 inhibitor. And you might say, "Why do I need another PDE4 inhibitor? We already have some." What's interesting is that not all PDE4 inhibitors are the same. Roflumilast is up to 300 times more potent than the other PDE4 inhibitors that we have in dermatology, including crisaborole and apremilast. This drug has already been FDA approved in the oral formulation for COPD. So it has an established safety profile. 

Now, how does this drug work? We know that phosphodiesterase type 4 inhibitors block the enzyme PDE4. And why is that important? Well, this works, again, inside the cell, and the job of this particular enzyme is to break down cyclic AMP into AMP, and the ratio and the profile of cyclic AMP to AMP actually modulates the inflammatory milieu within the cell. If we have high levels of cyclic AMP, it has a more anti-inflammatory profile within the cell. So if we block the enzyme and prevent the breakdown of cyclic AMP, we have a more anti-inflammatory environment. And that's been shown to have a positive effect on downregulating the pro-inflammatory cytokines that we see in psoriasis. 

So let's take a look at the clinical trial data. Roflumilast cream was studied once daily in patients with chronic plaque psoriasis. Again, we have two phase 3 clinical trials that were conducted in the same way. This is DERMIS-1 and DERMIS-2. We studied the 0.3% cream once a day as compared to vehicle cream once a day in patients with plaque psoriasis. And in this case, we treated every day for 8 weeks. We actually involved the pediatric patients as well as the adult patients in these phase 3 clinical trials. And the primary endpoint is again getting to clear or almost clear with that 2 great improvement. And we have a number of secondary endpoints, as listed here. 

So, how did it do? Well, again, this is monotherapy, a nonsteroidal topical agent being looked at for plaque psoriasis. And again, very good reproducibility of the data of the 2 clinical trials. And we see that over 40% of patients got to clear, almost clear, a highly statistically significant difference between the active drug and the vehicle, and this was true with both clinical trials. What's interesting is with roflumilast, we specifically analyzed the intertriginous areas because the sense of skin and the skin folds, we can't use potent steroids there. So a nonsteroidal option is a great option. And in this case, when we look at the intertriginous disease, we see the vast majority of the patients got to clear or almost clear. And in fact, the majority of patients actually got completely clear of their intertriginous disease. 

What about the response to itch? And again, itching for psoriasis patients can be severe. For a lot of patients, it drives them crazy. So we looked at the reduction of itch. We look at itch on a scale of 0 to 10, and we looked for patients who had at least a 4-point reduction of itch, and we found that in one study. We found a statistically significant difference at week two, the second study by week 4. But we found that about two thirds of patients by week 8 had at least a 4-point reduction in their worst itch. Here's an example of 2 different areas where you can use one drug for these nonsteroidal drugs, I like to call it one-stop shopping. You can use the same drug on the sensitive areas like the face, or the skin folds, or the axilla as the thicker areas like the elbows, or the knees, or the trunk, or the hands. 

So here's a first patient with a lesion fairly thick on the knee. We start to see an improvement by week 2 and by week 8 we see that this patient went from moderate disease all the way down to an almost clear. Here's an axilla, so again, the same drug can be used on the elbows, knees, as well as the skin folds, moderate disease at baseline. And in this case, by week eight, using this nonsteroidal drug once a day, they got all the way to completely clear. 

So, what about safety and tolerability? This drug was also well tolerated. We see as listed here the most common adverse events. Notice that headache and diarrhea are listed here. There is a little bit of systemic absorption, but again, we know that this drug has already been FDA approved for COPD. A little bit of systemic absorption, a little bit of a side effect, but these are generally mild and really well tolerated. We have a long-term safety study where this drug was used on and off as needed over the course of the entire year. And the good news is we didn't find any new safety signals throughout the year long use. And again, patients who got to clear, almost clear could go off or stop using it and then went back on as needed. Very importantly, again, in terms of tolerability, even when using this drug in sensitive areas, the vast majority of these patients found that this drug was very well tolerated and no tolerability issues. 

Well, we also have roflumilast that's being studied in another formulation. This is the foam formulation, a 0.3%. A foam is a great vehicle to use for hairy areas like the scalp. So we have a phase 2B study that looked at patients who had psoriasis in their scalp as well as their body, looking at a double blind vehicle controlled trial with this other formulation. So here we see patients were randomized for every 2 patients who are on the roflumilast foam, 1 patient was on the vehicle foam. Again, they're treating every day for 8 weeks. And we're looking, the primary endpoint was the scalp actually seeing how many patients got to clear or almost clear with that 2 great improvement and a number of secondary assessments including the body psoriasis as well as listed here. 

And what we found was this drug actually works quite well for scalp psoriasis. About 60% of patients getting to clear, almost clear using this drug once a day for 8 weeks. And again, also worked as we saw with the cream, very similar ways for the foam on the body. So again, one drug, in this case, the foam formulation that can be used for scalp psoriasis as well as body psoriasis. And what about itching? Remember, patients who have scalp psoriasis tend to scratch their scalp, they Koebnerize, they can exacerbate their condition. And we saw a statistically significant reduction in that worst itch, at least a 4-point reduction, statistically significant at week two. And we saw continued nice improvement through week 8. 

What about safety? Well, we've already seen the safety results from the Phase 3 clinical trials in the long-term study. With the cream, we found that the foam vehicle was very similar and no new safety signals or tolerability signals were identified with the foam formulation. So we have 2 new options, 2 new nonsteroidal options that have both been FDA approved for plaque psoriasis. When would I consider using these? Well, pretty much all of our psoriasis patients have already used a topical steroid or a potent topical steroid. I think topical steroids continue to have an important place in the topical treatment of plaque psoriasis. Yet these agents actually offer us something that we haven't seen before. These agents work well, they work quickly, and they are able to be used on multiple body surface areas. One of the things with potent steroids, we worry about thinning of the skin, we worry about lightning of the skin, especially in patients with skin of color. We don't see that with tapinarof or roflumilast. 

So I think these are wonderful options. I can't think of a reason not to use these for plaque psoriasis patients. It helps to simplify the regimen and set our patients up for success. So in conclusion, topical treatment of psoriasis remains the cornerstone of treatment for our psoriasis patients. The good news is we have 2 new nonsteroidal agents that will help us get our patients under control even better than we have before. We have topical tapinarof. This is a topical oral hydrocarbon receptor agonist. It works inside the cell and has been shown to down regulate Th17 cells, which are so important for the pathogenesis of psoriasis. We saw that this drug, which is a cream formulation used once a day over the course of 12 weeks, was highly effective in getting our psoriasis patients under control. It was well tolerated. 

And we also found that in long-term use, when we treated to completely clear skin and then stopped treatment completely, we were able to have a durable remission that lasted on average for about 4 months. So this is something new for our patients. We actually give them the possibility of a drug holiday. Again, this is a drug that can be used on multiple body surface areas. It simplifies the regimen for our patients. And then we have another nonsteroidal option. This is topical roflumilast, it's a topical phosphodiesterase type 4 inhibitor, but it's not like the other PDE4 inhibitors. In fact, it's much more potent than what we've seen in the past. This is the drug that also is used once a day in elegant cream formulation. And again, as monotherapy, highly effective in getting our psoriasis patients under control. 

It was studied specifically on regular plaque psoriasis as well as skin folds or intertriginous areas, and was again shown to be highly effective, whether you use it in skin folds or elbows or knees in getting those psoriasis patients under control. And what's new is we now have nonsteroidal options that are well tolerated. They don't have stingy and burning, so we don't have to have necessarily that tolerability conversation with our patients when we prescribe these new drugs. So efficacious, well tolerated, good safety profiles. So bottom line is aim for clear skin. We now have the tools to get our patients under control better than before, and I think this is a win-win for both patients and for dermatologists.

Thank you so much for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation. 

This transcript has been edited for style and clarity.