Latest developments for new treatment strategies in atopic dermatitis

An unmet clinical need exists for patients with moderate to severe AD. Advances in our understanding of the pathogenesis of AD are paving the way for development of new targeted treatments. Dr Kristian Reich reviews emerging therapies for AD, focusing on a number of novel antibodies targeted against key cytokines involved in the pathology of AD, including IL-4, IL-13 and IL-31.

My name is Professor Kristian Reich, I am a dermatologist in Hamburg. I am an immunologist by training. I have a strong interest, and have had a strong interest for many years, in immunologic skin diseases, inflammatory skin diseases, including psoriasis and atopic dermatitis. Which already brings me to the topic I want to discuss with you today: which is atopic dermatitis. Where do we stand with atopic dermatitis? What is the latest on new therapies of atopic dermatitis?

You’re probably all aware that in the recent years enormous progress has been made when it comes to new treatments of psoriasis, and the main breakthrough for many many years has been what we call the targeted therapies. And with targeted therapies we mean antibodies that specifically antagonize cytokines that are believed to play a major role in the inflammatory process. Now, in atopic dermatitis we have not seen a similar development going on; we still have an enormous unmet need in atopic dermatitis. If you look at the labelled therapies (the labelled systemic therapies) it’s corticosteroids and cyclosporine. This hasn’t been changing for many many years. So, I think the hope is that we see in the next years in atopic dermatitis what we have been seeing in psoriasis in the last two decades. And that with the help of the targeted therapies, and eventually other small molecules, we will be able to manage our patients with more severe forms of atopic dermatitis a lot better than we can actually manage them today.

The immunology of atopic dermatitis has been investigated in great detail. There is a recent publication that summarizes our current concepts on the immunopathology of atopic dermatitis, and there are a number of publications on new therapies. One treatment that I want to discuss with you is about an antibody called dupilumab that blocks the alpha chain of the interleukin-4 receptor, and by doing so it actually blocks two cytokines, namely IL-4 and IL-13, because these two cytokines share the IL-4 alpha chain in their receptor. So by using dupilumab you will be able to block both the IL-4 and the IL-13 pathway. Earlier this year there has been a publication in The Lancet, a Phase 2 study with dupilumab in patients with moderate to severe atopic dermatitis. Moderate to severe atopic dermatitis was defined by using the Eczema Area and Severity Index, or “EASI”, and the EASI actually functions pretty much in the same way than the PASI. So it looks at different signs of the disease and it also looks at the area that is involved by the atopic eczema. The definition used for moderate to severe atopic dermatitis was an EASI of 12, which I believe pretty much comes from psoriasis where a PASI of 12 has been used in clinical trials with targeted therapies to define moderate to severe psoriatic disease.

In the study, published in The Lancet earlier this year, a wide dose range of dupilumab was tested, from 100 mg per injection every 4 weeks to 300 mg weekly. And there is a dose response seen in the clinical improvements induced by the therapy with the highest dose (the weekly injection of 300 mg dupilumab). Approximately 80% of the patients at Week 16 (which was the primary endpoint in the clinical trial) achieved an at least 50% reduction of the EASI, and similar to PASI we call this an EASI 50 response. Up to 60% of the patients achieved an EASI 75 response and up to 30% achieved an EASI 90 response, meaning in at least 75 or 90% improvement of atopic dermatitis at Week 16 compared to baseline. In other words, with this new therapy in this Phase 2 trial that included up to 380 patients, you can say that two-thirds of the patients achieved an at least 75% improvement of atopic dermatitis. If I go back to the old cyclosporine data this is probably in the range of cyclosporine, so it is a very good response compared to what we have and indicates that with blocking IL-4 and IL-13 the door opens to, what I would call, the first promising targeted therapy for the treatment of atopic dermatitis.

Now this is Phase 2 and a large Phase 3 program is underway. We haven’t seen a publication of the Phase 3 data yet, but there has been a press release earlier this year on a Phase 3 study with dupilumab, called SOLO 2, that used the high dose (the 300 mg weekly), which is the dose that the company has decided to take into the Phase 3 program, which pretty much supports the data I just told you to be a major finding in the Phase 2 program.

We are also interested in the safety profile. Now within the first 16 weeks the safety of dupilumab was generally good; there was a good benefit-risk profile of the drug. The only signal that I could see is that across all dose groups patients developed herpes infections, up to eczema herpeticum—which as we know is a risk in patients with severe atopic dermatitis—compared to zero patients in the placebo group. I wouldn’t call it a signal but this is definitely something we carefully will have to follow and we will have to see what is going on with this signal, or with herpes infections, in the Phase 3 program.

Another clinical finding that we are very interested in is the long-term control. We separate the treatment of chronic inflammatory skin diseases into the induction phase, which is likely to be the 16 weeks I just talked about, but then of course the maintenance therapy. And we will have to await the long-term results from the Phase 3 program to judge the maintenance potential of dupilumab in atopic dermatitis.

Other developments in the treatment of atopic dermatitis are coming from antibodies that target directly IL-13. So their specific interference with the immunopathology of atopic dermatitis, if you will, is more narrow than what dupilumab is doing, in that it does not block two pathways but only the IL-13 pathway. We do not have a full publication yet on what IL-13 blockade alone can do in atopic dermatitis, but we do have Phase 2 data from a study in allergic asthma and there are Phase 2 data in allergic asthma from dupilumab. And it appears that dupilumab is superior in allergic asthma than tralokinumab, which is the IL-13-only blocking antibody. So it might be (it’s a little bit hard to transfer data from allergic asthma to atopic dermatitis) but it could be, we’ll really have to carefully follow this, that blocking both cytokine pathways is more successful in treating atopic diseases than just blocking IL-13.

The third targeted therapy that is currently emerging is an antibody that blocks the IL-31 receptor. We know that IL-31 is a Th2 cytokine, so another mediator released from Th2 cells that are believed to play a major role in the pathology of atopic dermatitis. And IL-31 is specifically linked to pruritus which is, of course, a very annoying symptom of atopic dermatitis. In this Phase 1 study that was recently published, blocking the IL-31 receptor significantly improved the pruritus. This was a very small study (just 30 to 40 patients enrolled in there), there was no specific mentioning of the improvement of atopic dermatitis, but it points to the fact that blocking IL-31 would be an interesting therapeutic approach to addressing one of the most annoying symptoms of atopic dermatitis, namely the pruritus.

So to summarize: we have dupilumab blocking IL-4 and IL-13, we have IL-13 blockers, we have antibodies that block the IL-31 receptor, we also have an antibody that directly blocks IL-31. So we have these three approaches using targeted therapies, with dupilumab being the most advanced in bringing up to 60% of the patients to a PASI 75 [EASI 75] response.

Two other new approaches I just briefly want to mention because as yet there are no publications of the data, but there are ongoing clinical trials, is the use of novel small molecules. Small molecules usually interfere with the signal transduction, so the processes that go on inside the cell and then eventually lead to inflammatory reaction of these cells. The two new small molecules that are currently being tested in psoriasis, although we already have data, is number 1: the Janus kinase inhibitors, such as baricitinib; and the phosphodiesterase 4 inhibitor apremilast. Apremilast is already labeled for the treatment of moderate to severe psoriasis and I am aware of ongoing clinical trials, or planned clinical trials, where apremilast and baricitinib (the Janus kinase inhibitor) are being tested or will be tested in atopic dermatitis. So the current treatment environment, the emerging treatment environment, includes targeted therapies—dupilumab, IL-13 blockers, IL-31 blockers—and small molecules such as the Janus kinase inhibitors and also the PDE4 inhibitors.

A last new therapy I want to mention for atopic dermatitis is something that was published from our group, where we have used immunoadsorption to remove excessive IgE levels from the circulation of patients with severe atopic dermatitis. It is very well known that many patients with severe atopic dermatitis have largely elevated levels of IgE. It is known that IgE is a trigger factor also for the skin inflammation because the dendritic cells in atopic dermatitis skin carry the receptor (the high-affinity receptor for IgE) and the dendritic cells can actually use this structure to initiate and perpetuate T cell responses. So the whole concept of immunoadsorption is aiming to reduce IgE. There was, several years ago, a pilot trial published where a panimmunoglobulin immunoadsorption was used, in other words a technology that reduced all immunoglobulin classes. Of course, carrying the risk that in addition to the big IgE that you want to remove, you also remove IgG or IgM antibodies that play a potentially protective role in patients with atopic dermatitis and in healthy individuals.

More recently, an IgE-specific column became available. The principle of immunoadsorption is, similar to dialysis, that you have two catheters in your peripheral veins. On one side the blood is taken out of the body, it is guided over columns that can bind (in the case of IgE-specific columns) the IgE, and then the blood minus the IgE is brought back into the body. Now in our pilot trial with 50 patients, half of the patients were treated with a panimmunoglobulin adsorber, half of the patients were treated with the IgE-selective adsorber. And these were very recalcitrant patients: they had already failed or had contraindications to all labeled therapies, and despite being on systemic therapy they still had very active disease or, as I said, they could no longer be treated with systemic diseases [treatments]. So, in contrast to the dupilumab patients—where eligible patients just had to have or had to be candidates for systemic therapy—these were really recalcitrant patients that according to the guidelines and according to current labels could no longer be offered any therapy. And in this subgroup of patients 50% achieved a response defined by at least 50% reduction of the EASI. The immunoadsorption in these cases were done in three cycles, over a 2-month period, and interestingly 6 months after the last immunoadsorption the vast majority of patients were still under clinical control. This is a small pilot trial, it was not double blind, it was a comparison (an open-label comparison) of the two immunoabsorption procedures, but I take this as evidence that removing IgE by this procedure is another potentially successful strategy. And interestingly in this small study all drug-related side effects exclusively occurred in the panimmunoglobulin immunoadsorption group, in fact indicating that you can achieve the same efficacy with specific IgE immunoadsorption without having safety problems. Again, small study: larger trials are needed to fully confirm that this will be an interesting option in the future.

So to summarize: in the field of targeted therapies, and especially with dupilumab (the antibody that blocks the common receptor chain for IL-4 and IL-13)—maybe in the future with small molecules, maybe with IgE-selective immunoadbsorption and other targeted therapies—the door is now opening to a completely new era in the treatment of atopic dermatitis, and I think many of you will have to stay tuned to see what will happen in the future. Thank you very much for your attention.

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