Leon Kircik, MD

I think it’s very important when we consider a treatment option for a chronic inflammatory disease such as atopic dermatitis, psoriasis, or acne, etc…We deal with those a lot in dermatology, but in this case we are focusing on psoriasis to have long-term, not only safety, but also efficacy data. Because we do know that, unfortunately, sometimes patients that are very responsive originally to a drug, the first 6 months or a year, they lose their response to the same drug a year or 2 years later. Now, we really don’t know why that is. Is it because non-compliant patients stop using the drug? Is it because really the drug doesn’t work? But regardless, for one reason or another, it seems to happen. In conditions like this when we don’t have a cure, when people have to use a drug for long term, it’s important to know the long-term safety and efficacy.

And here, with topical roflumilast, I think we have that—not only we have that safety data that puts our minds at ease, unlike topical corticosteroids where we have a limited amount of time to use, we worry about the concerns, we worry that what if the patient is using it on their face, what if the patient is using it in their genital area, what if the patient didn’t tell me about genital psoriasis? It’s ironic. I do want to address genital psoriasis and intertriginous psoriasis since it’s relevant here when it comes to roflumilast, since they do have that in the label. Most of the time, genital psoriasis is quite underdiagnosed and we miss it because patients don’t tell, there is stigma attached to it, they think it might be a venereal disease that they don’t want to discuss with us. But it’s actually psoriasis, and then they use the steroid, and they use it in their genital area, and we don’t even know, sometimes. There were actually some very interesting surveys that showed that 42% of the patients used the steroids in the genital area without letting the doctor know. So, again, the safety of the topical here, roflumilast, becomes very important since there is no limitation or safety concern on the face, the genital area, or other intertriginous area.

A nonsteroidal topical such as roflumilast is going to be very welcome in our new armamentarium for psoriasis treatment. First of all, there’s a big unmet need for topical treatments for psoriasis in the nonsteroidal area. It can be a first-line but it can also be used in combination in our practice with systemic medications, or with other topicals. Sometimes we do need the topical steroids, you need to put that flare out as fast as you can. So, why not use a topical steroid in addition to a topical nonsteroidal? And then we can keep that patient on the topical nonsteroidal. But now, we do have really quite impressive efficacy with roflumilast that there may not be a reason to start the patient with a topical steroid. We may directly go to that topical nonsteroidal that we now have available. But I think the fact that the drug also has intertriginous efficacy history and data, and that is in the label, it makes it quite advantageous for us to start it with topical roflumilast.

In dermatology we do a lot of combination treatments. I say that the drugs are studied as monotherapy to get the drug approved. That’s how the drugs get approved, but when it comes in our hands in clinical treatment, we do use a lot of combinations. I don’t see why not to use it for a patient. For example, if you are using some systemic treatments or biologic, but they have a couple of resistant plaques, why not use an effective topical here such as roflumilast? So, I think the drug can be used as monotherapy, as first-line treatment, but also as a maintenance treatment, as well as a combination treatment with other systemics, or even with other topicals.

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Leon Kircik, MD, shares his impressions of the long-term data of roflumilast, and where it fits into clinical practice.

Importance of Long-Term Data in Plaque Psoriasis

First, why don’t we look at the study design and then we’ll discuss the safety and efficacy. Here we had 2 different cohorts. Originally, the study inclusion criteria were a diagnosis of at least mild plaque psoriasis, but it could have been mild, moderate, or severe. An age requirement of 18 years of age and above. The body surface area requirement was anywhere from 2% to 20% body surface area. We had a randomization period. The first 12 weeks people were randomized into…the vehicle once a day, roflumilast 0.15% once a day and roflumilast 0.3% cream once a day. After that, those patients were rolled over into the open-label, long-term study that was cohort 1.

Then we had the cohort 2 people that came from another study that had basically very similar inclusion criteria. In this case, they had 2% to 25% body surface area and again, age 18 years and above, and they had to have at least mild plaque psoriasis for at least 6 months. So the body surface area requirement was a little bit different here. They were also using roflumilast 0.3% once a day, but those were the fresh people that this was the first study they were in. That study was over 2 weeks. The primary end point was safety, which looked at the occurrence of treatment emergent adverse events, or the occurrence of serious adverse events. The secondary end points—of course when the sponsor spends the money doing an open-label, long-term study, they’re going to look at efficacy, as well. That was clear or almost clear overall. But also, as I mentioned earlier, intertriginous psoriasis IGA [Investigator’s Global Assessment] was looked at [and found to be] clear or almost clear. PASI, which is psoriasis area severity index, as well as the improvement in body surface area, were also considered.

Safety is very important for us as dermatology providers. Let’s just touch upon a couple of points on that. What we saw is on the long-term data, we have about 50% any adverse events, but that doesn’t mean those are related to the study drug. We do clinical studies all the time and unfortunately, or fortunately, whatever happens to the patient as an adverse event, we have to report that to the agency. That’s where that 50% number comes down. Out of those 50%, 94% were mild to moderate and there were no SAEs, meaning serious adverse events or deaths that were related to the study drug. That’s important. But, most importantly, there are 2 things when you do a clinical study when it comes to safety. Number 1, is anybody dropping off the study? Think about it, when you’re giving the patients a free drug and when you’re paying them to stay in the study, why would they drop out? So here, that number is quite low. It was 3.9% of all the patients from the pooled data that dropped out of the study due to adverse events. So that’s good news. Number 2 is, that when we think about the topical treatment, we have to consider what I call the local adverse event profile, and the biggest one is irritation. With this drug, more than 90% of the patients did not have any evidence of irritation. What does that mean? Less than 3% of all the patients had irritation, which is quite a very low number. I think those are important parameters that we evaluate safety when we are looking at a clinical trial.

I think the long-term efficacy is important because we are able to see if the patients are maintaining their efficacy over a long-term period that they achieved during the first treatment period. So, this is an important question when you are treating a chronic disease such as psoriasis. Despite the fact that I said we have so many new treatment options—we have 11 biologics, a bunch of new orals and topicals—we don’t have a cure yet. We do not have a cure for psoriasis, which makes it a chronic disease, which makes its long-term efficacy and safety very important and very relevant to both providers, as we treat the disease, but also to the patients. So, when we look at those numbers, there were 2 cohorts that we basically enrolled them in the long-term study and we have data up to week 64 from cohort 1.

The number who maintained clear or almost clear was 35% and cohort 2 was 40% at week 64. Another way of looking at it is, if you start 10 patients on this drug, when they reach at week 12 with clear or almost clear status, which is a 2 grade improvement, at week 64 almost 3 to 4 of them still will be maintaining that status, which is more than a year. So that, I think, summarizes those important aspects of efficacy and safety for this drug over the long term.

Leon Kircik, MD, reviews a recent study of roflumilast and its long-term efficacy and safety data in chronic plaque psoriasis.

Long-Term Safety and Efficacy of Roflumilast Cream in Plaque Psoriasis

I’ve been lucky enough to get involved with the roflumilast studies from day 1. Of course, in order to get any drug approved in this country, we have to have the early studies, and then we have phase 2 and phase 2b, then the phase 3 study that gets the drug approved. Now the agency also requires an open label long-term extension, which is 1 year for topicals and 5 years for systemic treatments.

Roflumilast 0.3% cream has been approved already for plaque-type psoriasis in patients 12 years of age and older. Also, we are studying roflumilast 0.3% foam for scalp psoriasis, as well as body psoriasis, which I think is going to make life easier for our patients, applicationwise. In addition to that, the foam is also being studied for seborrheic dermatitis. Ironically, that’s one of the biggest unmet needs in dermatology. I don’t even remember when was the last time we did a clinical study for the seborrheic dermatitis indication. I think it was years ago. The only drug that we had approved by the agency for seborrheic dermatitis indication was ketoconazole foam and ketoconazole gel, and that was quite a few years ago, if I remember correctly.

Now, the other indication that we are studying for roflumilast is for atopic dermatitis. There it’s 0.1% concentration rather than the 0.3% concentration. However, I do want to touch one more point that I think is crucial here. In the psoriasis approval label we have information about intertriginous psoriasis indication. This is the only topical that I know of that we have labeled for intertriginous psoriasis. We did study that in the psoriasis studies. It’s a big unmet need because we are very concerned with overusing topical steroids in intertriginous areas. As you know, we’re not supposed to overuse because of the adverse event profile of topical steroids, especially in these areas where the skin is really thin and delicate. Having an unmet need in this area, and roflumilast finally addressing this as a new topical development, I think is a big improvement in our armamentarium for the treatment of intertriginous psoriasis.

Leon Kircik, MD, discusses the recent FDA approval of roflumilast for plaque psoriasis treatment.

Roflumilast Clinical Development Program in Plaque Psoriasis

When we started a long time ago when I was a resident, we only had topical steroids to treat plaque-type psoriasis. Now, we are very lucky, we have so many new options in our armamentarium to treat plaque-type psoriasis. We have almost 11 biosimilars, and more coming. But when it comes to the topical world of treatment, we are still very behind, ironically. We still rely upon topical steroids, however, as you know, it is very difficult to maintain a chronic disease with topical corticosteroids. I think the biggest unmet need nowadays, for us in plaque-type psoriasis treatment, is to have nonsteroidal treatment options where we can use those safely and efficaciously.

The history of PDE4 inhibitors goes back to our first exposure that I remember, which was topical crisaborole, which is actually indicated for atopic dermatitis. Then we ended up with apremilast, which is an oral PDE4 inhibitor. But as we go along, we are learning that there are many different types of PDE4 inhibitors with different binding affinity, and different efficacies. Now we have topical roflumilast, which has been approved for plaque-type psoriasis. This is what I call “not your grandfather’s Chevy,” so it’s not your grandfather’s PDE4 inhibitor. We know from in vitro studies that roflumilast is actually 20 to 300 times more effective and more powerful than existing PDE4 inhibitors that we had in the market. Of course, this is shown in vitro, but we also see in the clinical studies its efficacy is higher. So, it’s a different PDE4 inhibitor and I’m really happy that we are able now to offer a new topical, a nonsteroidal, and a new PDE4 inhibitor to our patients.

Most of our patients will be OK with topical treatment when they have a couple of plaques on their elbows and knees. My limit is around 7% to 8% body surface area. In all honesty, once you pass that 10% body surface area, I think it’s very difficult to use a topical. How much can you smear a cream all over your body? It’s almost impossible physically for our patients. On the other hand, I never separate the oral and topical treatments from each other. I think topical treatment is the mainstream treatment for us in dermatology. We are in the business of topical treatment. We can use both topical and oral treatments together, and we do it all the time.

Leon Kircik, MD, provides an overview of PDE4 inhibitors in the treatment of plaque psoriasis.

Leon Kircik, MD

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