Management of Type 2 Inflammation in Atopic Dermatitis - Episode 8

Interleukin Pathway Inhibitors for Atopic Dermatitis

March 18, 2022
Peter Lio, MD

,
Neal Jain, MD

,
Marc Serota, MD

,
Matt Feldman, MD

Expert perspectives on the interleukin pathway inhibitors, dupilumab and tralokinumab, and their role in managing atopic dermatitis.

Transcript:

Peter A. Lio, MD: I thought that might be a nice segue into going through the medicines a little bit one by one. Maybe we can start with dupilumab [Dupixent] as a monoclonal antibody that blocks IL-4 [interleukin 4] and IL-13 by binding to that IL-4 receptor alpha, tralokinumab [Adtralza], and IL-13 cytokine binder itself, monoclonal antibody.

I think what’s fascinating about these is that they’re very similar. In fact, when they were being developed, I thought this will be interesting to see if we can differentiate between these pathways. But I would argue largely both, in terms of safety, efficacy, [and] tolerability, they’re quite similar.

What’s interesting right now is the approvals. Dupilumab has gotten lower and lower age approvals. [Dupilumab is] approved down to age 6 years [old] in the United States, which is pretty interesting.

Now tralokinumab is only approved in the adult cohort 18 [years old] and up. Although, I presume eventually, they will at least apply to get younger age groups, which would be interesting.

Tralokinumab also has other disease indications. Beyond atopic dermatitis, it has asthma, and it also has chronic sinusitis with nasal polyposis. Tralo [tralokinumab] right now is only approved in atopic dermatitis.

Does this shape the way that you think of them, or are there certain aspects that might make one more favorable than the other? [What] do you think about them?

Matt Feldman, MD: They do and as the allergists, I think Dr Jain would probably agree with me. I think being able to block both IL-4 and IL-13 pathways for atopic patients may be more attractive in certain situations, especially in these comorbid patients, which many of our patients are comorbid patients.

The IL-13 only pathway was looked at for asthma… even in inhaled anti-IL-13 [pathways] and didn’t come to market because it wasn’t successful from [an] asthma standpoint. While I think blocking IL-13 [pathways]…you see the data as very similar from [an] atopic dermatitis therapy standpoint.

We’re seeing a lot of other patients that may benefit [from] their kind of more moderate asthma. I think the longer the safety profile, the lower age [range] indication for dupilumab is appealing to me. I’m not surprised that tralokinumab [had] similar results from [an] atopic dermatitis standpoint.

Neal Jain, MD: I think there are some definite similarities that we see between these drugs. From a safety standpoint, if you compare dupilumab to tralokinumab, they look very similar. I think there are some study design differences.

If you look at the population [and] say, “Can we compare these as apples to apples or are they apples to oranges?” One way to maybe get an imperfect, but I think best sort of idea as whether you’re looking at a similar population [is] to first look at [the] trial design but then also to look at the background characteristics of these individuals before they enroll, or when they enroll, as well as what happens to the placebo arm in those 2 different groups of patients in the different studies.

I think what you see in the dupilumab trials, SOLO1, SOLO2, which seem very similar to ECZTRA 1 or ECZema 1 and ECZema 2 with tralo [tralokinumab] is that they have this sort of 16-week monotherapy treatment arm with that respective biologic, where you’re looking at these primary outcomes of IGA [Investigator Global Assessment] 01.

Are you achieving an IGA01 in these individuals and percent of patients who hit that easy 75? I think when you look at the Delta in these trials it appears to me that dupilumab might be slightly superior in that population to what we saw with tralo [tralokinumab].

I think what’s interesting is in the tralo [tralokinumab] studies [is] there seems to be this continued effect in some individuals, but this loss of effect for some individuals also. We don’t have that data for dupilumab because SOLO1 and SOLO2 weren’t conducted in that same way.

I think when you look at CHRONOS and compare the CHRONOS study, which is a concomitant TCS trial with dupilumab, to the ECZema 3 trial…time is going to tell us how this all plays out.

Peter A. Lio, MD: It is a good lesson. I feel like we’re always told never compare across trials because you can come to false conclusions, and you pointed out the reasons why.

There are subtle differences in the population. That the time of year could potentially have an effect [on] the specifics in the study design. But we can get a bit of a gestalt and you get a sense between the placebo group and the active group.

What’s remarkable is in the tralo [tralokinumab] trials, the 3 that you mentioned, there is quite a bit of variability. It’s fascinating. It calls that into close attention even with the same drug, with the same kind of parameters, you can see some variability. I agree with everything you said.

I think that brings us to these other age indications. One of the things that has now been done is dupilumab in the preschool age—6 months to 6 years [old]—and I think that’s really exciting.

We’re waiting to see if that will be approved, but that would be a big game-changer because…atopic dermatitis as a population is still largely a pediatric disease.

Neal Jain, MD: We see these kids that have tried everything. We see these patients in our clinics. We were one of the sites…to enroll these kids who have tried everything. They’re doing appropriate skincare. They’re doing wet wraps. And they’re suffering and failing.

To see the data come out in this preschool age population that looks very reassuring from a safety standpoint, 1, but also 2, from an efficacy standpoint whereby you see data that looks very similar to what we saw in the pediatric population, the adolescent population, the adult population, I think is exciting for us moving forward.

Matt Feldman, MD: I would agree, and I would add that as allergists, I hope we get more and more data following those little ones with time because we don’t think of these agents as disease-modifying therapies long-term.

We don’t think of these as immunomodulatory drugs. But with…[what] we know about the atopic march and how transcutaneous sensitization, both from a food standpoint and the airborne standpoint as well potentially, can really drive a lot of other type 2 inflammatory diseases as we get older.

Can we get at these kids when they’re in their miserable stage, at 3 and a half [years old], itching and bleeding everywhere? Can we fix their skin, but can we also potentially impact their other type 2 inflammatory disease states longitudinally as they get older? I think that will be fascinating to look at as we get 5 or 10 years down the line with data.

Neal Jain, MD: Well, I think we’re seeing some abstracts coming out of this upcoming meeting where they’re really going to be presenting data on skin barrier restoration, which I think is going to be exciting to see.

If we see that same sort of thing in these pediatric populations and get this restoration of the skin barrier function, do [we] achieve that goal of preventing the progression of these diseases to being more chronic and ongoing, but also prevention of asthma, allergic rhinitis, chronic sinus disease, eosinophilic GI [gastrointestinal] diseases, etc.?

Peter A. Lio, MD: It’s so funny because it’s been ingrained in us that these are inflammatory diseases and thus our medicines are anti-inflammatory. They have this very direct effect on [the] skin barrier as well.

IL-4 and IL-13 directly damage [the skin barrier], so it’s incredible. They decrease flagrant, they decrease ceramides, they decrease cathelicidins on the skin. This is so important.

Transcript edited for clarity.

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