Analyzing Efficacy and Safety in Diverse Clinical Trials: New Roflumilast Data

Following Arcutis Biotherapeutics’ release of promising new data from its phase 3 clinical trials, INTEGUMENT-1 and INTEGUMENT-2, Chief Medical Officer Patrick Burnett, MD, PhD, FAAD, spoke with Dermatology Times on the importance of diversity within clinical trials. He touched on subjects such as clinician prescribing confidence, subgroup specific data, and upcoming trials for roflumilast.

Transcript

Patrick Burnett: Hi, I'm Patrick Burnett. I'm the chief medical officer for Arcutis Biotherapeutics, and I'm a dermatologist.

Dermatology Times: With the current lack of diversity within clinical data, was this a priority when designing the trial?

Burnett: When we're designing our clinical trials, we place a priority on making sure that we have diversity incorporated into the studies. Right from the beginning, it's actually been incorporated into our guidance as a company to make sure that this is something that we're focusing on.We started that even very earlyon, when the company was just being formed. We recognize that, especially in dermatology, where you have patients who are coming in with different skin and hair practices, with different skin types and even diseases that are seen sometimes more commonly in different races and ethnicities than in others, it's particularly important to make sure that you have that diversity. Even as we're designing the clinical study protocol, we'll think about if there are assessments that need to be done to make sure that we're capturing the right kinds of data to be able to answer questions once this drug would get into clinical practice. Then also, really critical is making sure that you have the investigators who are familiar with the different patient types that you need to recruit. Do they have the right type of patients coming into their clinical practice? Do they understand how to do those assessments in patients who may have different skin of color or have different hair types?It may be challenging for some other investigators. Really kind of partnering with the dermatology community to make sure we're getting them the data that they need in order to use a drug once it's approved.

DT: What clarity or confidence do you hope this brings to clinicians?

Burnett: Our goal when we're running a clinical trial is to make sure that we have the data that clinicians might ask once they are in their practice, once a patient's sitting in front of them, and they want to be able to answer those questions that the patient might have, or answer their own questions. Especially in atopic dermatitis, when we were studying integument 1 and integument 2, which is the result of our recent data release on diversity within these studies. We wanted them to be able to understand:Is this going to be just as safe and effective in this patient who might be sitting in front of me, who is Hispanic or who is Black or African American, and will they have the same results that might be listed in the prescribing information or the top line data that was released by the company?So I think it's really important to be able to kind of give them that subgroup analysis that really shares, this is the efficacy, and they're consistent across different patient types. This is the safety, and it's also consistent because, as an individual patient, you maybe interested in theoverall results. But what you really want to know is: What can I expect when I start taking a treatment?

DT: Are these data points something you hope to analyze in future studies?

Burnett: Absolutely. I think this data that we just released in atopic dermatitis, were from 2very large trials that each had around 650 patients in them. The power of having those combined analyzes from 2 large phase 3 studies really gives you the chance to do a deeper analysis like this. But I think it's just as important even when you're doing smaller, earlier phase trials, like a phase 1 or a phase 2 or 2b trial, that you're asking those same questions. I think that you can learn at every 1 of those stages. You can learn about how it is that you can refine those analyzes, make sure that you're including the right endpoints and capturing the right data so that you can answer the questions down the road. I think it is important to do in every single trial, but the power of that analysis grows as your clinical trial size grows, and I think that this is a really good example, as I said, these are big studies, and that allowed us to do a more comprehensive analysis that you might otherwise do.

DT: Did you see any subgroup specific adverse events?

Burnett: That was 1 of the analyzes that we did. We looked both at efficacy as well as safety. We didn't see any adverse events that were related to a specific race or ethnicity or change in pigmentation. One of the things that we assessed, if you if you look at the the data, is you can assess a patient's response to sun. Do they burn? Do they not burn? And alsotheir baseline pigmentation, and that's called the Fitzpatrick skin type. We were able to do analyzes across all of these different types of subgroups. We didn't see a difference based on safety. But if we're focusing on the Fitzpatrick skin types, then we know thatsome patients, as they have more baseline pigmentation, are prone to some types of impact, not just from a treatment, but also from the disease itself. For instance, in atopic dermatitis, we know that patients who are Fitzpatrick, 5 or 6 who have a lot of baseline pigmentation can get hypopigmented patches, just as a part of their natural disease. Sometimes this can be exacerbated by some treatment. We know particularly that topical corticosteroids are something that can actually alter pigmentation.So1 of the things that we've done, and we focused on this a lot in our seborrheic dermatitis program for the foam, was to actually show restoring the pigmentation that a patient might normally have at their baseline, and that's not really looking at it so much as an adverse event. That's more looking at it also as a as an efficacy outcome. Becausepatients want to restore their normal baseline pigmentation. They want to be returned totheir normal state, as if they didn't have the disease. That's a part of it as well.Pigmentation changes are really interesting, and I think that this is something that hasn't been really well studied in the past.Kind of going along with this idea that we didn't have adequate diversity in our clinical trials, if you don't have enough patients of any given group, then you're not able to really make conclusions about whether you'reexacerbating a problem or actually helping the problem. I think it all kind of goes hand in hand that if we can increase the number of patients, make sure we have the right investigators, right patients in our study, then we're going to be able to capture information about whether we'rehelping or hurting some of these effects of the disease.

DT: Was there anything you were pleasantly surprised to see within these trials?
Burnett: That was exactly what we saw with seborrheic dermatitis. Going into the trial I, as a dermatologist, have taken care of a lot of patients who experience hypopigmentation, whether it's from seborrheic dermatitis or atopic dermatitis or psoriasis. We know that it can take a long time for that pigmentation to come back. Sometimesmonths, even a year, for that to kind of normalize after something affects it. We were surprised to see how quickly, even in an 8-weektrial, we were able to show a change in pigmentation and resolution of some of that patient described at baseline. You don't know until you actually ask the question and run the clinical trial.That was 1 thing, as you said, that we were really pleasantly surprised to see, and we had a lot of good conversations with investigators and dermatologists afterward, as the drug has been approved, to try and understand how that could be taking place. We need to kind of reset our idea of what's going on in the skin, if we can change that in actually 8 weeks in a situation of seborrheic dermatitis with a patient with Fitzpatrick 5 or 6 skin.

DT: Are there any upcoming studies into roflumilast that you're excited about?

Burnett: Yeah, I'm really excited to be focused on reducing the age for the patients that we're studying.That's always something, when you're in an ongoing dialog with the FDA and other health authorities as you're developing a drug, is you want to prove safety in older patients, and then you're allowed to step down into younger age groups. Our initial approval was in ages 6 and above for atopic dermatitis. We have our data for integument PS, which is in 2- to 5-year-olds. And in fact, we just released about a month ago, the open label data for long term treatment in 2- to 5-year-olds.I'm really excited about kind of bringing those data to a scientific meeting and really showing the consistency in the data as we get into younger age groups. Because we were able to show safety and efficacy down to the age of 2 in our investigational studies so far is kind of already turning towards looking for younger than the age of 2, because especially in those young children, the impact of steroids is quite significant. They tend to have a very high body surface area and easily absorb any kind of drug across their skin. I think that the profile of a non-steroidal like roflumilast in those very young age patients should be a good fit. I'm really looking forward to kind of moving into younger and younger age groups where steroid impact is quite substantial. Parents have a healthy child sitting in front of them, and then they also have atopic dermatitis. They oftentimes, at the those young ages, they really struggle with using any kind of treatment on the right. They really want to avoid any kind of exposures and just let the child kind of grow up the way they're meant to. But at the same time, they are struggling becausethey see the impact of the disease. Those are usually quite different discussions that you have with the parents of quite young children, versus even teenagers or adolescents.

[This transcript has been edited for clarity.]